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Antonello PIETRANGELO

Professore Ordinario
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto


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Pubblicazioni

- Esters Of Hyaluronic Acid With Rhein, Process For Their Preparation And Compositions Comprising The Same [Brevetto]
Pietrangelo, Antonello; V., Travagli
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- Mutations in the scl40a100000 gene associated to impaired iron homeostasis [Brevetto]
Pietrangelo, Antonello
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- OZONIZED COMPOSITION OF ANIMAL ORIGIN [Brevetto]
Pietrangelo, Antonello; V., Travagli
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2024 - Recovery of chronic motor neuropathy due to acute intermittent porphyria after givosiran treatment in a young boy: a case report [Articolo su rivista]
Mazzoli, M.; Ricci, A.; Vaudano, A. E.; Marcacci, M.; Marchini, S.; Bergonzini, P.; DI PIERRO, E.; Pischik, E.; Iughetti, L.; Pietrangelo, A.; Meletti, S.; Ventura, P.
abstract

BACKGROUND: We describe the first case of a pediatric patient with acute intermittent porphyria and severe chronic porphyric neuropathy treated with givosiran, a small-interfering RNA that drastically decreases delta-aminolevulinic acid production and reduces porphyric attacks’ recurrence. CASE REPORT: A 12-year-old male patient with refractory acute intermittent porphyria and severe porphyric neuropathy was followed prospectively for 12 months after givosiran initiation (subcutaneous, 2.5 mg/kg monthly). Serial neurological, structural, and resting-state functional magnetic resonance imaging (MRI) evaluations were performed, including clinical scales and neurophysiological tests. Delta-aminolevulinic acid urinary levels dropped drastically during treatment. In parallel, all the administered neurological rating scales and neurophysiological assessments showed improvement in all domains. Moreover, an improvement in central motor conduction parameters and resting-state functional connectivity in the sensory- motor network was noticed. At the end of the follow-up, the patient could walk unaided after using a wheelchair for 5 years. CONCLUSIONS: A clear beneficial effect of givosiran was demonstrated in our patient with both clinical and peripheral nerve neurophysiologic outcome measures. Moreover, we first reported a potential role of givosiran in recovering central motor network impairment in acute intermittent porphyria (AIP), which was previously unknown. This study provides Class IV evidence that givosiran improves chronic porphyric neuropathy.


2023 - A Fatal Case of Pseudomonas aeruginosa Community-Acquired Pneumonia in an Immunocompetent Patient: Clinical and Molecular Characterization and Literature Review [Articolo su rivista]
Barp, Nicole; Marcacci, Matteo; Biagioni, Emanuela; Serio, Lucia; Busani, Stefano; Ventura, Paolo; Franceschini, Erica; Orlando, Gabriella; Venturelli, Claudia; Menozzi, Ilaria; Tambassi, Martina; Scaltriti, Erika; Pongolini, Stefano; Sarti, Mario; Pietrangelo, Antonello; Girardis, Massimo; Mussini, Cristina; Meschiari, Marianna
abstract

Rare cases of Pseudomonas aeruginosa community-acquired pneumonia (PA-CAP) were reported in non-immunocompromised patients. We describe a case of Pseudomonas aeruginosa (PA) necrotizing cavitary CAP with a fatal outcome in a 53-year-old man previously infected with SARS-CoV-2, who was admitted for dyspnea, fever, cough, hemoptysis, acute respiratory failure and a right upper lobe opacification. Six hours after admission, despite effective antibiotic therapy, he experienced multi-organ failure and died. Autopsy confirmed necrotizing pneumonia with alveolar hemorrhage. Blood and bronchoalveolar lavage cultures were positive for PA serotype O:9 belonging to ST1184. The strain shares the same virulence factor profile with reference genome PA01. With the aim to better investigate the clinical and molecular characteristics of PA-CAP, we considered the literature of the last 13 years concerning this topic. The prevalence of hospitalized PA-CAP is about 4% and has a mortality rate of 33–66%. Smoking, alcohol abuse and contaminated fluid exposure were the recognized risk factors; most cases presented the same symptoms described above and needed intensive care. Co-infection of PA-influenza A is described, which is possibly caused by influenza-inducing respiratory epithelial cell dysfunction: the same pathophysiological mechanism could be assumed with SARS-CoV-2 infection. Considering the high rate of fatal outcomes, additional studies are needed to identify sources of infections and new risk factors, along with genetic and immunological features. Current CAP guidelines should be revised in light of these results.


2023 - Author Correction: Consensus Statement on the definition and classification of metabolic hyperferritinaemia (Nature Reviews Endocrinology, (2023), 19, 5, (299-310), 10.1038/s41574-023-00807-6) [Articolo su rivista]
Valenti, L.; Corradini, E.; Adams, L. A.; Aigner, E.; Alqahtani, S.; Arrese, M.; Bardou-Jacquet, E.; Bugianesi, E.; Fernandez-Real, J. M.; Girelli, D.; Hagström, H.; Henninger, B.; Kowdley, K.; Ligabue, G.; Mcclain, D.; Lainé, F.; Miyanishi, K.; Muckenthaler, M. U.; Pagani, A.; Pedrotti, P.; Pietrangelo, A.; Prati, D.; Ryan, J. D.; Silvestri, L.; Spearman, C. W.; Stål, P.; Tsochatzis, E. A.; Vinchi, F.; Zheng, M. H.; Zoller, H.
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2023 - CREB-H is a stress-regulator of hepcidin gene expression during early postnatal development [Articolo su rivista]
Vecchi, C.; Montosi, G.; Garuti, C.; Canali, S.; Sabelli, M.; Bergamini, E.; Ricci, A.; Buzzetti, E.; Corradini, E.; Pietrangelo, A.
abstract

Hepcidin, the hepatic iron hormone, is the central regulator of iron homeostasis. Cyclic AMP-Responsive Element-Binding protein 3-like 3 (CREB3L3/CREB-H) is a liver homeostatic regulator of essential nutrients (i.e. glucose and lipids) and has been previously involved in hepcidin response to pathologic stress signals. Here, we asked whether CREB-H has also a physiologic role in iron homeostasis through hepcidin. To this end, we analyzed hepcidin gene expression and regulation in the liver of wild type and Creb3l3 knockout mice during early postnatal development, as a model of "physiologic" stressful condition. The effect of iron challenge in vivo and BMP6 stimulation in vitro have been also addressed. In addition, we investigated the BMP signaling pathway and hepcidin promoter activity following CREB3L3 silencing and hepcidin promoter mutation in HepG2 cells. Creb3l3 knockout suckling and young-adult mice showed a prominent serum and hepatic iron accumulation, respectively, due to impaired hepcidin mRNA expression which progressively returned to normal level in adult mice. Interestingly, upon iron challenge, while the upstream BMP/SMAD signaling pathway controlling hepcidin was equally responsive in both strains, hepcidin gene expression was impaired in knockout mice and more iron accumulated in the liver. Accordingly, hepcidin gene response to BMP6 was blunted in primary CREB-H knockout hepatocytes and in HepG2 cells transfected with CREB-H siRNA or carrying a hepcidin promoter mutated in the CREB-H binding site. In conclusion, CREB-H has a role in maintaining the homeostatic balance of iron traffic through hepcidin during the critical postnatal period and in response to iron challenge.Key messagesCREB-H KO mice develop liver iron overload shortly after weaning that normalizes in adulthood.CHEB-H is involved in hepcidin gene response to oral iron in vivo.CREB-H loss hampers hepcidin promoter response to BMP6.CREB-H is a key stress-sensor controlling hepcidin gene transcription in physiologic and pathophysiologic states.


2023 - Clinical application of NGS in the diagnosis of iron overload disorders or hyperferritinemia of genetic origin [Abstract in Rivista]
Ricci, A.; Bergamini, E.; Scarlini, S.; Buzzetti, E.; Caleffi, A.; Rabacchi, C.; Ventura, P.; Artuso, L.; Tenedini, E.; Tagliafico, E.; Pietrangelo, A.; Corradini, E.
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2023 - Consensus Statement on the definition and classification of metabolic hyperferritinaemia [Articolo su rivista]
Valenti, Luca; Corradini, Elena; Adams, Leon A.; Aigner, Elmar; Alqahtani, Saleh; Arrese, Marco; Bardou-Jacquet, Edouard; Bugianesi, Elisabetta; Fernandez-Real, Jose-Manuel; Girelli, Domenico; Hagström, Hannes; Henninger, Benjamin; Kowdley, Kris; Ligabue, Guido; Mcclain, Donald; Lainé, Fabrice; Miyanishi, Koji; Muckenthaler, Martina U.; Pagani, Alessia; Pedrotti, Patrizia; Pietrangelo, Antonello; Prati, Daniele; Ryan, John D.; Silvestri, Laura; Spearman, C. Wendy; Stål, Per; Tsochatzis, Emmanuel A.; Vinchi, Francesca; Zheng, Ming-Hua; Zoller, Heinz
abstract

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.


2023 - Do all critically ill patients with COVID-19 disease benefit from adding tocilizumab to glucocorticoids? A retrospective cohort study. [Articolo su rivista]
Mussini, Cristina; Cozzi-Lepri, Alessandro; Meschiari, Marianna; Franceschini, Erica; Jole Burastero, Giulia; Faltoni, Matteo; Franceschi, Giacomo; Iadisernia, Vittorio; Volpi, Sara; Dessilani, Andrea; Gozzi, Licia; Conti, Jacopo; DEL MONTE, Martina; Milic, Jovana; Borghi, Vanni; Tonelli, Roberto; Brugioni, Lucio; Romagnoli, Elisa; Pietrangelo, Antonello; Corradini, Elena; Girardis, Massimo; Busani, Stefano; Cossarizza, Andrea; Clini, Enrico; Guaraldi, Giovanni
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2023 - Hepatic encephalopathy increases the risk for mortality and hospital readmission in decompensated cirrhotic patients: a prospective multicenter study [Articolo su rivista]
Riggio, O.; Celsa, C.; Calvaruso, V.; Merli, M.; Caraceni, P.; Montagnese, S.; Mora, V.; Milana, M.; Saracco, G. M.; Raimondo, G.; Benedetti, A.; Burra, P.; Sacco, R.; Persico, M.; Schepis, F.; Villa, E.; Colecchia, A.; Fagiuoli, S.; Pirisi, M.; Barone, M.; Azzaroli, F.; Soardo, G.; Russello, M.; Morisco, F.; Labanca, S.; Fracanzani, A. L.; Pietrangelo, A.; Di Maria, G.; Nardelli, S.; Ridola, L.; Gasbarrini, A.; Camma, C.
abstract

Introduction: Hepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE. Methods: We prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT). Results: During follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01–1.06), HE (HR 1.67, 95% CI 1.08–2.56), ascites (HR 2.56, 95% CI 1.55–4.23), and sodium levels (HR 0.94, 95% CI 0.90–0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39–18.49) and BMI (HR 0.86, 95% CI 0.75–0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission. Conclusion: In patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT.


2023 - Labile plasma iron and echocardiographic parameters are associated to cardiac events in beta-thalassemic patients [Articolo su rivista]
Ferrara, F; Coppi, F; Riva, R; Ventura, P; Ricci, A; Mattioli, Av; Talarico, M; Garuti, C; Bevini, M; Rochira, V; Buzzetti, E; Pietrangelo, A; Corradini, E
abstract

Background and aim: Notwithstanding the improvement in therapies, patients affected by thalassemia major (TM) and intermedia (TI) are still at high risk of cardiac complications. This study aimed at evaluating the incidence and predictive factors for developing cardiac events in adult β-TM and TI patients. Population andmethods: Data on diagnosis and clinical historywere collected retrospectively; prospective data on new-onset cardiac failure and arrhythmias, echocardiographic parameters, biochemical variables including non-transferrin-bound iron (NTBI) and labile plasma iron (LPI), magnetic resonance imaging (MRI) T2* measurement of hepatic and cardiac iron deposits, and iron chelation therapy were recorded during a 6 year follow-up. Results: Thirty-seven patients, 29 TM and 8 TI, were included. At baseline, 8 TM patients and 1 TI patient had previously experienced a cardiac event (mainly heart failure). All patients were on chelation therapy and only 3 TM patients had mild-to-severe cardiac siderosis. During follow-up, 11 patients (29.7%) experienced a new cardiac event. The occurrence of cardiac events was correlated to high LPI levels (OR 12.0, 95% CI 1.56-92.3, p 0.017), low mean pre-transfusion hemoglobin (OR 0.21, 95% C.I. 0.051-0.761, p 0.21), and echocardiographic parameters suggestive of myocardial hypertrophy. Multivariate analysis disclosed high LPI and left ventricle mass index (LVMI) as independent variables significantly associated with cardiac events. Cardiac iron deposits measured by MRI T2* failed to predict cardiac events. Conclusion: LPI, Hb levels, and echocardiographic parameters assessing cardiac remodeling are associated to cardiac events in adult TM and TI patients. LPI might represent both a prognostic marker and a potential target for novel treatment strategies. Further studies are warranted to confirm our findings on larger populations


2023 - Post COVID-19 irritable bowel syndrome [Articolo su rivista]
Marasco, Giovanni; Cremon, Cesare; Barbaro, Maria Raffaella; Cacciari, Giulia; Falangone, Francesca; Kagramanova, Anna; Bordin, Dmitry; Drug, Vasile; Miftode, Egidia; Fusaroli, Pietro; Mohamed, Salem Youssef; Ricci, Chiara; Bellini, Massimo; Rahman, Mohammed Masudur; Melcarne, Luigi; Santos, Javier; Lobo, Beatriz; Bor, Serhat; Yapali, Suna; Akyol, Deniz; Sapmaz, Ferdane Pirincci; Urun, Yonca Yilmaz; Eskazan, Tugce; Celebi, Altay; Kacmaz, Huseyin; Ebik, Berat; Binicier, Hatice Cilem; Bugdayci, Mehmet Sait; Yağcı, Munkhtsetseg Banzragch; Pullukcu, Husnu; Kaya, Berrin Yalınbas; Tureyen, Ali; Hatemi, İbrahim; Koc, Elif Sitre; Sirin, Goktug; Calıskan, Ali Riza; Bengi, Goksel; Alıs, Esra Ergun; Lukic, Snezana; Trajkovska, Meri; Hod, Keren; Dumitrascu, Dan; Pietrangelo, Antonello; Corradini, Elena; Simren, Magnus; Sjölund, Jessica; Tornkvist, Navkiran; Ghoshal, Uday C; Kolokolnikova, Olga; Colecchia, Antonio; Serra, Jordi; Maconi, Giovanni; De Giorgio, Roberto; Danese, Silvio; Portincasa, Piero; Di Sabatino, Antonio; Maggio, Marcello; Philippou, Elena; Lee, Yeong Yeh; Salvi, Daniele; Venturi, Alessandro; Borghi, Claudio; Zoli, Marco; Gionchetti, Paolo; Viale, Pierluigi; Stanghellini, Vincenzo; Barbara, Giovanni
abstract

Objectives: The long-term consequences of COVID-19 infection on the gastrointestinal tract remain unclear. Here, we aimed to evaluate the prevalence of gastrointestinal symptoms and post-COVID-19 disorders of gut-brain interaction after hospitalisation for SARS-CoV-2 infection. Design: GI-COVID-19 is a prospective, multicentre, controlled study. Patients with and without COVID-19 diagnosis were evaluated on hospital admission and after 1, 6 and 12 months post hospitalisation. Gastrointestinal symptoms, anxiety and depression were assessed using validated questionnaires. Results: The study included 2183 hospitalised patients. The primary analysis included a total of 883 patients (614 patients with COVID-19 and 269 controls) due to the exclusion of patients with pre-existing gastrointestinal symptoms and/or surgery. At enrolment, gastrointestinal symptoms were more frequent among patients with COVID-19 than in the control group (59.3% vs 39.7%, p<0.001). At the 12-month follow-up, constipation and hard stools were significantly more prevalent in controls than in patients with COVID-19 (16% vs 9.6%, p=0.019 and 17.7% vs 10.9%, p=0.011, respectively). Compared with controls, patients with COVID-19 reported higher rates of irritable bowel syndrome (IBS) according to Rome IV criteria: 0.5% versus 3.2%, p=0.045. Factors significantly associated with IBS diagnosis included history of allergies, chronic intake of proton pump inhibitors and presence of dyspnoea. At the 6-month follow-up, the rate of patients with COVID-19 fulfilling the criteria for depression was higher than among controls. Conclusion: Compared with controls, hospitalised patients with COVID-19 had fewer problems of constipation and hard stools at 12 months after acute infection. Patients with COVID-19 had significantly higher rates of IBS than controls. Trial registration number: NCT04691895.


2023 - Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS) [Articolo su rivista]
Francesco, Salton; Paola, Confalonieri; Stefano, Centanni; Michele, Mondoni; Nicola, Petrosillo; Paolo, Bonfanti; Giuseppe, Lapadula; Donato, Lacedonia; Antonio, Voza; Nicoletta, Carpenè; Marcella, Montico; Nicolò, Reccardini; Gianfranco Umberto, Meduri; Barbara, Ruaro; Collaborative Group, Medeas; Confalonieri, Marco; Collaborative Group, Medeas; Maria Citton, Gloria; Lapadula, Giulia; Bozzi, Chiara; Tavano, Stefano; Pozzan, Riccardo; Giovanna Andrisano, Alessia; Jaber, Mohamad; Mari, Marco; Trotta, Liliana; Mondini, Lucrezia; Barbieri, Mariangela; Ruggero, Luca; Antonaglia, Caterina; Soave, Sara; Torregiani, Chiara; Bogatec, Tjaša; Baccelli, Andrea; Nalesso, Giulia; Re, Beatrice; Pavesi, Stefano; Pia Foschino Barbaro, Maria; Giuliani, Antonella; Ravaglia, Claudia; Poletti, Venerino; Scala, Raffaele; Guidelli, Luca; Golfi, Nicoletta; Vianello, Andrea; Achille, Alessia; Lucernoni, Paolo; Talia Gaccione, Anna; Romagnoli, Micaela; Fraccaro, Alessia; Malacchini, Nicola; Malerba, Mario; Sanduzzi Zamparelli, Alessandro; Bocchino, Marialuisa; Blasi, Francesco; Spotti, Maura; Miele, Carmen; Piedepalumbo, Federica; Barone, Ivan; Baglioni, Stefano; Dodaj, Meridiana; Franco, Cosimo; Andrani, Francesco; Mangia, Angelo; Mancini, Annalisa; Carrozzi, Laura; Rafanelli, Annalisa; Casto, Elisabetta; Rogliani, Paola; Ora, Josuel; Elisiana Carpagnano, Giovanna; Di Lecce, Valentina; Tamburrini, Mario; Papi, Alberto; Contoli, Marco; Luzzati, Roberto; Zatta, Marta; Di Bella, Stefano; Caraffa, Emanuela; Francisci, Daniela; Tosti, Andrea; Pallotto, Carlo; Giuseppe De Rosa, Francesco; Pecori, Alessio; Franceschini, Marta; Carlin, Massimiliano; Orsini, Valentina; Spolti, Anna; Inannace, Marta; Santantonio, Teresa; Meli, Rossella; Sauro, Sara; Fedeli, Carlo; Mangini, Elisabetta; Biolo, Gianni; Nunnari, Alessio; Pietrangelo, Antonello; Corradini, Elena; Bocchi, Davide; Boarini, Chiara; Zucchetto, Antonella; Lanini, Simone
abstract

Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day-1. A comparative RCT with a higher dose and a longer duration of intervention was lacking.


2022 - A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages [Articolo su rivista]
Ekaputri, Stella; Choi, Eun-Kyung; Sabelli, Manuela; Aring, Luisa; Green, Kelsie J; Chang, Juoae; Bao, Kai; Choi, Hak Soo; Iwase, Shigeki; Kim, Jonghan; Corradini, Elena; Pietrangelo, Antonello; Burke, Martin D; Seo, Young Ah
abstract

Deficiencies of the transmembrane iron-transporting protein ferroportin (FPN1) cause the iron misdistribution that underlies ferroportin disease, anemia of inflammation, and several other human diseases and conditions. A small molecule natural product, hinokitiol, was recently shown to serve as a surrogate transmembrane iron transporter that can restore hemoglobinization in zebrafish deficient in other iron transporting proteins and can increase gut iron absorption in FPN1-deficient flatiron mice. However, whether hinokitiol can restore normal iron physiology in FPN1-deficient animals or primary cells from patients and the mechanisms underlying such targeted activities remain unknown. Here, we show that hinokitiol redistributes iron from the liver to red blood cells in flatiron mice, thereby increasing hemoglobin and hematocrit. Mechanistic studies confirm that hinokitiol functions as a surrogate transmembrane iron transporter to release iron trapped within liver macrophages, that hinokitiol-Fe complexes transfer iron to transferrin, and that the resulting transferrin-Fe complexes drive red blood cell maturation in a transferrin-receptor-dependent manner. We also show in FPN1-deficient primary macrophages derived from patients with ferroportin disease that hinokitiol moves labile iron from inside to outside cells and decreases intracellular ferritin levels. The mobilization of nonlabile iron is accompanied by reductions in intracellular ferritin, consistent with the activation of regulated ferritin proteolysis. These findings collectively provide foundational support for the translation of small molecule iron transporters into therapies for human diseases caused by iron misdistribution.


2022 - Ataxia-myoclonus syndrome in patients with SARS-CoV2 infection [Articolo su rivista]
Guerra, A. F.; Martinelli, I.; Rispoli, V.; Marcacci, M.; Cavallieri, F.; Nizzoli, S.; Valzania, F.; Ventura, P.; Meletti, S.; Pietrangelo, A.
abstract


2022 - Can Disruption of Basal Ganglia-Thalamocortical Circuit in Wilson Disease Be Associated with Juvenile Myoclonic Epilepsy Phenotype? [Articolo su rivista]
Rossi, J.; Cavallieri, F.; Giovannini, G.; Benuzzi, F.; Ballotta, D.; Vaudano, A. E.; Ferrara, F.; Contardi, S.; Pietrangelo, A.; Corradini, E.; Lui, F.; Meletti, S.
abstract

In this paper, we describe the multimodal MRI findings in a patient with Wilson disease and a seizure disorder, characterized by an electroclinical picture resembling juvenile myoclonic epilepsy. The brain structural MRI showed a deposition of ferromagnetic materials in the basal ganglia, with marked hypointensities in T2-weighted images of globus pallidus internus bilaterally. A resting-state fMRI study revealed increased functional connectivity in the patient, compared to control subjects, in the following networks: (1) between the primary motor cortex and several cortical regions, including the secondary somatosensory cortex and (2) between the globus pallidus and the thalamo-frontal network. These findings suggest that globus pallidus alterations, due to metal accumulation, can lead to a reduction in the normal globus pallidus inhibitory tone on the thalamo-(motor)-cortical pathway. This, in turn, can result in hyperconnectivity in the motor cortex circuitry, leading to myoclonus and tonic-clonic seizures. We suppose that, in this patient, Wilson disease generated a ‘lesion model’ of myoclonic epilepsy.


2022 - Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives [Articolo su rivista]
Marcacci, Matteo; Ricci, Andrea; Cuoghi, Chiara; Marchini, Stefano; Pietrangelo, Antonello; Ventura, Paolo
abstract

Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks, characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion, hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, -aminolaevulinic acid and porphyrins using a single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe, potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges, and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations.


2022 - Endothelial Dysfunction in Acute Hepatic Porphyrias [Articolo su rivista]
Ricci, Andrea; Sandri, Gilda; Marcacci, Matteo; Di Pierro, Elena; Granata, Francesca; Cuoghi, Chiara; Marchini, Stefano; Pietrangelo, Antonello; Ventura, Paolo
abstract

Background Acute hepatic porphyrias (AHPs) are a group of rare diseases caused by dysfunctions in the pathway of heme biosynthesis. Although acute neurovisceral attacks are the most dramatic manifestations, patients are at risk of developing long-term complications, several of which are of a vascular nature. The accumulation of non-porphyrin heme precursors is deemed to cause most clinical symptoms. AimWe measured the serum levels of endothelin-1 (ET-1) and nitric oxide (NO) to assess the presence of endothelial dysfunction (ED) in patients with AHPs. Forty-six patients were classified, according to their clinical phenotype, as symptomatic (AP-SP), asymptomatic with biochemical alterations (AP-BA), and asymptomatic without biochemical alterations (AP-AC). Results Even excluding those under hemin treatment, AP-SP patients had the lowest NO and highest ET-1 levels, whereas no significant differences were found between AP-BA and AP-AC patients. AP-SP patients had significantly more often abnormal levels of ED markers. Patients with the highest heme precursor urinary levels had the greatest alterations in ED markers, although no significant correlation was detected. Conclusions ED is more closely related to the clinical phenotype of AHPs than to their classical biochemical alterations. Some still undefined disease modifiers may possibly determine the clinical picture of AHPs through an effect on endothelial functions.


2022 - First and second wave among hospitalized COVID-19 patients with severe pneumonia: a comparison of 28-day mortality over 1-year pandemic in a tertiary university hospital in Italy. [Articolo su rivista]
Meschiari, M; Cozzi-Lepri, A; Tonelli, R; Bacca, E; Menozzi, M; Franceschini, E; Cuomo, G; Bedini, A; Volpi, S; Milic, J; Brugioni, L; Romagnoli, E; Pietrangelo, A; Corradini, E; Coloretti, I; Biagioni, E; Busani, S; Girardis, M; Cossarizza, A; Clini, E; Guaraldi, G; Mussini, C.
abstract

Objectives: The first COVID-19-19 epidemic wave was over the period February-May 2020. Since October 1st, 2020 Italy, as many other European countries, faced a second wave. The aim of this analysis was to compare the 28-day mortality between the two waves among COVID-19 hospitalised patients. Design: Observational cohort study. Standard survival analysis was performed to compare all-cause mortality within 28 days after hospital admission in the two waves. Kaplan-Meier curves as well as Cox regression model analysis were used. The effect of wave on risk of death was shown by means of hazard ratios (HRs) with 95% confidence intervals (CI). A sensitivity analysis around the impact of the circulating variant as a potential unmeasured confounder was performed. Setting: University Hospital of Modena, Italy. Patients admitted to hospital for severe COVID-19 pneumonia during the first (February 22nd – May 31st, 2020) and second wave (October 1st- December 31st, 2020) were included. Results: During the two study periods, a total of 1,472 patients with severe COVID-19 pneumonia were admitted to our hospital, 449 during the first wave and 1,023 during the second. Median age was 70 years (IQR:56-80), 37% females, 49% with PaO /FiO < 250 mmHg, 82% with ≥1 comorbidity, median duration of symptoms was 6 days. 28-day mortality rate was 20.0% (95% CI:16.3-23.7) during the first wave vs. 14.2% (95% CI:12.0-16.3) in the second (log-rank test p-value= 0.03). After including key predictors of death in the multivariable Cox regression model, the data still strongly suggested a lower 28-day mortality rate in the 2nd wave (aHR=0.64, 95% CI: 0.45, 0.90, p- value=0.01). Conclusions: In our hospitalized COVID-19 patients with severe pneumonia, the 28-day mortality appeared to be reduced by 36% during the second as compared to the first wave. Further studies are needed to identify factors that may have contributed to this improved survival.


2022 - Impact of Diabetes Mellitus and Its Comorbidities on Elderly Patients Hospitalized in Internal Medicine Wards: Data from the RePoSi Registry [Articolo su rivista]
Argano, C.; Natoli, G.; Mularo, S.; Nobili, A.; Lo Monaco, M.; Mannucci, P. M.; Perticone, F.; Pietrangelo, A.; Corrao, S.
abstract

Background: Currently, diabetes represents the seventh leading cause of death worldwide, with a significant economic burden. The number and severity of comorbidities increase with age, and are identified as important determinants that influence the prognosis. We aimed to investigate comorbidities and outcomes in a cohort of hospitalized elderly patients affected by diabetes. Methods: In this observational study, we retrospectively analyzed data collected from the REgistro dei pazienti per lo studio delle POlipatologie e politerapie in reparti della rete Simi (RePoSi) reg-istry. Socio-demographic, clinical characteristics, and laboratory findings were considered. The association between variables and in-hospital and 1-year follow-up were analyzed. Results: Among 4708 in-patients, 1378 (29.3%) had a diagnosis of diabetes. Patients with diabetes had more previous hospitalization, a clinically significant disability, and more need for a urinary catheter in comparison with subjects without diabetes. Patients affected by diabetes took more drugs, both at admission, at in-hospital stay, at discharge, and at 1-year follow-up. Thirty-five comorbidities were more frequent in patients with diabetes, and the first five were hypertension (57.1%), ischemic heart disease (31.4%), chronic renal failure (28.8%), atrial fibrillation (25.6%), and chronic obstructive pulmonary disease (22.7%). Heart rate was an independent predictor of in-hospital mortality. At 1-year follow-up, cancer and male sex were strongly independently associated with mortality. Conclusions: Our findings showed the severity of the impact of diabetes and its comorbidities in the real life of internal medicine and geriatric wards, and provide data to be used for a better tailored management of elderly in-patients with diabetes.


2022 - Internists or specialists-that is the question! [Articolo su rivista]
Pietrangelo, A.
abstract


2022 - Phenotyping congestion in patients with acutely decompensated heart failure with preserved and reduced ejection fraction: The Decongestion duRing therapY for acute decOmpensated heart failure in HFpEF vs HFrEF- DRY-OFF study [Articolo su rivista]
Cogliati, C.; Ceriani, E.; Gambassi, G.; De Matteis, G.; Perlini, S.; Perrone, T.; Muiesan, M. L.; Salvetti, M.; Leidi, F.; Ferrara, F.; Sabba, C.; Suppressa, P.; Fracanzani, A.; Montano, N.; Fiorelli, E.; Tripepi, G.; Gori, M.; Pitino, A.; Pietrangelo, A.
abstract

Aims: : To evaluate pulmonary and intravascular congestion at admission and repeatedly during hospitalization for acute decompensated heart failure (ADHF) in HFrEF and HFpEF patients using lung (LUS) and inferior vena cava (IVC) ultrasound. Methods and results: : Three-hundred-fourteen patients (82±9 years; HFpEF =172; HFrEF=142) admitted to Internal Medicine wards for ADHF were enrolled in a multi-center prospective study. At admission HFrEF presented higher indexes of pulmonary and intravascular congestion (LUS-score: 0.9 ± 0.4 vs 0.7 ± 0.4; p<0.01; IVC end-expiratory diameter: 21.6 ± 5.1 mm vs 20±5.5 mm, p<0.01; IVC collapsibility index 24.4 ± 17.4% vs 30.9 ± 21.1% p<0.01) and higher Nt-proBNP values (8010 vs 3900 ng/l; p<0.001). At discharge, HFrEF still presented higher B-scores (0.4 ± 4 vs 0.3 ± 0.4; p = 0.023), while intravascular congestion improved to a greater extent, thus IVC measurements were similar in the two groups. No differences in diuretic doses, urine output, hemoconcentration, worsening renal function were found. At 90-days follow up HF readmission/death did not differ in HFpEF and HFrEF (28% vs 31%, p = 0,48). Residual congestion was associated with HF readmission/death considering the whole population; while intravascular congestion predicted readmission/death in the HFrEF, no association between sonographic indexes and the outcome was found in HFpEF. Conclusions: : Serial assessment of pulmonary and intravascular congestion revealed a higher burden of fluid overload in HFrEF and, conversely, a greater reduction in intravascular venous congestion with diuretic treatment. Although other factors beyond EF could play a role in congestion/decongestion patterns, our data may be relevant for further phenotyping HF patients, considering the importance of decongestion optimization in the clinical approach.


2022 - Prevalence of Gastrointestinal Symptoms in Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Results of the Prospective Controlled Multinational GI-COVID-19 Study [Articolo su rivista]
Marasco, Giovanni; Cremon, Cesare; Barbaro, Maria Raffaella; Salvi, Daniele; Cacciari, Giulia; Kagramanova, Anna; Bordin, Dmitry; Drug, Vasile; Miftode, Edgidia; Fusaroli, Pietro; Mohamed, Salem Youssef; Ricci, Chiara; Bellini, Massimo; Rahman, M Masudur; Melcarne, Luigi; Santos, Javier; Lobo, Beatriz; Bor, Serhat; Yapali, Suna; Akyol, Deniz; Sapmaz, Ferdane Pirincci; Urun, Yonca Yilmaz; Eskazan, Tugce; Celebi, Altay; Kacmaz, Huseyin; Ebik, Berat; Binicier, Hatice Cilem; Bugdayci, Mehmet Sait; Yağcı, Munkhtsetseg Banzragch; Pullukcu, Husnu; Kaya, Berrin Yalınbas; Tureyen, Ali; Hatemi, İbrahim; Koc, Elif Sitre; Sirin, Goktug; Calıskan, Ali Riza; Bengi, Goksel; Alıs, Esra Ergun; Lukic, Snezana; Trajkovska, Meri; Hod, Keren; Dumitrascu, Dan; Pietrangelo, Antonello; Corradini, Elena; Simren, Magnus; Sjolund, Jessica; Tornkvist, Navkiran; Ghoshal, Uday C; Kolokolnikova, Olga; Colecchia, Antonio; Serra, Jordi; Maconi, Giovanni; De Giorgio, Roberto; Danese, Silvio; Portincasa, Pietro; Di Stefano, Michele; Maggio, Marcello; Philippou, Elena; Lee, Yeong Yeh; Venturi, Alessandro; Borghi, Claudio; Zoli, Marco; Gionchetti, Paolo; Viale, Pierluigi; Stanghellini, Vincenzo; Barbara, Giovanni
abstract

INTRODUCTION: Gastrointestinal (GI) symptoms in coronavirus-19 disease (COVID-19) have been reported with great variability and without standardization. In hospitalized patients, we aimed to evaluate the prevalence of GI symptoms, factors associated with their occurrence, and variation at 1 month. METHODS: TheGI-COVID-19 is a prospective,multicenter, controlled study. Patientswith and without COVID-19 diagnosis were recruited at hospital admission and asked for GI symptoms at admission and after 1 month, using the validated Gastrointestinal Symptom Rating Scale questionnaire. RESULTS: The study included 2036 hospitalized patients. A total of 871 patients (575 COVID1and 296 COVID2) were included for the primary analysis. GI symptoms occurred more frequently in patients with COVID-19 (59.7%; 343/575 patients) than in the control group (43.2%; 128/296 patients) (P < 0.001). Patients with COVID-19 complained of higher presence or intensity of nausea, diarrhea, loose stools, and urgency as compared with controls. At a 1-month follow-up, a reduction in the presence or intensity of GI symptoms was found in COVID-19 patients with GI symptoms at hospital admission. Nausea remained increased over controls. Factors significantly associated with nausea persistence in COVID-19 were female sex, high body mass index, the presence of dyspnea, and increased C-reactive protein levels. DISCUSSION: The prevalence of GI symptoms in hospitalized patients with COVID-19 is higher than previously reported. Systemic and respiratory symptoms are often associated with GI complaints. Nausea may persist after the resolution of COVID-19 infection.


2022 - Serum HBsAg and ddPCR HBV-DNA as predictive parameters of HBsAg loss after nucleo(s)tide analogue (NA) treatment discontinuation in non-cirrhotic patients with Chronic Hepatitis B [Poster]
Guerra, A. F.; Tomassoli, G.; Piermatteo, L.; D’Anna, S.; Salpini, R.; Svicher, V.; Abbati, G.; Pietrangelo, A.; Ventura, P.
abstract

Introduction: Stopping nucleo(s)tide analogue (NA) treatment in selected non-cirrhotic Chronic Hepatitis B (CHB) often leads to virus-induced flares, which may result to life-threatening liver failure. Aim: to identify predictive parameters of off-NAs response at the end of treatment and their association with HBsAg loss or HBsAg < 100IU/ml, for a safe discontinuation of treatment. Materials and Methods: 38 non-cirrhotic CHB patients, with complete virological suppression ( > 4 years), were prospectively monitored after suspending NA treatment for a median (IQR) time of 16 (10-19) months. Plasma samples at suspension date (baseline, BL) were collected and used to quantify serum HBV-DNA by highly sensitive droplet digital PCR (ddPCR). HBsAg was quantified by the ARCHITECT HBsAg assay at BL, every 2 weeks from suspension in the first month, followed by every month until the sixth month, then every 3 months. Results: At BL, 28 (73.7%) pts had detectable serum HBV-DNA (median[ IQR] 5[2-11] IU/mL), while 10 (26.3%) were completely negative to HBV-DNA. After NA suspension, 7 (18.4%) achieved HBsAg < 100IU/mL (median [IQR]: 43 [35-53]IU/ml) and 8 (21.1%) lost HBsAg at last follow-up. Patients achieving HBsAg loss had lower HBsAg levels at BL (140 [70-480]IU/ml with vs 1162 [439- 3135] without HBsAg loss, p = 0.014). The negativity to HBV-DNA by ddPCR at BL strongly correlated with the achievement of HBsAg < 100IU/mL or HBsAg loss after NA suspension (70% [7/10] with vs 28.6% [8/28] without negative BL HBV-DNA; OR [95%CI]: 5.8 [1.3- 23.6], p = 0.03).The combination of HBsAg < 500IU/mL + negativity HBV-DNA by ddPCR at BL was the best predictor for achieving HBsAg < 100IU/mL or HBsAg loss (85.7% with vs 27.6% without this combination; OR [95%CI]: 15.8 (1.6-152.2; p = 0.008; PPV = 86%; NPV = 72%). Conclusions: Residual HBV replicative activity at NA suspension, measured by highly sensitive assays, provides an added value in identifying patients more prone to achieve HBV functional cure.


2021 - Better prognosis in females with severe COVID-19 pneumonia: possible role of inflammation as potential mediator. [Articolo su rivista]
Mussini, C; Cozzi-Lepri, A; Menozzi, M; Meschiari, M; Franceschini, E; Rogati, C; Cuomo, G; Bedini, A; Iadisernia, M; Volpi, S; Milic, J; Tonelli, R; Brugioni, L; Pietrangelo, A; Girardis, M; Cossarizza, A; Clini, E; Guaraldi, G.; De biasi, S; Gibellini, Lara
abstract

Objectives: Sex differences in COVID-19 severity and mortality have been described. Key aims of this analysis were to compare the risk of invasive mechanical ventilation (IMV) and mortality by sex and to explore whether variation in specific biomarkers could mediate this difference. Methods: This was a retrospective, observational cohort study among patients with severe COVID- 19 pneumonia. A survival analysis was conducted to compare time to the composite endpoint of IMV or death by sex. Interaction was formally tested to compare the risk difference by sex in subsets. Mediation analysis with a binary endpoint IMV or death (yes/no) by end of follow-up for a number of inflammation/coagulation biomarkers in the context of counterfactual prediction was also conducted. Results: Among 415 patients, 134 were females (32%) and 281 males (67%), median age 66 years (IQR 54-77). At admission, females showed a significantly less severe clinical and respiratory profiles with a higher PaO2/FiO2 (254 mmHg vs 191 mmHg; p=0.023). By 28 days from admission, 49.2% (95% CI: 39.6-58.9%) of males vs. 31.7% (17.9-45.4%) of females underwent IMV or death (log-rank pvalue<0.0001) and this amounted to a difference in HR of 0.40 (0.26-0.63, p=0.0001). The AUC in Creactive protein (CRP) over the study period appeared to explain 85% of this difference in risk by sex. Conclusions: Our analysis confirms a difference in the risk of COVID-19 clinical progression by sex and provides a hypothesis for potential mechanisms leading to this. CRP showed a predominant role to mediate the difference in risk by sex.


2021 - Ceruloplasmin gene variants are associated with hyperferritinemia and increased liver iron in patients with {NAFLD} [Articolo su rivista]
Corradini, Elena; Buzzetti, Elena; Dongiovanni, Paola; Scarlini, Stefania; Caleffi, Angela; Pelusi, Serena; Bernardis, Isabella; Ventura, Paolo; Rametta, Raffaela; Tenedini, Elena; Tagliafico, Enrico; Ludovica Fracanzani, Anna; Fargion, Silvia; Pietrangelo, Antonello; Vittorio Valenti, Luca
abstract

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disorder resulting from genetic and environmental factors. Hyperferritinemia has been associated with increased hepatic iron stores and worse outcomes in patients with NAFLD. The aim of this study was to evaluate the prevalence of variants of iron-related genes and their association with hyperferritinemia, hepatic iron stores and liver disease severity in patients with NAFLD.


2021 - Clinical factors associated with death in 3044 COVID-19 patients managed in internal medicine wards in Italy: results from the SIMI-COVID-19 study of the Italian Society of Internal Medicine (SIMI) [Articolo su rivista]
Corradini, Elena; Ventura, Paolo; Ageno, Walter; Cogliati, Chiara Beatrice; Muiesan, Maria Lorenza; Girelli, Domenico; Pirisi, Mario; Gasbarrini, Antonio; Angeli, Paolo; Querini, Patrizia Rovere; Bosi, Emanuele; Tresoldi, Moreno; Vettor, Roberto; Cattaneo, Marco; Piscaglia, Fabio; Brucato, Antonio Luca; Perlini, Stefano; Martelletti, Paolo; Pontremoli, Roberto; Porta, Massimo; Minuz, Pietro; Olivieri, Oliviero; Sesti, Giorgio; Biolo, Gianni; Rizzoni, Damiano; Serviddio, Gaetano; Cipollone, Francesco; Grassi, Davide; Manfredini, Roberto; Moreo, Guido Luigi; Pietrangelo, Antonello
abstract

During the COVID-19 2020 outbreak, a large body of data has been provided on general management and outcomes of hospitalized COVID-19 patients. Yet, relatively little is known on characteristics and outcome of patients managed in Internal Medicine Units (IMU). To address this gap, the Italian Society of Internal Medicine has conducted a nationwide cohort multicentre study on death outcome in adult COVID-19 patients admitted and managed in IMU. This study assessed 3044 COVID-19 patients at 41 referral hospitals across Italy from February 3rd to May 8th 2020. Demographics, comorbidities, organ dysfunction, treatment, and outcomes including death were assessed. During the study period, 697 patients (22.9%) were transferred to intensive care units, and 351 died in IMU (death rate 14.9%). At admission, factors independently associated with in-hospital mortality were age (OR 2.46, p = 0.000), productive cough (OR 2.04, p = 0.000), pre-existing chronic heart failure (OR 1.58, p = 0.017) and chronic obstructive pulmonary disease (OR 1.17, p = 0.048), the number of comorbidities (OR 1.34, p = 0.000) and polypharmacy (OR 1.20, p = 0.000). Of note, up to 40% of elderly patients did not report fever at admission. Decreasing PaO2/FiO2 ratio at admission was strongly inversely associated with survival. The use of conventional oxygen supplementation increased with the number of pre-existing comorbidities, but it did not associate with better survival in patients with PaO2/FiO2 ratio < 100. The latter, significantly benefited by the early use of non-invasive mechanical ventilation. Our study identified PaO2/FiO2 ratio at admission and comorbidity as the main alert signs to inform clinical decisions and resource allocation in non-critically ill COVID-19 patients admitted to IMU.


2021 - Clinical risk scores for the early prediction of severe outcomes in patients hospitalized for COVID-19 [Articolo su rivista]
Ageno, W.; Cogliati, C.; Perego, M.; Girelli, D.; Crisafulli, E.; Pizzolo, F.; Olivieri, O.; Cattaneo, M.; Benetti, A.; Corradini, E.; Bertu, L.; Pietrangelo, A.; Caiano, L. M.; Magni, F.; Tombolini, E.; Aloise, C.; Casanova, F. M.; Peroni, B.; Ricci, A.; Scarlini, S.; Silvestri, I.; Morandi, M.; Pezzato, S.; Stefani, F.; Trevisan, V.
abstract

Coronavirus disease of 2019 (COVID-19) is associated with severe acute respiratory failure. Early identification of high-risk COVID-19 patients is crucial. We aimed to derive and validate a simple score for the prediction of severe outcomes. A retrospective cohort study of patients hospitalized for COVID-19 was carried out by the Italian Society of Internal Medicine. Epidemiological, clinical, laboratory, and treatment variables were collected at hospital admission at five hospitals. Three algorithm selection models were used to construct a predictive risk score: backward Selection, Least Absolute Shrinkage and Selection Operator (LASSO), and Random Forest. Severe outcome was defined as the composite of need for non-invasive ventilation, need for orotracheal intubation, or death. A total of 610 patients were included in the analysis, 313 had a severe outcome. The subset for the derivation analysis included 335 patients, the subset for the validation analysis 275 patients. The LASSO selection identified 6 variables (age, history of coronary heart disease, CRP, AST, D-dimer, and neutrophil/lymphocyte ratio) and resulted in the best performing score with an area under the curve of 0.79 in the derivation cohort and 0.80 in the validation cohort. Using a cut-off of 7 out of 13 points, sensitivity was 0.93, specificity 0.34, positive predictive value 0.59, and negative predictive value 0.82. The proposed score can identify patients at low risk for severe outcome who can be safely managed in a low-intensity setting after hospital admission for COVID-19.


2021 - Correction to: Hyperglycemia at admission, comorbidities, and in-hospital mortality in elderly patients hospitalized in internal medicine wards: data from the RePoSI Registry (Acta Diabetologica, (2021), 58, 9, (1225-1236), 10.1007/s00592-021-01716-8) [Articolo su rivista]
Corrao, S.; Nobili, A.; Natoli, G.; Mannucci, P. M.; Perticone, F.; Pietrangelo, A.; Argano, C.
abstract

Authors would like to update the list of Reposi Investigators as collaborators and update "on behalf of the RePoSi Collaborators" to the end of authors list. The original article has been corrected.


2021 - Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection [Articolo su rivista]
Mussini, C; Cozzi-Lepri, A; Menozzi, M; Meschiari, M; Franceschini, E; Milic, J; Brugioni, L; Pietrangelo, A; Girardis, M; Cossarizza, A; Tonelli, R; Clini, E; Massari, M; Bartoletti, M; Ferrari, A; Cattelan, Am; Zuccalà, P; Lichtner, M; Rossotti, R; Girardi, E; Nicastri, E; Puoti, M; Antinori, A; Viale, Pl; Guaraldi, G.
abstract

Background: The aim of this secondary analysis of the TESEO cohort is to identify, early in the course of treatment with tocilizumab, factors associated with the risk of progressing to mechanical ventilation and death and develop a risk score to estimate the risk of this outcome according to patients’ profile. Methods: Patients with COVID-19 severe pneumonia receiving standard of care + tocilizumab who were alive and free from mechanical ventilation at day6 after treatment initiation were included in this retrospective, multicenter cohort study. Multivariable logistic regression models were built to identify predictors of mechanical ventilation or death by day-28 from treatment initiation and β-coefficients were used to develop a risk score. Secondary outcome was mortality. Patients with the same inclusion criteria as the derivation cohort from 3 independent hospitals were used as validation cohort. Results: 266 patients treated with tocilizumab were included. By day 28 of hospital follow-up post treatment initiation, 40 (15%) underwent mechanical ventilation or died [26 (10%)]. At multivariable analysis, sex, day-4 PaO2/FiO2 ratio, platelets and CRP were independently associated with the risk of developing the study outcomes and were used to generate the proposed risk score. The accuracy of the score in AUC was 0.80 and 0.70 in internal validation and test for the composite endpoint and 0.92 and 0.69 for death, respectively. Conclusions: Our score could assist clinicians in identifying, early after tocilizumab, patients who are likely to progress to mechanical ventilation or death so that they could be selected for eventual rescue therapies.


2021 - Development of post-COVID-19 cardiovascular events: An analysis of clinical features and risk factors from a single hospital retrospective study [Articolo su rivista]
Cuomo, G.; Puzzolante, C.; Iadisernia, V.; Santoro, A.; Menozzi, M.; Carli, F.; Digaetano, M.; Orlando, G.; Franceschini, E.; Bedini, A.; Meschiari, M.; Manzini, L.; Corradi, L.; Milic, J.; Borghi, V.; Brugioni, L.; Pietrangelo, A.; Clini, E.; Girardis, M.; Guaraldi, G.; Mussini, C.
abstract

Cardiovascular complications after a SARS-CoV-2 infection are a phenomenon of relevant scientific inter-est. The aim of this study was to analyze the onset of post-COVID-19 cardiovascular events in patients hospitalized in a tertiary care center. This is a retrospective study conducted on patients hospitalized over a period of three months. The patients were older than 18 years of age and had a diagnosis of COVID-19 infection confirmed from a nasopharyngeal swab sample. Anamnestic and clinical-laboratory data were collected. Cardiovascular events at 30 days were defined as follows: arrhythmias, myocardial infarction, myocarditis, and pulmonary embolism. Univariate analysis (Student’s t-test or Mann-Whitney U test, as appropriate) and multivariate analysis (multinomial logistic regression) were applied to the data. A total of 394 patients were included; they were mostly males and had a median age of 65.5 years. Previous cardiovascular disease was present in 14.7% of patients. Oxygen therapy was required for 77.9%, and 53% received anticoagulant therapy. The overall 30-day mortality was 20.3%. A cardiovascular event developed in 15.7% of the subjects. These were mainly pulmonary embolism (9.4%), followed by arrhythmias (3.3%), myocardial infarction (2.3%), and myocarditis (0.8%). Patients who developed cardiovascular events upon univariate analysis were significantly older, with major comorbidities, a more compromised respiratory situation, and a higher mortality rate. Multivariate analysis revealed independent factors that were significantly associated with the development of cardiovascular events: hypertension, endotracheal intubation, and age older than 75 years. In patients with COVID-19, the development of a cardiovascular event occurs quite frequently and is mainly seen in elderly subjects with comorbidities (especially hypertension) in the presence of a severe respiratory picture.


2021 - Hyperglycemia at admission, comorbidities, and in-hospital mortality in elderly patients hospitalized in internal medicine wards: data from the RePoSI Registry [Articolo su rivista]
Corrao, S.; Nobili, A.; Natoli, G.; Mannucci, P. M.; Perticone, F.; Pietrangelo, A.; Argano, C.; Licata, G.; Violi, F.; Corazza, G. R.; Corrao, S.; Marengoni, A.; Salerno, F.; Cesari, M.; Tettamanti, M.; Pasina, L.; Franchi, C.; Franchi, C.; Cortesi, L.; Tettamanti, M.; Miglio, G.; Tettamanti, M.; Cortesi, L.; Ardoino, I.; Novella, A.; Prisco, D.; Silvestri, E.; Emmi, G.; Bettiol, A.; Caterina, C.; Biolo, G.; Zanetti, M.; Guadagni, M.; Zaccari, M.; Chiuch, M.; Zaccari, M.; Vanoli, M.; Grignani, G.; Pulixi, E. A.; Bernardi, M.; Bassi, S. L.; Santi, L.; Zaccherini, G.; Lupattelli, G.; Mannarino, E.; Bianconi, V.; Paciullo, F.; Alcidi, R.; Nuti, R.; Valenti, R.; Ruvio, M.; Cappelli, S.; Palazzuoli, A.; Girelli, D.; Busti, F.; Marchi, G.; Barbagallo, M.; Dominguez, L.; Cocita, F.; Beneduce, V.; Plances, L.; Mularo, S.; Raspanti, M.; Zoli, M.; Lazzari, I.; Brunori, M.; Fabbri, E.; Magalotti, D.; Arno, R.; Pasini, F. L.; Capecchi, P. L.; Palasciano, G.; Modeo, M. E.; Di Gennaro, C.; Cappellini, M. D.; Maira, D.; Di Stefano, V.; Fabio, G.; Seghezzi, S.; Mancarella, M.; De Amicis, M. M.; De Luca, G.; Scaramellini, N.; Cesari, M.; Rossi, P. D.; Damanti, S.; Clerici, M.; Conti, F.; Bonini, G.; Ottolini, B. B.; Di Sabatino, A.; Miceli, E.; Lenti, M. V.; Pisati, M.; Dominioni, C. C.; Murialdo, G.; Marra, A.; Cattaneo, F.; Pontremoli, R.; Beccati, V.; Nobili, G.; Secchi, M. B.; Ghelfi, D.; Anastasio, L.; Sofia, L.; Carbone, M.; Cipollone, F.; Guagnano, M. T.; Valeriani, E.; Rossi, I.; Mancuso, G.; Calipari, D.; Bartone, M.; Delitala, G.; Berria, M.; Pes, C.; Delitala, A.; Muscaritoli, M.; Molfino, A.; Petrillo, E.; Zuccala, G.; D'Aurizio, G.; Romanelli, G.; Marengoni, A.; Zucchelli, A.; Manzoni, F.; Volpini, A.; Picardi, A.; Gentilucci, U. V.; Gallo, P.; Dell'Unto, C.; Annoni, G.; Corsi, M.; Bellelli, G.; Zazzetta, S.; Mazzola, P.; Szabo, H.; Bonfanti, A.; Arturi, F.; Succurro, E.; Rubino, M.; Tassone, B.; Sesti, G.; Serra, M. G.; Bleve, M. A.; Gasbarrone, L.; Sajeva, M. R.; Brucato, A.; Ghidoni, S.; Fabris, F.; Bertozzi, I.; Bogoni, G.; Rabuini, M. V.; Cosi, E.; Scarinzi, P.; Amabile, A.; Omenetto, E.; Prandini, T.; Manfredini, R.; Fabbian, F.; Boari, B.; De Giorgi, A.; Tiseo, R.; De Giorgio, R.; Paolisso, G.; Rizzo, M. R.; Borghi, C.; Strocchi, E.; Ianniello, E.; Soldati, M.; Sabba, C.; Vella, F. S.; Suppressa, P.; Schilardi, A.; Loparco, F.; De Vincenzo, G. M.; Comitangelo, A.; Amoruso, E.; Fenoglio, L.; Falcetta, A.; Bracco, C.; Fargion, A. L. F. S.; Tiraboschi, S.; Cespiati, A.; Oberti, G.; Sigon, G.; Peyvandi, F.; Rossio, R.; Ferrari, B.; Colombo, G.; Agosti, P.; Monzani, V.; Savojardo, V.; Folli, C.; Ceriani, G.; Salerno, F.; Pallini, G.; Dallegri, F.; Ottonello, L.; Liberale, L.; Caserza, L.; Salam, K.; Liberato, N. L.; Tognin, T.; Bianchi, G. B.; Giaquinto, S.; Purrello, F.; Di Pino, A.; Piro, S.; Rozzini, R.; Falanga, L.; Spazzini, E.; Ferrandina, C.; Montrucchio, G.; Petitti, P.; Peasso, P.; Favale, E.; Poletto, C.; Salmi, R.; Gaudenzi, P.; Violi, F.; Perri, L.; Landolfi, R.; Montalto, M.; Mirijello, A.; Guasti, L.; Castiglioni, L.; Maresca, A.; Squizzato, A.; Campiotti, L.; Grossi, A.; Bertolotti, M.; Mussi, C.; Lancellotti, G.; Libbra, M. V.; Dondi, G.; Pellegrini, E.; Carulli, L.; Galassi, M.; Grassi, Y.; Perticone, M.; Battaglia, R.; Filice, M.; Maio, R.; Stanghellini, V.; Ruggeri, E.; del Vecchio, S.; Salvi, A.; Leonardi, R.; Damiani, G.; Capeci, W.; Gabrielli, A.; Mattioli, M.; Martino, G. P.; Biondi, L.; Pettinari, P.; Ghio, R.; Col, A. D.; Minisola, S.; Colangelo, L.; Cilli, M.; Labbadia, G.; Afeltra, A.; Marigliano, B.; Pipita, M. E.; Castellino, P.; Zanoli, L.; Pignataro, S.; Gennaro, A.; Blanco, J.; Saracco, V.; Fogliati, M.; Bussolino, C.; Mete, F.; Gino, M.; Cittadini, A.; Vigorito, C.; Arcopinto, M.; Salzano, A.; Bobbio, E.; Marra, A. M.; Sirico, D.; Moreo, G.; Gasparini, F.; Prolo, S.; Pina, G.; Ballestrero, A.; Ferrando, F.; Berra, S.; Dassi, S.; Nava, M. C.; Graziella, B.; Baldassarre, S.; Fragapani, S.; Gruden,
abstract

Aims: The association between hyperglycemia at hospital admission and relevant short- and long-term outcomes in elderly population is known. We assessed the effects on mortality of hyperglycemia, disability, and multimorbidity at admission in internal medicine ward in patients aged ≥ 65 years. Methods: Data were collected from an active register of 102 internal medicine and geriatric wards in Italy (RePoSi project). Patients were recruited during four index weeks of a year. Socio-demographic data, reason for hospitalization, diagnoses, treatment, severity and comorbidity indexes (Cumulative Illness rating Scale CIRS-SI and CIRS-CI), renal function, functional (Barthel Index), and cognitive status (Short Blessed Test) and mood disorders (Geriatric Depression Scale) were recorded. Mortality rates were assessed in hospital 3 and 12 months after discharge. Results: Of the 4714 elderly patients hospitalized, 361 had a glycemia level ≥ 250 mg/dL at admission. Compared to subjects with lower glycemia level, patients with glycemia ≥ 250 mg/dL showed higher rates of male sex, smoke and class III obesity. These patients had a significantly lower Barthel Index (p = 0.0249), higher CIRS-SI and CIRS-CI scores (p = 0.0025 and p = 0.0013, respectively), and took more drugs. In-hospital mortality rate was 9.2% and 5.1% in subjects with glycemia ≥ 250 and < 250 mg/dL, respectively (p = 0.0010). Regression analysis showed a strong association between in-hospital death and glycemia ≥ 250 mg/dL (OR 2.07; [95% CI 1.34–3.19]), Barthel Index ≤ 40 (3.28[2.44–4.42]), CIRS-SI (1.87[1.27–2.77]), and male sex (1.54[1.16–2.03]). Conclusions: The stronger predictors of in-hospital mortality for older patients admitted in general wards were glycemia level ≥ 250 mg/dL, Barthel Index ≤ 40, CIRS-SI, and male sex.


2021 - Hyperhomocysteinemia in patients with acute porphyrias: a possible effect of ALAS1 modulation by siRNAm therapy and its control by vitamin supplementation [Articolo su rivista]
Ricci, A.; Marcacci, M.; Cuoghi, C.; Pietrangelo, A.; Ventura, P.
abstract


2021 - Impact of implementing a Choosing Wisely educational intervention into clinical practice: The CW-SIMI study (a multicenter-controlled study) [Articolo su rivista]
Costantino, G.; Furlan, L.; Bracco, C.; Cappellini, M. D.; Casazza, G.; Nunziata, V.; Cogliati, C. B.; Fracanzani, A.; Furlan, R.; Gambassi, G.; Manetti, R.; Manna, R.; Piccoli, A.; Pignone, A. M.; Podda, G.; Salvatore, T.; Sella, S.; Squizzato, A.; Tresoldi, M.; Perticone, F.; Pietrangelo, A.; Corazza, G. R.; Montano, N.
abstract

Objectives: To evaluate the impact of an educational intervention based on the Italian Society of Internal Medicine Choosing Wisely (CW-SIMI) recommendations. Design: Multicenter, interventional, controlled study. Setting: Twenty-three acute-care hospital wards in Italy. Participants: 303 Physicians working in internal medicine wards. Intervention: An online educational course. Main outcomes: The rate of proton pump inhibitor (PPI) prescriptions, the number of days of central venous catheter (CVC) usage, and the duration of intravenous (IV) antibiotic prescriptions evaluated at one month (T1) and at six months (T2) after course completion. Patients admitted and discharged during a 30-day period before the educational intervention (T0, one year before T2) were considered the comparison group. Results: A total of 232 physicians completed the course, while 71 did not attend the course. Data from 608, 662, and 555 patients were analyzed at T0, T1, and T2, respectively. The rate of PPI prescriptions declined at one month (RR: 0.67, 95% CI: 0.52–0.87, p = 0.0005) and at six months (RR: 0.62, 95% CI: 0.46–0.84, p = 0.003), and the number of days of CVC usage was reduced at six months (9.13 days at T0 vs. 5.52 days at T2, p = 0.007). The duration of IV antibiotic prescriptions displayed a decreasing trend (7.94 days at T0 vs. 7.42 days at T2, p = 0.081). Conclusions: A simple online educational intervention based on the CW-SIMI recommendations was associated with a clinically relevant reduction in the usage of PPIs and CVCs. Further studies are needed to confirm these findings and a possible benefit on patients’ outcomes.


2021 - Pattern of comorbidities and 1-year mortality in elderly patients with COPD hospitalized in internal medicine wards: data from the RePoSI Registry [Articolo su rivista]
Argano, C.; Scichilone, N.; Natoli, G.; Nobili, A.; Corazza, G. R.; Mannucci, P. M.; Perticone, F.; Corrao, S.; Pietrangelo, A.; Licata, G.; Violi, F.; Corrao, S.; Marengoni, A.; Salerno, F.; Cesari, M.; Tettamanti, M.; Pasina, L.; Franchi, C.; Miglio, G.; Cortesi, L.; Ardoino, I.; Novella, A.; Prisco, D.; Silvestri, E.; Emmi, G.; Bettiol, A.; Caterina, C.; Biolo, G.; Zanetti, M.; Guadagni, M.; Zaccari, M.; Chiuch, M.; Zaccari, M.; Vanoli, M.; Grignani, G.; Pulixi, E. A.; Bernardi, M.; Bassi, S. L.; Santi, L.; Zaccherini, G.; Lupattelli, G.; Mannarino, E.; Bianconi, V.; Paciullo, F.; Alcidi, R.; Nuti, R.; Valenti, R.; Ruvio, M.; Cappelli, S.; Palazzuoli, A.; Girelli, D.; Busti, F.; Marchi, G.; Barbagallo, M.; Dominguez, L.; Cocita, F.; Beneduce, V.; Plances, L.; Corrao, S.; Mularo, S.; Raspanti, M.; Cavallaro, F.; Zoli, M.; Lazzari, I.; Brunori, M.; Fabbri, E.; Magalotti, D.; Arno, R.; Pasini, F. L.; Capecchi, P. L.; Palasciano, G.; Modeo, M. E.; Di Gennaro, C.; Cappellini, M. D.; Maira, D.; Di Stefano, V.; Fabio, G.; Seghezzi, S.; Mancarella, M.; De Amicis, M. M.; De Luca, G.; Scaramellini, N.; Cesari, M.; Rossi, P. D.; Damanti, S.; Clerici, M.; Conti, F.; Bonini, G.; Ottolini, B. B.; Di Sabatino, A.; Miceli, E.; Lenti, M. V.; Pisati, M.; Dominioni, C. C.; Murialdo, G.; Marra, A.; Cattaneo, F.; Pontremoli, R.; Beccati, V.; Nobili, G.; Secchi, M. B.; Ghelfi, D.; Anastasio, L.; Sofia, L.; Carbone, M.; Cipollone, F.; Guagnano, M. T.; Valeriani, E.; Rossi, I.; Mancuso, G.; Calipari, D.; Bartone, M.; Delitala, G.; Berria, M.; Pes, C.; Delitala, A.; Muscaritoli, M.; Molfino, A.; Petrillo, E.; Zuccala, G.; D'Aurizio, G.; Romanelli, G.; Zucchelli, A.; Manzoni, F.; Volpini, A.; Picardi, A.; Gentilucci, U. V.; Gallo, P.; Dell'Unto, C.; Annoni, G.; Corsi, M.; Bellelli, G.; Zazzetta, S.; Mazzola, P.; Szabo, H.; Bonfanti, A.; Arturi, F.; Succurro, E.; Rubino, M.; Tassone, B.; Sesti, G.; Serra, M. G.; Bleve, M. A.; Gasbarrone, L.; Sajeva, M. R.; Brucato, A.; Ghidoni, S.; Fabris, F.; Bertozzi, I.; Bogoni, G.; Rabuini, M. V.; Cosi, E.; Scarinzi, P.; Amabile, A.; Omenetto, E.; Prandini, T.; Manfredini, R.; Fabbian, F.; Boari, B.; De Giorgi, A.; Tiseo, R.; De Giorgio, R.; Paolisso, G.; Rizzo, M. R.; Borghi, C.; Strocchi, E.; Ianniello, E.; Soldati, M.; Sabba, C.; Vella, F. S.; Suppressa, P.; Schilardi, A.; Loparco, F.; De Vincenzo, G. M.; Comitangelo, A.; Amoruso, E.; Fenoglio, L.; Falcetta, A.; Bracco, C.; Fracanzani Silvia Fargion, A. L.; Tiraboschi, S.; Cespiati, A.; Oberti, G.; Sigon, G.; Peyvandi, F.; Rossio, R.; Ferrari, B.; Colombo, G.; Agosti, P.; Monzani, V.; Savojardo, V.; Folli, C.; Ceriani, G.; Salerno, F.; Pallini, G.; Dallegri, F.; Ottonello, L.; Liberale, L.; Caserza, L.; Salam, K.; Liberato, N. L.; Tognin, T.; Bianchi, G. B.; Giaquinto, S.; Purrello, F.; Di Pino, A.; Piro, S.; Rozzini, R.; Falanga, L.; Spazzini, E.; Ferrandina, C.; Montrucchio, G.; Petitti, P.; Peasso, P.; Favale, E.; Poletto, C.; Salmi, R.; Gaudenzi, P.; Violi, F.; Perri, L.; Landolfi, R.; Montalto, M.; Mirijello, A.; Guasti, L.; Castiglioni, L.; Maresca, A.; Squizzato, A.; Campiotti, L.; Grossi, A.; Bertolotti, M.; Mussi, C.; Lancellotti, G.; Libbra, M. V.; Dondi, G.; Pellegrini, E.; Carulli, L.; Galassi, M.; Grassi, Y.; Perticone, M.; Battaglia, R.; Filice, M.; Maio, R.; Stanghellini, V.; Ruggeri, E.; del Vecchio, S.; Salvi, A.; Leonardi, R.; Damiani, G.; Capeci, W.; Gabrielli, A.; Mattioli, M.; Martino, G. P.; Biondi, L.; Pettinari, P.; Ghio, R.; Col, A. D.; Minisola, S.; Colangelo, L.; Cilli, M.; Labbadia, G.; Afeltra, A.; Marigliano, B.; Pipita, M. E.; Castellino, P.; Zanoli, L.; Pignataro, S.; Gennaro, A.; Blanco, J.; Saracco, V.; Fogliati, M.; Bussolino, C.; Mete, F.; Gino, M.; Cittadini, A.; Vigorito, C.; Arcopinto, M.; Salzano, A.; Bobbio, E.; Marra, A. M.; Sirico, D.; Moreo, G.; Gasparini, F.; Prolo, S.; Pina, G.; Ballestrero, A.; Ferrando, F.; Berra, S.; Dassi, S.; Nava, M. C.; Graziella, B.; Baldassarre, S.; Fragapani, S.; Gruden, G.; Galanti, G.;
abstract

Currently, chronic obstructive pulmonary disease (COPD) represents the fourth cause of death worldwide with significant economic burden. Comorbidities increase in number and severity with age and are identified as important determinants that influence the prognosis. In this observational study, we retrospectively analyzed data collected from the RePoSI register. We aimed to investigate comorbidities and outcomes in a cohort of hospitalized elderly patients with the clinical diagnosis of COPD. Socio-demographic, clinical characteristics and laboratory findings were considered. The association between variables and in-hospital, 3-month and 1-year follow-up were analyzed. Among 4696 in-patients, 932 (19.8%) had a diagnosis of COPD. Patients with COPD had more hospitalization, a significant overt cognitive impairment, a clinically significant disability and more depression in comparison with non-COPD subjects. COPD patients took more drugs, both at admission, in-hospital stay, discharge and 3-month and 1-year follow-up. 14 comorbidities were more frequent in COPD patients. Cerebrovascular disease was an independent predictor of in-hospital mortality. At 3-month follow-up, male sex and hepatic cirrhosis were independently associated with mortality. ICS-LABA therapy was predictor of mortality at in-hospital, 3-month and 1-year follow-up. This analysis showed the severity of impact of COPD and its comorbidities in the real life of internal medicine and geriatric wards.


2021 - Subclinical liver fibrosis in patients with idiopathic pulmonary fibrosis [Articolo su rivista]
Cocconcelli, E; Tonelli, R; Abbati, G; Marchioni, A; Castaniere, I; Pelizzaro, F; Russo, Fp; Vegetti, A; Balestro, E; Pietrangelo, A; Richeldi, L; Luppi, F; Spagnolo, P; Clini, E; Cerri, S.
abstract

Background - Data on the presence of subclinical fibrosis across multiple organs in patients with idiopathic lung fibrosis (IPF) are lacking. Our study aimed at investigating through hepatic transient elastography (HTE) the prevalence and clinical impact of subclinical liver fibrosis in a cohort of patients with IPF. Methods - Patients referred to the Centre for Rare Lung Disease of the University Hospital of Modena (Italy) from March 2012 to February 2013with established diagnosis of IPF and without a documented history of liver diseases were consecutively enrolled and underwent HTE. Based on hepatic stiffness status as assessed through METAVIR score patients were categorized as “ with liver fibrosis ” (corresponding to a METAVIR score of F1-F4) and “ without liver fibrosis” (METAVIR F0). Potential predictors of liver fibrosis were investigated through logistic regression model among clinical and serological variables. The overall survival (OS) was assessed according to liver fibrosis and multivariate Cox regression analysis was used to identify independent predictors. Results - In 13 out of 37 patients (35%) with IPF a certain degree of liver fibrosis was documented.No correlation was found between liver stiffness and clinical-functional parameters. OS was lower in patients ‘ with liver fibrosis’ than in patients ‘ without liver fibrosis’ (median months 33[23-55] vs. 63[26-94], p=0.038). Patients ‘ with liver fibrosis’ presented a higher risk of death at seven years as compared to patients ‘without liver fibrosis’ (HR=2.6, 95%CI[1.003–6.7],p= 0.049). Higher level of AST to platelet ratio Index (APRI)was an independent predictor of survival (HR=4.52 95%CI[1.3–15.6], p=0.02). Conclusions - In our cohort, more than one third of IPF patients had concomitant subclinical liver fibrosis that negatively affected OS. These preliminary claims further investigation aimed at clarifying the mechanisms beyond multiorgan fibrosis and its clinical implication in patients with IPF.


2021 - The multifaceted spectrum of liver cirrhosis in older hospitalised patients: Analysis of the REPOSI registry [Articolo su rivista]
De Vincentis, A.; Vespasiani-Gentilucci, U.; Costanzo, L.; Novella, A.; Cortesi, L.; Nobili, A.; Mannucci, P. M.; Incalzi, R. A.; Mannucci, P. M.; Nobili, A.; Pietrangelo, A.; Perticone, F.; Licata, G.; Violi, F.; Corazza, G. R.; Corrao, S.; Marengoni, A.; Salerno, F.; Cesari, M.; Tettamanti, M.; Pasina, L.; Franchi, C.; Franchi, C.; Cortesi, L.; Tettamanti, M.; Miglio, G.; Tettamanti, M.; Cortesi, L.; Ardoino, I.; Novella, A.; Prisco, D.; Silvestri, E.; Emmi, G.; Bettiol, A.; Mattioli, I.; Biolo, G.; Zanetti, M.; Bartelloni, G.; Vanoli, M.; Grignani, G.; Pulixi, E. A.; Lupattelli, G.; Bianconi, V.; Alcidi, R.; Girelli, D.; Busti, F.; Marchi, G.; Barbagallo, M.; Dominguez, L.; Beneduce, V.; Cacioppo, F.; Corrao, S.; Natoli, G.; Mularo, S.; Raspanti, M.; Zoli, M.; Matacena, M. L.; Orio, G.; Magnolfi, E.; Serafini, G.; Simili, A.; Palasciano, G.; Modeo, M. E.; Gennaro, C. D.; Cappellini, M. D.; Fabio, G.; De Amicis, M. M.; De Luca, G.; Scaramellini, N.; Cesari, M.; Rossi, P. D.; Damanti, S.; Clerici, M.; Leoni, S.; Di Mauro, A. D.; Di Sabatino, A.; Miceli, E.; Lenti, M. V.; Pisati, M.; Dominioni, C. C.; Pontremoli, R.; Beccati, V.; Nobili, G.; Leoncini, G.; Anastasio, L.; Carbone, M.; Cipollone, F.; Guagnano, M. T.; Rossi, I.; Mancuso, G.; Calipari, D.; Bartone, M.; Delitala, G.; Berria, M.; Delitala, A.; Muscaritoli, M.; Molfino, A.; Petrillo, E.; Giorgi, A.; Gracin, C.; Zuccala, G.; D'Aurizio, G.; Romanelli, G.; Marengoni, A.; Volpini, A.; Lucente, D.; Picardi, A.; Gentilucci, U. V.; Bellelli, G.; Corsi, M.; Antonucci, C.; Sidoli, C.; Principato, G.; Arturi, F.; Succurro, E.; Tassone, B.; Giofre, F.; Serra, M. G.; Bleve, M. A.; Brucato, A.; De Falco, T.; Fabris, F.; Bertozzi, I.; Bogoni, G.; Rabuini, M. V.; Prandini, T.; Manfredini, R.; Fabbian, F.; Boari, B.; De Giorgi, A.; Tiseo, R.; Paolisso, G.; Rizzo, M. R.; Catalano, C.; Borghi, C.; Strocchi, E.; Ianniello, E.; Soldati, M.; Schiavone, S.; Bragagni, A.; Sabba, C.; Vella, F. S.; Suppressa, P.; De Vincenzo, G. M.; Comitangelo, A.; Amoruso, E.; Custodero, C.; Fenoglio, L.; Falcetta, A.; Fracanzani, A. L.; Tiraboschi, S.; Cespiati, A.; Oberti, G.; Sigon, G.; Peyvandi, F.; Rossio, R.; Colombo, G.; Agosti, P.; Monzani, V.; Savojardo, V.; Ceriani, G.; Salerno, F.; Pallini, G.; Montecucco, F.; Ottonello, L.; Caserza, L.; Vischi, G.; Liberato, N. L.; Tognin, T.; Purrello, F.; Di Pino, A.; Piro, S.; Rozzini, R.; Falanga, L.; Pisciotta, M. S.; Bellucci, F. B.; Buffelli, S.; Montrucchio, G.; Peasso, P.; Favale, E.; Poletto, C.; Margaria, C.; Sanino, M.; Violi, F.; Perri, L.; Guasti, L.; Castiglioni, L.; Maresca, A.; Squizzato, A.; Campiotti, L.; Grossi, A.; Diprizio, R. D.; Bertolotti, M.; Mussi, C.; Lancellotti, G.; Libbra, M. V.; Galassi, M.; Grassi, Y.; Greco, A.; Sciacqua, A.; Perticone, M.; Battaglia, R.; Maio, R.; Stanghellini, V.; Ruggeri, E.; Del Vecchio, S.; Salvi, A.; Leonardi, R.; Damiani, G.; Capeci, W.; Mattioli, M.; Martino, G. P.; Biondi, L.; Pettinari, P.; Ghio, R.; Col, A. D.; Minisola, S.; Colangelo, L.; Cilli, M.; Labbadia, G.; Afeltra, A.; Pipita, M. E.; Castellino, P.; Zanoli, L.; Gennaro, A.; Gaudio, A.; Saracco, V.; Fogliati, M.; Bussolino, C.; Mete, F.; Gino, M.; Vigorito, C.; Cittadini, A.; Moreo, G.; Prolo, S.; Pina, G.; Ballestrero, A.; Ferrando, F.; Gonella, R.; Cerminara, D.; Berra, S.; Dassi, S.; Nava, M. C.; Graziella, B.; Baldassarre, S.; Fragapani, S.; Gruden, G.; Galanti, G.; Mascherini, G.; Petri, C.; Stefani, L.; Girino, M.; Piccinelli, V.; Nasso, F.; Gioffre, V.; Pasquale, M.; Sechi, L.; Catena, C.; Colussi, G.; Cavarape, A.; Da Porto, A.; Passariello, N.; Rinaldi, L.; Berti, F.; Famularo, G.; Tarsitani, P.; Castello, R.; Pasino, M.; Ceda, G. P.; Maggio, M. G.; Morganti, S.; Artoni, A.; Grossi, M.; Del Giacco, S.; Firinu, D.; Costanzo, G.; Argiolas, G.; Montalto, G.; Licata, A.; Montalto, F. A.; Corica, F.; Basile, G.; Catalano, A.; Bellone, F.; Principato, C.; Malatino, L.; Stancanelli, B.; Terranova, V.; Di Marca, S.; Di Quattro, R.; Malfa, L. L
abstract

Background: Knowledge on the main clinical and prognostic characteristics of older multimorbid subjects with liver cirrhosis (LC) admitted to acute medical wards is scarce. Objectives: To estimate the prevalence of LC among older patients admitted to acute medical wards and to assess the main clinical characteristics of LC along with its association with major clinical outcomes and to explore the possibility that well-distinguished phenotypic profiles of LC have classificatory and prognostic properties. Methods: A cohort of 6,193 older subjects hospitalised between 2010 and 2018 and included in the REPOSI registry was analysed. Results: LC was diagnosed in 315 patients (5%). LC was associated with rehospitalisation (age-sex adjusted hazard ratio, [aHR] 1.44; 95% CI, 1.10-1.88) and with mortality after discharge, independently of all confounders (multiple aHR, 2.1; 95% CI, 1.37-3.22), but not with in-hospital mortality and incident disability. Three main clinical phenotypes of LC patients were recognised: relatively fit subjects (FIT, N = 150), subjects characterised by poor social support (PSS, N = 89) and, finally, subjects with disability and multimorbidity (D&M, N = 76). PSS subjects had an increased incident disability (35% vs 13%, P < 0.05) compared to FIT. D&M patients had a higher mortality (in-hospital: 12% vs 3%/1%, P < 0.01; post-discharge: 41% vs 12%/15%, P < 0.01) and less rehospitalisation (10% vs 32%/34%, P < 0.01) compared to PSS and FIT. Conclusions: LC has a relatively low prevalence in older hospitalised subjects but, when present, accounts for worse post-discharge outcomes. Phenotypic analysis unravelled the heterogeneity of LC older population and the association of selected phenotypes with different clinical and prognostic features.


2021 - Underdiagnosis and undertreatment of osteoporotic patients admitted in internal medicine wards in Italy between 2010 and 2016 (the REPOSI Register) [Articolo su rivista]
Pepe, J.; Agosti, P.; Cipriani, C.; Tettamanti, M.; Nobili, A.; Colangelo, L.; Santori, R.; Cilli, M.; Minisola, S.; Mannucci, P. M.; Pietrangelo, A.; Perticone, F.; Violi, F.; Corazza, G. R.; Corrao, S.; Marengoni, A.; Salerno, F.; Cesari, M.; Pasina, L.; Cortesi, C. F. L.; Miglio, G.; Ardoino, I.; Novella, A.; Prisco, D.; Silvestri, E.; Emmi, G.; Bettiol, A.; Mattioli, I.; Biolo, G.; Zanetti, M.; Bartelloni, G.; Vanoli, M.; Grignani, G.; Pulixi, E. A.; Lupattelli, G.; Bianconi, V.; Alcidi, R.; Girelli, D.; Busti, F.; Marchi, G.; Barbagallo, M.; Dominguez, L.; Beneduce, V.; Cacioppo, F.; Corrao, S.; Natoli, G.; Mularo, S.; Raspanti, M.; Zoli, M.; Matacena, M. L.; Orio, G.; Magnolfi, E.; Serafini, G.; Simili, A.; Palasciano, G.; Modeo, M. E.; Di Gennaro, C.; Cappellini, M. D.; Fabio, G.; De Amicis, M. M.; De Luca, G.; Scaramellini, N.; Cesari, M.; Rossi, P. D.; Damanti, S.; Clerici, M.; Leoni, S.; Di Mauro, A. D.; Di Sabatino, A.; Miceli, E.; Lenti, M. V.; Pisati, M.; Dominioni, C. C.; Pontremoli, R.; Beccati, V.; Nobili, G.; Leoncini, G.; Anastasio, L.; Carbone, M.; Cipollone, F.; Guagnano, M. T.; Rossi, I.; Mancuso, G.; Calipari, D.; Bartone, M.; Delitala, G.; Berria, M.; Delitala, A.; Muscaritoli, M.; Molfino, A.; Petrillo, E.; Giorgi, A.; Gracin, C.; Zuccala, G.; D'Aurizio, G.; Romanelli, G.; Volpini, A.; Lucente, D.; Picardi, A.; Gentilucci, U. V.; Gallo, P.; Bellelli, G.; Corsi, M.; Antonucci, C.; Sidoli, C.; Principato, G.; Arturi, F.; Succurro, E.; Tassone, B.; Giofre, F.; Serra, M. G.; Bleve, M. A.; Brucato, A.; De Falco, T.; Fabris, F.; Bertozzi, I.; Bogoni, G.; Rabuini, M. V.; Prandini, T.; Manfredini, R.; Fabbian, F.; Boari, B.; De Giorgi, A.; Tiseo, R.; Paolisso, G.; Rizzo, M. R.; Catalano, C.; Borghi, C.; Strocchi, E.; Ianniello, E.; Soldati, M.; Schiavone, S.; Bragagni, A.; Sabba, C.; Vella, F. S.; Suppressa, P.; De Vincenzo, G. M.; Comitangelo, A.; Amoruso, E.; Custodero, C.; Fenoglio, L.; Falcetta, A.; Fracanzani, A. L.; Tiraboschi, S.; Cespiati, A.; Oberti, G.; Sigon, G.; Peyvandi, F.; Rossio, R.; Colombo, G.; Monzani, V.; Savojardo, V.; Ceriani, G.; Salerno, F.; Pallini, G.; Montecucco, F.; Ottonello, L.; Caserza, L.; Vischi, G.; Liberato, N. L.; Tognin, T.; Purrello, F.; Di Pino, A.; Piro, S.; Rozzini, R.; Falanga, L.; Pisciotta, M. S.; Bellucci, F. B.; Buffelli, S.; Montrucchio, G.; Peasso, P.; Favale, E.; Poletto, C.; Margaria, C.; Sanino, M.; Perri, L.; Guasti, L.; Castiglioni, L.; Maresca, A.; Squizzato, A.; Campiotti, L.; Grossi, A.; Diprizio, R. D.; Bertolotti, M.; Mussi, C.; Lancellotti, G.; Libbra, M. V.; Galassi, M.; Grassi, Y.; Greco, A.; Sciacqua, A.; Perticone, M.; Battaglia, R.; Maio, R.; Stanghellini, V.; Ruggeri, E.; del Vecchio, S.; Salvi, A.; Leonardi, R.; Damiani, G.; Capeci, W.; Mattioli, M.; Martino, G. P.; Biondi, L.; Pettinari, P.; Ghio, R.; Col, A. D.; Labbadia, G.; Afeltra, A.; Marigliano, B.; Pipita, M. E.; Castellino, P.; Zanoli, L.; Gennaro, A.; Gaudio, A.; Saracco, V.; Fogliati, M.; Bussolino, C.; Mete, F.; Gino, M.; Vigorito, C.; Cittadini, A.; Moreo, G.; Prolo, S.; Pina, G.; Ballestrero, A.; Ferrando, F.; Gonella, R.; Cerminara, D.; Berra, S.; Dassi, S.; Nava, M. C.; Graziella, B.; Baldassarre, S.; Fragapani, S.; Gruden, G.; Galanti, G.; Mascherini, G.; Petri, C.; Stefani, L.; Girino, M.; Piccinelli, V.; Nasso, F.; Gioffre, V.; Pasquale, M.; Sechi, L.; Catena, C.; Colussi, G.; Cavarape, A.; Da Porto, A.; Passariello, N.; Rinaldi, L.; Berti, F.; Famularo, G.; Tarsitani, P.; Castello, R.; Pasino, M.; Ceda, G. P.; Maggio, M. G.; Morganti, S.; Artoni, A.; Grossi, M.; Del Giacco, S.; Firinu, D.; Costanzo, G.; Argiolas, G.; Montalto, G.; Licata, A.; Montalto, F. A.; Corica, F.; Basile, G.; Catalano, A.; Bellone, F.; Principato, C.; Malatino, L.; Stancanelli, B.; Terranova, V.; Di Marca, S.; Di Quattro, R.; La Malfa, L.; Caruso, R.; Mecocci, P.; Ruggiero, C.; Boccardi, V.; Meschi, T.; Ticinesi, A.; Nouvenne, A.; Minuz, P.; Fondrieschi, L.; Imperiale, G. N.; Pirisi, M.; Fra, G. P.; Sol
abstract

Purpose: To evaluate clinical features, treatments, and outcomes of osteoporotic patients admitted to internal medicine and geriatric wards compared with non-osteoporotic patients (REPOSI registry). Methods: We studied 4714 patients hospitalized between 2010 and 2016. We reported age, sex, educational level, living status, comorbidities and drugs taken, Cumulative Illness Rating Scale (CIRS), Barthel Index, Short-Blessed Test, 4-item Geriatric Depression Scale, serum hemoglobin, creatinine, and clinical outcomes. Osteoporosis was defined based on the diagnoses recorded at admission, according to the following ICD9: 733, 805–813, 820–823. Results: Twelve percent of the patients had a preadmission diagnosis of osteoporosis. Only 20% of these had been prescribed oral bisphosphonates; 34% were taking vitamin D supplements. Osteoporotic patients were significantly older, with lower BMI, higher CIRS, and taking more drugs. They were significantly more depressed, less independent, with a higher severity of cognitive impairment compared with non-osteoporotic patients. At discharge, the number of patients receiving treatment for osteoporosis did not change. Length of stay and inhospital mortality did not differ between groups. Osteoporotic patients were more frequently nonhome discharged compared with those without osteoporosis (14.8 vs. 7.9%, p = 0.0007), mostly discharged to physical therapy or rehabilitation (8.8 vs. 2.5% of patients, p < 0.0001). Among osteoporotic patients deceased 3 months after discharge, the number of those treated with vitamin D, with or without calcium supplements, was significantly lower compared with survivors (12 vs. 32%, p = 0.0168). Conclusions: The diagnosis of osteoporosis is poorly considered both during hospital stay and at discharge; osteoporotic patients are frailer compared to non-osteoporotic patients.


2021 - What changed in the Italian internal medicine and geriatric wards during the lockdown [Articolo su rivista]
D'Avanzo, B.; Nobili, A.; Tettamanti, M.; Pasina, L.; Mannucci, P. M.; Pietrangelo, A.; Perticone, F.; Violi, F.; Corazza, G. R.; Corrao, S.; Marengoni, A.; Salerno, F.; Cesari, M.; Franchi, C.; Cortesi, L.; Miglio, G.; Ardoino, I.; Novella, A.; Prisco, D.; Silvestri, E.; Emmi, G.; Bettiol, A.; Mattioli, I.; Biolo, G.; Zanetti, M.; Bartelloni, G.; Vanoli, M.; Grignani, G.; Pulixi, E. A.; Lupattelli, G.; Bianconi, V.; Alcidi, R.; Girelli, D.; Busti, F.; Marchi, G.; Barbagallo, M.; Dominguez, L.; Beneduce, V.; Cacioppo, F.; Natoli, G.; Mularo, S.; Raspanti, M.; Zoli, M.; Matacena, M. L.; Orio, G.; Magnolfi, E.; Serafini, G.; Simili, A.; Palasciano, G.; Modeo, M. E.; Di Gennaro, C.; Cappellini, M. D.; Fabio, G.; de Amicis, M. M.; de Luca, G.; Scaramellini, N.; Rossi, P. D.; Damanti, S.; Clerici, M.; Leoni, S.; Di Mauro, A. D.; Di Sabatino, A.; Miceli, E.; Lenti, M. V.; Pisati, M.; Dominioni, C. C.; Pontremoli, R.; Beccati, V.; Nobili, G.; Leoncini, G.; Anastasio, L.; Carbone, M.; Cipollone, F.; Guagnano, M. T.; Rossi, I.; Mancuso, G.; Calipari, D.; Bartone, M.; Delitala, G.; Berria, M.; Delitala, A.; Muscaritoli, M.; Molfino, A.; Petrillo, E.; Giorgi, A.; Gracin, C.; Zuccala, G.; D'Aurizio, G.; Romanelli, G.; Volpini, A.; Lucente, D.; Picardi, A.; Gentilucci, U. V.; Gallo, P.; Bellelli, G.; Corsi, M.; Antonucci, C.; Sidoli, C.; Principato, G.; Arturi, F.; Succurro, E.; Tassone, B.; Giofre, F.; Serra, M. G.; Bleve, M. A.; Brucato, A.; de Falco, T.; Fabris, F.; Bertozzi, I.; Bogoni, G.; Rabuini, M. V.; Prandini, T.; Manfredini, R.; Fabbian, F.; Boari, B.; de Giorgi, A.; Tiseo, R.; Paolisso, G.; Rizzo, M. R.; Catalano, C.; Borghi, C.; Strocchi, E.; Ianniello, E.; Soldati, M.; Schiavone, S.; Bragagni, A.; Sabba, C.; Vella, F. S.; Suppressa, P.; de Vincenzo, G. M.; Comitangelo, A.; Amoruso, E.; Custodero, C.; Fenoglio, L.; Falcetta, A.; Fracanzani, A. L.; Tiraboschi, S.; Cespiati, A.; Oberti, G.; Sigon, G.; Peyvandi, F.; Rossio, R.; Colombo, G.; Agosti, P.; Monzani, V.; Savojardo, V.; Ceriani, G.; Pallini, G.; Montecucco, F.; Ottonello, L.; Caserza, L.; Vischi, G.; Liberato, N. L.; Tognin, T.; Purrello, F.; Di Pino, A.; Piro, S.; Rozzini, R.; Falanga, L.; Pisciotta, M. S.; Bellucci, F. B.; Buffelli, S.; Montrucchio, G.; Peasso, P.; Favale, E.; Poletto, C.; Margaria, C.; Sanino, M.; Guasti, L.; Castiglioni, L.; Maresca, A.; Squizzato, A.; Campiotti, L.; Grossi, A.; Diprizio, R. D.; Bertolotti, M.; Mussi, C.; Lancellotti, G.; Libbra, M. V.; Galassi, M.; Grassi, Y.; Greco, A.; Sciacqua, A.; Perticone, M.; Battaglia, R.; Maio, R.; Stanghellini, V.; Ruggeri, E.; del Vecchio, S.; Salvi, A.; Leonardi, R.; Damiani, G.; Capeci, W.; Mattioli, M.; Martino, G. P.; Biondi, L.; Pettinari, P.; Ghio, R.; Dal Col, A.; Minisola, S.; Colangelo, L.; Cilli, M.; Labbadia, G.; Afeltra, A.; Marigliano, B.; Pipita, M. E.; Castellino, P.; Zanoli, L.; Gennaro, A.; Gaudio, A.; Saracco, V.; Fogliati, M.; Bussolino, C.; Mete, F.; Gino, M.; Vigorito, C.; Cittadini, A.; Moreo, G.; Prolo, S.; Pina, G.; Ballestrero, A.; Ferrando, F.; Gonella, R.; Cerminara, D.; Berra, S.; Dassi, S.; Nava, M. C.; Graziella, B.; Baldassarre, S.; Fragapani, S.; Gruden, G.; Galanti, G.; Mascherini, G.; Petri, C.; Stefani, L.; Girino, M.; Piccinelli, V.; Nasso, F.; Gioffre, V.; Pasquale, M.; Sechi, L.; Catena, C.; Colussi, G.; Cavarape, A.; da Porto, A.; Passariello, N.; Rinaldi, L.; Berti, F.; Famularo, G.; Tarsitani, P.; Castello, R.; Pasino, M.; Ceda, G. P.; Maggio, M. G.; Morganti, S.; Artoni, A.; Grossi, M.; Del Giacco, S.; Firinu, D.; Costanzo, G.; Argiolas, G.; Montalto, G.; Licata, A.; Montalto, F. A.; Corica, F.; Basile, G.; Catalano, A.; Bellone, F.; Principato, C.; Malatino, L.; Stancanelli, B.; Terranova, V.; Di Marca, S.; Di Quattro, R.; la Malfa, L.; Caruso, R.; Mecocci, P.; Ruggiero, C.; Boccardi, V.; Meschi, T.; Ticinesi, A.; Nouvenne, A.; Minuz, P.; Fondrieschi, L.; Imperiale, G. N.; Pirisi, M.; Fra, G. P.; Sola, D.; Bellan, M.; Porta, M.; Riva, P.; Quadri, R.; Larovere, E
abstract


2020 - Clinical and molecular epidemiology of erythropoietic protoporphyria in Italy [Articolo su rivista]
Ventura, Paolo; Brancaleoni, Valentina; Di Pierro, Elena; Graziadei, Giovanna; Macrì, Annelise; Carmine Guida, Claudio; Nicolli, Annamaria; Teresa Rossi, Maria; Granata, Francesca; Fiorentino, Valeria.; Fustinoni, Silvia; Sala, Raffella; Calzavara Pinton, Piergiacomo; Trevisan, Andrea; Marchini, Stefano; Cuoghi, Chiara; Marcacci, Matteo; Corradini, Elena; Sorge, Fiammetta; Aurizi, Caterina; Grazia Savino, Maria; Cappellini, Maria Domenica; Pietrangelo, Antonello
abstract

Background: Erythropoietic protoporphyria (EPP) is a rare inherited disease associated with heme metabolism, characterized by severe life-long photosensitivity and liver involvement. Objectives: To provide epidemiological data of EPP in Italy. Materials and Methods: Prospective/retrospective data of EPP patients were collected by an Italian network of porphyria specialist centres (Gruppo Italiano Porfiria, GrIP) over a 20-year period (1996-2017). Results: In total, 179 patients (79 females) with a clinical and biochemical diagnosis of EPP were assessed, revealing a prevalence of 3.15 cases per million persons and an incidence of 0.13 cases per million persons/year. Incidence significantly increased after 2009 (due to the availability of alfa-melanotide, which effectively limits skin photosensitivity). Mean age at diagnosis was 28 years, with only 22 patients (12.2%) diagnosed ≤10 years old. Gene mutations were assessed in 173 (96.6%) patients; most (164; 91.3%) were FECH mutations on one allele in association with the hypomorphic variant, c.315-48C, on the other (classic EPP), and nine (5.2%) were ALAS2 mutations (X-linked EPP). Only one case of autosomal recessive EPP was observed. Of the 42 different FECH mutations, 15 are novel, three mutations collectively accounted for 45.9% (75/164) of the mutations (c.215dupT [27.2%], c.901_902delTG [11.5%] and c.67 + 5G > A [7.2%]), and frameshift mutations were prevalent (33.3%). A form of light protection was used by 109/179 (60.8%) patients, and 100 (56%) had at least one α-melanotide implant. Three cases of severe acute liver involvement, requiring OLT, were observed. Conclusions: These data define, for the first time, the clinical and molecular epidemiology of EPP in Italy.


2020 - Comorbidity does not mean clinical complexity: evidence from the RePoSI register [Articolo su rivista]
Corrao, S.; Natoli, G.; Nobili, A.; Mannucci, P. M.; Pietrangelo, A.; Perticone, F.; Argano, C.
abstract

In the last 2–3 decades internists have confronted dramatic changes in the pattern of patients acutely admitted to hospital wards. Internists observed a shift from younger subjects affected by a single organ disease to more complex patients, usually older, with multiple chronic conditions, attended by different specialists, with poor integration and treated with multiple drugs. In this regard, the concept of complex patients is addressed daily in clinical practice even if there is no agreed definition of patient complexity. To try to evaluate clinical complexity different instruments have been proposed. Among these, the number of comorbidities (NoC) was considered a marker of clinical complexity. However, this instrument would not give information about the clinical relevance of each condition. On the contrary, cumulative illness rating scale (CIRS) addresses the problem calculating both CIRS severity index (CIRS-SI) and CIRS comorbidity index (CIRS-CI). In light of this, 4714 patients from the RePoSI register were retrospectively analyzed to show if CIRS assessment of comorbidity burden is different from the simple count of comorbidities in predicting the length of hospital stay (LOS) and all-cause of mortality in hospitalized elderly patients and if NoC could be a valid tool to measure patient’s complexity. CIRS-SI resulted the best predictor of all-cause in-hospital mortality [OR: 2.66 (1.88–3.77)] in comparison with NoC that did not result statistically significant (p = 0.551). CIRS-SI was also the best predictor of all-cause of post-discharge mortality corrected for age and sex [OR: 2.12 (1.53–2.95)]. CIRS-SI (coefficient ± standard error: 1.23 ± 0.59; p < 0.0381) and CIRS-CI (coefficient ± standard error: 0.27 ± 0.10; p < 0.011) were strong predictors of LOS in comparison with NoC that did not result statistically significant (coefficient ± standard error: 0.04 ± 0.06 p < 0.0561). In conclusion, CIRS assessment of comorbidity burden is a better clinical tool in comparison with the simple count of comorbidities especially considering the length of hospital stay and all-cause mortality in hospitalized elderly patients.


2020 - Genetic iron overload disorders [Articolo su rivista]
Corradini, E.; Buzzetti, E.; Pietrangelo, A.
abstract

Due to its pivotal role in orchestrating vital cellular functions and metabolic processes, iron is an essential component of the human body and a main micronutrient in the human diet. However, excess iron causes an increased production of reactive oxygen species leading to cell dysfunction or death, tissue damage and organ disease. Iron overload disorders encompass a wide spectrum of pathological conditions of hereditary or acquired origin. A number of ‘iron genes’ have been identified as being associated with hereditary iron overload syndromes, the most common of which is hemochromatosis. Although linked to at least five different genes, hemochromatosis is recognized as a unique syndromic entity based on a common pathogenetic mechanism leading to excessive entry of unneeded iron into the bloodstream. In this review, we focus on the pathophysiologic basis and clinical aspects of the most common genetic iron overload syndromes in humans.


2020 - Hereditary hyperferritinemia cataract syndrome: Case report [Articolo su rivista]
Guzelkucuk, Z.; Cakmakli, H. F.; Onen, M.; Pietrangelo, A.; Yarali, N.
abstract

Hereditary Hyperferritinemia-Cataract Syndrome (HHCS) is a rare disease characterized by cataract and hyperferritinemia. Herein, we present a pediatric patient diagnosed with HHCS.


2020 - Hyperferritinemia and diagnosis of type 1 Gaucher disease [Articolo su rivista]
Marchi, Giacomo; Nascimbeni, Fabio; Motta, Irene; Busti, Fabiana; Carubbi, Francesca; Cappellini, Maria Domenica; Pietrangelo, Antonello; Corradini, Elena; Piperno, Alberto; Girelli, Domenico
abstract

Given the difficulties in diagnosis of type 1 GD in adults because of disease heterogeneity and lack of awareness, appropriate diagnostic algorithms or flow-charts starting from non-specific findings may help. Case reports help to establish the usefulness of our proposed flowchart in patients presenting with “unexplained hyperferritinemia”.


2020 - Hyperhomocysteinemia in patients with acute porphyrias: A potentially dangerous metabolic crossroad? [Articolo su rivista]
Ventura, P.; Corradini, E.; Di Pierro, E.; Marchini, S.; Marcacci, M.; Cuoghi, C.; Buzzetti, E.; Pietrangelo, A.
abstract

Background: Acute porphyrias (AP) are characterized by heme deficiency and induction of hepatic 5-aminolevulinate synthase (ALAS1). Hyperhomocysteinemia (HHcy) is associated with endothelial damage, neurotoxicity and increased risk for vascular diseases. Interestingly, both heme biosynthesis and sulphur amino acid metabolism require vitamin B6, (Pyridoxal-phosphate, PLP) an important cofactor of ALAS1 and of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGL) enzymes that catabolize homocysteine (Hcy). Moreover, heme itself is an important cofactor for CBS. Aim: to assess plasma Hcy status and HHcy main determinants in patients with AP. Materials and methods: A total of 46 patients with AP (31 with Acute Intermittent Porphyria,15 with Variegate Porphyria) were assessed for clinical status (symptomatic vs. asymptomatic), serum Hcy, Cysteine (Cys), Vit.B6, Vit.B12, red blood cell folates and urinary delta-aminolevulinic acid (ALA) and porphobilinogen(PBG) levels (mean of six measurements). Results: Symptomatic AP patients had significantly higher urinary ALA and PBG levels, plasma Hcy, HHcy prevalence and Hcy/Cys ratio when compared to asymptomatic carriers of AP. Even though no significant correlation was observed between ALA/PBG urinary levels and serum Hcy levels, patients with higher levels of ALA and PBG had significantly higher levels of Hcy, a higher prevalence of moderate-to severe HHcy and serum PLP levels below the 25th percentile of a reference assessment with 300 healthy Italian subjects(<45nmol/L). Conclusions: Most patients with symptomatic AP present HHcy resulting from alterations in sulphur amino acid metabolism. HHcy may represent an indirect marker of ALAS1 induction and its prevalence may be suggestive of a role of HHcy in the pathogenesis and/or comorbidities of AP.


2020 - Idiopathic brain calcification in a patient with hereditary hemochromatosis [Articolo su rivista]
Scarlini, Stefania; Cavallieri, Francesco; Fiorini, Massimo; Menozzi, Elisa; Ferrara, Francesca; Cavalleri, Francesca; Reale, Chiara; Garavaglia, Barbara; Pietrangelo, Antonello; Valzania, Franco; Corradini, Elena
abstract

Background Detection of brain-MRI T2/T2* gradient echo images (T2*GRE)-hypointensity can be compatible with iron accumulation and leads to a differential diagnosis work-up including neurodegeneration with brain iron accumulation (NBIA) and Wilson Disease. Idiopathic or secondary brain calcification can be also associated with neurological involvement and brain-MRI T2/T2*GRE-hypointensity. Hereditary hemochromatosis (HH), characterized by systemic iron loading, usually does not involve the CNS, and only sporadic cases of neurological abnormalities or brain-MRI T2/T2*GRE-hypointensity have been reported. Case presentation A 59-year-old man came to our observation after a diagnosis of HH carried out in another hospital 2 years before. First-level genetic test had revealed a homozygous HFE p.Cys282Tyr (C282Y) mutation compatible with the diagnosis of HFE-related HH, thus phlebotomy treatment was started. The patient had a history of metabolic syndrome, type-2 diabetes, autoimmune thyroiditis and severe chondrocalcinosis. Brain-MRI showed the presence of bilateral T2*GRE hypointensities within globus pallidus, substantia nigra, dentate nucleus and left pulvinar that were considered expression of cerebral siderosis. No neurological symptoms or family history of neurological disease were reported. Neurological examination revealed only mild right-sided hypokinetic-rigid syndrome. Vitamin D–PTH axis, measurements of serum ceruloplasmin and copper, and urinary copper were within the normal range. A brain computed tomography (CT) was performed to better characterize the suspected and unexplained brain iron accumulation. On the CT images, the hypointense regions in the brain MRI were hyperdense. DNA sequence analysis of genes associated with primary familial brain calcification and NBIA was negative. Conclusions This report highlights the importance of brain CT-scan in ambiguous cases of suspected cerebral siderosis, and suggests that HH patients with a severe phenotype, and likely associated with chondrocalcinosis, may display also brain calcifications. Further studies are needed to confirm this hypothesis. So far, we can speculate that iron and calcium homeostasis could be reciprocally connected within the basal ganglia.


2020 - Impact of natural neuromedin-B receptor variants on iron metabolism [Articolo su rivista]
Rametta, R.; Dongiovanni, P.; Baselli, G. A.; Pelusi, S.; Meroni, M.; Fracanzani, A. L.; Busti, F.; Castagna, A.; Scarlini, S.; Corradini, E.; Pietrangelo, A.; Girelli, D.; Fargion, S.; Valenti, L.
abstract

Iron overload heritability remains partly unexplained. By performing whole exome sequencing in three patients with a clinical phenotype of hemochromatosis not accounted by known genetic risk factors, we identified in all patients rare variants predicted to alter activity of Neuromedin-B receptor (NMBR). Coding NMBR mutations were enriched in 129 patients with hereditary hemochromatosis or iron overload phenotype, as compared to ethnically matched controls, including 100 local healthy blood donors and 1000Genomes project participants (15.5% vs 5%, P =.0038 at burden test), and were associated with higher transferrin saturation in regular blood donors (P =.04). Consistently, in 191 patients with nonalcoholic fatty liver, the most common low-frequency p.L390 M variant was independently associated with higher ferritin (P =.03). In 58 individuals, who underwent oral iron challenge, carriage of the p.L390 M variant was associated with higher transferrin saturation and lower hepcidin release. Furthermore, the circulating concentration of the natural NMBR ligand, Neuromedin-B, was reduced in response to iron challenge. It was also decreased in individuals carrying the p.L390 M variant and with hemochromatosis in parallel with increased transferrin saturation. In mice, Nmbr was induced by chronic dietary iron overload in the liver, gut, pancreas, spleen, and skeletal muscle, while Nmb was downregulated in gut, pancreas and spleen. Finally, Nmb amplified holo-transferrin dependent induction of hepcidin in primary mouse hepatocytes, which was associated with Jak2 induction and abolished by the NMBR antagonist PD168368. In conclusion, NMBR natural variants were enriched in patients with iron overload, and associated with facilitated iron absorption, possibly related to a defect of iron-induced hepcidin release.


2020 - Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with Covid-19 pneumonia. [Articolo su rivista]
De Biasi, S; Meschiari, M; Gibellini, L; Bellinazzi, C; Borella, R; Fidanza, L; Gozzi, L; Iannone, A; Lo Tartaro, D; Mattioli, M; Paolini, A; Menozzi, M; Milić, J; Franceschi, G; Fantini, R; Tonelli, R; Sita, M; Sarti, M; Trenti, T; Brugioni, L; Cicchetti, L; Facchinetti, F; Pietrangelo, A; Clini, E; Girardis, M; Guaraldi, G; Mussini, C; Cossarizza, A.
abstract

We provide an in-depth investigation of the T cell compartment and functionality, cytokine production and plasma levels in a total of 39 patients affected by Covid-19 pneumonia. At admission, patients were lymphopenic; for all, SARS-CoV-2 was detected in a nasopharyngeal swab specimen by real-time RT-PCR, and pneumonia was subsequently confirmed by X-rays. Detailed 18-parameter flow cytometry coupled with unsupervised data analysis revealed that patients showed similar percentages of CD4+ and CD8+ T cells, but a decreased absolute number in both populations. For CD4+ T lymphocytes, we found a significant decrease in the number of naïve, central and effector memory cells and an increased percentage of terminally differentiated cells, regulatory T cells, and of those that were activated or that were expressing PD1 and CD57 markers. Studies on chemokine receptors and lineage-specifying transcription factors revealed that, among CD4+ T cells, patients displayed a lower percentage of cells expressing CCR6 or CXCR3, and of those co-expressing CCR6 and CD161, but higher percentages of 62 CXCR4+ or CCR4+ cells. No differences were noted in the expression of T-bet or GATA-3. Analyses of patients' CD8+ T cells showed decreased numbers of naïve and central memory and increased amounts of activated cells, accompanied by increased percentages of activated cells and of lymphocytes expressing CD57, PD1, or both. CD8+ T cells expressed lower percentages of CCR6+, CXCR3+ or T-bet+ cells and of CXCR3+,T-bet+ or CCR6+,CD161+ lymphocytes. We also found higher percentages of cells expressing CCR4+, CXCR4 or GATA-3. Analyses of lymphocyte proliferation revealed that terminally differentiated CD4+ and CD8+ T cell from patients had a lower proliferative index than controls, whereas cellular bioenergetics, measured by the quantification of mitochondrial oxygen consumption and extracellular acidification rate, was similar in CD4+ T cells from both groups. We measured plasma level of 31 cytokines linked to inflammation, including T helper (TH)type-1 and TH2 cytokines, chemokines, galectins, pro- and anti-inflammatory mediators, finding that most were dramatically increased in Covid-19 patients, confirming the presence of a massive cytokine storm. Analysis of the production of different cytokines after stimulation by anti-CD3/CD28 monoclonal antibodies revealed that patients not only had a high capacity to produce tumour necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-2, but also showed a significant skewing of CD4+ T cells towards the TH17 phenotype. A therapeutic approach now exists based on the administration of drugs that block IL-6pathway, and seems to improve the disease. IL-17 is crucial in recruiting and activating neutrophils, cells that can migrate to the lung and are heavily involved in the pathogenesis of Covid-19. We show here that a skewing of activated T cells towards the TH17 functional phenotype exists in Covid-19 patients. We therefore suggest that blocking the IL-17 pathway by biological drugs that are already used to treat different pathologies could provide a novel, additional strategy to improve the health of patients infected by SARS-CoV-2.


2020 - Randomised controlled trial comparing efficacy and safety of high versus low Low-Molecular Weight Heparin dosages in hospitalized patients with severe COVID-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation (COVID-19 HD): A structured summary of a study protocol [Articolo su rivista]
Marietta, M; Vandelli, P; Mighali, P; Vicini, R; Coluccio, V; D'Amico, R; Aschieri, D; Brugioni, L; Clini, E; Codeluppi, M; Imberti, D; Magnacavallo, A; Meschiari, M; Mussini, C; Orlando, S; Pinelli, G; Pietrangelo, A; Sarti, L; Silva, M.
abstract

To assess whether high doses of Low Molecular Weight Heparin (LMWH) (i.e. Enoxaparin 70 IU/kg twice daily) compared to standard prophylactic dose (i.e., Enoxaparin 4000 IU once day), in hospitalized patients with COVID19 not requiring Invasive Mechanical Ventilation [IMV], are: a)more effective in preventing clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were receiving standard oxygen therapy5.IMV in patients who at randomisation were receiving non-invasive mechanical ventilationb)Similar in terms of major bleeding risk TRIAL DESIGN: Multicentre, randomised controlled, superiority, open label, parallel group, two arms (1:1 ratio), in-hospital study.


2020 - Tocilizumab in patients with severe COVID-19: a retrospective cohort study [Articolo su rivista]
Guaraldi, G; Meschiari, M; Cozzi-Lepri, A; Milic, J; Tonelli, R; Menozzi, M; Franceschini, E; Cuomo, G; Orlando, G; Borghi, V; Santoro, A; Di Gaetano, M; Puzzolante, C; Carli, F; Bedini, A; Corradi, L; Fantini, R; Castaniere, I; Tabbì, L; Girardis, M; Tedeschi, S; Giannella, M; Bartoletti, M; Pascale, R; Dolci, G; Brugioni, L; Pietrangelo, A; Cossarizza, A; Pea, F; Clini, E; Salvarani, C; Massari, M; Viale, Pl; Mussini, C.
abstract

Background- There is no approved therapy for COVID-19 pneumonia. The aim of this multicentre cohort study was to assess the role of tocilizumab in reducing the risk of invasive mechanical ventilation and/or death in patients with severe COVID-19 pneumonia who received standard of care (SoC) treatment. Methods- The TESEO Cohort Study is a retrospective, multicentre observational cohort study of patients with COVID-19 severe pneumonia treated with SoC with or without tocilizumab using intravenous (IV) or subcutaneous (SC) formulations, identifying respectively treated and comparator groups. Survival analysis was performed with participants’ follow-up accruing from the date of entry into clinics until initiation of invasive mechanical ventilation or death, used as a composite outcome. Treatment groups were compared using Kaplan-Meier curves and Cox regression analysis after adjusting for gender, age and baseline Sequential Organ Failure Assessment (SOFA) score. Findings- Of 544 patients included, 179 patients were treated with tocilizumab: 88 with the IV (16.1%) and 91 with SC formulation (16.7%). Mortality was significantly higher in the comparator group (20%) as opposed to tocilizumab IV (6.8%) and tocilizumab SC (7.7%) (p<0.001). A reduced risk of invasive mechanical ventilation/death was shown for participants treated with tocilizumab from fitting a Cox regression analysis adjusted for gender, age and SOFA score (aHR=0.61, 95% CI:0.40-0.92; p=0.02). We found no evidence for a difference between IV and SC administration route of tocilizumab. With regards to the mortality endpoint alone, a reduced risk was observed comparing tocilizumab with the comparator group (aHR=0.38 95% CI:0.17-0.83, p=0.02) . Interpretation- Tocilizumab, regardless of IV or SC administration may be capable of reducing invasive mechanical ventilation or death in severe COVID-19 pneumonia. Our observations should be confirmed in randomised studies. Funding- This study was not funded.


2019 - Current challenges in the management of patients with sickle cell disease - A report of the Italian experience [Articolo su rivista]
Russo, G.; De Franceschi, L.; Colombatti, R.; Rigano, P.; Perrotta, S.; Voi, V.; Palazzi, G.; Fidone, C.; Quota, A.; Graziadei, G.; Pietrangelo, A.; Pinto, V.; Ruffo, G. B.; Sorrentino, F.; Venturelli, D.; Casale, M.; Ferrara, F.; Sainati, L.; Cappellini, M. D.; Piga, A.; Maggio, A.; Forni, G. L.
abstract

Sickle cell disease (SCD) is an inherited red blood cell disorder caused by a structural abnormality of hemoglobin called sickle hemoglobin (HbS). Clinical manifestations of SCD are mainly characterized by chronic hemolysis and acute vaso-occlusive crisis, which are responsible for severe acute and chronic organ damage. SCD is widespread in sub-Saharan Africa, in the Middle East, Indian subcontinent, and some Mediterranean regions. With voluntary population migrations, people harboring the HbS gene have spread globally. In 2006, the World Health Organization recognized hemoglobinopathies, including SCD, as a global public health problem and urged national health systems worldwide to design and establish programs for the prevention and management of SCD. Herein we describe the historical experience of the network of hemoglobinopathy centers and their approach to SCD in Italy, a country where hemoglobinopathies have a high prevalence and where SCD, associated with different genotypes including ß-thalassemia, is present in the native population.


2019 - Evaluating the association of serum ferritin and hepatic iron with disease severity in non-alcoholic fatty liver disease [Articolo su rivista]
Buzzetti, E.; Petta, S.; Manuguerra, R.; Luong, T. V.; Cabibi, D.; Corradini, E.; Craxi, A.; Pinzani, M.; Tsochatzis, E.; Pietrangelo, A.
abstract

Background & Aims: Hyperferritinemia, with or without increased hepatic iron, represents a common finding in non-alcoholic fatty liver disease (NAFLD). However, it is unclear whether it reflects hepatic inflammation or true iron-overload and, in case the latter is confirmed, whether this influences disease progression. We therefore explored the association between serum ferritin, degree and pattern of hepatic iron deposition and liver disease severity in patients with NAFLD. Methods: We selected 468 patients with biopsy-proven NAFLD from 2 European centres. Iron, hepatic and metabolic parameters were collected at the time of liver biopsy. Iron deposits in hepatocytes and reticuloendothelial cells were assessed and graded. Diagnosis of non-alcoholic steatohepatitis (NASH) and fibrosis staging were performed. Results: A total of 122 (26%) patients had hyperferritinemia, whereas stainable hepatic iron was found in 116 (25%) patients (38% predominantly in hepatocytes, 20% in reticuloendothelial cells and 42% in both). Subjects with stainable hepatic iron, particularly those with a mixed pattern, had higher serum ferritin and transaminases but only a mixed pattern of iron deposition was among the variables significantly associated with presence of NASH. Serum ferritin was not associated with presence of NASH, however it increased with worsening fibrosis stage (F3 compared to F0-F1), and significantly decreased in stage F4. Conclusions: A mixed pattern of hepatic iron deposition is associated with the presence of steatohepatitis, while serum ferritin increases with worsening fibrosis up to pre-cirrhotic stage. In individual NAFLD patients, serum ferritin could be evaluated as part of non-invasive diagnostic panels but not on its own.


2019 - In vitro functional characterization of splicing variants of the APOB gene found in familial hypobetalipoproteinemia [Articolo su rivista]
Rabacchi, C.; Simone, M. L.; Pisciotta, L.; Di Leo, E.; Bocchi, D.; Pietrangelo, A.; D'Addato, S.; Bertolini, S.; Calandra, S.; Tarugi, P.
abstract

Background: Familial hypobetalipoproteinemia type 1 (FHBL-1) is a codominant disorder characterized by greatly reduced plasma levels of total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B. Rare exonic pathogenic variants of APOB gene (nonsense variants, minute deletions/insertions and nonsynonymous variants) have been frequently reported in subjects with FHBL-1. Also, rare intronic variants of APOB located at intron/exon junctions and assumed to affect splicing have been reported. However, the pathogenicity of most of these intronic variants remains to be established. Objective: The objective of this study was the in vitro functional characterization of six splicing variants of APOB gene identified in seven putative FHBL-1 heterozygotes. Methods: ApoB minigenes harboring each variant were expressed in COS-1 cells and their transcripts were sequenced. Results: Four novel variants (c.237+1G>A, c.818+5G>A, c.3000-1G>T, and c.3842+1G>A), predicted in silico to obliterate splice site activity, were found to generate abnormal transcripts. The abnormal transcripts were generated by the activation of cryptic splice sites or exon skipping. All these transcripts harbored a premature termination codon and were predicted to encode truncated apoBs devoid of function. The predicted translation products were: i) p.(Lys41Serfs*2) and p.(Val80Ilefs*10) for c.237+1G>A; ii) p.(Asn274*) for c.818+5G>A; iii) p.(Leu1001Alafs*10) for c.3000-1G>T, and iv) p.(Ser1281Argfs*2) for c.3842+1G>A. Two previously annotated rare variants (c.905-15C>G and c.1618-4G>A) with uncertain effect in silico were found to generate only wild-type transcripts. Conclusions: These in vitro minigene expression studies support the assignment of pathogenicity to four novel splice site variants of APOB gene found in FHBL-1.


2019 - Incidence and Recurrence of Portal Vein Thrombosis in Cirrhotic Patients [Articolo su rivista]
Violi, F.; Corazza, G. R.; Caldwell, S. H.; Talerico, G.; Romiti, G. F.; Napoleone, L.; Perticone, F.; Bolondi, L.; Pietrangelo, A.; Vestri, A. R.; Raparelli, V.; Basili, S.; Elena, A. M.; Paola, A.; Angelo, A.; Francesco, A.; Mario, A.; Antonio, F.; Massimiliano, A.; Umberto, A.; Maurizio, A.; Milena, B.; Cristina, B.; Gaetano, B.; Michele, B.; Battista, B. G.; Ilaria, B. P.; Benedetta, B.; Giancarlo, B.; Christian, B.; Silvia, B.; Agostino, B.; Carmelo, B.; Buzzetti, E.; Irene, C.; Stefano, C.; Roberto, C.; William, C.; Federica, C.; Isabella, C.; Pietro, C.; Benedetto, C.; Domenica, C. M.; Luigi, C.; Maurizio, C.; Lara, C.; Flavio, C.; Sebastiano, C.; Claudia, C.; Maria, C. B.; Elena, C.; Salvatore, C.; Giorgio, C.; Filippo, C.; Giuseppe, C.; Chiara, C.; Valentina, C.; Felicia, D.; Gennaro, D.; Roberto, D. F.; Alfredo, D. G.; Stefano, D. V.; Wilma, D. V.; Maria, D. B.; Lisette, D. C.; Giuseppe, D.; Andrea, D.; Valentina, D. C.; Paolo, D. G.; Dario, D. M.; Giovanni, D. M.; Emilia, D.; Davide, D.; Emanuele, D. -M.; Lorenzo, F.; Alessio, F.; Vincenza, F.; Silvano, F.; Giovanni, F.; Tiziana, F.; Alessandra, F.; Pierluigi, F.; Giovanni, G.; Paolo, G.; Matteo, G.; Ruggiero, G.; Antonio, G.; Angelo, G.; Antonina, G.; Gianluigi, G.; Paolo, G.; Paolo, G.; Alessandro, G.; Davide, G.; Antonio, G.; Alessandro, G.; Paolo, G.; Daniel, H.; Angelo, I.; Luigi, I.; Pietro, I.; Antonio, I.; Giacomo, L.; Anna, L.; Livia, L. M.; Giusi, L.; Sergio, M.; Roberto, M.; Matteo, M.; Alessandra, M.; Sara, M.; Maria, M. A.; Pio, M. G.; Maristella, M.; Michela, M.; Antonio, M.; Giuseppe, M.; Ludovico, M. A.; Ignazio, M.; Olivia, M.; Giuseppe, M.; Paola, N.; Sergio, N.; Grazia, N.; Lorenzo, N.; Donatella, P.; Giuseppe, P.; Ostilio, P. V.; Daniele, P.; Paolo, P.; Francesca, P.; Maria, P.; Paola, P.; Luigi, P.; Irene, P.; Salvatore, P.; Antonio, P.; Serena, P. F.; Pietro, P.; Pasquale, P.; Miriam, P.; Antonio, P.; Daniela, P.; Licia, P.; Vincenzo, P.; Graziella, P.; Marco, P.; Giacomo, P.; Francesco, P.; Enrico, R.; Giovanni, R.; Tea, R.; Laura, R.; Mario, R.; Isabel, R. -C. K.; Giulio, R. R.; Eleonora, R.; David, S.; Francesco, S.; Aldo, S.; Andrea, S.; Giuseppe, S.; Claudia, S.; Francesca, S.; Daniela, S.; Francesca, S.; Cosima, S.; Roberto, S.; Marco, S.; Carla, S.; Gaetano, S.; Domenico, S.; Maurizio, S.; Nicolo, S.; Silvia, S.; Orietta, S.; Stasi, C.; Patrizia, S.; Gianluca, S. B.; Michela, T.; Claudio, T.; Joseph, T. E.; Tommaso, T.; Filippo, T.; Daniele, T.; Matteo, T.; Giovanni, T.; Antonella, T.; Antonino, T.; Doriana, V.; Natale, V.; Rita, V. C.; Gianluigi, V.; Paolo, V.; Umberto, V. -G.; Elia, V.; Gianpaolo, V.; Villani, R.; Ronca, V.; Giacomo, V.; Francesco, V.; Assunta, Z. M.
abstract


2019 - Low Rate of Intrahospital Deep Venous Thrombosis in Acutely Ill Medical Patients: Results From the AURELIO Study [Articolo su rivista]
Loffredo, L.; Arienti, V.; Vidili, G.; Cogliati, C.; Battaglia, S.; Perri, L.; Di Giulio, R.; Bernardini, S.; Summa, M. L.; Sciacqua, A.; Perticone, F.; Boddi, M.; Di Minno, G.; Lodigiani, C.; Pietrangelo, A.; Farcomeni, A.; Violi, F.; Basili, S.; Pignatelli, P.; Ferro, D.; Rossi, E.; Casciaro, M. A.; Pirillo, L. S.; Palumbo, I. M.; Pannunzio, A.; Pesci, L.; Baldini, L.; Meloni, P. L.; Sauchella, A.; Melis, S.; Berria, M.; Cringoli, M.; Blanca, D.; Casella, F.; Ettorre, E.; Cacciafesta, M.; Vegetti, A.; Crociani, A.; Donnarumma, E.; Pacciani, G.; Rovereto, R.; Lunardi, S.; Tufano, A.; Pacetti, V.
abstract

Objective: To evaluate the effect of hospitalization on deep venous thrombosis (DVT) rate by the cumulative incidence of DVT in the proximal venous tract of the lower limbs at admission and discharge. Methods: The AURELIO (rAte of venoUs thRombosis in acutEly iLl patIents hOspitalized in internal medicine wards) multicenter observational study was carried out in hospital-university internal medicine wards including consecutive acutely ill medical patients. Patients underwent compression ultrasonography (CUS) of proximal lower limb veins at admission and discharge. The occurrence of DVT was the primary end point of the study. Results: Among 1340 patients, 26 (1.9%; 95% CI, 1.3%-2.8%) had asymptomatic DVT at admission and were excluded. During the follow-up, 144 patients were excluded because of hospitalization less than 5 days. The remaining 1170 patients underwent a CUS at discharge. Two hundred fifty (21%) underwent prophylaxis with parenteral anticoagulants; the remaining 920 (79%) were not treated with anticoagulants. The mean length of hospitalization was 13±8 days. Compared with patients without prophylaxis, those treated with parenteral anticoagulants had a higher incidence of active cancer, heart and respiratory failure, pneumonia, renal failure, previous venous thromboembolism, reduced mobility, and elderly age. During the hospital stay, 3 patients with a negative CUS at admission experienced DVT in the proximal tract (0.025%, rate of 1 per 5017 patient-days); 2 of them were in prophylaxis with parenteral anticoagulants. Conclusion: We provide evidence that in the real world acutely ill medical patients display more than 90% (1.9%) asymptomatic DVT at admission, whereas the intrahospital DVT occurrence is very low. This suggests a novel diagnostic workup and a careful reanalysis of anticoagulant prophylaxis.


2019 - Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with b-thalassemia [Articolo su rivista]
Piga, A.; Perrotta, S.; Gamberini, M. R.; Voskaridou, E.; Melpignano, A.; Filosa, A.; Caruso, V.; Pietrangelo, A.; Longo, F.; Tartaglione, I.; Borgna-Pignatti, C.; Zhang, X.; Laadem, A.; Sherman, M. L.; Attie, K. M.
abstract

b-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with b-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non–transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (‡4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ‡5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ‡1.5 g/dL from baseline for ‡14 consecutive days (without RBC transfusions) for non–transfusion-dependent patients or RBC transfusion burden reduction ‡20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non–transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ‡1.5 g/dL over ‡14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ‡20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of b-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409.


2019 - Multicenter observational study on the reliability of the HEART score [Articolo su rivista]
Parenti, Nicola; Lippi, Giuseppe; Letizia Bacchi Reggiani, Maria; Luciani, Antonio; Cavazza, Mario; Pietrangelo, Antonello; Vegetti, Alberto; Brugioni, Lucio; Bonfanti, Laura; Cervellin, Gianfranco
abstract

Objective To rapidly and safely identify the risk of developing acute coronary syndrome in patients with chest pain who present to the emergency department, the clinical use of the History, Electrocardiogram, Age, Risk Factors, and Troponin (HEART) scoring has recently been proposed. This study aimed to assess the inter-rater reliability of the HEART score calculated by a large number of Italian emergency physicians. Methods The study was conducted in three academic emergency departments using clinical scenarios obtained from medical records of patients with chest pain. Twenty physicians, who took the HEART score course, independently assigned a score to different clinical scenarios, which were randomly administered to the participants, and data were collected and recorded in a spreadsheet by an independent investigator who was blinded to the study’s aim. Results After applying the exclusion criteria, 53 scenarios were finally included in the analysis. The general inter-rater reliability was good (kappa statistics [κ], 0.63; 95% confidence interval, 0.57 to 0.70), and a good inter-rater agreement for the high- and low-risk classes (HEART score, 7 to 10 and 0 to 3, respectively; κ, 0.60 to 0.73) was observed, whereas a moderate agreement was found for the intermediate-risk class (HEART score, 4 to 6; κ, 0.51). Among the different items of the HEART score, history and electrocardiogram had the worse agreement (κ, 0.37 and 0.42, respectively). Conclusion The HEART score had good inter-rater reliability, particularly among the high- and low-risk classes. The modest agreement for history suggests that major improvements are needed for objectively assessing this component. Keywords HEART score; HEART pathway; Chest pain; Acute coronary syndrome; Emergency service, hospital


2019 - Prevalence of use and appropriateness of antidepressants prescription in acutely hospitalized elderly patients [Articolo su rivista]
Carlotta, F.; Raffaella, R.; Ilaria, A.; Alessandro, N.; Mannuccio, M. P.; Mannucci, P. M.; Nobili, A.; Pietrangelo, A.; Perticone, F.; Licata, G.; Violi, F.; Corazza, G. R.; Corrao, S.; Marengoni, A.; Salerno, F.; Cesari, M.; Tettamanti, M.; Pasina, L.; Franchi, C.; Cortesi, L.; Miglio, G.; Ardoino, I.; Novella, A.; Prisco, D.; Silvestri, E.; Emmi, G.; Bettiol, A.; Caterina, C.; Biolo, G.; Zanetti, M.; Guadagni, M.; Zaccari, M.; Chiuch, M.; Vanoli, M.; Grignani, G.; Pulixi, E. A.; Bernardi, M.; Bassi, S. L.; Santi, L.; Zaccherini, G.; Lupattelli, G.; Mannarino, E.; Bianconi, V.; Paciullo, F.; Alcidi, R.; Nuti, R.; Valenti, R.; Ruvio, M.; Cappelli, S.; Palazzuoli, A.; Girelli, D.; Busti, F.; Marchi, G.; Barbagallo, M.; Dominguez, L.; Cocita, F.; Beneduce, V.; Plances, L.; Natoli, G.; Mularo, S.; Raspanti, M.; Cavallaro, F.; Zoli, M.; Lazzari, I.; Brunori, M.; Fabbri, E.; Magalotti, D.; Arno, R.; Pasini, F. L.; Capecchi, P. L.; Palasciano, G.; Modeo, M. E.; Gennaro, C. D.; Cappellini, M. D.; Maira, D.; Di Stefano, V.; Fabio, G.; Seghezzi, S.; Mancarella, M.; De Amicis, M. M.; De Luca, G.; Scaramellini, N.; Rossi, P. D.; Damanti, S.; Clerici, M.; Conti, F.; Bonini, G.; Ottolini, B. B.; Di Sabatino, A.; Miceli, E.; Lenti, M. V.; Pisati, M.; Dominioni, C. C.; Murialdo, G.; Marra, A.; Cattaneo, F.; Pontremoli, R.; Beccati, V.; Nobili, G.; Secchi, M. B.; Ghelfi, D.; Anastasio, L.; Sofia, L.; Carbone, M.; Cipollone, F.; Guagnano, M. T.; Valeriani, E.; Rossi, I.; Mancuso, G.; Calipari, D.; Bartone, M.; Delitala, G.; Berria, M.; Pes, C.; Delitala, A.; Muscaritoli, M.; Molfino, A.; Petrillo, E.; Zuccala, G.; D'Aurizio, G.; Romanelli, G.; Zucchelli, A.; Manzoni, F.; Volpini, A.; Picardi, A.; Gentilucci, U. V.; Gallo, P.; Dell'Unto, C.; Annoni, G.; Corsi, M.; Bellelli, G.; Zazzetta, S.; Mazzola, P.; Szabo, H.; Bonfanti, A.; Arturi, F.; Succurro, E.; Rubino, M.; Tassone, B.; Sesti, G.; Interna, M.; Serra, M. G.; Bleve, M. A.; Gasbarrone, L.; Sajeva, M. R.; Brucato, A.; Ghidoni, S.; Fabris, F.; Bertozzi, I.; Bogoni, G.; Rabuini, M. V.; Cosi, E.; Scarinzi, P.; Amabile, A.; Omenetto, E.; Prandini, T.; Manfredini, R.; Fabbian, F.; Boari, B.; Giorgi, A. D.; Tiseo, R.; De Giorgio, R.; Paolisso, G.; Rizzo, M. R.; Borghi, C.; Strocchi, E.; Ianniello, E.; Soldati, M.; Sabba, C.; Vella, F. S.; Suppressa, P.; Schilardi, A.; Loparco, F.; De Vincenzo, G. M.; Comitangelo, A.; Amoruso, E.; Fenoglio, L.; Falcetta, A.; Bracco, C.; Fracanzani, A. L.; Fargion, S.; Tiraboschi, S.; Cespiati, A.; Oberti, G.; Sigon, G.; Peyvandi, F.; Rossio, R.; Ferrari, B.; Colombo, G.; Agosti, P.; Monzani, V.; Savojardo, V.; Folli, C.; Ceriani, G.; Pallini, G.; Dallegri, F.; Ottonello, L.; Liberale, L.; Caserza, L.; Salam, K.; Liberato, N. L.; Tognin, T.; Bianchi, G. B.; Giaquinto, S.; Purrello, F.; Di Pino, A.; Piro, S.; Rozzini, R.; Falanga, L.; Spazzini, E.; Ferrandina, C.; Montrucchio, G.; Petitti, P.; Peasso, P.; Favale, E.; Poletto, C.; Salmi, Rudy; Gaudenzi, P.; Perri, L.; Landolfi, R.; Montalto, M.; Mirijello, A.; Guasti, L.; Castiglioni, L.; Maresca, A.; Squizzato, A.; Campiotti, L.; Grossi, A.; Bertolotti, M.; Mussi, C.; Lancellotti, G.; Libbra, M. V.; Dondi, G.; Pellegrini, E.; Carulli, L.; Galassi, M.; Grassi, Y.; Perticone, M.; Battaglia, R.; Filice, M.; Maio, R.; Stanghellini, V.; Ruggeri, E.; del Vecchio, S.; Salvi, A.; Leonardi, R.; Damiani, G.; Capeci, W.; Gabrielli, A.; Mattioli, M.; Martino, G. P.; Biondi, L.; Pettinari, P.; Ghio, R.; Col, A. D.; Minisola, S.; Colangelo, L.; Cilli, M.; Labbadia, G.; Afeltra, A.; Marigliano, B.; Pipita, M. E.; Castellino, P.; Zanoli, L.; Pignataro, S.; Gennaro, A.; Blanco, J.; Saracco, V.; Fogliati, M.; Bussolino, C.; Mete, F.; Gino, M.; Cittadini, A.; Vigorito, C.; Arcopinto, M.; Salzano, A.; Bobbio, E.; Marra, A. M.; Sirico, D.; Moreo, G.; Gasparini, F.; Prolo, S.; Pina, G.; Ballestrero, A.; Ferrando, F.; Berra, S.; Dassi, S.; Nava, M. C.; Graziella, B.; Baldassarre, S.; Fragapani, S.; Gruden, G.; Galanti, G.; Mascherini, G
abstract

N/A


2019 - Safety and efficacy of sucrosomal iron in inflammatory bowel disease patients with iron deficiency anemia [Articolo su rivista]
Abbati, G.; Incerti, F.; Boarini, C.; Bocchi, D.; Ventura, P.; Buzzetti, E.; Pietrangelo, A.
abstract

Iron deficiency anemia (IDA) is one of the most common complications of inflammatory bowel disease (IBD). We planned a prospective study to address tolerability and efficacy of sucrosomial iron, a new oral formulation of ferric pyrophosphate, in IBD patients. Thirty patients with a confirmed diagnosis of Crohn’s Disease (CD) or ulcerative colitis (UC) and mild IDA were enrolled. Patients with severe IBD were excluded. All patients underwent 12 weeks of oral treatment with 30 mg/day of sucrosomial iron. Treatment compliance and adverse events were investigated every 4 weeks. Iron status, hematological parameters and IBD activity scores were determined at baseline and at the end of treatment, as well as serum hepcidin and non-transferrin bound iron (NTBI) levels. Twenty-four (80%) patients took more than 90% of the prescribed regimen. Forty-four adverse events (AEs) were recorded, but none of them is considered certainly or probably related to the study treatment. Interestingly, only eleven gastrointestinal events were recorded in 9 (30%) patients. At the end of treatment, all iron parameters improved significantly and Hb increased in 86% of patients (from 11.67 to 12.37 g/dl, p = 0.001). Serum hepcidin showed a significant increase in 79% of patients and became positively correlated with C-reactive protein (CRP) at the end of the study, while NTBI remained below the detection threshold after iron supplementation. The IBD activity scores improved in both CD and UC. This pilot interventional study supports the therapeutic use of sucrosomial iron in IBD and paves the way for future studies in larger or more difficult IBD populations.


2019 - Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis [Articolo su rivista]
Basili, Stefania; Carnevale, Roberto; Nocella, Cristina; Bartimoccia, Simona; Raparelli, Valeria; Talerico, Giovanni; Stefanini, Lucia; Romiti, Giulio F; Perticone, Francesco; Corazza, Gino R; Piscaglia, Fabio; Pietrangelo, Antonello; Violi, Francesco; and PRO-LIVER collaborators, : Ainora Maria Elena; Andreozzi, Paola; Andriulli, Angelo; Angelico, Francesco; Angelico, Mario; Figliomeni, Antonio; Anzaldi, Massimiliano; Arena, Umberto; Averna, Maurizio; Barone, Milena; Bazzini, Cristina; Bergamaschi, Gaetano; Bertoni, Michele; Bianchi Giovanni, Battista; Bianchi Paola, Ilaria; Boari, Benedetta; Bombonato, Giancarlo; Bracco, Christian; Brocco, Silvia; Buonauro, Agostino; Buttà, Carmelo; Buzzetti, Elena; Cacciola, Irene; Calabria, Stefano; Cangemi, Roberto; Capeci, William; Caradio, Federica; Carderi, Isabella; Carleo, Pietro; Caroleo, Benedetto; Carrabba Maria, Domenica; Castorani, Luigi; Cavallo, Maurizio; Cecchetto, Lara; Cesaro, Flavio; Cicco, Sebastiano; Cimini, Claudia; Colombo Barbara, Maria; Corradini, Elena; Corrao, Salvatore; Costantino, Giorgio; Costanzo, Filippo; Croce, Giuseppe; Cuoghi, Chiara; Curigliano, Valentina; D’Alitto, Felicia; D’Amico, Gennaro; De Franchis, Roberto; De Giorgi, Alfredo; De Vuono, Stefano; Debernardi Venon, Wilma; Del Ben, Maria; Del Corso, Lisette; Delitala, Giuseppe; Denegri, Andrea; Di Cesare, Valentina; Di Giosia, Paolo; Di Michele, Dario; Di Minno, Giovanni; Donnarumma, Emilia; Drenaggi, Davide; Durante-Mangoni, Emanuele; Falsetti, Lorenzo; Farcomeni, Alessio; Farinaro, Vincenza; Fasolato, Silvano; Ferrari, Giovanni; Fierro, Tiziana; Forgione, Alessandra; Frugiuele, Pierluigi; Galati, Giovanni; Gallo, Paolo; Garcovich, Matteo; Gargano, Ruggiero; Gasbarrini, Antonio; Gatta, Angelo; Giammanco, Antonina; Giannelli, Gianluigi; Giorgini, Paolo; Gobbi, Paolo; Granito, Alessandro; Grassi, Davide; Greco, Antonio; Grembiale, Alessandro; Gresele, Paolo; Hijazi, Daniel; Iacobellis, Angelo; Iamele, Luigi; Invernizzi, Pietro; Ippolito, Antonio; Laffi, Giacomo; Licata, Anna; Liguori Maria, Livia; Lorusso, Giusi; Maimone, Sergio; Manfredini, Roberto; Marcacci, Matteo; Marchese, Alessandra; Marinelli, Sara; Marra Alberto, Maria; Martino Giuseppe, Pio; Masala, Maristella; Masotti, Michela; Merla, Antonio; Miceli, Giuseppe; Montebianco Abenavoli, Ludovico; Morana, Ignazio; Morelli, Olivia; Murgia, Giuseppe; Naccarato, Paola; Neri, Sergio; Niro, Grazia; Nobili, Lorenzo; Padula, Donatella; Palasciano, Giuseppe; Palmieri Vincenzo, Ostilio; Pastori, Daniele; Pattoneri, Paolo; Perego, Francesca; Perticone, Maria; Pesce, Paola; Petramala, Luigi; Pettinari, Irene; Piano, Salvatore; Picardi, Antonio; Pignataro Francesca, Serena; Pignataro, Pietro; Pignatelli, Pasquale; Pinna, Miriam; Pinto, Antonio; Pinto, Daniela; Polimeni, Licia; Pretti, Vincenzo; Privitera, Graziella; Proietti, Marco; Pucci, Giacomo; Purrello, Francesco; Ragone, Enrico; Raimondo, Giovanni; Restuccia, Tea; Riccardi, Laura; Rizzetto, Mario; Rodríguez-Castro Kryssia, Isabel; Romanelli Roberto, Giulio; Ruscio, Eleonora; Sacerdoti, David; Salinaro, Francesco; Salvi, Aldo; Salzano, Andrea; Santangelo, Giuseppe; Santarossa, Claudia; Santilli, Francesca; Santovito, Daniela; Scarpini, Francesca; Schiavone, Cosima; Scicali, Roberto; Senzolo, Marco; Serra, Carla; Serviddio, Gaetano; Sirico, Domenico; Soresi, Maurizio; Sperduti, Nicolò; Staffolani, Silvia; Staltari, Orietta; Stasi, Cristina; Suppressa, Patrizia; Svegliati Baroni, Gianluca; Talia, Michela; Tana, Claudio; Tassone Eliezer, Joseph; Todisco, Tommaso; Toriello, Filippo; Torres, Daniele; Traversa, Matteo; Tripepi, Giovanni; Tufano, Antonella; Tuttolomondo, Antonino; Varvara, Doriana; Vazzana, Natale; Vecchio Claudia, Rita; Vendemiale, Gianluigi; Ventura, Paolo; Vespasiani-Gentilucci, Umberto; Vettore, Elia; Vidili, Gianpaolo; Villani, Rosanna; Vincenzo, Ronca; Visioli, Giacomo; Vitale, Francesco; Zocco Maria, Assunta.
abstract

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation.


2018 - Clinical impact of application of risk assessment models (Padua Prediction Score and Improve Bleeding Score) on venous thromboembolism, major hemorrhage and health expenditure associated with pharmacologic VTE prophylaxis: a “real life” prospective and retrospective observational study on patients hospitalized in a Single Internal Medicine Unit (the STIME study) [Articolo su rivista]
Depietri, Luca; Marietta, Marco; Scarlini, Stefania; Marcacci, Matteo; Corradini, Elena; Pietrangelo, Antonello; Ventura, Paolo
abstract

International guidelines recommend the use of pharmacological prophylaxis in hospitalized medical patients at high risk of venous thromboembolism (VTE). The same international guidelines suggest the employment of standardized risk assessment models (RAMs) when evaluating the administration of pharmacological prophylaxis in acutely ill medical patients. The Padua Prediction Score and the Improve Bleeding Score have been indicated as the best available RAMs to predict thrombotic and haemorrhagic risk in hospitalized medical patients, but it is still unknown whether their combined use may lead to a significant reduction in thrombotic and haemorrhagic events. It is also unclear whether their extensive use can affect to some extent health expenditure associated with pharmacological VTE prophylaxis. The purpose of this single-centre, prospective and retrospective observational study is to investigate these unanswered questions. All patients admitted to our Internal Medicine Department between May 2015 and August 2015, i.e., before the introduction and extensive use of RAMs, were consecutively enrolled (retrospective group). Similarly, all patients admitted between November 2016 and February 2017—once RAMs clinical use became a consolidated practice—have also been consecutively recruited (prospective group). Consecutively, 203 patients were enrolled in the retrospective group and 210 patients were enrolled in the prospective group. Three events of major bleeding and one event of pulmonary embolism were observed in the prospective group; three events of major hemorrhage and two events of pulmonary embolism were observed in the retrospective group (p = not significant). A statistically significant decrease in pharmacological VTE prophylaxis among study groups was detected: 43.3% of prospective group patients and 56.7% of retrospective group patients received pharmacological prophylaxis (p = .028). Overall, 299 drug doses for VTE prophylaxis have been spared after RAMs introduction (p = .0001) and health expenditure decreased by 27.2% (i.e., 1.67 € saved for each single patient). In conclusion, the extensive use of RAMs in our population of hospitalized medical patients did not statistically affect VTE rate or incidence of major bleeding, but it resulted in a significant drop in health expenditure related with pharmacological prophylaxis. Awaiting new clinical trials, a broad use of RAMs may be a safe strategy for reducing health expenditure associated with VTE prophylaxis in hospitalized medical patients.


2018 - Disorders of Iron Overload [Capitolo/Saggio]
Pietrangelo, A.; Torbenson, M.
abstract


2018 - Fegato, pancreas e vie biliari. [Capitolo/Saggio]
Pietrangelo, Antonello; Abbati, Gianluca; Corradini, Elena; Ventura, Paolo
abstract

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2018 - Haemochromatosis [Articolo su rivista]
Brissot, Pierre; Pietrangelo, Antonello; Adams, Paul C.; Graaff, Barbara De; McLaren, Christine E.; Loreál, Olivier
abstract

Haemochromatosis is defined as systemic iron overload of genetic origin, caused by a reduction in the concentration of the iron regulatory hormone hepcidin, or a reduction in hepcidin-ferroportin binding. Hepcidin regulates the activity of ferroportin, which is the only identified cellular iron exporter. The most common form of haemochromatosis is due to homozygous mutations (specifically, the C282Y mutation) in HFE, which encodes hereditary haemochromatosis protein. Non-HFE forms of haemochromatosis due to mutations in HAMP, HJV or TFR2 are much rarer. Mutations in SLC40A1 (also known as FPN1; encoding ferroportin) that prevent hepcidin-ferroportin binding also cause haemochromatosis. Cellular iron excess in HFE and non-HFE forms of haemochromatosis is caused by increased concentrations of plasma iron, which can lead to the accumulation of iron in parenchymal cells, particularly hepatocytes, pancreatic cells and cardiomyocytes. Diagnosis is noninvasive and includes clinical examination, assessment of plasma iron parameters, imaging and genetic testing. The mainstay therapy is phlebotomy, although iron chelation can be used in some patients. Hepcidin supplementation might be an innovative future approach.


2018 - Platelet count does not predict bleeding in cirrhotic patients: Results from the PRO-LIVER Study [Articolo su rivista]
Basili, S. a; Raparelli V., B; Napoleone L., B; Talerico G., A; Corazza G. R., C; Perticone F., D; Sacerdoti D., E; Andriulli A., F; Licata A., G; Pietrangelo, A.; Picardi A., I; Raimondo G., J; Violi, F.; Palasciano, G.; D’Alitto, F.; Palmieri, V. O.; Santovito, D.; Di, Michele; D., Croce; G., Brocco; S., Fasolato; S., Cecchetto; L., Bombonato; G., Bertoni; M., Restuccia; T., Andreozzi; P., Liguori; M. L., Caroleo; B., Perticone; M., Staltari; O., Manfredini; De, Giorgi; A., Averna; M., Giammanco; A., Granito; A., Pettinari; I., Marinelli; S., Bolondi; L., Falsetti; L., Salvi; A., Durante-Mangoni; E., Cesaro; F., Farinaro; V., Ragone; E., Morana; I., Ippolito; A., Iacobellis; A., Niro; G., Merla; A., Maimone; S., Cacciola; I., Varvara; D., Drenaggi; D., Staffolani; S., Vespasiani-Gentilucci; U., Galati; G., Gallo; P., Davì; G., Schiavone; C., Santilli; F., Tana; C., Soresi; Bianchi, Giovanni; B., Carderi; I., Pinto; A., Tuttolomondo; A., Ferrari; G., Gresele; P., Fierro; T., Morelli; O., Laffi; G., Romanelli; R. G., Arena; U., Stasi; Gasbarrini, A.; Garcovich, M.; Zocco, M. A.; Riccardi, L.; Ainora, M. E.; Capeci, W.; Martino, Giuseppe; P., Nobili; L., Cavallo; M., Frugiuele; P., Greco; Ventura, P.; Cuoghi, C.; Marcacci, M.; Serviddio, G.; Vendemiale, G.; Villani, R.; Gargano, R.; Vidili, G.; Di, Cesare; V., Masala; M., Delitala; G., Invernizzi; P., Vincenzo; Di, Minno; G., Tufano; A., Purrello; F., Privitera; G., Forgione; A., Curigliano; V., Senzolo; M., Rodríguez-Castro; K. I., Giannelli; G., Serra; C., Neri; S., Pignataro; P., Rizzetto; M., Debernardi; V. W., Svegliati; B. G., Bergamaschi; G., Masotti; M., Costanzo; F., Antonio; F., Angelico; Del, Ben; M., Polimeni; L., Proietti; M., Cangemi; R., Romiti; G. F., Toriello; F., Sperduti; N., Santangelo; G., Visioli; G., Todisco; Vestri, Anna; R., Farcomeni; A., Corrao; S., Gobbi; Corradini, E.; Costantino, G.; Tripepi, G.; Angelico, M.; Bolondi, L.; Granito, A.; D’Amico, G.; Franchis, De; R., Gatta; A., Tassone; E. J., Anzaldi; M., Barone; M., Bazzini; C., Bianchi; P. I., Boari; B., Bracco; C., Buonauro; A., Buttà; Buzzetti, E.; Calabria, S.; Caradio, F.; Carleo, P.; Carrabba, Maria; D., Castorani; L., Cecchetto; L., Cicco; S., Cimini; C., Colombo; B., M.; De, Giorgi; De, Vuono; S., Denegri; Del, Corso; Di, Giosia; P., Donnarumma; E., Giorgini; P., Grassi; D., Grembiale; A., Hijazi; D., Iamele; L., Lorusso; G., Marchese; Marra, Alberto; M., Masala; M., Miceli; G., Montebianco; A. L., Murgia; G., Naccarato; P., Padula; D., Pattoneri; P., Perego; F., Pesce; P., Petramala; L., Piano; S., Pinto; D., Pinna; M., Pignataro; F. S., Pretti; V., Pucci; G., Salinaro; F., Salzano; A., Santarossa; C., Scarpini; F., Scicali; R., Sirico; D., Suppressa; P., Talia; M., Torres; D., Traversa; M., Vazzana; Vecchio, Claudia; R., Vettore; E., Vitale
abstract

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child–Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800–1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50×103/μl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11–3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16–3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients.


2017 - A Pair of Brothers with Aceruloplasminemia Due To A Novel Nonsense Mutation: Unusual Phenotype And Neurological Improvement After Iron-Chelation Therapy With Deferasirox [Abstract in Atti di Convegno]
Valzania, F; Cavallieri, F; Fiorini, M; Contardi, S; Ferrara, F; Menozzi, E; Scarlini, S; Cavalleri, F; Molinari, M; Pietrangelo, A; Corradini, E
abstract

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2017 - An unfortunate case of post-ERCP complications [Articolo su rivista]
Fiorini, Massimo; Pietrangelo, Antonello; Vegetti, Alberto
abstract

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2017 - Ferroportin disease: Pathogenesis, diagnosis and treatment [Articolo su rivista]
Pietrangelo, Antonello
abstract

Ferroportin Disease (FD) is an autosomal dominant hereditary iron loading disorder associated with heterozygote mutations of the fer-roportin-1 (FPN) gene. It represents one of the commonest causes of genetic hyperferritinemia, regardless of ethnicity. FPN1 transfers iron from the intestine, macrophages and placenta into the bloodstream. In FD, loss-of-function mutations of FPN1 limit but do not impair iron export in enterocytes, but they do severely affect iron transfer in macrophages. This leads to progressive and preferential iron trapping in tissue macrophages, reduced iron release to serum transferrin (i.e. inappropriately low transferrin saturation) and a tendency towards anemia at menarche or after intense bloodletting. The hallmark of FD is marked iron accumulation in hepatic Kupffer cells. Numerous FD-associated mutations have been reported worldwide, with a few occurring in different populations and some more commonly reported (e.g. Val192del, A77D, and G80S). FPN1 polymorphisms also represent the gene variants most commonly responsible for hyperferritinemia in Africans. Differential diagnosis includes mainly hereditary hemochromatosis, the syndrome commonly due to either HFE or TfR2, HJV, HAMP, and, in rare instances, FPN1 itself. Here, unlike FD, hyperferritinemia associates with high transferrin saturation, iron-spared macrophages, and progressive parenchymal cell iron load. Abdominal magnetic resonance imaging (MRI), the key non-invasive diagnostic tool for the diagnosis of FD, shows the characteristic iron loading SSL triad (spleen, spine and liver). A non-aggressive phlebotomy regimen is recommended, with careful monitoring of transferrin saturation and hemoglobin due to the risk of anemia. Family screening is mandatory since siblings and offspring have a 50% chance of carrying the pathogenic mutation.


2017 - Human macrophage ferroportin biology and the basis for the ferroportin disease [Articolo su rivista]
Sabelli, Manuela; Montosi, Giuliana; Garuti, Cinzia; Caleffi, Angela; Oliveto, Stefania; Biffo, Stefano; Pietrangelo, Antonello
abstract

Ferroportin (FPN1) is the sole iron exporter in mammals, but its cell-specific function and regulation are still elusive. This study examined FPN1 expression in human macrophages, the cells that are primarily responsible on a daily basis for plasma iron turnover and are central in the pathogenesis of ferroportin disease (FD), the disease attributed to lack-of-function FPN1 mutations. We characterized FPN1 protein expression and traffic by confocal microscopy, western blotting, gel filtration, and immunoprecipitation studies in macrophages from control blood donors (donor) and patients with either FPN1 p.A77D, p.G80S, and p.Val162del lack-of-function or p.A69T gain-of-function mutations. We found that in normal macrophages, FPN1 cycles in the early endocytic compartment does not multimerize and is promptly degraded by hepcidin (Hepc), its physiological inhibitor, within 3-6 hours. In FD macrophages, endogenous FPN1 showed a similar localization, except for greater accumulation in lysosomes. However, in contrast with previous studies using overexpressed mutant protein in cell lines, FPN1 could still reach the cell surface and be normally internalized and degraded upon exposure to Hepc. However, when FD macrophages were exposed to large amounts of heme iron, in contrast to donor and p.A69T macrophages, FPN1 could no longer reach the cell surface, leading to intracellular iron retention. Conclusion: FPN1 cycles as a monomer within the endocytic/plasma membrane compartment and responds to its physiological inhibitor, Hepc, in both control and FD cells. However, in FD, FPN1 fails to reach the cell surface when cells undergo high iron turnover. Our findings provide a basis for the FD characterized by a preserved iron transfer in the enterocytes (i.e., cells with low iron turnover) and iron retention in cells exposed to high iron flux, such as liver and spleen macrophages. (Hepatology 2017;65:1512-1525).


2017 - Iron Overload in the Liver of 2 Children: Nonalcoholic Steatohepatitis and Juvenile Hemochromatosis [Articolo su rivista]
Ünlüsoy Aksu, Aysel; Caleffi, Angela; Pietrangelo, Antonello; Sari, Sinan; Eǧritaş Gürkan, Ödül; Demirtaş, Zeliha; Yilmaz, Güldal; Dalgiç, Buket
abstract

Background: Iron overload disorders are hereditary hemochromatosis and secondary etiologies other than hereditary hemochromatosis. We describe 2 boys presenting with iron overload. Juvenile hemochromatosis and nonalcoholic steatohepatitis (NASH) related iron overload are the genetic and secondary causes, respectively. Observations: Both patients benefited from phlebotomy even if they had different etiologies. Conclusions: In childhood, the diagnosis of iron overload syndromes is crucial because they do not confront us with obvious symptoms and findings. Early initiation of a phlebotomy program can prevent mortality. NASH might lead to iron overload and iron overload might aggravate the clinical course of NASH.


2017 - What to start with in first line treatment of chronic hepatitis B patients: an Italian multicentre observational cohort, HBV-RER study group [Articolo su rivista]
Cuomo, Gianluca; Borghi, Vanni; Giuberti, Tiziana; Andreone, Pietro; Massari, Marco; Villa, Erica; Pietrangelo, Antonello; Verucchi, Gabriella; Levantesi, Fabio; Ferrari, Carlo
abstract

Treatment options for chronic hepatitis B (CHB) are pegylated interferon (Peg-IFN) in minimal-mild liver fibrosis and nucleot(s)ide analogues (NUC) in more advanced disease. Since little is known about their use in daily clinical practice, we conducted a multicentre prospective study to investigate treatment regimens applied to naïve CHB patients in real life. HBV-RER is an observational multicentre Italian network that collect clinic and virologic data of patients with CHB. Among the 2527 CHB patients seen during the study period (2009 - 2012), 502 patients started a first line antiviral treatment. Liver biopsy was performed in 30.9% of the patients, with high levels of fibrosis being detected in 19.4% of them. In 216 patients (43%) Peg-IFN was used as first-line therapy while the remaining patients started NUC therapy (entecavir and tenofovir in 75%, lamivudine in 15%, telbivudine and adefovir 10%). By multivariate logistic regression, an age under 40 (OR 0.92, 95%IC 0.90-0.94; p <0.001) and the execution of liver biopsy (OR 3.83; 95%IQR 1.76-8.36; p <0.001) were the only determinants of choice between Peg-IFN vs NUC. Peg-IFN was expected to be used in first-line treatment for CHB in 70% of the patients based on Italian recommendations, but a much lower proportion of patients were actually treated with Peg-IFN with a limited use of the biopsy. Thus, in daily clinical practice physicians prefer to use NUCs, presumably because of their optimal tolerability and anti-viral efficacy, even if they frequently require life-long treatment as opposed to the short duration of Peg-IFN.


2016 - A PAIR OF BROTHERS WITH ACERULOPLASMINEMIA DUE TO A NOVEL NONSENSE MUTATION: UNUSUAL PHENOTYPE AND EFFECTIVENESS OF IRON-CHELATION THERAPY BY DEFERASIROX [Abstract in Atti di Convegno]
Fiorini, Massimo; Ferrara, F; Scarlini, Stefania; Bocchi, Davide; Cavallieri, Francesco; Valzania, F; Caleffi, A; Pietrangelo, Antonello; Corradini, Elena
abstract

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2016 - Activin B induces noncanonical SMAD1/5/8 signaling via BMP type I receptors in hepatocytes: Evidence for a role in hepcidin induction by inflammation in male mice [Articolo su rivista]
Canali, Susanna; Core, Amanda B.; Zumbrennen Bullough, Kimberly B.; Merkulova, Maria; Wang, Chia Yu; Schneyer, Alan L.; Pietrangelo, Antonello; Babitt, Jodie L.
abstract

Induction of the iron regulatory hormone hepcidin contributes to the anemia of inflammation. Bone morphogenetic protein 6 (BMP6) signaling is a central regulator of hepcidin expression in the liver. Recently, the TGF-β/BMPsuperfamily member activin B was implicated in hepcidin induction by inflammation via noncanonical SMAD1/5/8 signaling, but its mechanism of action and functional significance in vivo remain uncertain. Here, we show that low concentrations of activin B, but not activin A, stimulate prolonged SMAD1/5/8 signaling and hepcidin expression in liver cells to a similar degree as canonical SMAD2β signaling, and with similar or modestly reduced potency compared with BMP6. Activin B stimulates hepcidin via classical activin type II receptors ACVR2A and ACVR2B, noncanonical BMP type I receptors activin receptor-like kinase 2 and activin receptorlike kinase 3, and SMAD5. The coreceptor hemojuvelin binds to activin B and facilitates activin B-SMAD1/5/8 signaling. Activin B-SMAD1/5/8 signaling has some selectivity for hepatocyte-derived cells and is not enabled by hemojuvelin in other cell types. Liver activin B mRNA expression is up-regulated in multiple mouse models of inflammation associated with increased hepcidin and hypoferremia, including lipopolysaccharide, turpentine, and heat-killed Brucella abortus models. Finally, the activin inhibitor follistatin-315 blunts hepcidin induction by lipopolysaccharide or B. abortus in mice. Our data elucidate a novel mechanism for noncanonical SMAD activation and support a likely functional role for activin B in hepcidin stimulation during inflammation in vivo.


2016 - Capitolo 31 "Malattia di Wilson ed emocromatosi", in Sezione V "Malattie del fegato" [Capitolo/Saggio]
Corradini, Elena; Demelia, Luigi; Pietrangelo, Antonello
abstract

Definizione, epidemiologia, eziopatogenesi, clinica, diagnosi e terapia dell'emocromatosi e della malattia di Wilson.


2016 - Fifty meanings of grey [Abstract in Atti di Convegno]
Scarlini, Stefania; Fiorini, Massimo; Cavalieri, Francesca; Bocchi, Davide; Riva, Roberta; Ferrara, F; Vegetti, A; Valzania, F; Pietrangelo, Antonello; Corradini, Elena
abstract

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2016 - Fortune favours the bold: finding the right route in the anemia's sea [Abstract in Atti di Convegno]
Fiorini, Massimo; Scarlini, Stefania; Bocchi, Davide; Pietrangelo, Antonello; Corradini, Elena
abstract

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2016 - HYPERHOMOCYSTEINEMIA AND MTHFR C677T POLYMORPHISM IN PATIENTS WITH PORTAL VEIN THROMBOSIS COMPLICATING LIVER CIRRHOSIS [Articolo su rivista]
Ventura, Paolo; Venturelli, Giorgia; Marcacci, Matteo; Fiorini, Massimo; Marchini, Stefano; Cuoghi, Chiara; Pietrangelo, Antonello
abstract

Background: Portal vein thrombosis (PVT) is serious complication of liver cirrhosis (LC), especially in the presence of hepatocellular carcinoma (HCC). The liver plays a key role in homocysteine (Hcy) metabolism: mild hyperhomocysteinemia (HHcy) has been described in LC. HHcy is a risk factor for deep vein thrombosis. Methylentetrahydrofolate- reductase (MTHFR) C677T polymorphism is the commonest determinant of mild HHcy and has been involved also in cancer development. Aim: To investigate a possible relation between HHcy, MTHFR status, HCC and PVT in patients affected by LC. Materials and methods: 100 patients affected by LC, 38 with (PVT group, 24 with HCC) and 62 without PVT (LC group, 14 with HCC) sex-, age-, liver disease stage and etiology-matched were assessed for thrombophilia, smoking status, plasma Hcy, MTHFRC677T polymorphism and homocysteine-related vitamin status. Results: A higher prevalence of HCC, HHcy and MTHFR TT status was observed in PVT group. No significant difference in vitamin statuswas observed between groups. PatientswithHCC showed significantly higher plasma Hcy and higher prevalence of HHcy than patients without HCC. They had also higher prevalence of MTHFR TT status. In patients with TT status (n = 11) and HCC, 10 had HHcy e 9 had PVT. Conclusions: Mild HHcy is associated to LC may have a role in PVT development and assessment of plasma Hcy may be suggested in patients with LC (especially if complicated by HCC). Association between HCC and MTHFR TT status is intriguing, due the postulated role for this polymorphism in cancer: it may represent a possible link between HCC and PVT.


2016 - Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort [Articolo su rivista]
Foster, Graham R.; Coppola, Carmine; Derbala, Moutaz; Ferenci, Peter; Orlandini, Alessandra; Reddy, K. Rajender; Tallarico, Ludovico; Shiffman, Mitchell L.; Ahlers, Silke; Bakalos, Georgios; Hassanein, Tarek; Basho, Jovan; Shabanaj, Gentian; Harxhi, Arjan; Debzi, Nabil; Afredj, Nawel; Guessab, Nawal; Mahindad, Nadir; Mahiou, Hassene; Aissaoui, Magda; Al Qameesh, Jihad; Al Ghandoor, Zuhal; Assene, Collins; Bastens, Boris; Brixko, Christian; Cool, Mike; De Galocsy, Chantal; Delwaide, Jean; George, Christophe; Laukens, Pierre; Lefebvre, Veronique; Mulkay, Jean Pierre; Nevens, Frederik; Servais, Benoit; Van Vlierberghe, Hans; Horsmans, Yves; Henrion, Jean; Sprengers, Dirk; Michielsen, Peter; Bourgeois, Stefan; Lasser, Luc; Langlet, Philippe; Robaeys, Geert; Martinet, Jean Paul; Warzee, Philippe; Hoste, Paul; Reynaert, Hendrik; Juriens, Irène; Decaestecker, Jochen; Van Der Meersch, Filip; Janssens, Filip; Ahmetagic, Sead; Verhaz, Antonija; Bevanda, Milenko; Calkic, Lejla; Ibrahimpasic, Nevzeta; Mesihovic, Rusmir; Mello, Carlos Eduardo; Ruiz, Fernando Jose; Junior, Elson Martins; Ferraz, Maria Lucia; Silva, Giovanni; Mendes, Claudio; Lyra, Andre; Silva, Mariliza Henrique; Gomide, Geisa; Fernandes, Julio Cesar; Pereira, Patricia; Correa, Maria Cassia; Teixeira, Rosangela; Yousry, Ayman; Hanno, Abdelfatah; Gabr, Mamdouh; Omar, Ashraf; Esmat, Gamal; Karatapanis, Stilianos; Nikolopoulou, Vassiliki; Giannoulis, Grigoris; Manolakopoulos, Spilios; Elefsiniotis, Ioannis; Drakoulis, Christos; Dimitroulopoulos, Dimitrios; Kanatakis, Stilianos; Ketikoglou, Ioannis; Mimidis, Konstantinos; Evgenidis, Nikolaos; Akriviades, Euaggelos; Vafiadi Zoubouli, Irini; Tsianos, Epameinondas; Mela, Maria; Orfanou, Eleni; Mousoulis, Georgios; Karagiannis, Ioannis; Manesis, Emmanuel; Varga, Marta; Nemesánszky, Elemér; Fried, Katalin; Schuller, János; Szalay, Ferenc; Lengyel, Gabriella; Tornai, Istvan; Banyai, Tivadar; Lesch, Miklos; Nagy, Istvan; Gervain, Judit; Tusnadi, Anna; Schneider, Ferenc; Szentgyörgyi, László; Hunyady, Bela; Vincze, Aron; Tolvaj, Gyula; Varkonyi, Istvan; Makkai, Erzsébet; Enyedi, Judit; Racz, Istvan; Hausinger, Péter; Váczi, Zsuzsanna; Patai, Árpád; Ozsvár, Zsófia; Lakner, Lilla; Ribiczey, Pál; Bhalla, Ajay; Somani, Sanjay; Luaia, Rosang; Rao, Padaki; Philip, Mathew; Lawate, Parimal; Nagral, Aabha; Sood, Ajit; Parikh, Samir; Merat, Shahin; Nassiri Toosi, Mohsen; Alavian, Seyed Moayed; Zali, Mohammad Reza; Daryani, Nasser Ebrahimi; Drenaggi, Davide; Attili, Adolfo Francesco; Bandiera, Franco; Bassi, Paolo; Bellati, Giorgio; Bellantani, Stefano; Brunetto, Maurizia; Bruno, Savino; Castelli, Francesco; Castellacci, Roberto; Cattelan, Anna Maria; Colombo, Massimo; Craxi, Antonio; D'Angelo, Salvatore; Colombo, Silvia; Demelia, Luigi; Di Perri, Giovanni; Di Giacomo, Antonio; Ferrari, Carlo; Francisci, Daniela; Casinelli, Katia; Ganga, Roberto; Costa, Chiara; Mangia, Alessandra; Russo, Francesco Paolo; Matarazzo, Filippo; Mazzella, Giuseppe; Mazzeo, Maurizio; Memoli, Massimo; Montalbano, Marzia; Montalto, Giuseppe; Pieri, Alessandro; Passariello, Nicola; Picciotto, Antonio; Pietrangelo, Antonello; Pirisi, Mario; Quirino, Tiziana; Raimondo, Giovanni; Rapaccini, Gian Ludovico; Rizzardini, Giuliano; Rizzetto, Mario; Russello, Maurizio; Sabusco, Giuseppe; Santantonio, Teresa; Soardo, Giorgio; Amedea, Alessandri; Verucchi, Gabriella; Vinelli, Francesco; Zignego, Anna Linda; Zuin, Massimo; Ascione, Antonio; Vinci, Maria; Pigozzi, Maria Graziella; Tundo, Paolo; Saracco, Giorgio Maria; Amoroso, Pietro; Andreoni, Massimo; Colletta, Cosimo; Erne, Elke; Megna, Angelo Salomone; Biglino, Alberto; Chiriaco, Piergiorgio; Foti, Giuseppe; Spinzi, Giancarlo; D'Amico, Emilio; Paik, Seung Woon; Ahn, Sang Hoon; Lee, Yun Nah; Kim, Yoonjun; Yang, Jinmo; Han, Sang Young; Varghese, Rosh; Al Gharabally, Abeer; Askar, Haifa; Sharara, Ala; Yaghi, Cesar; Abou Rached, Antoine; Houmani, Zaher; Zaarour, Fouad; Dohaibi, Ahmad;
abstract

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA &lt;50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and &lt;5 represent high and low probability of SVR24, respectively. Results: SVR24 rates were 46.1 % (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1,2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores &lt;5 but not ≥5. Conclusions: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginter-feron alfa-2a/ribavirin.


2016 - Iron and the liver [Articolo su rivista]
Pietrangelo, Antonello
abstract

Humans have evolved to retain iron in the body and are exposed to a high risk of iron overload and iron-related toxicity. Excess iron in the blood, in the absence of increased erythropoietic needs, can saturate the buffering capacity of serum transferrin and result in non-transferrin-bound highly reactive forms of iron that can cause damage, as well as promote fibrogenesis and carcinogenesis in the parenchymatous organs. A number of hereditary or acquired diseases are associated with systemic or local iron deposition or iron misdistribution in organs or cells. Two of these, the HFE- and non-HFE hemochromatosis syndromes represent the paradigms of genetic iron overload. They share common clinical features and the same pathogenic basis, in particular, a lack of synthesis or activity of hepcidin, the iron hormone. Before hepcidin was discovered, the liver was simply regarded as the main site of iron storage and, as such, the main target of iron toxicity. Now, as the main source of hepcidin, it appears that the loss of the hepcidin-producing liver mass or genetic and acquired factors that repress hepcidin synthesis in the liver may also lead to iron overload. Usually, there is low-grade excess iron which, through oxidative stress, is sufficient to worsen the course of the underlying liver disease or other chronic diseases that are apparently unrelated to iron, such as chronic metabolic and cardiovascular diseases. In the future, modulation of hepcidin synthesis and activity or hepcidin hormone-replacing strategies may become therapeutic options to cure iron-related disorders.


2016 - Luspatercept Increases Hemoglobin, Decreases Transfusion Burden and Improves Iron Overload in Adults with Beta-Thalassemia [Abstract in Atti di Convegno]
Piga, Ag; Tartaglione, I; Gamberini, R; Voskaridou, E; Melpignano, Angelo; Ricchi, P; Caruso, V; Pietrangelo, Antonello; Zhang, Xs; Wilson, Dm; Leneus, A; Laadem, A; Sherman, Ml; Attie, Km
abstract

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2016 - Mechanisms of iron hepatotoxicity [Articolo su rivista]
Pietrangelo, Antonello
abstract

Iron is a vital micronutrient that is essential for fundamental cell functions. However, due to its structural chemistry, water-soluble ferrous iron (Fe2+) is able to exchange electrons with water-insoluble ferric iron (Fe3+), limiting its use and forming the basis of its toxicity. The human body has a natural tendency to retain iron, which leaves it vulnerable to overload and toxicity. Despite this, the liver is highly resilient to iron toxicity, and additional host and environmental factors are required for iron damage to fully manifest. Excess hepatic iron is common to a number of diseases, both hereditary (e.g., hemochromatosis (HC)) or acquired (e.g., chronic liver diseases). In the former, accumulation of iron leads to direct liver damage and slow progression to both micronodular cirrhosis and hepatocellular carcinoma (HCC). In the latter, low to moderate grade excess iron is sufficient to cause an underlying liver disease to worsen and accelerate [1].


2016 - Missed treatment in an Italian HBV infected patients cohort: HBV RER [Articolo su rivista]
Cuomo, Gianluca; Borghi, Vanni; Andreone, Pietro; Massari, Marco; Villa, Erica; Pietrangelo, Antonello; Verucchi, Gabriella; Ferrari, Carlo
abstract

Very little is known about the access to treatment for Chronic Hepatitis B in the real clinical practice and the characteristics of the patients who do not receive antiviral therapy.


2016 - POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking [Articolo su rivista]
Schindler, Roland F. R.; Scotton, Chiara; Zhang, Jianguo; Passarelli, Chiara; Ortiz Bonnin, Beatriz; Simrick, Subreena; Schwerte, Thorsten; Poon, Kar Lai; Fang, Mingyan; Rinné, Susanne; Froese, Alexander; Nikolaev, Viacheslav O.; Grunert, Christiane; Müller, Thomas; Tasca, Giorgio; Sarathchandra, Padmini; Drago, Fabrizio; Dallapiccola, Bruno; Rapezzi, Claudio; Arbustini, Eloisa; Romana Di Raimo, Francesca; Neri, Marcella; Selvatici, Rita; Gualandi, Francesca; Fattori, Fabiana; Pietrangelo, Antonello; Li, Wenyan; Jiang, Hui; Xu, Xun; Bertini, Enrico; Decher, Niels; Wang, Jun; Brand, Thomas; Ferlini, Alessandra
abstract

The Popeye domain-containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C&gt;T, p.S201F) in POPDC1, identified by wholeexome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1S201F displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1S201F and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1S201F in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1S191F) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases.


2016 - The SMAD pathway is required for hepcidin response during endoplasmic reticulum stress [Articolo su rivista]
Canali, Susanna; Vecchi, Chiara; Garuti, Cinzia; Montosi, Giuliana; Babitt, Jodie L; Pietrangelo, Antonello
abstract

Hepcidin, the iron hormone, is regulated by a number of stimulatory and inhibitory signals. The cAMP responsive element binding protein 3-like 3, CREB3L3, mediates hepcidin response to endoplasmic reticulum (ER) stress. In this study we asked whether hepcidin response to ER stress also requires the SMAD1/5/8 pathway that has a major role in hepcidin regulation in response to iron and other stimuli. We analyzed hepcidin mRNA expression and promoter activity in response to ER stressors in HepG2 cells in the presence of the BMP type I receptor inhibitor LDN-193189, mutated hepcidin promoter or siRNA against different SMAD proteins. We then used a similar approach in vivo in wild-type, Smad1/5 or Creb3l3 -/- animals undergoing ER stress. In vitro, LDN-193189 prevented hepcidin mRNA induction by different ER stressors. Seemingly, mutation of a BMP-responsive element in the hepcidin promoter prevented ER stress-mediated upregulation. Moreover, in vitro silencing of SMAD proteins by siRNA, in particular SMAD5, blunted hepcidin response to ER stress. On the contrary, hepcidin induction by ER stress was maintained when using antibodies against canonical BMP receptor ligands. In vivo, hepcidin was induced by ER stress and prevented by LDN-193189. In addition, in Smad1/5 knock-out mice, ER stress was unable to induce hepcidin expression. Finally, in Creb3l3 knock-out mice, in response to ER stress, SMAD1/5 were correctly phosphorylated and hepcidin induction was still appreciable, although to a lesser extent as compared to control mice. In conclusion, our study indicates that hepcidin induction by ER stress involves the central regulatory SMAD1/5 pathway.


2016 - Unravelling the Complexity of Inherited Retinal Dystrophies Molecular Testing: Added Value of Targeted Next-Generation Sequencing [Articolo su rivista]
Bernardis, Isabella; Chiesi, Laura; Tenedini, Elena; Artuso, Lucia; Percesepe, Antonio; Artusi, Valentina; Simone, Maria Luisa; Manfredini, Rossella; Camparini, Monica; Rinaldi, Chiara; Ciardella, Antonio; Graziano, Claudio; Balducci, Nicole; Tranchina, Antonia; Cavallini, Gian Maria; Pietrangelo, Antonello; Marigo, Valeria; Tagliafico, Enrico
abstract

To assess the clinical utility of targeted Next-Generation Sequencing (NGS) for the diagnosis of Inherited Retinal Dystrophies (IRDs), a total of 109 subjects were enrolled in the study, including 88 IRD affected probands and 21 healthy relatives. Clinical diagnoses included Retinitis Pigmentosa (RP), Leber Congenital Amaurosis (LCA), Stargardt Disease (STGD), Best Macular Dystrophy (BMD), Usher Syndrome (USH), and other IRDs with undefined clinical diagnosis. Participants underwent a complete ophthalmologic examination followed by genetic counseling. A custom AmpliSeq� panel of 72 IRD-related genes was designed for the analysis and tested using Ion semiconductor Next-Generation Sequencing (NGS). Potential disease-causing mutations were identified in 59.1% of probands, comprising mutations in 16 genes. The highest diagnostic yields were achieved for BMD, LCA, USH, and STGD patients, whereas RP confirmed its high genetic heterogeneity. Causative mutations were identified in 17.6% of probands with undefined diagnosis. Revision of the initial diagnosis was performed for 9.6% of genetically diagnosed patients. This study demonstrates that NGS represents a comprehensive cost-effective approach for IRDs molecular diagnosis. The identification of the genetic alterations underlying the phenotype enabled the clinicians to achieve a more accurate diagnosis. The results emphasize the importance of molecular diagnosis coupled with clinic information to unravel the extensive phenotypic heterogeneity of these diseases.


2015 - Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years since Hepcidin [Articolo su rivista]
Pietrangelo, Antonello
abstract

The discovery of hepcidin in 2000 and the subsequent unprecedented explosion of research and discoveries in the iron field have dramatically changed our understanding of human disorders of iron metabolism. Today, hereditary hemochromatosis, the paradigmatic iron-loading disorder, is recognized as an endocrine disease due to the genetic loss of hepcidin, the iron hormone produced by the liver. This syndrome is due to unchecked transfer of iron into the bloodstream in the absence of increased erythropoietic needs and its toxic effects in parenchymatous organs. It is caused by mutations that affect any of the proteins that help hepcidin to monitor serum iron, including HFE and, in rarer instances, transferrin-receptor 2 and hemojuvelin, or make its receptor ferroportin, resistant to the hormone. In Caucasians, C282Y HFE homozygotes are numerous, but they are only predisposed to hemochromatosis; complete organ disease develops in a minority, due to alcohol abuse or concurrent genetic modifiers that are now being identified. HFE gene testing can be used to diagnose hemochromatosis in symptomatic patients, but analyses of liver histology and full gene sequencing are required to identify patients with rare, non-HFE forms of the disease. Due to the central pathogenic role of hepcidin, it is anticipated that nongenetic causes of hepcidin loss (eg, end-stage liver disease) can cause acquired forms of hemochromatosis. The mainstay of hemochromatosis management is still removal of iron by phlebotomy, first introduced in 1950s, but identification of hepcidin has not only shed new light on the pathogenesis of the disease and the approach to diagnosis, but etiologic therapeutic applications from these advances are now foreseen.


2015 - Hepcidin and iron [Capitolo/Saggio]
Vecchi, C.; Pietrangelo, A.
abstract

This chapter focuses on the signaling pathways involved in the synthesis of hepcidin, the iron hormone, and discusses the pathophysiological consequences of genetic and nongenetic disruption of its regulation. Hepcidin acts as the principal physiological inhibitor of iron flux into the bloodstream by inhibiting its receptor, the iron exporter ferroportin. Hepcidin likely evolved to protect humans from excess iron, which favors pathogen growth or oxidant damage to vital organs. To do so, it senses iron, inflammatory, nutrient and stress signals and rapidly turns on its transcriptional machinery in response to distinct signaling pathways. However, whenever iron demand increases in the erythroid compartment, hepatic hepcidin transcription is readily repressed by bone marrow-derived factors so that more iron can enter the bloodstream to support the increased erythroid activity. Dissecting the regulatory mechanisms of hepcidin transcription in the liver has profoundly changed our view of human diseases associated with disturbances of iron homeostasis and opened the way for novel therapeutic applications.


2015 - Improvement of survival in patients with intermediate stage (BCLC-B) hepatocellular acrcinoma complicating liver cirrhosis by combination therapy with radiofrequency ablation and transcatheter chemioembolization [Abstract in Rivista]
Ventura, Paolo; Santis, Mario De; Venturelli, Giorgia; Gangi, Pietro Di; Marcacci, Matteo; Fiorini, Massimo; Cuoghi, Chiara; Famiglietti, Elena; Torricelli, Pietro; Pietrangelo, Antonello
abstract

Efficacia del trattamento combinato di radiofrequenza e chemioembolizzazione vs. chemioembolizzaione semplice in pazienti selezionati con HCC in stadio intermedio (BCLC score). Approccio con Propensity score matching


2015 - Markers of Endothelial Dysfunction in patients with liver cirrhosis with anh without portal hypertension [Abstract in Rivista]
Marcacci, Matteo; Fiorini, Massimo; Marchini, Stefano; Cuoghi, Chiara; Pietrangelo, Antonello; Ventura, Paolo
abstract

Studio sulla determinazione qualitativa e quantitativa dei marcatori di disfunzione endoteliale in pazienti affetti da cirrosi epatica con senza ipertensione portale significativa


2015 - Pathogens, Metabolic Adaptation, and Human Diseases--An Iron-Thrifty Genetic Model [Articolo su rivista]
Pietrangelo, Antonello
abstract

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2015 - Primary hypoparathyroidism is common in adult patients with b-thalassemia and protect patients from osteoporosis. [Abstract in Rivista]
Ansaloni, Anna; Ferrara, F.; Diazzi, Chiara; Pietrangelo, Antonello; Simoni, Manuela; Rochira, Vincenzo
abstract

Introduction b-thalassemia (bT) is associated to several endocrine abnormalities mainly due to iron overload. With the increase in bT-patients life expectancy, due to progresses in iron chelation therapy, more patients enter into adulthood than in the past and the prevalence of endocrine diseases is being reconsidered. The aim of the study is to investigate the prevalence of primary hypoparathyroidism (pHPT) in adult bT-patients and to characterize the relative clinical phenotype with particular regard to bone health. Methods We enrolled 26 adult patients with major or intermedia bT (12M and 14F; mean ageGS.D. of 38.1G7.5 years). Serum PTH, 25-hydroxyvitamin D (25OHD), calcium, phosphorous, albumin, bone turnover markers, and bone mineral density (BMD) by dual-energy X-ray absorptiometry (Hologic) at lumbar and femoral site were measured. Results pHPT (PTH !15 pg/ml) was found in seven of the 26 patients (27%). Of them, four patients (57%) had hypocalcemia and two were on chronic calcium therapy. Lumbar BMD was significantly higher in patients with pHPT (0.884G 0.189 g/cm2) than in patients without pHPT (0.731G0.124 g/cm2) (PZ0.023). No significant difference was found in femoral BMD, even though a trend for higher BMD was present in pHPT (0.704G0.117 vs 0.670G0.143 g/cm2 in pHPT and no-pHPT respectively) (PZ0.578). The prevalence of osteoporosis was higher in patients without pHPT (68%) than in patients with pHPT (29%). Two patients had a history of bone osteoporotic fractures and both of them did not present pHPT. Bone turnover markers were no different in the two groups. Conclusions The prevalence of pHPT in adult bT-patients is higher if compared to that observed in pediatric bT-patients, the latter ranging from 8 to 11%. Moreover we found an higher prevalence of pHPT compared to that reported in literature on adult bT patients. As expected, pHPT seems to exert a protective role on the development of osteoporosis in these patients.


2015 - Reducing the risk of hospital admission: A call to action from the Italian Society of Internal Medicine [Articolo su rivista]
Sbrojavacca, Rodolfo; Pietrangelo, Antonello; Fenoglio, Luigi; Violi, Francesco; Perticone, Francesco; Corazza, Gino Roberto
abstract

The belief that hospital stays may constitute per se a risk for patients is not widespread among patients and health care professionals. In the balance between advantages and disadvantages of admission, we rarely take into account the impact of the hospital stay itself on the well-being of the patient. In a society that is getting older the hospital may become a hostile environment for the complex and frail patient. Reducing the risks associated with hospital admission implies a radical cultural change accepted and shared by all health care professionals. The critical reconsideration of admission is a way of reasoning not only on hospitalisation but also on what the correct health outcome paradigms should be.


2014 - Ferroportin-related haemochromatosis associated with novel Y64H mutation of the SCL40A1 gene [Articolo su rivista]
Raszeja Wyszomirska, Joanna; Caleffi, Angela; Milkiewicz, Piotr; Pietrangelo, Antonello
abstract

In this paper we described the first Polish patient with ferroportin disease. Hereditary haemochromatosis (HH) is a condition associated with universal iron overload, and it is divided into four types, according to the Online Mendelian Inheritance in Man (OMIM) database. Ferroportin disease represented a rare type of HH, with autosomal dominant trait of inheritance. In our patient we detected a novel mutation in the ferroportin gene, with non-classical phenotype.


2014 - GLUCONEOGENIC SIGNALS DIRECTLY CONTROL IRON HOMEOSTASIS THROUGH HEPCIDIN [Abstract in Atti di Convegno]
Vecchi, Chiara; Montosi, Giuliana; Garuti, Cinzia; Corradini, Elena; Sabelli, Manuela; Qian, J; Liu, C; Canali, S; Pietrangelo, Antonello
abstract

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2014 - Gluconeogenic Signals Regulate Iron Homeostasis via Hepcidin in Mice. [Articolo su rivista]
Vecchi, Chiara; Montosi, Giuliana; Garuti, Cinzia; Corradini, Elena; Sabelli, Manuela; Canali, Susanna; Pietrangelo, Antonello
abstract

Hepatic gluconeogenesis provides fuel during starvation, and is abnormally induced in obese individuals or those with diabetes. Common metabolic disorders associated with active gluconeogenesis and insulin resistance (obesity, metabolic syndrome, diabetes, and nonalcoholic fatty liver disease) have been associated with alterations in iron homeostasis that disrupt insulin sensitivity and promote disease progression. We investigated whether gluconeogenic signals directly control Hepcidin, an important regulator of iron homeostasis, in starving mice (a model of persistently activated gluconeogenesis and insulin resistance).|We investigated hepatic regulation of Hepcidin expression in C57BL/6Crl, 129S2/SvPas, BALB/c, and wild-type and Creb3l3-/- null mice. Mice were fed a standard, iron-balanced chow diet or an iron-deficient diet for 9 days before death, or for 7 days before a 24- to 48-hour starvation period; liver and spleen tissues then were collected and analyzed by quantitative reverse-transcription polymerase chain reaction and immunoblot analyses. Serum levels of iron, hemoglobin, Hepcidin, and glucose also were measured. We analyzed human hepatoma (HepG2) cells and mouse primary hepatocytes to study transcriptional control of Hamp (the gene that encodes Hepcidin) in response to gluconeogenic stimuli using small interfering RNA, luciferase promoter, and chromatin immunoprecipitation analyses.|Starvation led to increased transcription of encodes phosphoenolpyruvate carboxykinase 1 (a protein involved in gluconeogenesis) in livers of mice, increased levels of Hepcidin, and degradation of Ferroportin, compared with nonstarved mice. These changes resulted in hypoferremia and iron retention in liver tissue. Livers of starved mice also had increased levels of Ppargc1a messenger RNA and Creb3l3 messenger RNA, which encode a transcriptional co-activator involved in energy metabolism and a liverspecific transcription factor, respectively. Glucagon and a cyclic adenosine monophosphate analog increased promoter activity and transcription of Hamp in cultured liver cells; levels of Hamp were reduced after administration of small interfering RNAs against Ppargc1a and Creb3l3. PPARGC1A and CREB3L3 bound the Hamp promoter to activate its transcription in response to a cyclic adenosine monophosphate analog. Creb3l3-/- mice did not up-regulate Hamp or become hypoferremic during starvation.|We identified a link between glucose and iron homeostasis, showing that Hepcidin is a gluconeogenic sensor in mice during starvation. This response is involved in hepatic metabolic adaptation to increased energy demands; it preserves tissue iron for vital activities during food withdrawal, but can cause excessive iron retention and hypoferremia in disorders with persistently activated gluconeogenesis and insulin resistance.


2014 - Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB [Articolo su rivista]
T., Sonnweber; D., Nachbaur; A., Schroll; M., Nairz; M., Seifert; E., Demetz; D., Haschka; A. M., Mitterstiller; A., Kleinsasser; M., Burtscher; S., Trubsbach; A. T., Murphy; V., Wroblewski; D. R., Witcher; K., Mleczko Sanecka; Vecchi, Chiara; M. U., Muckenthaler; Pietrangelo, Antonello; I., Theurl; G., Weiss
abstract

OBJECTIVE: Hypoxia affects body iron homeostasis; however, the underlying mechanisms are incompletely understood. DESIGN: Using a standardised hypoxia chamber, 23 healthy volunteers were subjected to hypoxic conditions, equivalent to an altitude of 5600 m, for 6 h. Subsequent experiments were performed in C57BL/6 mice, CREB-H knockout mice, primary hepatocytes and HepG2 cells. RESULTS: Exposure of subjects to hypoxia resulted in a significant decrease of serum levels of the master regulator of iron homeostasis hepcidin and elevated concentrations of platelet derived growth factor (PDGF)-BB. Using correlation analysis, we identified PDGF-BB to be associated with hypoxia mediated hepcidin repression in humans. We then exposed mice to hypoxia using a standardised chamber and observed downregulation of hepatic hepcidin mRNA expression that was paralleled by elevated serum PDGF-BB protein concentrations and higher serum iron levels as compared with mice housed under normoxic conditions. PDGF-BB treatment in vitro and in vivo resulted in suppression of both steady state and BMP6 inducible hepcidin expression. Mechanistically, PDGF-BB inhibits hepcidin transcription by downregulating the protein expression of the transcription factors CREB and CREB-H, and pharmacological blockade or genetic ablation of these pathways abrogated the effects of PDGF-BB toward hepcidin expression. CONCLUSIONS: Hypoxia decreases hepatic hepcidin expression by a novel regulatory pathway exerted via PDGF-BB, leading to increased availability of circulating iron that can be used for erythropoiesis.


2014 - Il volume tiroideo è ridotto in pazienti adulti affetti da beta-talassemia rispetto ai controlli [Abstract in Atti di Convegno]
Ansaloni, Anna; Diazzi, Chiara; Santi, Daniele; Brigante, Giulia; Ferrara, Francesca; Pietrangelo, Antonello; Simoni, Manuela; Rochira, Vincenzo
abstract

This study demonstrates that thyroid volume in adult patients with beta-thalassemia is reduced when compared with that of matched control subjects


2014 - Impact of D181V and A69T on the function of ferroportin as an iron export pump and hepcidin receptor [Articolo su rivista]
Roman, Praschberger; Melanie, Schranz; William, J. H. Griffiths; Nadja, Baumgartner; Martin, Hermann; David, J. Lomas; Pietrangelo, Antonello; Timothy, M. Cox; Wolfgang, Vogel; Heinz, Zoller
abstract

Mutations in the only known mammalian iron exporter ferroportin cause a rare iron overload disorder termed ferroportin disease. Two distinct clinical phenotypes are caused bi different disease mechanisms: mutations in ferroportin either cause loss of iron export function or gain of function due to resistance to hepcidin, the peptide hormone that normally downregulates ferroportin. The aim of the present study was to examine the disease mechanisms of the thus far unclassified A69T and D181V ferroportin mutations. We overexpressed wild-type and mutant ferroportin fused to green fluorescent protein in human embryonic kidney cells and used a F-59-eassay, intracellular ferritin concentrations, confocal microscopy and flow cytometry to study iron export function, subcellular localization and the responsiveness to hepcidin. While the A69T ferroportin mutation seems not to affect the iron export function it causes dose-dependent hepcidin resistance. We further found that D181V mutated ferroportin is iron export defective and hepcidin resistant, similar to the loss of function mutations A77D and C367X. This indicates that intact iron export might be necessary for hepcidin-induced downregulation of ferroportin. This hypothesis was investigated by studying the hepcidin response under modulation of iron availability. Incubation of wild-type ferroportin overexpressing cells with holo-transferrin increases the hepcidin effect whereas chelating extracellular ferrous iron causes hepcidin resistance. In this study we present data that postulates to classify the D181V ferroportin mutation as loss of function and the A69T mutation as dose-dependent hepcidin resistant and outline a possible causal link between iron export function and the hepcidin effect. (C) 2014 Elsevier B.V. All rights reserved.


2014 - Pegylated interferon α plus ribavirin for the treatment of chronic hepatitis C: A multicentre independent study supported by the Italian Drug Agency [Articolo su rivista]
Rosina, F.; Tosti, M. E.; Borghesio, E.; Masocco, M.; Mele, A.; Coppola, C.; Milella, M.; Borgia, G.; Andreone, P.; Koch, M.; Zignego, A. L.; Romano, M.; Carrara, M.; Almasio, P. L.; Azzola, E.; Nardone, G.; Benedetti, A.; Carosi, G.; Mazzotta, F.; Sagnelli, E.; Rizzetto, M.; Mascolo, M. C.; Cursaro, C.; Scuteri, A.; Crespi, C.; Gianstefani, A.; Ranieri, J.; Monti, M.; Corti, G.; Blanc, P. L.; Baragli, F.; Bellentani, S.; Gasbarrini, A.; Pompili, M.; Mecenate, F.; Picardi, A.; Vespasiani, U.; Nosotti, ; Gasbarrini, A.; Pompili, M.; Mecenate, F.; A., Picardi; Nosotti, ; Ricci, G. L.; Paffetti, A.; Mastropietro, C.; Moretti, A.; Spagnolo, A. L.; Puoti, C.; Bellis, L.; Regazzetti, A.; Maffezzini, E.; Pietrangelo, A.; Abbati, G.; Borghi, A.; Sardini, C.; Raimondo, G.; Scribano, L.; Martines, D.; Svegliati Baroni, G.; Faraci, G.; Schi-anchi, S.; Fornaciari, G.; Massari, M.; Fabris, P.; Bertin, T.; Salvagnini, M.; Madonia, S.; Cali, A.; Civitavecchia, G.; Pirisi, M.; Smirne, C.; Andreoletti, M.; Morisco, F.; Caporaso, N.; Gentile, I.; Brancaccio, G.; Gaeta, G. B.; Liberti, A.; Iannece, M. D.; Rocco, A.; Federico, A.; Loguercio, C.; Riegler, G.; Esposito, P.; Fargion, S.; Fatta, E.; Masutti, F.; Bonaventura, M. E.; Autolitano, A.; Russello, M.; Bellia, A.; Toniutto, P.; Bitetto, D.; Pasulo, L.; Luca, M. G.; Grattagliano, I.; Palasciano, G.; Romagno, D.; Giannelli, G.; Napoli, N.; Plattella, M. S.; Cassano, P.; Gobbo, G.; Monti, V.; Raspanti, A.; Cuccorese, ; Colombo, A. E.; Mandelli, G.; Spinzi, G. C.; Floridia, ; Messina, V.; Bonfante, S.; Bellissima, P.; Toti, M.; Vecchiet, J.; Falasca, K.; Portelli, V.; Stefano, G. D.; Pietromatera, G.; Vigano, P.; Re, T.; Andreoni, M.; G., Raineri; Grossi, P. A.; Caputo, S.; Cassola, G.; Feasi, M.; Biagio, A. D.; Nicolini, L.; Giannini, E. G.; Corbo, M.; Foti, G.; Kunkar, A.; Caterini, L.; Migliorini, D.; Chiodera, A.; Calleri, G.; Spezia, C.; Framarin, L.; M., Berrutti; Ciancio, A.; Baiguera, C.; Puoti, M.; Vento, S.; Contini, C.; Boccia, S.; Casiraghi, M. A.; Simone, L.; Tacconi, D.; Caremani, M.; Almi, P.; Chimenti, M.; Cosco, ; Messeri, D.; Esperti, F. C.; Lomonaco, L.; Pazzi, P.; Fornari, F.; Comparato, G.; Casetti, T.; Foschi, F. G.; Samori, A.; Ferretti, E.; Marin, R.; Campo, N.; Testa, R.; Rizzo, S.
abstract

Background: Data on the efficacy of Peg-interferon/ribavirin therapy for chronic hepatitis C are mostly derived from treatment of selected patients enrolled in clinical trials. This study aimed to assess the effectiveness of Peg-interferon/ribavirin therapy in "real world" chronic hepatitis C patients in Italy. Methods: Independent observational multicentre study including consecutive patients receiving Peg-interferon/ribavirin in the 18 months before (retrospective phase) and after (prospective phase) the start of the study. Results: 4176 patients were eligible. The final study population consisted of 2051 patients in the retrospective and 2073 in the prospective phase.Sustained virological response was achieved by 1036 patients (50.5%) during the retrospective phase: 325 were genotypes 1/4 (34.1%) and 684 were genotypes 2/3 (67.2%) and by 800 patients (38.6%) during the prospective phase: 300 were genotypes 1/4 (28.4%) and 473 were genotypes 2/3 (51.5%).During multivariate analysis genotypes 2/3 were significantly associated with higher sustained virological response rates; cirrhosis and γ-glutamil-transpeptidase &gt;2 times the normal limit were associated with poorer response. Conclusions: The response to Peg-interferon/ribavirin therapy in "real world" clinical practice is distinctly lower than in registration trials. The difference in response rates was more pronounced among easy-to-treat than among difficult-to-treat hepatitis C virus genotypes. © 2014 Editrice Gastroenterologica Italiana S.r.l.


2014 - Porfiria acuta intermittente: un caso "eccezionale" [Articolo su rivista]
Rosafio, Cristiano; P., Bergonzini; S., Marchini; S., Leoni; C., Fusco; Colli, Serena; Pietrangelo, Antonello; Paolucci, Paolo; Ventura, Paolo; Iughetti, Lorenzo
abstract

Le porfirie, disordini metabolici ereditari ed eterogenei, comprendono 8 quadri clinici causati da mutazioni enzimatiche nella catena biosintetica dell’eme che esitano in un accumulo di precursori tossici e patogenetici. Si distinguono porfirie acute e porfirie cutanee. Le prime, tra le quali la più comune è la porfiria acuta intermittente (AIP), si manifestano con crisi neuroviscerali e a carico del SNP, anche letali, descritte in letteratura quasi esclusivamente in soggetti puberi.


2014 - Prevalence Of Subclinical Liver Fibrosis Among Patients With Idiopathic Pulmonary Fibrosis [Abstract in Rivista]
Cocconcelli, Elisabetta; Cerri, Stefania; Spagnolo, Paolo; Tonelli, Roberto; Ventura, Paolo; Abbati, Gianluca; Vegetti, Alberto; Pileri, Francesca; DEL GIOVANE, Cinzia; Balduzzi, Sara; Pietrangelo, Antonello; Richeldi, Luca; Luppi, Fabrizio
abstract

Rationale Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive fibrosing interstitial pneumonia of unknown cause. Common pathogenic mechanisms with chronic fibrotic disorders involving other organs are likely. Yet, data on the co-existence of subclinical fibrotic disease across multiple organs in patients with IPF are lacking. The present study aimed to investigate the prevalence of subclinical liver fibrosis among patients with IPF. Methods Patients referred to the Center for Rare Lung Disease of the University Hospital of Modena, with a diagnosis of IPF according to recent guidelines and without previous history of liver diseases underwent hepatic transient elastography (FibroScan®), a non-invasive technique measuring liver stiffness, which routinely used for the assessment of hepatic fibrosis in patients with chronic liver diseases. Hepatic fibrotic status is expressed in a scale from 0 (absence of hepatic fibrosis) to 4 (severe liver fibrosis / cirrhosis). Patients with body mass index (BMI) ≥29 (confidence limit of the instrument) were excluded. Patients, in which any degree of hepatic fibrosis was detected, underwent screening for possible secondary causes of liver fibrosis. Results Among 48 IPF patients (34 males, mean age 69 years), 11 (23%) were excluded because of high BMI. In 8 out 37 patients (22%) it was not possible to obtain successful measurements due to the excess of subcutaneous adipose tissue in the chest wall, or narrow intercostal spaces. Thirteen of 37 patients (35%) had abnormal hepatic transient elastography results: 4 patients fell within the range F1-F2 (6.1-7.6 kPa), 6 in F2 (7.4-8.4 kPa), one in F2-F3 (9.5 kPa), 1 in F4 (14.3 kPa) and 1 was identified as probable fibrosis not otherwise classifiable. In all cases, secondary causes of hepatic fibrosis were excluded. Minor impairment of markers of liver injury was found in a minority of patients with liver fibrosis, with AST and ALT values exceeding the threshold value respectively in 2 and 3 patients with liver fibrosis, detected on elastography. Conclusions Over one third of patients in this IPF cohort had a concomitant fibrosing subclinical process in the liver. These preliminary data prompt the need for a large prospective study aimed at clarifying the correlation between the fibrosing processes in the lung and in the liver and the possibility of shared pathogenic mechanisms.


2014 - SEX HORMONES DIFFERENTLY REGULATE HEPATIC HEPCIDIN EXPRESSION AND SYSTEMIC IRON HOMEOSTASIS IN VIVO [Abstract in Rivista]
Garuti, Cinzia; Montosi, Giuliana; Barelli, S; Pietrangelo, Antonello; Corradini, Elena
abstract

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2014 - The ferroportin disease [Articolo su rivista]
Pietrangelo, A.
abstract


2014 - Thyroid volume in adult beta-thalassemic patients is smaller than in controls [Abstract in Rivista]
Ansaloni, Anna; Diazzi, Chiara; Santi, Daniele; Brigante, Giulia; F., Ferrara; Pietrangelo, Antonello; Rochira, Vincenzo
abstract

Patients with beta-thalassemia have lower thyroid volume estimated at ultrasound than matched controls.


2014 - Thyroid volume in adult beta-thalassemic patients is smaller than in controls [Abstract in Rivista]
Ansaloni, Anna; Diazzi, Chiara; Santi, Daniele; Brigante, Giulia; Ferrara, Francesca; Carani, Cesare; Pietrangelo, Antonello; Simoni, Manuela; Rochira, Vincenzo
abstract

Thyroid volume is significantly reduced in adult patients with beta-thalassemia than in matched controls


2013 - A VALIDATED ELISA FOR QUANTITATING HUMAN SERUM HEMOJUVELIN. [Abstract in Rivista]
C. C., Sun; W. J., Chen; O., Gutierrez; Pietrangelo, Antonello; J., Babitt; H. L. i., N.
abstract

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2013 - Anemia and chronic inflammatory disease [Articolo su rivista]
Pietrangelo, A.
abstract


2013 - Capitolo 8 "Epatopatie da accumulo: malattia di Wilson ed emocromatosi", in Sezione I "Epatiti acute e croniche" [Capitolo/Saggio]
Corradini, Elena; Demelia, Luigi; Pietrangelo, Antonello
abstract

Rassegna delle diverse forme di emocromatosi ereditaria, illustrandone i principali elementi di sospetto e di diagnostica differenziale


2013 - EFFICACY AND SAFETY OF ENTECAVIR (ETV) PROPHYLAXIS IN INACTIVE HBV CARRIERS WHO UNDERWENT CHEMOTHERAPY FOR SOLID OR HAEMATOLOGICAL CANCER: INTERIM ANALYSIS OF A COHORT STUDY. [Abstract in Rivista]
V., Di Marco; E., Angelucci; Pietrangelo, Antonello; F., Salerno; G. A., Niro; B., Daniele; M., Vinci; Villa, Erica
abstract

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2013 - Flow-mediated dilatation (FMD) assessment as a marker of endothelial dysfunction in liver cirrhosis [Abstract in Rivista]
Marcacci, Matteo; Fiorini, Massimo; A., Lattanzi; Venturelli, Giorgia; G., Roveri; C., Boni; F., Zappia; Pietrangelo, Antonello; Rossi, Rosario; Ventura, Paolo; Mario Coppo Liver Research, Group; Cardiology Unit, University of Modena; Reggio, Emilia; Modena, Italy
abstract

Background/aims: Portal hypertension (PH) complications are leading causes of death in patients with liver cirrhosis (LC). PH development in chronic liver disease depends on increased vascular intra-hepatic resistance and on hyperdynamic splanchnic circulation. Disturbances in “Endothelium-dependent” vasodilation, a condition known as “endothelial dysfunction” (ED), has been claimed as an important factor responsible for increased vascular hepatic resistance and PH development in LC. Aims of this study were to assess in LC patients: (1) the presence of ED and its correlation with disease stage and (2) correlation between of ED serum markers (MED) and flow-mediated dilatation (FMD), the gold standard test for evaluating ED. Material and methods: 60 consecutive LC patients (mean age 65±10 years, 17 female) without portal thrombosis (40 with compensated and 20 with decompensated disease) underwent a complete clinical, radiological and biochemical evaluation in order to assess the stage of disease and drug history; all subjects were assessed for MED [P-selectin, von Willebrand factor (vWF), endothelin-1 (ET-1), thrombomodulin (TM) and nitric oxide (NO)] serum levels and FMD (measured by ultrasound at brachial artery according to guidelines). MED and FMD were also assessed in 11 healthy subjects (mean age 26±6.6 female; controls). Results: MED plasma levels increased with the degree of liver dysfunction (p for trend <0.001 in all cases); accordingly, FMD values decreased with worsening of the stage of liver cirrhosis [controls (9.9±1.1%), compensated cirrhosis (6.1±1.8%), decompensated cirrhosis (5±1.3%), p for trend <0.01]. In LC patients a statistically significant correlation between MED markers and FMD was observed for ET-1: r= –0.4427 (p=0.0004) and P-selectin: r= –0.477 (p=0.0001), vWF (r= –0.166, p=0.05), but not for TM (r= –0.245, p=0.05951) and NO (p=0.961). At multivariate analysis, ET-1 and P-selectin remained significantly associated to FMD. Conclusions: Our data confirm the presence of ED in LC patients, as indicated by the significant increase in serum MED and by FMD reduction observed in LC patients. All these parameters show also a significant correlation with the severity of liver disease. Significant correlation and association of FMD with serum MED values also suggest that FMD may be a reliable marker of ED in patients with LC.


2013 - Hepatitis B virus DNA integration in tumour tissue of a non-cirrhotic HFE-haemochromatosis patient with hepatocellular carcinoma. [Articolo su rivista]
T., Pollicino; Vegetti, Alberto; C., Saitta; Ferrara, Francesca; Corradini, Elena; G., Raffa; Pietrangelo, Antonello; G., Raimondo
abstract

Co-existence of multiple causes of liver injury increases the risk of hepatocellular carcinoma (HCC) development. HCC usually develops in patients with cirrhosis although it may also occur in individuals with no or mild liver disease, in particular in cases with hepatitis B virus (HBV) infection. Here we report the case of a 43year-old man with HFE-haemochromatosis, seronegative for hepatitis B and C infections, who developed HCC in the absence of severe liver damage. Both tumoural and non-tumoural liver DNA extracts were tested by nested-PCR and primers specific for four different HBV genomic regions in order to evaluate the presence of occult HBV infection. Only X gene sequences were detected in tumour (but not in non-tumour) DNA extracts. HBV-Alu PCR showed a HBV integration involving a 5'-deleted X gene with an intact enhancer-II/basal-core promoter region. The viral-host junction sequencing revealed that this integrant was located upstream of the partitioning-defective-6-homolog-gamma gene (PARD6G) and real time-PCR quantification demonstrated that PARD6G was overexpressed in tumour compared to non-tumour liver tissues. In conclusion, the combination of HFE-haemochromatosis and occult HBV infection in this patient might have led to a sequel of cellular events that determined the development of HCC even in the absence of cirrhosis.


2013 - IMPACT OF D181V AND A69T ON THE FUNCTION OF FERROPORTIN AS AN IRON EXPORT PUMP AND HEPCIDIN RECEPTOR. [Abstract in Rivista]
Praschberger, Roman; Schranz, Melanie; Hermann, Martin; Griffiths, William; Lomas, David J.; Pietrangelo, Antonello; Cox, Timothy M.; Vogel, Wolfgang; Zoller, Heinz
abstract

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2013 - IS FLOW-MEDIATED DILATATION (FMD) ASSESSMENT A RELIABLE MARKER OF ENDOTHELIAL DYSFUNCTION IN LIVER CIRRHOSIS? [Abstract in Atti di Convegno]
Marcacci, Matteo; Fiorini, Massimo; Lattanzi, Antonella; Venturelli, Giorgia; Roveri, Giulia; Boni, Chiara; Zappia, Federica; Pietrangelo, Antonello; Rossi, Rosario; Ventura, Paolo
abstract

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2013 - MARKERS OF ENDOTHELIAL DYSFUNCTION AS PREDICTORS OF ASCITIC DECOMPENSATION IN PATIENTS WITH LIVER CIRRHOSIS. [Abstract in Rivista]
Fiorini, Massimo; Marcacci, Matteo; C., Boni; F., Zappia; G., Roveri; Venturelli, Giorgia; Pietrangelo, Antonello; Ventura, Paolo
abstract

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2013 - SEX HORMONES DIFFERENTLY REGULATE HEPCIDIN EXPRESSION AND IRON HOMEOSTASIS IN VIVO. [Abstract in Rivista]
Garuti, Cinzia; Montosi, Giuliana; S., Barelli; Pietrangelo, Antonello; Corradini, Elena
abstract

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2013 - Serum endothelin-1 as predictor of ascitic decompensation in patients with liver cirrhosis [Abstract in Rivista]
Fiorini, Massimo; Marcacci, Matteo; C., Boni; F., Zappia; G., Roveri; Venturelli, Giorgia; Pietrangelo, Antonello; Ventura, Paolo
abstract

Background and aims: Intra- and extrahepatic endothelial dysfunction (ED) is considered to have a pivotal role in the development of portal hypertension (PH) in liver cirrhosis (LC). Serum levels of markers of ED (MED) are increased in LC patients; they correlate with the stage of liver disease. Aims of the present study were to assess 1) differences between MED in patients with compensated and decompensated LC; 2) possible prognostic role of MED in ascites development in compensated LC patients. Methods: 90 consecutive LC patients (mean age 65±9 years, 24 female) underwent a complete clinical, radiological and biochemical evaluation in order to assess stage and characteritics of disease; all subjects were assessed for MED [P-selectin, von Willebrand factor (vWF), endothelin-1 (ET-1), thrombomodulin (TM) and nitric oxide (NO)]. The 70 patients (mean age 65±9 years,19 female) with compensated LC (no ascites, cLC) underwent a 2 years-follow-up; their data were also compared with those of 20 (mean age 63±10 years, 5 female) LC patients with decompensated LC (presence of ascites, dLC) and those of 11 healthy controls (mean age 26±6.6 female). Results: ET-1, P-selectin and TM serum levels were significantly higher in LC and in dLC patients with respect to controls. NO and vWF serum levels were higher in dLC patients, whereas no difference was observed in cLC with respect to controls. 33/70 (47.1%) of cLC patients developed ascites at follow-up. At univariate analysis, predictors of ascites development in cLC patients were serum concentrations of ET-1 (OR=3.56, p=0.000), TM (OR=1.95, p=0.000) and P-selectin (OR=1.033, p=0.004) and Child-Pugh score (OR=1.05, p=0.041). At multivariate analysis (Cox regression), serum ET-1 and diabetes were independent predictors of early development of ascites during the follow-up (HR=2.631, p=0.004) in cLC patients. Efficiency (ROC method) of high levels (cut-off value=6 pg/ml) of ET-1 in predicting ascites development was good (AUC=0.803).


2013 - THE BMP'S PATHWAY IN HEPCIDIN REGULATION DURING ENDOPLASMIC RETICULUM STRESS RESPONSE. [Abstract in Rivista]
Canali, Susanna; Vecchi, Chiara; Garuti, Cinzia; Pietrangelo, Antonello
abstract

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2012 - Combination of radiofrequency ablation and transcatheter arterial chemoembolization improves survival in advanced hepatocellular carcinoma complicating liver cirrhosis [Poster]
Ventura, Paolo; M., De Santis; Bonetti, Francesco; Venturelli, Giorgia; P., Di Gangi; M., Marcacci; Torricelli, Pietro; Pietrangelo, Antonello
abstract

Background: Treatment of hepatocellular carcinoma (HCC) still remains a controversial issue. In particular, for patients with HCC status exceeding the criteria for “curative” options (advanced HCC) there is no defined standard of therapy. Aim: To evaluate efficacy of combined treatment with radiofrequency ablation (RFA) and transcatether arterial chemio-embolization (TACE) in advanced HCC. Materials and Methods: We performed a retrospective study to compare the cumulative survival rate of patients with advanced HCC treated with combined therapy (simultaneous application of TACE and RFA) [RFA-TACE group, n=35] vs. those treated only by TACE [TACE group, n=36] or those treated only by conservative option [Control group, n=36]. HCC was confirmed by imaging and/or histology. All patients were monitored at one-three months after treatment and every six months by imaging to check for treatment success and/or HCC recurrence. In order to minimize possible bias due to the retrospective design, a propensity score approach was used in analysing the results. Results: The median survival time were 31 months for TACE-RFA group, 21 months for patients in TACE group and 10 months in control group, respectively. The 6-month survival rate was 96%, 90% and 78% in TACE-RFA group, TACE group and control group, respectively; the 1-year survival rate was 89%, 75% and 20.3%. At 3 years from HCC diagnosis, 6% of control group patients were alive, versus 34% and 45% of TACE and TACE-RFA group, respectively. Survival rates difference between groups were significant (p=0.011 and p<0.001 TACE and Controls with respect to TACE-RFA group). Treatment allocation (HR 2.14, p=0.022), and complete treatment response were important independent predictors (HR 3.25, p=0.018) of survival. Conclusion: Based on the results of this study we conclude that the combination of RFA and TACE may represent a promising approach for the treatment of advanced HCC complicating liver cirrhosis. nevertheless, a better definition of patient’s characteristics and technical approaches together with larger scale-randomized trials are needed.


2012 - Disorders of iron overload [Capitolo/Saggio]
Paterson, A. C.; Pietrangelo, A.
abstract


2012 - Efficacy and safety of combination therapy with pegylated interferon and ribavirin in aged patients with chronic hepatitis C [Poster]
G., Abbati; Ventura, Paolo; Sardini, Carla; A., Vegetti; Pileri, Francesca; Cagnacci, Sara; Venturelli, Giorgia; Incerti, Federica; Pietrangelo, Antonello
abstract

Background & Aims: Combination therapy with pegylated interferon (PEGIFN) and ribavirin has significantly improved virus eradication rate in patients affected by HCV-related chronic hepatitis (C-HC). However, only few data are available with respect to efficacy and safety of this therapy in aged patients. This study aimed at investigating efficacy and tolerability of combination therapy in aged patients with CH-C. Methods: 473 patients [319 (67.4%) naive, 195 (41,2% female) with CH-C (genotype 1, n=266; genotype 2, n=112, genotype 3, n=72, genotype 4, n=23), of whom 68 (14.4%) over 65 years old (mean age 69±2 years), were treated with Peg-IFN (alpha-2a or alpha-2b) plus ribavirin according to international guidelines from January 2007 to July 2011. These patients were assessed for sustained viral response (SVR) rate and for all known main predictors of SVR in CH-C. Results: The overall SVR rate resulted similar in both age groups [270/405 (66.6%) in subjects <65 years vs. 41/68 (60.3%) in subjects ≥65 years, respectively, p=0.334)]. Overall, therapy discontinuance rate was low, with no significant difference between patients over or under age 65 (4.4% vs. 4.9%, respectively), the most common reason for discontinuance being anemia in both groups.For patients over 65, at multivariate analysis, non-naïve status, EVR and use of hematological growth factors were independent predictors of SVR. Factors independently related to EVR at multivariate analysis were non-naive, staging, genotype 2-3 vs. genotype1-4 and use of hematological growth factors Conclusions: Aged patients can be candidates for Peg-IFN plus ribavirin therapy. The appropriate use of hematological factors in these patients may be useful to achieve a significant reduction in the rate of therapy discontinuation due to hematological side-effects. The response-guided therapy may be applied in predicting therapy efficacy in this patient group


2012 - Hemochromatosis [Capitolo/Saggio]
Pietrangelo, A.
abstract

Hemochromatosis (HC) is an iron-loading disorder caused by a genetically determined failure to prevent unrequired iron from entering the body. It is characterized by progressive parenchymal iron overload with potential for multiorgan damage and disease. Hepcidin, the iron hormone, normally limits iron transfer from the intestine and macrophages into the bloodstream. Pathogenic mutations in genes involved in hepcidin synthesis in the liver (HFE, TfR2, HJV, and HAMP) may all cause HC. Depending on the gene involved and its role in hepcidin regulation, the phenotype of HC varies, ranging from the rare HJV- and HAMP-juvenile forms characterized by massive iron loading with severe heart and endocrine disorders, to the late-onset phenotype dominated by liver disease and usually associated with HFE and, rarely, with TfR2 mutations. Homozygosity for the C282Y polymorphism of HFE is associated with the most common form of HC. Although C282Y homozygosity is frequent in Caucasians, its clinical expression is low and requires concurrence of host-related and environmental factors to cause disease. Phlebotomy is effective in preventing complications and improves survival in all forms of HC. © 2012 Blackwell Publishing Ltd.


2012 - Iron and steatohepatitis. [Articolo su rivista]
Corradini, Elena; Pietrangelo, Antonello
abstract

As the main iron storage site in the body and the main source of the iron-regulatory hormone, hepcidin, the liver plays a pivotal role in iron homeostasis. A variable degree of hepatic iron accumulation has long been recognized in a number of chronic liver diseases. Both alcoholic and non-alcoholic steatohepatitis display increased iron deposits in the liver, with an hepatocellular, mesenchymal, or mixed pattern, and recent reports have documented a concomitant aberrant hepcidin expression that could be linked to different coincidental pathogenic events (e.g. the etiological agent itself, necroinflammation, metabolic derangements, genetic predisposition). The present study reviews the pathogenic mechanisms of iron accumulation in steatohepatitis during alcoholic and non-alcoholic liver disease and the role of excess iron in chronic disease progression.


2012 - Studies in Hemochromatosis Type 3: How Does TfR2 Control Hepatic Hepcidin Expression? [Abstract in Rivista]
M., Schranz; L., Dorn; M. P., Strasser; N., Baumgartner; Pietrangelo, Antonello; W., Vogel; H. M., Zoller
abstract

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2011 - Association between celiac disease and idiopathic dilated cardiomyopathy: a case report. [Articolo su rivista]
Romagnoli, Elisa; Boldrini, Elena; Pietrangelo, Antonello
abstract

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2011 - Erratum to: The porphyrias: Pathophysiology(Intern Emerg Med, (2010), 5, Suppl 1 (S65-S71), 10.1007/s11739-010-0452-z) [Articolo su rivista]
Pietrangelo, A.
abstract


2011 - Erratum: Ferroportin disease: A systematic meta-analysis of clinical and molecular findings (Journal of Hepatology (2010) 53:5 (941-949)) [Articolo su rivista]
Mayr, R.; Janecke, A. R.; Schranz, M.; Griffiths, W. J. H.; Vogel, W.; Pietrangelo, A.; Zoller, H.
abstract


2011 - Hepatocellular Carcinoma in HIV-infected Patients: Check Ealy, Treat Hard [Articolo su rivista]
M., Berretta; Garlassi, Elisa; B., Cacopardo; A., Cappellani; Guaraldi, Giovanni; S., Cocchi; P., de Paoli; A., Lleshi; I., Izzi; A., Torresin; P., Di Gangi; Pietrangelo, Antonello; M. C., Ferrari; A., Beraz; S., Berretta; G., Nasti; DI BENEDETTO, Fabrizio; L., Balestreri; U., Tirelli; Ventura, Paolo
abstract

Purpose. Hepatocellular carcinoma (HCC) is an increasingcause of mortality in HIV-infected patients inthe highly active antiretroviral therapy (HAART) era.The aims of this study were to describe HCC tumorcharacteristics and different therapeutic approaches, toevaluate patient survival time from HCC diagnosis, andto identify clinical prognostic predictors in patients withand without HIV infection.Patients and Methods. A multicenter observationalretrospective comparison of 104 HIV-infected patientsand 484 uninfected patients was performed in four Italiancenters. HCC was staged according to the BarcelonaClinic Liver Cancer (BCLC) criteria.Results. Tumor characteristics of patients with andwithout HIV were significantly different for age, EasternCooperative Oncology Group performance status(PS) score <1, and etiology of chronic liver disease. Despitethe similar potentially curative option rate and better BCLC stage at diagnosis, the median survivaltime was significantly shorter in HIV patients. HIVpatients were less frequently retreated at relapse.Independent predictors of survival were: BCLC stage,potentially effective HCC therapy, tumor dimension <3cm, HCC diagnosis under a screening program, HCC recurrence,and portal vein thrombosis. Restricting the analysisto HIV patients only, all positive prognostic factorswere confirmed together with HAART exposure.Conclusion. This study confirms a significantlyshorter survival time in HIV HCC patients. The lessaggressive retreatment at recurrence approach does notbalance the benefit of younger age and better BCLCstage and PS score of HIV patients. Thus, consideringthe prognosis of HIV HCC patients, effective screeningtechniques, programs, and specific managementguidelines are urgently needed.


2011 - Hepcidin in human iron disorders: therapeutic implications. [Articolo su rivista]
Pietrangelo, Antonello
abstract

The discovery of hepcidin has triggered a virtual explosion of studies on iron metabolism and related disorders, the results of which have profoundly changed our view of human diseases associated with excess of iron, iron deficiency or iron misdistribution. Not only has new light been shed on the pathogenesis of these disorders, but therapeutic applications from these advances are now foreseen. The notion that hepcidin excess or deficiency may contribute to the dysregulation of iron homeostasis in hereditary and acquired iron disorders raises the possibility that hepcidin-lowering or enhancing agents may be an effective strategy for curing the main consequences of hepcidinopathies, anemia or iron overload, respectively. Experimental pre-clinical and clinical studies have shown that hepcidin antibodies, agonists or antagonists, cytokine receptor antibodies and small-molecules that modify hepcidin expression also reverse iron abnormalities in vivo, in a number of disease models. While future studies addressing safety and long-term efficacy of hepcidin-targeted treatments will clarify risks and benefits, a new era has begun based on the treatment of disorders of iron homeostasis through the modulation of its regulatory hormone, hepcidin.


2011 - Metal Storage Disorders FOREWORD [Articolo su rivista]
Pietrangelo, Antonello; Schilsky, M.
abstract

The current issue of Seminars in Liver Disease is devoted to iron and copper metabolism and related diseases. Iron and copper are transition metals, essential for the survival of most organisms, particularly those existing in an oxygen-rich environment, due to their capacity to participate in one-electron exchange reactions. Their “essentiality” relates both to our need to obtain a supply of these transitional metals from our diet and from their function as critical cofactors in numerous essential proteins: iron in the heme-containing proteins, electron transport chain, and microsomal electron transport proteins; and copper in superoxide dismutase, lysyl oxidase, cytochrome c oxidase, tyrosinase and dopamine-β-hydroxylase. Interestingly, the same property that makes iron and copper essential also may generate noxious free radicals that can cause injury to cell membranes and organelles. Therefore, concentrations of circulating iron and copper demand a concerted and tight regulation as both excess or deficiency impairs cellular functions and causes cell toxicity and organ disease. Excess tissue iron or copper is found in numerous human diseases, and is typified by hereditary hemochromatosis (HH) and Wilson disease (WD), two of the more common genetic disease states associated with deranged metabolism of metals in humans. Recently, we have witnessed dramatic advances in iron and copper biology and learned how their dysregulated metabolism in the liver may lead to severe systemic diseases. The parallel rapid progress in genetics has impacted diagnostic strategies and management of common iron and copper disorders. Since the identification of the gene responsible for classic HFE-HH, there have been further major advances in understanding the handling of iron, and the liver, the source of the iron-regulatory hormone hepcidin, is now placed at the center of iron homeostasis. In this issue of the Seminars, two distinct chapters are devoted to the dramatic advances made over the past few years in the field of iron metabolism. De Domenico, Ward, and Kaplan, from the University of Utah, Salt Lake City, review the basic regulatory mechanisms of iron homeostasis as elucidated by the hepcidin–ferroportin axis. They especially focus on ferroportin biology, its hepcidin-dependent and independent degradation pathways, and the relevance of ferroportin mutations in human diseases, as recapitulated in the recently described ferroportin disease. Babitt and Lin, from the Massachusetts General Hospital and Harvard Medical School in Boston, review the current understanding of hepcidin regulation, with emphasis on the molecular mechanisms by which iron regulates the hormone and the key role played by the bone morphogenetic protein-hemojuvelin-SMAD signaling pathway in this process. They also show the central role of this hormone–peptide in the pathogenesis of human hemochromatosis syndromes that, despite their genetic and phenotypic diversity, all appear to be caused by reduced hepcidin synthesis/activity, leading to a failure to prevent excess iron from entering the circulation. Olynyk and collaborators from the Fremantle Hospital, in Fremantle, Australia, discuss management and natural history of classic HFE-HH in the post-HFE era. Longitudinal population studies have now defined the natural history of HH and recognized the influence of genetic and environmental modifiers on phenotypic expressivity. The authors extensively discuss how the diagnostic workout of HH has been refined to incorporate new biochemical, genetic, and noninvasive methods that complement more traditional approaches, and propose a diagnostic algorithm to manage HH. Pietrangelo and collaborators from the “Mario Coppo” Liver Research Center in Modena, Italy, review pathogenesis and clinical manifestations of hepatic iron overload. They update the genetics, epidemiology, and clinical features of non HFE-hemochromatosis synd


2011 - Non-HFE Hepatic Iron Overload. [Articolo su rivista]
Pietrangelo, Antonello; Caleffi, A; Corradini, Elena
abstract

Numerous clinical entities have now been identified to cause pathologic iron accumulation in the liver. Some are well described and have a verified hereditary basis; in others the genetic basis is still speculative, while in several cases nongenetic iron-loading factors are apparent. The non-HFE hemochromatosis syndromes identifies a subgroup of hereditary iron loading disorders that share with classic HFE-hemochromatosis, the autosomal recessive trait, the pathogenic basis (i.e., lack of hepcidin synthesis or activity), and key clinical features. Yet, they are caused by pathogenic mutations in other genes, such as transferrin receptor 2 (TFR2), hepcidin (HAMP), hemojuvelin (HJV), and ferroportin (FPN), and, unlike HFE-hemochromatosis, are not restricted to Caucasians. Ferroportin disease, the most common non-HFE hereditary iron-loading disorder, is caused by a loss of iron export function of FPN resulting in early and preferential iron accumulation in Kupffer cells and macrophages with high ferritin levels and low-to-normal transferrin saturation. This autosomal dominant disorder has milder expressivity than hemochromatosis. Other much rarer genetic disorders are associated with hepatic iron load, but the clinical picture is usually dominated by symptoms and signs due to failure of other organs (e. g., anemia in atransferrinemia or neurologic defects in aceruloplasminemia). Finally, in the context of various necro-inflammatory or disease processes (i.e., chronic viral or metabolic liver diseases), regional or local iron accumulation may occur that aggravates the clinical course of the underlying disease or limits efficacy of therapy.


2011 - Serum and Liver Iron Differently Regulate the Bone Morphogenetic Protein 6 (BMP6)-SMAD Signaling Pathway in Mice [Articolo su rivista]
Corradini, Elena; Meynard, D; Wu, Qf; Chen, S; Ventura, Paolo; Pietrangelo, Antonello; Babitt, J. L.
abstract

The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is a central regulator of hepcidin expression and systemic iron balance. However, the molecular mechanisms by which iron is sensed to regulate BMP6-SMAD signaling and hepcidin expression are unknown. Here we examined the effects of circulating and tissue iron on Bmp6-Smad pathway activation and hepcidin expression in vivo after acute and chronic enteral iron administration in mice. We demonstrated that both transferrin saturation and liver iron content independently influence hepcidin expression. Although liver iron content is independently positively correlated with hepatic Bmp6 messenger RNA (mRNA) expression and overall activation of the Smad1/5/8 signaling pathway, transferrin saturation activates the downstream Smad1/5/8 signaling cascade, but does not induce Bmp6 mRNA expression in the liver. Hepatic inhibitory Smad7 mRNA expression is increased by both acute and chronic iron administration and mirrors overall activation of the Smad1/5/8 signaling cascade. In contrast to the Smad pathway, the extracellular signal-regulated kinase 1 and 2 (Erk1/2) mitogen-activated protein kinase (Mapk) signaling pathway in the liver is not activated by acute or chronic iron administration in mice. Conclusion: Our data demonstrate that the hepatic Bmp6-Smad signaling pathway is differentially activated by circulating and tissue iron to induce hepcidin expression, whereas the hepatic Erk1/2 signaling pathway is not activated by iron in vivo.


2011 - THE IMPACT OF DISEASE CAUSING MUTATIONS AND BENIGN SEQUENCE VARIANTS OF FERROPORTIN ON IRON EXPORT AND HEPCIDIN RESPONSE. [Abstract in Rivista]
M., Schranz; R., Praschberger; R., Mayr; M., Hermann; W., Vogel; Pietrangelo, Antonello; H. M., Zoller
abstract

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2011 - THE MOLECULAR BASIS FOR THE HEPATIC REGULATION OF HEPCIDIN, THE IRON HORMONE, BY BONE MORPHOGENETIC PROTEINS. [Abstract in Rivista]
Corradini, Elena; Meynard, D; Montosi, Giuliana; Garuti, Cinzia; Wu, Q; Ventura, Paolo; Babitt, Jl; Lin, Hy; Pietrangelo, Antonello
abstract

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2011 - Treatment of chronic hepatitis C by pegylated interferon plus ribavirin combination therapy in aged patients : why not ? [Abstract in Rivista]
A., Vegetti; G., Abbati; C., Sardini; Venturelli, Giorgia; Cagnacci, Sara; Incerti, Federica; Pietrangelo, Antonello; Ventura, Paolo
abstract

Background & Aims: Pegylated interferon (PEG-IFN) plus ribavirin combination therapy has significantly improved the successful rate in virus eradication in patients affected by chronic hepatitis C. However, only few data are available with respect to antiviral effect and safety in aged patients. This study aimed at investigating the efficacy and tolerability of pegylated interferon (Peg-IFN) plus ribavirin therapy in aged patients with chronic hepatitis C (CH-C). Methods: A total of 473 patients [319 (67.4%) naive, 195 (41,2% female) with CH-C (genotype 1, n = 266; genotype 2, n = 112, genotype 3 = 72, genotype 4=23), of whom 68 (14.4%) over 65 years old (y.o.) (mean age 69±2 years) , were treated with Peg-IFN (alfa-2a or alfa-2b) plus ribavirin according to international guidelines. These patients were assessed for sustained viral response (SVR) rate and for all known main predictors of SVR in CH-C. Results: The overall SVR rate resulted similar in both age groups (270/405 (66.6%) in subjects <65 y.o vs. 41/68 (60.3%) in subjects ≥ 65 y.o, respectively, p=0.334). No significant difference in therapy discontinuance rate was observed between patients over and under 65 y.o. (4.4% vs. 4.9%, respectively), the most common reason being anemia in both groups. The table resumes the distribution of main known SVR predictors in the two considered groups < 65 years (n=405) ≥ 65 years (n=68) p Genotype (1-4/2-3) 252/153 37/31 0.229 High viral load (cut off 500.000 UI/ml) (yes/no) 154/251 16/52 0.028 PegIFN alfa 2a / PegIFN alfa 2b use 244/161 59/9 <.001 Rapid Viral Response (RVR) (yes/no)* 106/107 28/28 1.000 Early Viral Response (EVR) (yes/no) 308/97 50/18 0.76 Naive (yes/no) 275/130 44/24 0.675 Sex (male/female) 248/157 30/38 0.011 Grading (Ishak score) 4.89±2.13 5.77±1.88 0.022 Staging (Ishak score) 2.08±1.49 2.73±1.51 0.029 Liver cirrhosis (yes/no) 42/363 13/55 0.043 Therapy reduction (yes/no) 123/282 20/48 0.888 Ribavirin reduction (yes/no) 87/318 18/50 0.430 Use of erythropoietic fatctors (yes/no) 43/362 26/42 <.001 *data not available for all patients For patients over 65 y.o., at multivariate analysis, genotype 2/3 (OR, 2.56,95% CI 1.89-5.65 p = 0.026) and EVR (OR, 45.5,95% CI 26.2-125.3 p <0.001) were significant predictors of SVR. Factors related to EVR at multivariate analysis were naive status (OR 2.58, 95%CI 1.26-3.69, p=.001), therapy with PEGIFNalfa 2a (OR 3.56, 95% CI 1.68-5.65, p=.014) and ribavirin reduction (OR 0.789, 95% CI 0.568-0.895, p=.015). Conclusions: Aged patients can be candidates for Peg-IFN plus ribavirin therapy.The appropriate use of erythropietic factors in these patients may be useful to achieve a significant reduction in the rate of therapy discontinuation due to hematological side-effects. The response-guided therapy may be applied in predicting therapy efficay in these patients.


2010 - A Phase 1/2, Dose-Escalation Trial of Deferasirox for the Treatment of Iron Overload in HFE-Related Hereditary Hemochromatosis. [Articolo su rivista]
Phatak, P; Brissot, P; Wurster, M; Adams, Pg; Bonkovsky, Hl; Gross, J; Malfertheiner, P; Mclaren, Gd; 10, ; Niederau, C; Piperno, A; Powell, Lw; Russo, Mw; Stoelzel, U; Stremmel, W; Griffel, L; Lynch, N; Zhang, Yy; Pietrangelo, Antonello
abstract

Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption that may result in iron overload. Although phlebotomy is widely practiced, it is poorly tolerated or contraindicated in patients with anemias, severe heart disease, or poor venous access, and compliance can vary. The once-daily, oral iron chelator, deferasirox (Exjade) may provide an alternative treatment option. Patients with HH carrying the HFE gene who were homozygous for the Cys282Tyr mutation, serum ferritin levels of 300-2000 ng/mL, transferrin saturation &gt;= 45%, and no known history of cirrhosis were enrolled in this dose-escalation study to characterize the safety and efficacy of deferasirox, comprising a core and an extension phase (each 24 weeks). Forty-nine patients were enrolled and received starting deferasirox doses of 5 (n = 11), 10 (n = 15), or 15 (n = 23) mg/kg/day. Adverse events were generally dose-dependent, the most common being diarrhea, headache, and nausea (n = 18, n = 10, and n = 8 in the core and n = 1, n = 1, and n = 0 in the extension, respectively). More patients in the 15 mg/kg/day than in the 5 or 10 mg/kg/day cohorts experienced increases in alanine aminotransferase and serum creatinine levels during the 48-week treatment period; six patients had alanine aminotransferase &gt;3x baseline and greater than the upper limit of normal range, and eight patients had serum creatinine &gt;33% above baseline and greater than upper limit of normal on two consecutive occasions. After receiving deferasirox for 48 weeks, median serum ferritin levels decreased by 63.5%, 74.8%, and 74.1% in the 5, 10, and 15 mg/kg/day cohorts, respectively. In all cohorts, median serum ferritin decreased to &lt;250 ng/mL. Conclusion: Deferasirox doses of 5, 10, and 15 mg/kg/day can reduce iron burden in patients with HH. Based on the safety and efficacy results, starting deferasirox at 10 mg/kg/day appears to be most appropriate for further study in this patient population.


2010 - ANTIALDOSTERONE THERAPY IN LIVER CIRRHOSIS: A ROLE FOR PREVENTION OF CIRROTHIC CARDIOMIOPATHY? [Abstract in Rivista]
Ventura, Paolo; Ferrari, Mariachiara; Nuzzo, Anna Chiara; Nascimbeni, Fabio; Romagnoli, Elisa; Rossi, Rosario; Moriondo, V; Vegetti, Alberto; Modena, Maria Grazia; Pietrangelo, Antonello
abstract

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2010 - Altered hepatic BMP signaling pathway in human HFE hemochromatosis. [Articolo su rivista]
Bolondi, G; Garuti, Cinzia; Corradini, Elena; Zoller, H; Vogel, W; Finkenstedt, A; Babitt, Jl; Lin, Hy; Pietrangelo, Antonello
abstract

Human hemochromatosis (HC) has been associated with the common C282Y polymorphism of HFE or rare pathogenic mutations of TfR2, HJV, FPN and HAMP. All forms of human HC seem to be caused by low or inadequate levels of hepcidin, the iron hormone. We and others have recently shown that Hfe(-/-) mice exhibit an impairment in the bone morphogenetic protein (BMP) signaling pathway controlling hepcidin. However, all data indicating the central role of BMPs in hepcidin regulation and an impaired BMP/SMAD signaling in HC have been collected in mice. In this study we investigated whether also in humans the expression of BMP signaling targets, SMAD7 and Id1, are associated with liver iron concentration (LIC) and whether such regulation is disrupted in HFE-HC. We correlated the mRNA expression, assessed by RT-PCR, of HAMP, SMAD7 and Id1 with LIC in liver biopsies from patients with normal iron status. HFE-HC or non-HC hepatic iron overload. We found that in human liver, not only HAMP, but also SMAD7 and Id1 mRNA significantly correlate with the extent of hepatic iron burden. However, this correlation is lost in patients with HFE-HC, but maintained in subjects with non-hemochromatotic iron overload. These data indicate that in human HFE-HC a disrupted BMP/SMAD signaling in the liver is key in the pathogenesis of the disease.


2010 - Antialdosterone therapy in liver cirrhosis: a role for prevention of cirrhitc cardiomiopathy ? [Abstract in Rivista]
Ventura, Paolo; Ferrari, Mariachiara; Nuzzo, Anna Chiara; Nascimbeni, Fabio; Romagnoli, Elisa; Rossi, Rosario; Moriondo, Valeria; Vegetti, Alberto; Modena, Maria Grazia; Pietrangelo, Antonello
abstract

Background and aims: Cirrhotic cardiomiopathy (CC) comprises a constellation of cardiac abnormalities associated with liver cirrhosis (LC) progression and due to multiple pathogenetic mechanisms; even if not responsible of overt heart failure, CC plays a major role in cardiac dysfunction complicating OLT or TIPPS placement. Our work aims at assessing the prevalence of CC and the different role of possible CC-associated factors. Materials and methods: 50 patients (17 f) affected by LC and 17 (6f) by chronic hepatitis were studied. Hemochromatosis, cardiopulmonary or alcohol-related diseases were excluded. All subjects were assessed for cardiac parameters (EF, Ea, TAPSE, E/A ratio and Deceleration time (DT), QTc interval); Child-Pugh score; ANF ,BNF, Epinephrine (E), Norepinephrine (NE), PRA, Aldosterone (A), nitric oxide (NO), IL-6 and TNF-a, PIIINP plasma levels; APRI, Fibroscore, 4-parameter scores; drugs history (type and exposition time). Results: We observed a significant prevalence of diastolic dysfunction in LC group (50% of patients had abnormal E/A ratio and 62% abnormal DT) with a higher prevalence in advanced disease (100% and 92 % of Child C patients had abnormal E/A ratio and DT, respectively). Prolonged QT (pQT) was present in 19 LC patients (38%) vs. 1 (6.25%) in ECA subjects (p<.001). At univariate analysis, diastolic dysfunction indices (abnormal DT and E/A ratio) resulted significantly related to NO, TNF-alfa, NE, E , A , PRA, ANP and BNP plasma levels; they both were also significantly related to plasma PIIINP levels , Fibroscore and 4-parameters fibrosis scores. A significant correlation between pQT interval and Child score, duration of disease (years), plasma levels of TNF-a, A, ANP, BNP, PIIINP and Fibroscore and 4-parameters scores was also present. E/A ratio, DT and pQT resulted significantly inversely related to antialdosterone therapy exposition (measured as AUC of time x dose). The table resumes the multivariate analysis’ results (stepwise multiple logistic regression) using E/A ratio <1 as dependent variable. Similar result were obtained when using pQT as dependent variable.  SE OR 95% CI p Antialdosterone exposition -.539 .137 0.66 0.43-0.78 .011 Child Score .621 .292 1.35 1.26-2.13 .019 Aldosterone .728 .325 1.26 1.15-3.58 .026 PIIINP .345 .121 1.06 1.02-1.18 .042 Conclusions: Antialdosterone exposition results inversely and independentely related to CC abnormalities, this suggesting a role for optimized (in terms of dose and timing) antialdosterone therapy in prevention of CC development.


2010 - BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. [Articolo su rivista]
Corradini, Elena; Schmidt, Pj; Meynard, D; Garuti, Cinzia; Montosi, Giuliana; Chen, S; Vukicevic, S; Pietrangelo, Antonello; Lin, Hy; Babitt, J. L.
abstract

BACKGROUND AND AIMS: Abnormal hepcidin regulation is central to the pathogenesis of HFE hemochromatosis. Hepatic bone morphogenetic protein 6 (BMP6)-SMAD signaling is a main regulatory mechanism controlling hepcidin expression, and this pathway was recently demonstrated to be impaired in Hfe knockout (Hfe(-/-)) mice. To more definitively determine whether HFE regulates hepcidin expression through an interaction with the BMP6-SMAD signaling pathway, we investigated whether hepatic Hfe overexpression activates the BMP6-SMAD pathway to induce hepcidin expression. We then investigated whether excess exogenous BMP6 administration overcomes the BMP6-SMAD signaling impairment and ameliorates hemochromatosis in Hfe(-/-) mice.METHODS: The BMP6-SMAD pathway and the effects of neutralizing BMP6 antibody were examined in Hfe transgenic mice (Hfe Tg) compared with wildtype (WT) mice. Hfe(-/-) and WT mice were treated with exogenous BMP6 and analyzed for hepcidin expression and iron parameters.RESULTS: Hfe Tg mice exhibited hepcidin excess and iron deficiency anemia. Hfe Tg mice also exhibited increased hepatic BMP6-SMAD target gene expression compared with WT mice, while anti-BMP6 antibody administration to Hfe Tg mice improved the hepcidin excess and iron deficiency. In Hfe(-/-) mice, supraphysiologic doses of exogenous BMP6 improved hepcidin deficiency, reduced serum iron, and redistributed tissue iron to appropriate storage sites.CONCLUSIONS: HFE interacts with the BMP6-SMAD signaling pathway to regulate hepcidin expression, but HFE is not necessary for hepcidin induction by BMP6. Exogenous BMP6 treatment in mice compensates for the molecular defect underlying Hfe hemochromatosis, and BMP6-like agonists may have a role as an alternative therapeutic strategy for this disease.


2010 - CLINICAL OUTCOMES AND SURVIVAL IN PATIENTS WITH HEPATOCELLULAR CARCINOMA AND HIV INFECTION [Abstract in Rivista]
Berretta, M; Garlassi, E; Ventura, Paolo; Cacopardo, B; Lleshi, A; Cocchi, S; Guaraldi, Giovanni; Pietrangelo, Antonello; Tirelli, U.
abstract

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2010 - Ferroportin disease: A systematic meta-analysis of clinical and molecular findings. [Articolo su rivista]
Mayr, R; Janecke, Ar; Schranz, M; Griffiths, Wjh; Vogel, W; Pietrangelo, Antonello; Zoller, H.
abstract

Background &amp; Aims: Classical ferroportin disease is characterized by hyperferritinemia, normal transferrin saturation, and iron overload in macrophages. A non-classical form is characterized by additional hepatocellular iron deposits and a high transferrin saturation. Both forms demonstrate autosomal dominant transmission and are associated with ferroportin gene (SLC40A1) mutations. SLC40A1 encodes a cellular iron exporter expressed in macrophages, enterocytes, and hepatocytes. The aim of the analysis is to determine the penetrance of SLC40A1 mutations and to evaluate in silica tools to predict the functional impairment of ferroportin mutations as an alternative to in vitro studies.Methods: We conducted a systematic review of the literature and meta-analysis of the biochemical presentation, genetics, and pathology of ferroportin disease.Results: Of the 176 individuals reported with SLC40A1 mutations, 80 were classified as classical phenotype with hyperferritinemia and normal transferrin saturation. The non-classical phenotype with hyperferritinemia and elevated transferrin saturation was present in 53 patients. The remaining patients had normal serum ferritin or the data were reported incompletely. Despite an increased hepatic iron concentration in all biopsied patients, significant fibrosis or cirrhosis was present in only 11%. Hyperferritinemia was present in 86% of individuals with ferroportin mutations. Bio-informatic analysis of ferroportin mutations showed that the PolyPhen score has a sensitivity of 99% and a specificity of 67% for the discrimination between ferroportin mutations and polymorphisms.Conclusions: In contrast to HFE hemochromatosis, ferroportin disease has a high penetrance, is genetically heterogeneous and is rarely associated with fibrosis. Non-classical ferroportin disease is associated with a higher risk of fibrosis and a more severe overload of hepatic iron.


2010 - HIV INFECTION AND SURVIVAL IN PATIENTS WITH HCCAND LIVER CIRRHOSIS [Abstract in Rivista]
Ventura, Paolo; Garlassi, Elisa; B., Cacopardo; P., Di Gangi; Ferrari, Maria Chiara; Venturelli, Giorgia; U., Tirelli; Guaraldi, Giovanni; Pietrangelo, Antonello; M., Berretta
abstract

Background and Aims: HCC is an emerging problem for HIVpatients, particularly if HCV and/or HBV co-infected. At the present,few data are available on the effect of HCC treatment receipt in HIV+patients. Our data aim to retrospectively compare survival rates inpatients with and without HIV infection affected by liver cirrhosisand HCC (HCC-LC).Materials and Methods: 65 HIV positive (HIV+) (54 on HAART;34 A1-A3, 17 B1-B3 and 9 C1-C3 stage; 12 with CD4 lowerthan 200) and 267 HIV negative (HIV−) HCC-LC subjects werecompared in terms of survival rates considering age, tumor andliver disease characteristics at the diagnosis (etiology, BCLC stage,number of lesions, vascular invasion, progression), treatment receipt(no treatment, palliative or curative, treatment at the progression),HIV status. All subjects were male and had at least three-months ofdisease follow up.Results: The Table resumes median survival rates according todifferent treatment strategies in the considered groups.Median survival (months) pHIV+ HIV−Overall 31.3±4.91 (n = 65) 59.7±7.07 (n = 267) .010Untreated 4.52±1.83 (n = 6) 36.1±15.2 (n = 48) .000Treated (all treatment) 35.0±11.3 (n = 59) 65.0±7.23 (n = 219) .042Treated (curative) 35.1±11.9 (n = 25) 67.8±14.7 (n = 75) .000Treated (palliative) 31.1±10.2 (n = 34) 53.1±11.1 (n = 144) .052Factors independently related to survival (Cox regression) were:HIVab pos (HR = .567, 95% CI 0.317–0.912, p = 0.046), HCCTreatment (HR = 1.506, 95%–CI 1.154–2.549, p = 0.035), tumor size>5 cm (HR = 1.257, 95% CI 1.106–1.636, p = 0.025) BCLC 0−1(HR = 1.247, 95% CI 1.100–1.576, P = 0.034), such as HAARTtherapy (HR = 2.25, 95% CI 1.01–5.048, p = .048) and treatment atprogression (TaP) (HR = 2.801, 95% CI 1.78–4.56, p = 0.000). HIV−patients had a higher frequency of TaP (88.6% vs. 67.3%, p = 0.001).Conclusions: HIV infection negatively influences HCC outcome,even in treated patients. The role of reduced re-treatment rate in caseof HCC progression in these patients needs be evaluated.


2010 - Hemochromatosis and Hemojuvelin G320V Homozygosity in a Hungarian Woman [Articolo su rivista]
Varkonyi, J; Lueff, S; Szucs, N; Pozsonyi, Z; Toth, A; Karadi, I; Pietrangelo, Antonello
abstract

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2010 - Hepatocellular carcinoma in HIV infected patients: check early, treat hard. [Abstract in Rivista]
E., Garlassi; Ventura, Paolo; M., Beretta; S., Cocchi; B., Cacopardo; C., Stentarelli; P., Di Gangi; Pietrangelo, Antonello; U., Tirelli; Guaraldi, Giovanni
abstract

Hepatocellular carcinoma (HCC) is an emerging problem for HIV patients, particularly if HCV and/or HBV co-infected. The aim of the study was to evaluate the impact of early diagnosis and effective treatment on survival of HIV infected patients with HCC.


2010 - Hepcidin expression does not rescue the iron-poor phenotype of Kupffer cells in Hfe-null mice after liver transplantation. [Articolo su rivista]
Garuti, Cinzia; Tian, Y; Montosi, Giuliana; Sabelli, Manuela; Corradini, Elena; Graf, R; Ventura, Paolo; Vegetti, Alberto; Clavien, Pa; Pietrangelo, Antonello
abstract

BACKGROUND & AIMS: Hemochromatosis is a common hereditary disease caused by mutations in HFE and characterized by increased absorption of iron in the intestine. However, the intestine does not appear to be the site of mutant HFE activity in the disease; we investigated the role of the liver-the source of the iron regulatory hormone hepcidin-in pathogenesis in mice. METHODS: We exchanged livers between Hfe wild-type (+/+) and Hfe null (-/-) mice by orthotopic liver transplantation (OLT) and assessed histopathology, serum and tissue iron parameters, and hepatic hepcidin messenger RNA expression. RESULTS: At 6-8 months after OLT, Hfe(-/-) mice that received Hfe(-/-) livers maintained the hemochromatosis phenotype: iron accumulation in hepatocytes but not Kupffer cells (KC), increased transferrin levels, and low levels of iron in the spleen. Hfe(+/+) mice that received Hfe(-/-) livers had increased levels of iron in serum and liver and low levels of iron in spleen. However, they did not develop the iron-poor KCs that characterize hemochromatosis: KCs appeared iron rich, although hepatic hepcidin expression was low. Transplantation of Hfe(+/+) livers into Hfe(-/-) mice prevented hepatic iron accumulation but did not return spleen and plasma levels of iron to normal; KCs still appeared to be iron poor, despite normal hepcidin expression. CONCLUSIONS: In Hfe(-/-) mice, transplantation of livers from Hfe(+/+) mice reversed the iron-loading phenotype associated with hemochromatosis (regardless of Hfe expression in intestine). However, KCs still had low levels of iron that were not affected by hepatic hepcidin expression. These findings indicate an independent, iron-modifying effect of HFE in KCs.


2010 - Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment [Articolo su rivista]
Pietrangelo, Antonello
abstract

In the late 1800s, hemochromatosis was considered an odd autoptic finding. More than a century later, it was finally recognized as a hereditary, multi-organ disorder associated with a polymorphism that is common among white people: a 845G -> A change in HFE that results in C282Y in the gene product. Hemochromatosis is now a well-defined syndrome characterized by normal iron-driven erythropoiesis and the toxic accumulation of iron in parenchymal cells of liver, heart, and endocrine glands. It can be caused by mutations that affect any of the proteins that limit the entry of iron into the blood. In mice, deletion of the iron hormone hepcidin and any of 8 genes that regulate its biology, including Hfe, transferrin receptor 2 (Tfr2), and hemojuvelin (Hp)) (which all sense the accumulation of iron that hepcidin corrects) or ferroportin (Fpn) (the cellular iron exporter down-regulated by hepcidin), cause iron overload but not organ disease. In humans, loss of TfR2, HJV, and hepcidin itself or FPN mutations result in full-blown hemochromatosis. Unlike these rare instances, in white people, homozygotes for C282Y polymorphism in HFE are numerous, but they are only predisposed to hemochromatosis; complete organ disease develops in a minority, when these individuals abuse alcohol or from other unidentified modifying factors. HFE gene testing can be used to diagnose hemochromatosis, but analyses of liver histology and clinical features are still required to identify patients with rare, non-HFE forms of the disease. The role of hepcidin in the pathogenesis of hemochromatosis reveals its similarities to endocrine diseases such as diabetes and indicates new approaches to diagnosis and management of this common disorder in iron metabolism.


2010 - Huh-7: a human hemochromatotic cell line. [Articolo su rivista]
Vecchi, Chiara; Montosi, Giuliana; Pietrangelo, Antonello
abstract

Hereditary hemochromatosis (HC) is commonly associated with homozygosity for the cysteine-to-tyrosine substitution at position 282 (C282Y) of the HFE protein. This mutation prevents HFE from binding beta(2)-microglobulin (beta(2)M) and reaching the cell surface. We have discovered that a widely used hepatoma cell line, Huh-7, carries a HFE mutation similar to that associated with human HC. By HFE gene sequencing of Huh-7 genomic DNA, we found a TAC nucleotide deletion (c. 691_693del) responsible for loss of a tyrosine at position 231 (p. Y231del) of the HFE protein. This mutation affects a conserved hydrophobic region in a loop connecting two beta strands that make up the alpha3 domain of HFE, not far from the 282 site. HIE was detected by western blot in HepG2 but not in Huh-7 cell membrane fractions. In WRL-68 cells expressing wild-type HIE, the HIE protein was largely found at the plasma membrane where it colocalizes with beta(2)M. On the contrary, the HFE-Y231del mutant, similarly to an exogenously expressed HFE-C282Y mutant, failed to reach the plasma membrane and did not colocalize with membrane-expressed beta(2)M. C282Y mutant HFE in HC is associated with inadequate hepcidin expression. We found that Huh-7 cells display lower hepcidin messenger RNA levels as compared to HepG2 cells, which carry a wild-type HFE. Interestingly, hepcidin messenger RNA levels increased significantly in Huh-7 cells stably expressing exogenous wild-type HFE at the plasma membrane. Conclusion: Huh-7 cells may represent a novel and valuable tool to investigate the role of altered HFE traffic in iron metabolism and pathogenesis of human HIE HC. (HEPATOLOGY 2010;51:654-659.)


2010 - Management of chronic viral hepatitis in patients with thalassemia: recommendations from an international panel. [Articolo su rivista]
Di Marco, V; Capra, M; Angelucci, E; Borgna Pignatti, C; Telfer, P; Harmatz, P; Kattamis, A; Prossamariti, L; Filosa, A; Rund, D; Gamberini, Mr; Cianciulli, P; De Montalembert, M; Gagliardotto, F; Foster, G; Grange, Jd; Cassara, F; Iacono, A; Cappellini, Md; Brittenham, Gm; Prati, D; Pietrangelo, Antonello; Craxi, A; Maggio, A.
abstract

Chelation therapy with new drugs prevents cardiac damage and improves the survival of thalassemia patients. Liver diseases have emerged as a critical clinical issue. Chronic liver diseases play an important role in the prognosis of thalassemia patients because of the high frequency of viral infections and important role of the liver in regulating iron metabolism. Accurate assessment of liver iron overload is required to tailor iron chelation therapy. The diagnosis of hepatitis B virus- or hepatitis C virus- related chronic hepatitis is required to detect patients who have a high risk of developing liver complications and who may benefit by antiviral therapy. Moreover, clinical management of chronic liver disease in thalassemia patients is a team management issue requiring a multidisciplinary approach. The purposes of this paper are to summarize the knowledge on the epidemiology and the risks of transmission of viral infections, to analyze invasive and noninvasive methods for the diagnosis of chronic liver disease, to report the knowledge on clinical course of chronic viral hepatitis, and to suggest the management of antiviral therapy in thalassemia patients with chronic hepatitis B or C virus or cirrhosis.


2010 - Myocardial fibrosis by delayed enhancement cardiovascular magnetic resonance and HCV infection in thalassemia major patients [Articolo su rivista]
Pepe, A.; Meloni, A.; Borsellino, Z.; Dell'Amico, M. C.; Positano, V.; Borgna-Pignatti, C.; Maggio, A.; Restaino, G.; Gagliardotto, F.; Cianciulli, P.; Prossomariti, L.; Filosa, A.; Centra, M.; D'Ascola, D.; Quarta, A.; Peluso, A.; Pietrangelo, A.; Cracolici, E.; Lombardi, M.; Capra, M.
abstract


2010 - The porphyrias: Pathophysiology [Articolo su rivista]
Pietrangelo, A.
abstract

Porphyrias are a group of inherited and acquired metabolic disorders due to a defect in haem biosynthesis. An enzymatic defect at different steps of haem synthesis leads to tissue accumulation and excessive excretion of porphyrins and/or their toxic precursors. The specific patterns of accumulation determine the variety of clinical manifestations, ranging from acute neurovisceral attacks to skin lesions and liver disease. Most enzyme defects represent partial deficiencies, while familial cases are linked to autosomal or recessive traits. The incomplete penetrance of the genetic defects often requires the triggering or aggravating effect of host-related or environmental factors. While genetics has a role in confirming clinical suspicion and in family screening, biochemical and clinical studies are still central in the diagnosis. © 2010 SIMI.


2009 - BMP-6 is a Key Endogenous Regulator of Hepcidin Expression and Iron Metabolism [Articolo su rivista]
ANDRIOPOULOS B., Jr; Corradini, Elena; Xia, Y; Faasse, Sa; Chen, S; Grgurevic, L; Knutson, Md; Pietrangelo, Antonello; Vukicevic, S; Lin, Hy; Babitt, Jl
abstract

Juvenile hemochromatosis is an iron-overload disorder caused by mutations in the genes encoding the major iron regulatory hormone hepcidin ( HAMP) 1 and hemojuvelin (HFE2)(2). We have previously shown that hemojuvelin is a co-receptor for bone morphogenetic proteins (BMPs) and that BMP signals regulate hepcidin expression and iron metabolism(3,4). However, the endogenous BMP regulator(s) of hepcidin in vivo is unknown. Here we show that compared with soluble hemojuvelin (HJV.Fc), the homologous DRAGON.Fc is a more potent inhibitor of BMP2 or BMP4 but a less potent inhibitor of BMP6 in vitro. In vivo, HJV.Fc or a neutralizing antibody to BMP6 inhibits hepcidin expression and increases serum iron, whereas DRAGON.Fc has no effect. Notably, Bmp6-null mice have a phenotype resembling hereditary hemochromatosis, with reduced hepcidin expression and tissue iron overload. Finally, we demonstrate a physical interaction between HJV.Fc and BMP6, and we show that BMP6 increases hepcidin expression and reduces serum iron in mice. These data support a key role for BMP6 as a ligand for hemojuvelin and an endogenous regulator of hepcidin expression and iron metabolism in vivo.


2009 - Bone Morphogenetic Protein Signaling Is Impaired in an Hfe Knockout Mouse Model of Hemochromatosis. [Articolo su rivista]
Corradini, Elena; Garuti, Cinzia; Montosi, Giuliana; Ventura, Paolo; Andriopoulos, B; Lin, Hy; Pietrangelo, Antonello; Babitt, Jl
abstract

Mutations in HFE are the most common cause of the iron-overload disorder hereditary hemochromatosis. Levels of the main iron regulatory hormone, hepcidin, are inappropriately low in hereditary hemochromatosis mouse models and patients with HFE mutations, indicating that HFE regulates hepcidin. The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is an important endogenous regulator of hepcidin expression. We investigated whether HFE is involved in BMP6-SMAD regulation of hepcidin expression. METHODS: The BMP6-SMAD pathway was examined in Hfe knockout (KO) mice and in wild-type (WT) mice as controls. Mice were placed on diets of varying iron content. Hepcidin induction by BMP6 was examined in primary hepatocytes from Hfe KO mice; data were compared with those of WT mice. RESULTS: Liver levels of Bmp6 messenger RNA (mRNA) were higher in Hfe KO mice; these were appropriate for the increased hepatic levels of iron in these mice, compared with WT mice. However, levels of hepatic phosphorylated Smad 1/5/8 protein (an intracellular mediator of Bmp6 signaling) and Id1 mRNA (a target gene of Bmp6) were inappropriately low for the body iron burden and Bmp6 mRNA levels in Hfe KO, compared with WT mice. BMP6 induction of hepcidin expression was reduced in Hfe KO hepatocytes compared with WT hepatocytes. CONCLUSIONS: HFE is not involved in regulation of BMP6 by iron, but does regulate the downstream signals of BMP6 that are triggered by iron.


2009 - Clinical Questions in Iron Overload [Capitolo/Saggio]
Pietrangelo, A.; Magrini, N.; Lottenberg, R.
abstract


2009 - ER stress controls iron metabolism through induction of hepcidin. [Articolo su rivista]
Vecchi, Chiara; Montosi, Giuliana; K., Zhang; Lamberti, Igor; S. A., Duncan; R. J., Kaufman; Pietrangelo, Antonello
abstract

Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin overproduction causes anemia of inflammation, whereas its deficiency leads to hemochromatosis. Inflammation and iron are known extracellular stimuli for hepcidin expression. We found that endoplasmic reticulum (ER) stress also induces hepcidin expression and causes hypoferremia and spleen iron sequestration in mice. CREBH (cyclic AMP response element-binding protein H), an ER stress-activated transcription factor, binds to and transactivates the hepcidin promoter. Hepcidin induction in response to exogenously administered toxins or accumulation of unfolded protein in the ER is defective in CREBH knockout mice, indicating a role for CREBH in ER stress-regulated hepcidin expression. The regulation of hepcidin by ER stress links the intracellular response involved in protein quality control to innate immunity and iron homeostasis.


2009 - Fattori di rischio: malattie genetico-metaboliche. [Capitolo/Saggio]
Tremosini, Silvia; Pietrangelo, Antonello
abstract

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2009 - Inherited metabolic disease of the liver. [Articolo su rivista]
Pietrangelo, Antonello
abstract

Progress in the dissection of the molecular pathogenesis of most prevalent inherited liver diseases such as hereditary hemochromatosis, Wilson's disease, and alpha-1-antitrypsin deficiency is continuing. This review highlights recent achievements that have clarified defective molecular pathways and shed new lights on the complex interplay of genetic and environmental factors in determining disease phenotype. This advancement paves the way for development of new strategies to diagnose and cure metabolic liver diseases.Recent findingHepcidin, the iron hormone that is defective in hemochromatosis, is controlled not only by iron signals but also by a number of circulatory and membrane-associated regulators. Serum and urinary hepcidin can be now measured. New studies have provided important information on variable clinical expressivity of the genetic defect in hemochromatosis. The molecular and cellular events that accompany Wilson's disease and alpha-1-antitrypsin deficiency are being elucidated. In both, an unexpected pathogenic link with early metabolic abnormality in lipid or glycogen metabolism has emerged. Interference with apoptotic pathways may offer new therapeutic tools to prevent liver disease progression and acute liver failure associated with inherited metabolic diseases of the liver.SummaryThe field of inherited diseases of the liver is rapidly evolving. Understanding molecular pathogenesis of these disorders is improving our ability to diagnose and treat them. The most recent findings are detailed in this review.


2009 - Iron in NASH, chronic liver diseases and HCC: How much iron is too much? [Articolo su rivista]
Pietrangelo, Antonello
abstract

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2009 - Keratin variants are overrepresented in primary biliary cirrhosis and associate with disease severity. [Articolo su rivista]
Zhong, B; Strnad, P; Selmi, C; Invernizzi, P; Tao, Gz; Caleffi, A; Chen, M; Bianchi, I; Podda, M; Pietrangelo, Antonello; Gershwin, Me; Omary, M. B.
abstract

Keratins (K) 8 and 18 variants predispose carriers to the development of end-stage liver disease and patients with chronic hepatitis C to disease progression. Hepatocytes express K8/K18, whereas biliary epithelia express K8/K18/K19. K8-null mice, which are predisposed to liver injury, spontaneously develop anti-mitochondrial antibodies (AMA) and have altered hepatocyte mitochondrial size and function. There is no known association of K19 with human disease and no known association of K8/K18/K19 with human autoimmune liver disease. We tested the hypothesis that K8/K18/K19 variants associate with primary biliary cirrhosis (PBC), an autoimmune cholestatic liver disease characterized by the presence of serum AMA. In doing so, we analyzed the entire exonic regions of K8/K18/K19 in 201 Italian patients and 200 control blood bank donors. Five disease-associated keratin heterozygous variants were identified in patients versus controls (K8 G62C/R341H/V380I, K18 R411H, and K19 G17S). Four variants were novel and included K19 G17S/V229M/N184N and K18 R411H. Overall, heterozygous disease-associated keratin variants were found in 17 of 201 (8.5%) PBC patients and 4 of 200 (2%) blood bank donors (P < 0.004, odds ratio = 4.53, 95% confidence interval = 1.5-13.7). Of the K19 variants, K19 G17S was found in three patients but not in controls and all K8 R341H (eight patients and three controls) associated with concurrent presence of the previously described intronic K8 IVS7+10delC deletion. Notably, keratin variants associated with disease severity (12.4% variants in Ludwig stage III/IV versus 4.2% in stages I/II; P < 0.04, odds ratio = 3.25, 95% confidence interval = 1.02-10.40), but not with the presence of AMA. CONCLUSION: K8/K18/K19 variants are overrepresented in Italian PBC patients and associate with liver disease progression. Therefore, we hypothesize that K8/K18/K19 variants may serve as genetic modifiers in PBC.


2009 - MTHFR C677T polymorhism and hyperhomocysteinemia in patients with liver cirrhosis complicated by portal vein thrombosis and hepatocellular carcinoma [Abstract in Rivista]
Nascimbeni, Fabio; Ventura, Paolo; Moriondo, Valeria; Marchini, Stefano; M. C., Rosa; Ferrari, Mariachiara; G., Abbati; Romagnoli, Elisa; Pietrangelo, Antonello
abstract

BACKGROUND: Mild hyperhomocysteinemia (HHcy) is an independent risk factor for deep vein thrombosis; the liver plays a key role in homocysteine (Hcy) metabolism, being the sole tissue provided with the whole enzymatic set of transsulfuration and remethylation pathways; the liver has also a key-role in storage and metabolism of vitamins needed as cofactor in sulphur aminocid metabolism. Among different determinants of HHcy, the methylen-tetrahydrofolate reductase (MTHFR) C677T polymorphism has an high prevalence in general population (the homozygous state (TT) have been estimated in about 18% of italians). MTHFR gene anomalies have been also involved in cancer development, through a mechanism involving the impairment of folate metabolism and hence inducing alterations in DNA repair and methylation. Liver cirrhosis (LC) is by far the most important risk factor of portal vein thrombosis (PVT) especially if complicated by hepatocellular carcinoma (HCC). AIM: Considering the complex interaction between HHcy, MTHFR status and liver function impairment , aim of our study was to investigate a possible relation between HHcy, MTHFR status, HCC and PVT in patients with liver cirrhosisMATERIALS and METHODS: To these purposes, we have studied 86 patients (35 f, mean age 65±10 years) affected by LC, 53 without portal thrombosis (LC group) and 33 with portal thrombosis (doppler ultrasonography, angio-CT or angiography dcumented) (PVT group) . Patients in the two groups were age- ,Child Pugh score- , etiology- and sex–matched. All patients were assessed for plasma homocysteine (HPLC) , MTHFR C677T and vitamin (reb blood cell folate, serum B12 and B6) status. RESULTS: The table resumes the results regarding HCC presence and homocysteine parameters in the two studied groups.PVT (n=33)LC (n=53)pOR (95% CI)HCC presence (y/n)21/12 (63.6 %)12/41 (22.6%).0073.26 (1.31÷8.12)Mean plasma Hcy16.4 ± 6.112.1 ± 6.1.0151.07 (1.01÷1.15)HHcy prevalence (y/n)§21/12 (63.6%)15/38 (28.3%).0023.08 (1.61÷7.41)MTHFR status (CC/CT/TT)8/12/1335/14/4.001* .013***TT prevalence; **CT plus TT status vs. CC prevalence; §= >15 nmol/mlNo significant differences in vitamin status (red blood cell folate, and serum B12 and B6) were observed between groups. Patients with HCC (n=33) showed significant higher levels of plasma Hcy (17.7±5.9 vs. 13.5±5.8, p.039) and significant higher prevalence of HHcy (19/33, 57.5% vs.17/53, 32.1%, p=.025, OR 1.79, 95% CI 1.12÷2.99) than patients without HCC(n=53). Patients with HCC had also a significant higher prevalence of MTHFR TT status (10/33, 30.3% vs. 7/53, 13.2 %, p=.044, OR 2.67, 95% CI 1.07÷6.67). Interestingly, all patients with MTHFR TT status had HHcy and all patients MTHFR TT and HCC had PVT.CONCLUSION: Mild HHcy associated to liver cirrhosis may play a possible role for PVT development. Even if confirmations by larger and prospective studies are needed, assessment of homocysteine (simple and cheap) may be suggested in patients with liver cirrhosis (especially in case of advanced liver disease or in the presence of HCC).Our data concerning the association between HCC and MTHFR TT status is intriguing, due the postulated role for this polymorphism in cancerogenesis: it may represent a further link between HCC and PVT


2009 - Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C [Articolo su rivista]
F., Ferrara; Ventura, Paolo; Vegetti, Alberto; M., Guido; G., Abbati; Corradini, Elena; G., Fattovich; C., Ferrari; M., Tagliazucchi; A., Carbonieri; A., Orlandini; S., Fagiuoli; S., Boninsegna; E., Minola; G., Rizzo; F., Belussi; M., Felder; M., Massari; G., Pozzato; S., Bonetto; P., Rovere; C., Sardini; A., Borghi; M. L., Zeneroli; P., Toniutto; E., Rossi; Pietrangelo, Antonello
abstract

OBJECTIVES: Antiviral treatment in chronic hepatitis C (CHC) involves ribavirin, a hemolytic agent. We planned a prospective study to evaluate whether drug-induced iron perturbation is clinically relevant as it relates to therapeutic outcome. METHODS: Iron variables were sequentially assessed in 206 CHC patients undergoing antiviral therapy and were correlated with pretreatment iron status and histology, hemolysis, and therapeutic outcome. RESULTS: At week 1 of therapy, serum iron (SI), transferrin saturation (TS), and serum ferritin (SF) increased markedly in all patients. All iron parameters correlated with hemolysis up to week 4; this correlation was lost for SF at later time points. SF rise during treatment was inversely related to baseline SF and iron deposits in hepatic mesenchymal/Kupffer cells. Both baseline SF and mesenchymal iron significantly correlated with fibrosis at multivariate analysis (P=0.015 and 0.008, respectively). Interestingly, baseline SF, despite good specificity (89%), had low sensitivity in predicting siderosis (25%). During therapy, SI, TS, and hemolysis parameters did not correlate with sustained virological response (SVR), whereas SF rise became an independent predictor of therapeutic response: a 2.5-fold increase of SF at week 12 associated with higher likelihood of SVR (odds ratio 1.91, P=0.032). Accordingly, lack of mesenchymal iron deposits at the baseline biopsy correlated with SVR (odds ratio 3.02, P=0.043). CONCLUSIONS: In CHC, SF is a useful marker for assessing disease duration and progression before starting treatment and for predicting therapeutic response while on therapy. SF rise during antiviral therapy is largely independent of hemolysis and likely indicates activation of macrophages in response to antivirals.


2009 - Terapia antialadosteronica e prevenzione della cardiomiopatia cirrotica [Abstract in Rivista]
Ferrari, Mariachiara; Ventura, Paolo; A., Nuzzo; Nascimbeni, Fabio; Romagnoli, Elisa; Vegetti, Alberto; Rossi, Rosario; Moriondo, Valeria; Marchini, Stefano; Modena, Maria Grazia; Pietrangelo, Antonello
abstract

BACKGROUND: La “cardiomiopatia cirrotica” [CC] comprende una serie di alterazioni funzionali (disfunzione sistolica ma soprattutto diastolica; presenza di alterazioni strutturali e morfologiche a carico degli atri e dei ventricoli; allungamento del tratto QT all’elettrocardiogramma; presenza di markers sierici suggestivi di sofferenza e/o fibrosi cardiaca) che si instaurano a livello miocardico col progredire della malattia epatica. Poiché la CC è indipendente dall’eziologia dell’epatopatia, diversi fattori bioumorali cirrosi-associati sono stati considerati responsabili del suo sviluppo.SCOPO DEL LAVORO: (1) valutare la prevalenza di CC nei pazienti ricoverati presso un centro epatologico specialistico (2) valutare il grado di correlazione e importanza relativa dei vari fattori bioumorali CC-associati (3) costruire un algoritmo predittivo della presenza di coinvolgimento miocardico nel paziente con cirrosi.MATERIALI E METODI : Abbiamo studiato 50 pazienti (17 donne, età media 65 ± 9 anni) affetti da cirrosi epatica. Abbiamo escluso dallo studio pazienti affetti da cirrosi con storia o evidenza clinica di cardiopatia, pneumopatia, anemia grave, o altra patologia sistemica infiammatoria. Lo studio ha incluso anche un secondo gruppo di 17 pazienti (6 donne, età media 63 ± 7 anni) affetti da epatite cronica attiva (ECA) non cirrotica (biopsia con stadio ISHAK ≤ 4) non in trattamento attivo con terapia antivirale (interferone e/o antivirali) al momento dell’inclusione nello studio e senza storia clinica di cardiopatia, pneumopatia o altra patologia sistemica infiammatoria. Tutti i pazienti arruolati sono stati sottoposti a (1) determinazione della pressione arteriosa (2) ECG per valutazione del QT e QT corretto; (3) valutazione dello stadio di malattia (score Child-Pugh Turcotte e MELD); (4) determinazione dei livelli plasmatici di diverse sostanze coinvolte nella patogenesi della CC e/o considerate come marcatori bioumorali di insufficienza cardiaca [Fattori natriuretici (ANF e BNF), Epinefrina (E), Norepinefrina (NE), attività reninica plasmatica (PRA), Aldosterone (A), Ossido nitrico (NO), Interleuchina 6 (IL-6) e Tumor necrosis factor alfa (TNF-)]; (5) determinazione plasmatica di indici diretti [determinazione del pro peptide n-terminale del pro collagene di tipo III (PIIINP)] e indiretti di fibrosi (score non invasivi di fibrosi APRI, 4-parametrs e Fibroscore). (6) anamnesi farmacologica. Tutti i pazienti sono inoltre stati sottoposti a ecocardiogramma mono e bidimensionale per la determinazione degli indici di funzionalità sistolica e diastolica [FE, Ea, TAPSE, E/A ratio, Deceleration time (DT)].RISULTATI : La prevalenza di deficit diastolico nella nostra popolazione di cirrotici è risultata elevata (il 50% dei pazienti con cirrosi epatica presenta un E/A ratio patologico e il 62% presenta un DT patologico); per entrambi i parametri la prevalenza tende ad aumentare col peggiorare dello stadio di malattia (il 100% dei soggetti in Child C hanno un E/A ratio patologico e il 92% dei pazienti un DT patologico). QT allungato era presente in 19 pazienti con cirrosi epatica (38%) rispetto a 1/16 soggetti con ECA (6.25%) (p<.001). All’analisi univariata gli indici di funzione diastolica (DT e E/A ratio) apparivano significativamente correlati coi livelli di NO r=.414, p=.000 e r=.395, p=.001), TNF-alfa r=-514, p=.000, r=.481, p=.000) , NE r=-.615, p=.000, r=.-569, p=.000), E(r= -.605, p=.000, r= -.569,p=.000) Aldosterone (r= -.476,p=.000; r=.587, p=.000) PRA, (r= -.512, p= .012; r=-656, p=.001), ANP (r= - 521, p=.000; r=.560, p=.000) e BNP (r=-574, p=.001; r=669, p=.000); apparivano inoltre entrambi correlati agli indici di fibrosi diretti (PIIINP) (r=-546, p=.000; r=.524, p=.000) e al punteggio ottenuto con gli scores Fibroscore (r=-.490, p=.000) e 4-parameters (r= - .490, p=.000; r= .583, p=.002). Abbiamo osservato una associazione significativa fra presenza di QT lungo e pun


2009 - The impact of inherited thrombophilia on liver transplantation. [Articolo su rivista]
Spaggiari, Mario; DI BENEDETTO, Fabrizio; Masetti, Michele; Ballarin, Roberto; Romano, Antonio; Pietrangelo, Antonello; Gerunda, Giorgio Enrico
abstract

No abstract available


2008 - G80S-linked ferroportin disease: The first clinical description in a Greek family [Articolo su rivista]
Mougiou, A.; Kourakli, A.; Karakantza, M.; Zoumbos, N.; Pietrangelo, Antonello; Caleffi, A. .
abstract

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2008 - Haemochromatosis [Capitolo/Saggio]
Pietrangelo, A.
abstract


2008 - Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription [Articolo su rivista]
Nishina, S.; Hino, K.; Korenaga, M.; Vecchi, Chiara; Pietrangelo, Antonello; Mizukami, Y.; Furutani, T.; Sakai, A.; Okuda, M.; Hidaka, I.; Okita, K.; Sakaida, I.
abstract

Background & Aims: Despite abundant clinical evidence, the mechanisms by which hepatic iron overload develops in patients with hepatitis C virus (HCV)-associated chronic liver disease remain unknown. The aim of this study was to investigate how hepatic iron overload develops in the presence of HCV proteins. Methods: Male transgenic mice expressing the HCV polyprotein and nontransgenic control mice (C57BL/6) were assessed for iron concentrations in the liver, spleen, and serum and iron regulatory molecules in vivo and ex vivo. Results: Transgenic mice had increased hepatic and serum iron concentrations, decreased splenic iron concentration, and lower hepcidin expression in the liver accompanied by higher expression of ferroportin in the duodenum, spleen, and liver. In response to hepatocellular iron excess, transferrin receptor 1 expression decreased and ferritin expression increased in the transgenic liver. Transgenic mice showed no inflammation in the liver but preserved the ability to induce hepcidin in response to proinflammatory cytokines induced by lipopolysaccharide. Hepcidin promoter activity and the DNA binding activity of CCAAT/enhancer-binding protein alpha (C/EBP) were down-regulated concomitant with increased expression of C/EBP homology protein, an inhibitor of C/EBP DNA binding activity, and with increased levels of reactive oxygen species in transgenic mice at the ages of 8 and 14 months. Conclusions: HCV-induced reactive oxygen species may down-regulate hepcidin transcription through inhibition of C/EBP alpha DNA binding activity by C/EBP homology protein, which in turn leads to increased duodenal iron transport and macrophage iron release, causing hepatic iron accumulation.


2007 - American Journal of Hematology: Introduction [Articolo su rivista]
Pietrangelo, A.
abstract


2007 - Antiviral treatment profoundly affects iron status in HCV patients: Implications for management and treatment outcome [Abstract in Atti di Convegno]
Ferrara, F; Guido, M; Ventura, Paolo; Vegetti, A; Abbati, G; Corradmi, E; Ferrari, C; Fattovich, G; Pietrangelo, Antonello
abstract

No abstract available


2007 - Design of an ongoing phase I/II open-label, dose-escalation trial using the oral chelator deferasirox to treat iron overload in HFE-Related hereditary hemochromatosis (HH) [Abstract in Atti di Convegno]
Pietrangelo, Antonello; Brissot, P; Bonkovsky, H; Niederau, C; Rojkjaer, L; Weitzman, R; Bodner, J; Bailey, S; Phatak, Pd
abstract

no abstract available


2007 - Disease progression and liver cancer in the ferroportin disease [Articolo su rivista]
Corradini, Elena; Ferrara, F; Pollicino, T; Vegetti, Alberto; Abbati, Gl; Losi, L; Raimondo, G; Pietrangelo, Antonello
abstract

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2007 - Effect of anti-osteoarthritic drugs on interleukin 1-dependent activation of NF-kappa B in human chondrocytes [Abstract in Atti di Convegno]
S., Barelli; Garuti, Cinzia; Montosi, Giuliana; Pietrangelo, Antonello
abstract

No abstract available


2007 - Genetics in liver diseases [Articolo su rivista]
Pietrangelo, Antonello; OUDE ELFERINK, R; Prieto, J; Bacon, Br
abstract

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2007 - Hemochromatosis: an endocrine liver disease. [Articolo su rivista]
Pietrangelo, Antonello
abstract

This review acknowledges the recent and dramatic advancement in the field of hemochromatosis and highlights the surprising analogies with a prototypic endocrine disease, diabetes. The term hemochromatosis should refer to a unique clinicopathologic subset of iron-overload syndromes that currently includes the disorder related to the C282Y homozygote mutation of the hemochromatosis protein HFE (by far the most common form of hemochromatosis) and the rare disorders more recently attributed to the loss of transferrin receptor 2, HAMP (hepcidin antimicrobial peptide), or hemojuvelin or to certain ferroportin mutations. The defining characteristic of this subset is failure to prevent unneeded iron from entering the circulatory pool as a result of genetic changes compromising the synthesis or activity of hepcidin, the iron hormone. Like diabetes, hemochromatosis results from the complex, nonlinear interaction between genetic and acquired factors. Depending on the underlying mutation, the coinheritance of modifier genes, the presence of nongenetic hepcidin inhibitors, and other host-related factors, the clinical manifestation may vary from simple biochemical abnormalities to severe multiorgan disease. The recognition of the endocrine nature of hemochromatosis suggests intriguing possibilities for new and more effective approaches to diagnosis and treatment.


2007 - Hepatitis C virus-induced reactive oxygen species cause iron accumulation in mice by reducing hepcidin transcription [Abstract in Atti di Convegno]
Nishina, S; Hino, K; Korenaga, M; Pietrangelo, Antonello; Mizukami, Y; Furutani, T; Okuda, M; Hidaka, I; Okita, K; Sakaida, I.
abstract

No abstract available


2007 - Hereditary Hemochromatosis [Capitolo/Saggio]
Corradini, Elena; Ferrara, Francesca; Pietrangelo, Antonello
abstract

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2007 - Iron chelation beyond transfusion iron overload [Articolo su rivista]
Pietrangelo, Antonello
abstract

The effects of systemic iron overload in hereditary (e.g., classic HFE hemochromatosis) or acquired disorders (e.g., transfusion-dependent iron overload) are well known. Several other iron overload diseases, with an observed mild-to-moderate increase in iron in selected organs (e.g., the liver or the brain), or with ``misdistribution{''} of iron within cells (e.g., reticuloendothelial cells) or subcellular organelles (e.g., mitochondria), have been recognized more recently. The deleterious impact of any excess iron may be high as active redox iron may directly contribute to cell damage or affect signaling pathways involved in cell necrosis-apoptosis or organ fibrosis and cancer. This article discusses the potential use of iron chelation therapy to treat iron overload from causes other than transfusion overload.}


2007 - STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo [Articolo su rivista]
Pietrangelo, Antonello; U., Dierssen; L., Valli; Garuti, Cinzia; A., Rump; Corradini, Elena; M., Ernst; C., Klein; C., Trautwein
abstract

BBackground &amp; Aims: Hepcidin is a peptide hormone that is central to the regulation of iron homeostasis. In response to interleukin 6 (IL-6), hepatocytes produce hepcidin that decreases iron release/transfer from enterocytes and macrophages and causes hypoferremia. To clarify the molecular pathways involved in hepcidin activation by IL-6, we used different mice strains in which the main IL-6/gp130 signaling pathways have been genetically disrupted. Methods: We generated mice with hepatocyte-specific deletion of the IL-6 signaltransducing gp130 receptor (alfgp130 (LoxP/LoxP)), with a gp130 receptor lacking the essential region for STAT1 and -3 activation (alrpCre gp130(Delta STAT/LoxP)) or mice expressing a gp130 allele lacking the essential tyrosine for RAS-MAPK activation (alfpCregp130(Y757F/LoxP)). We studied gp130-dependent pathways and hepcidin mRNA expression by Western blot, reverse-transcription polymerase chain reaction, and Northern blot in vivo and ex vivo. Results: IL-6 stimulated phospho STAT3, serum amyloid A (SAA), and suppressor of cytokine signaling 3 (SOCS3) expression in livers of mild-type and alfpCregp130(Y757F/LoxP) mice, whereas this response was blocked in alfpCre gp130(LoxP/LoxP) and alfpCre gp130(Delta STAT/LoxP) mice. In wild-type and alfpCregP130(Y757F/LoxP) animals, significantly higher hepcidin mRNA expression was found 3 to 6 hours after IL-6 stimulation. In contrast, no IL-6-dependent regulation of hepcidin mRNA expression was found in alfpgp130(Delta STAT/LoxP) and AlfpCre gp130 (LoxP.LoxP) animals. In primary hepatocytes, higher hepcidin mRNA expression after IL-6 stimulation was only observed when gp130-STAT3-dependent signaling was intact. Conclusions: We have demonstrated that both in vivo and in vitro STAT3 is the key transcription factor responsible


2007 - The penetrance of hemochromatosis: mice to the rescue. [Articolo su rivista]
Pietrangelo, Antonello
abstract

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2006 - Ferroportin is a monomer in vivo in mice [Articolo su rivista]
Pignatti, Elisa; L., Mascheroni; M., Sabelli; S., Barelli; S., Biffo; Pietrangelo, Antonello
abstract

Ferroportin (FPN) is the main iron export protein in mammals. The actual structure of FPN in vivo and the pathogenesis of ferroportin-related disease are unknown. We aimed at studying the structure and biochemical properties of FPN in mouse tissues that are key for iron homeostasis during various iron manipulations in vivo. We performed glycosylation and oligomerization studies in spleen and liver extracts from mice fed a standard, iron-deprived or iron-enriched diet for 5 months. Purification by affinity chromatography and sucrose gradient show that FPN is not part of a large multiprotein complex. Dietary manipulations did not affect the monomeric status of the native or denatured protein. The glycosylation studies showed that ferroportin is digested by peptide: N-glycosidase F but not by endoglycosidase H. The same results were obtained using protein extracts from iron-deficient or iron-loaded mice. In conclusion, our studies indicate that mouse FPN, regardless of the tissue iron status, is glycosylated but not enriched in mannose residues, and that exists mainly in monomeric form. The latter finding may have important implications for understanding the pathogenesis of the disease due to ferroportin mutations.


2006 - Hereditary Haemochromatosis: the genes and the disease. [Relazione in Atti di Convegno]
Corradini, Elena; F., Ferrara; Pietrangelo, Antonello
abstract

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2006 - Hereditary hemochromatosis [Articolo su rivista]
Pietrangelo, Antonello
abstract

In recent years, the number of proteins implicated in iron homeostasis has increased dramatically, and genetic causes have apparently been identified for the major disorders associated with tissue iron overload. These dramatic steps forward have transformed the way we look at iron-related disorders, particularly hemochromatosis. This review presents a concept of this disease that is based on this new knowledge and stems from the idea that, beyond their genetic diversities, all known hemochromatoses originate from the same metabolic error, the genetic disruption of human tendency for circulatory iron constancy. Hepcidin, the iron hormone, seems to hold a central pathogenic place in hemochromatosis, similar to insulin in diabetes: Genetically determined lack of hepcidin synthesis or activity may cause the disease.


2006 - Hereditary hemochromatosis [Articolo su rivista]
Pietrangelo, Antonello
abstract

The advent of the genetics era has profoundly changed the way we look at iron related diseases, particularly hemochromatosis. New discoveries have challenged historical concepts about the disease, such as its monogenic nature, intestinal origin or complete phenotypic penetrance. This review presents a new concept of hemochromatosis which stems from the idea that, beyond their genetic diversities, all known hemochromatoses have in common the same metabolic abnormality: the genetically determined failure to prevent unneeded iron from entering the circulatory pool. Inappropriate levels of hepcidin, the iron hormone, appear now as the central pathogenic event in all forms of hemochromatosis: depending on the protein involved, and its effect on hepatic production of hepcidin, the phenotype varies, ranging from massive early-onset iron loading with severe organ disease (e.g., associated with homozygous mutations of hemojuvelin or hepcidin itself) to the milder late-onset phenotype characterizing the classic and highly prevalent HFE-related form or the rare transferrin receptor 2-related form. In vitro and in vivo studies will be needed to dissect the consequences of each hereditary hemochromatosis allele and increase our understanding of the precise contribution of each gene to the hereditary hemochromatosis phenotype. (c) 2006 Elsevier B.V. All rights reserved.


2006 - Hereditary hemochromatosis. [Capitolo/Saggio]
F., Ferrara; Corradini, Elena; Pietrangelo, Antonello
abstract

Iron is a major component of the Earth’s crust, but its own chemistry greatly limits utilization and also sets the basis for its toxicity. Hereditary hemochromatosis (HH) is the most common cause of iron overload in humans. For much of the twentieth century, HH was regarded as a monogenic disorder characterized by excess tissue deposits of iron inevitably producing organ damage. This view has been shattered by the identification of similar phenotypes associated with mutations of at least four different ironmetabolism genes (HFE, TfR2, HAMP, HJV) and the increasing appreciation of the disease’s multifactorial nature.


2006 - Juvenile hemochromatosis. [Articolo su rivista]
Pietrangelo, Antonello
abstract

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2006 - Magnetic resonance imaging to identify classic and nonclassic forms of ferroportin disease [Articolo su rivista]
Pietrangelo, Antonello; Corradini, Elena; Ferrara, F; Vegetti, Alberto; De Jong, G; Abbati, Gl; Arcuri, Pp; Martinelli, S; Cerofolini, E.
abstract

The ferroportin-related disorder is an increasingly recognized cause of hereditary iron overload. Based on the in vitro behavior of different ferroportin mutant subsets, it was suggested that different forms of the disorder might exist in humans. We used MRI to address this question in vivo in 22 patients from four different pedigrees carrying different ferroportin mutations: A77D, N144H, G80S and Val 162del. We found that, based on the iron status of spleen and bone macrophages, two different forms of the disease can be identified: a classic, common form, characterized by hepatocyte, splenic macrophage and bone marrow macrophage iron retention in patients carrying the A77D, G80S and Val 162del ferroportin variants; a rarer non-classic form, associated with liver iron overload but normal spleen and bone marrow iron content in patients with the N144H mutation. The two forms are likely caused by lack- or gain-of-protein function, respectively. Interestingly, in treated patients with the classic form, the spleen and the spine show appreciable iron accumulation even when serum ferritin is normal and liver iron content low. In conclusion, MRI is a useful non-invasive diagnostic tool to categorize and diagnose the disorder, monitor the status of iron depletion and gain insights on its natural history and management. (c) 2006 Elsevier Inc. All rights reserved.


2006 - Molecular and clinical correlates in iron overload associated with mutations in ferroportin [Articolo su rivista]
De Domenico, I.; Ward, D. M.; Nemeth, E.; Ganz, T.; Corradini, Elena; Ferrara, F.; Musci, G.; Pietrangelo, Antonello; Kaplan, J.
abstract

Mutations in ferroportin (Fpn) result in iron overload. We correlate the behavior of three Fpn mutants in vitro with patients' phenotypes. Patients with Fpn mutations A77D or N174I showed macrophage iron loading. In cultured cells, FpnA77D did not reach the cell surface and cells did not export iron. Fpn mutant N1741 showed plasma membrane and intracellular localization, and did not transport iron. Fpn mutation G80S was targeted to the cell surface and was transport competent, however patients showed macrophage iron. We suggest that FpnG80S represents a class of Fpn mutants whose behavior in vitro does not explain the patients' phenotype.


2006 - Molecular insights into the pathogenesis of hereditary haemochromatosis [Articolo su rivista]
Pietrangelo, Antonello
abstract

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2005 - HJV gene mutations in European patients with juvenile hemochromatosis [Articolo su rivista]
Sg, Gehrke; Pietrangelo, Antonello; M., Kascak; A., Braner; M., Eisold; H., Kulaksiz; T., Herrmann; U., Hebling; K., Bents; R., Gugler; W., Stremmel
abstract

A large variety of mutations within the genes encoding hepcidin (HAMP) and hemojuvelin (HJV) have been identified in patients with the severe iron overload disorder juvenile hemochromatosis (JH). The aim of the present study was to evaluate the molecular background of JH in patients from central parts of Europe. Sequence analyses of HAMP and HJV were performed in seven JH patients from six families from Germany, Slovakia, and Croatia. For detection of the G320V mutation in HJV, a rapid polymerase chain reaction-based assay was developed. No mutations were found within the HAMP gene. Six of seven (86%) JH patients carried at least one copy of the G320V mutation within the HJV gene. Four of these patients were homozygous for the G320V mutation. In addition, two novel HJV mutations were identified (C119F and S328fsX337). Taken together, the present study demonstrates that molecular analysis of the HJV gene is a powerful tool for an early and reliable diagnosis of JH. As in affected patients from Greece, the G320V mutation seems to be widely distributed among JH patients from central parts of Europe. Therefore, detection of the G320V mutation could identify the majority of JH cases from these regions non-invasively.


2005 - Haptoglobin modifies the hemochromatosis phenotype in mice [Articolo su rivista]
E., Tolosano; S., Fagoonee; Garuti, Cinzia; L., Valli; N. C., Andrews; F., Altruda; Pietrangelo, Antonello
abstract

Classic hereditary hemochromatosis (HH) is a common genetic disorder of iron metabolism caused by a mutation in the HFE gene. Whereas the prevalence of the mutation is very high, the clinical penetrance of the disease is low, suggesting that the HFE mutation is a necessary but not sufficient cause of clinical HH. Several candidate modifier genes have been proposed in mice and humans, including haptoglobin. Haptoglobin is the plasma protein with the highest binding affinity for hemoglobin. It delivers free plasma hemoglobin to the reticuloendothelial system, thus reducing loss of hemoglobin through the glomerull and allowing heme-iron recycling. To gain insight into the role of haptoglobin as a modifier gene in HH, we used Hfe and haptoglobin double-null mice. Here, we show that Hfe and haptoglobin compound mutant mice accumulate significantly less hepatic iron than Hfe-null mice, thus demonstrating that haptoglobin-mediated heme-iron recovery may contribute significantly to iron loading in HH.


2005 - Hemochromatosis [Capitolo/Saggio]
Pietrangelo, Antonello
abstract

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2005 - Impaired iron transport activity of ferroportin 1 in hereditary iron overload [Articolo su rivista]
Ja, Mcgregor; M., Shayeghi; Cd, Vulpe; Gj, Anderson; Pietrangelo, Antonello; Rj, Simpson; At, Mckie
abstract

To investigate the functional significance of mutations in Ferroportin that cause hereditary iron overload, we directly measured the iron efflux activity of the proteins expressed in Xenopus oocytes. We found that wild type and mutant Ferroportin molecules (A77D, N144H Q248H and V162 Delta) were all expressed at the plasma membrane at similar levels. All mutations caused significant reductions in Fe-59 efflux compared to wild type but all retained some residual transport activity. A77D had the strongest effect on Fe-59 efflux (remaining activity 9% of wildtype control), whereas the N144H mutation retained the highest efflux activity (42% of control). The Q248H and V162 Delta mutations were intermediate between these values. Co-injection of mutant and wildtype mRNAs revealed that the A77D and N144H mutations had a dominant negative effect on the function of the WT protein.


2005 - Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes [Articolo su rivista]
Pietrangelo, Antonello; Caleffi, Angela; Henrion, J.; Ferrara, F.; Corradini, Elena; Kulaksiz, H.; Stremmel, W.; Andreone, P.; Garuti, Cinzia
abstract

Background & Aims: Juvenile hemochromatosis is a severe form of hereditary iron overload that has thus far been linked to pathogenic mutations of the gene coding for hemojuvelin (HJV), on chromosome 1, or, more rarely, that coding for hepcidin (HAMP), on chromosome 19. A milder adult-onset form is due to pathogenic mutations of HFE or, rarely, serum transferrin receptor 2. Methods: We studied a pedigree with siblings affected by both juvenile and adult-onset hereditary hemochromatosis. Affected subjects underwent full clinical evaluation, as well as microsatellite and gene sequencing analysis. Results: Two siblings (male and female, aged 24 and 25 years, respectively) were hospitalized for severe endocrinopathy and cardiomyopathy. At age 18 and 17 years, they had presented with impotence and amenorrhea, respectively, and increased serum iron levels. Hypogonadotropic hypogonadism was confirmed in both, and liver biopsy showed marked hepatic iron accumulation and micronodular cirrhosis. Iron levels were normalized after 24 months (female) and 36 months (male) of weekly phlebotomies. Microsatellite analysis showed no linkage with chromosome I and 19, and gene sequencing showed no hemojuvelin or hepcidin gene mutations. Instead, combined mutations of HFE (C282Y/H63D compound heterozygosity) and serum transferrin receptor 2 (Q317X homozygosity) were found. A 21-year-old brother with a milder phenotype resembling classic adult-onset hereditary hemochromatosis carried only the Q317X serum transferrin receptor 2 homozygote mutation. Conclusions: Juvenile hereditary hemochromatosis is not a distinct monogenic disorder invariably due to hemojuvelin or hepcidin mutations: it may be genetically linked to the adult-onset form of hereditary hemochromatosis.


2005 - Juvenile hemocromatosis associated with pathogenetic mutations of adult hemocromatosis genes [Articolo su rivista]
Pietrangelo, A; Caleffi, A; Henrion, J; Ferrara, F; Corradini, E; Kulaksiz, H; Stremmel, W; Andreone, Pietro; Garuti, C.
abstract


2005 - Kupffer cells and macrophages are not required for hepatic hepcidin activation during iron overload [Articolo su rivista]
Montosi, Giuliana; Corradini, Elena; Garuti, Cinzia; S., Barelli; S., Recalcati; G., Cairo; L., Valli; Pignatti, Elisa; Vecchi, Chiara; F., Ferrara; Pietrangelo, Antonello
abstract

Hepcidin, the iron hormone, is produced by the liver in response to iron and inflammation. Its synthesis during inflammation is triggered by cytokines, but the details of iron activation are obscure. We tested the role of Kupffer cells and macrophages by studying iron-loaded or inflamed mice with selective inactivation of Kupffer cells or the in vitro effect of conditioned human macrophages on hepcidin expression. Hepcidin messenger RNA (mRNA) expression was studied by Northern blot and reverse transcriptase polymerase chain reaction analysis in mice that were treated with 40 mg/kg gadolinium (III) chloride (GdCl3) as a Kupffer cell inactivating agent and subjected to inflammatory challenges with either lipopolysaccharide (LPS) and turpentine or iron overload by iron-dextran administration. Similar analyses were performed in human hepatoma cells (HepG2) cultured with medium from LPS- or iron-conditioned macrophages from blood donors or patients with HFE-linked hereditary hemochromatosis (HH). In vivo, LPS and particularly turpentine stimulated hepcidin mRNA expression, and this effect was prevented by the inactivation of Kupffer cells. Also, iron overload markedly upregulated hepatic hepcidin mRNA, but this activity persisted in spite of Kupffer cell blockade. In vitro, the medium of LPS-treated normal or hemocromatotic macrophages turned on hepcidin expression. On the contrary, medium of iron-manipulated macrophages, regardless of their HFE status, did not affect hepcidin mRNA steady-state levels. In conclusion, Kupffer cells are required for the activation of hepcidin synthesis during inflammation, and HH inflamed macrophages are capable of mounting a normal response, eventually leading to hepcidin stimulation. However, both Kupffer cells and human macrophages are dispensable for the regulatory activity exerted by iron on hepatic hepcidin.


2005 - Lack of enterocyte iron accumulation in the ferroportin disease [Articolo su rivista]
Corradini, Elena; Montosi, Giuliana; F., Ferrara; A., Caleffi; Pignatti, Elisa; S., Barelli; Garuti, Cinzia; Pietrangelo, Antonello
abstract

Ferroportin-associated iron overload (also known as the ferroportin disease) is a common cause of hereditary hyperferritinemia. It was originally proposed that loss-of-protein function mutations account for iron overload in the FD. This hypothesis is consistent with the 14 phenotype reported in most patients with FD of early iron accumulation in tissues, particularly in macrophages, in spite of relatively normal-low circulatory iron. It was still unclear, however, how FPN mutations would affect iron retention in enterocytes. We studied histologically the intestine of six patients with different FPN mutations as compared to other subjects with various iron disorders. We found that regardless of the underlying FPN mutation, no iron accumulation was found in absorbing enterocytes while, intestinal villi showed marked signs of iron accumulation in the cells of lamina propria. Not surprisingly, in the liver, iron excess was found mainly in Kupffer cells. These results indicate that FPN haploinsufficiency is not limiting for iron export from enterocytes.


2005 - Non-HFE hemochromatosis [Articolo su rivista]
Pietrangelo, Antonello
abstract

The term non-HFE hemochromatosis (non-HFE HC) refers to several phenotypically similar but genetically distinct forms of hereditary hemochromatosis affecting individuals without pathogenic mutations of HFE. The involved genes are, sinsu strictu, transferrin receptor 2 (TfR2), hemojuvelin (HJV), and hepcidin (HAMP). Non-HFE HC share common pathogenic and clinical features with HFE HC. However, depending on the role of the affected gene in iron trafficking, the clinical onset may be earlier and phenotypic expressivity more severe than classic HC. Other forms of hereditary iron overload have distinct pathogenesis and phenotype. The most prevalent of these forms is ferroportin disease, characterized by autosomal dominant trait, predominant reticuloendothelial cell iron overload, and mild organ damage. Non-HFE HC gene products, while responsible for rarer cases of HC as compared with HFE, are much more central than HFE in human iron homeostasis and understanding their function will greatly advance our comprehension of iron trafficking in health and disease.


2005 - Non-invasive assessment of hepatic iron overload: are we finally there? [Articolo su rivista]
Pietrangelo, Antonello
abstract

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2004 - Erratum: Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene (Blood Cells, Molecules, and Diseases (2003) 31 (299-304) DOI: 10.1016/S1079-9796(03)00164-5) [Articolo su rivista]
Gordeuk, V. R.; Caleffi, A.; Corradini, E.; Ferrara, F.; Jones, R. A.; Castro, O.; Onyekwere, O.; Kittles, R.; Pignatti, E.; Montosi, G.; Garuti, C.; Gangaidzo, I. T.; Gomo, Z. A. R.; Moyo, V. M.; Rouault, T. A.; Macphail, P.; Pietrangelo, A.
abstract


2004 - Haemochromatosis [Capitolo/Saggio]
Corradini, Elena; F., Ferrara; Pietrangelo, Antonello
abstract

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2004 - Hereditary hemochromatosis [5] (multiple letters) [Articolo su rivista]
Castiella, A.; Alustiza, J. M.; Artetxe, J.; Pietrangelo, A.
abstract


2004 - Hereditary hemochromatosis--a new look at an old disease. [Articolo su rivista]
Pietrangelo, Antonello
abstract

This article has no abstract; the first 100 words appear below.For much of the 20th century, hereditary hemochromatosis was regarded as a clinically and genetically unique entity. The classic findings on presentation — diabetes, bronze pigmentation of the skin, and cirrhosis — were first described in the 19th century, when the term “hemochromatosis” was first used13; by 1935 it had become clear that the disease was hereditary and was caused by excess deposits of iron in the tissue.4 In the 1970s and 1980s, it was recognized as an autosomal recessive disorder linked to the region of the short arm of chromosome 6 encoding HLA-A*3 ,5,6 and in . . .


2004 - Iron and the liver [Articolo su rivista]
Corradini, Elena; Ferrara, F; Pietrangelo, Antonello
abstract

Iron is an important bio-catalyst of oxidation-reduction reactions in the cell and is essential for life. Paradoxically, it may also be lethal when the fraction of redox-active metal ions exceeds that sequestered in specialized proteins or cellular compartments, and uncontrolled production of free radical species may arise. The liver is the main body site for iron stores and central in the regulation of iron homeostasis. Important iron-proteins, such as hepcidin, the iron regulatory hormone, are specifically produced by the liver. Pathogenic mutations in hepatic iron transporters and regulators lead to hereditary iron overload diseases, including hemochromatosis. Iron toxicity depends on its excessive accumulation and is due to promotion of oxidant stress: free radicals and membrane oxidation by-products cause hepatocellular death by triggering organelle dysfunction, or by activating cells involved in hepatic inflammation and fibrogenesis, such as Kupffer cells and hepatic stellate cells. Xenobiotics and hepatotoxins as well as immunological and host defense mechanisms may cause subtle changes in the pool of redox-active metal ions and in metal compartmentalization that potentially contribute to hepatotoxic, inflammatory and fibrogenic events. The hepatotoxic and profibrogenic potential of metal ions, particularly iron, is dramatic at moderate levels of tissue metal overload in concomitance with other inciting insults, such as alcohol abuse and viral hepatitis. Removal of metal excess from the liver in iron overload diseases is beneficial and prevents progression toward cirrhosis. The development of drugs able to block catalytically active metals, particularly iron, may prove effective in other chronic liver diseases in which inflammatory, degenerative and fibrogenic processes are fueled by redox-active metal ions.


2004 - Mechanisms of disease: The role of hepcidin in iron homeostasis--implications for hemochromatosis and other disorders. [Articolo su rivista]
Pietrangelo, Antonello; Trautwein, C.
abstract

The defensin-like circulatory peptide hepcidin is the iron-regulatory hormone that links innate immunity and iron metabolism. In response to inflammatory stimuli, the liver produces hepcidin: this antimicrobial peptide then limits the iron that is vital to invading pathogens, by decreasing iron release/transfer from enterocytes and macrophages and causing secondary hypoferremia. This may lead, however, to reduced iron availability for erythropoiesis and therefore to anemia (and anemia of chronic disease). When iron is scarce, the rate at which it is released into the bloodstream must be enhanced: indeed, iron starvation and hypoxia readily abrogate hepcidin expression. Conversely, if excess iron enters the circulation, hepcidin transcription is turned on and iron release from the intestine and macrophages abrogated. Circumstantial evidence indicates that the effect of circulatory iron on hepcidin requires functional HFE and hemojuvelin, two proteins of unknown function that have recently been linked to human hereditary hemochromatosis. In this disease it is likely that inadequate levels of circulating hepcidin lead to the uncontrolled release of iron from the intestine and macrophages, followed by tissue iron overload and organ damage. Given its role as the iron-regulatory hormone, the modulation of hepcidin activity using agonists or antagonists might offer new treatment opportunities in different human iron-dependent disorders.


2004 - Non-HFE hemochromatosis [Articolo su rivista]
Pietrangelo, Antonello
abstract

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2004 - Strategies for liver support: From stem cells to xenotransplantation [Articolo su rivista]
Burra, P; Samuel, D; Wendon, J; Pietrangelo, Antonello; Gupta, S.
abstract

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2004 - The ferroportin disease [Articolo su rivista]
Pietrangelo, Antonello
abstract

A new inherited disorder of iron metabolism, hereafter called the ferroportin disease, is increasingly recognized worldwide. The disorder is due to pathogenic mutations in the SLC40A1 gene encoding for a main iron export protein in mammals, ferroportin1/IREG1/ MTP1, and it was originally identified as an autosomal-dominant form of iron overload not linked to the hemochromatosis (HFE) gene. It has distinctive clinical features such as early increase in serum ferritin in spite of low-normal transferrin saturation, progressive iron accumulation in organs, predominantly in reticuloendothelial macrophages, marginal anemia with low tolerance to phlebotomy. Ferroportin mutations have been reported in many countries regardless of ethnicity. They may lead to a loss of protein function responsible for reduced iron export from cells, particularly reticuloendothelial cells. Now, the disorder appears to be the most common cause of hereditary iron overload beyond HFE hemochromatosis.


2003 - EASL International Concensus Conference on Hepatitis B - 13-14 September, 2002 Geneva, Switzerland Consensus Statement (Long version) [Articolo su rivista]
DE FRANCHIS, R.; Hadengue, A.; Lau, G.; Lavanchy, D.; Lok, A.; Mcintyre, N.; Mele, A.; Paumgartner, G.; Pietrangelo, Antonello; Rodes, J.; Rosenberg, W.; Valla, D.
abstract

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2003 - EASL International Consensus Conference on Hepatitis B: 13-14 September, 2002 Geneva, Switzerland - Consensus statement (short version) [Articolo su rivista]
Pietrangelo, Antonello
abstract


2003 - Haemochromatosis [Articolo su rivista]
PIETRANGELO, Antonello
abstract

Iron is an important component of the Earth's crust, but its own chemistry greatly limits utilisation and also sets the basis for its toxicity. The capacity of readily exchanging electrons in aerobic conditions makes iron essential for fundamental cell functions, such as DNA synthesis, transport of oxygen and electrons, and cell respiration. On the other hand, as humans have no means to control iron excretion, excess iron, regardless of the route of entry, accumulates in parenchymal organs and threatens cell viability. In fact, a number of disease states (that is, iron overload diseases) attributable to genetic or acquired factors are pathogenetically linked to excess body iron stores and iron removal therapy is an effective lifesaving strategy in such circumstances.


2003 - Hemochromatosis gene modifies course of hepatitis C viral infection [Articolo su rivista]
Pietrangelo, Antonello
abstract

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2003 - Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene [Articolo su rivista]
Gordeuk, Vr; Caleffi, Angela; Corradini, Elena; Ferrara, Francesca; Jones, Ra; Castro, O; Onyekwere, O; Kittles, R; Pignatti, Elisa; Montosi, Giuliana; Garuti, Cinzia; Gangaidzo, It; Gomo, Zar; Moyo, Vm; Rouault, Ta; Macphail, P; Pietrangelo, Antonello
abstract

The product of the SLC40A1 gene, ferroportin 1, is a main iron export protein. Pathogenic mutations in ferroportin 1 lead to an autosomal dominant hereditary iron overload syndrome characterized by high serum ferritin concentration, normal transferrin saturation, iron accumulation predominantly in macrophages, and marginal anemia. Iron overload occurs in both the African and the African-American populations, but a possible genetic basis has not been established. We analyzed the ferroportin 1 gene in 19 unrelated patients from southern Africa (N = 15) and the United States (N = 4) presenting with primary iron overload. We found a new c. 744 C→T (Q248H) mutation in the SLC40A1 gene in 4 of these patients (3 Africans and 1 African-American). Among 22 first degree family members, 10 of whom were Q248H heterozygotes, the mutation was associated with a trend to higher serum ferritin to amino aspartate transferase ratios (means of 14.8 versus 4.3 μg/U; P = 0.1) and lower hemoglobin concentrations (means of 11.8 versus 13.2 g/dL; P = 0.1). The ratio corrects serum ferritin concentration for alcohol-induced hepatocellular damage. We also found heterozygosity for the Q248H mutation in 7 of 51 (14%) southern African community control participants selected because they had a serum ferritin concentration below 400 μg/L and in 5 of 100 (5%) anonymous African-Americans, but we did not find the change in 300 Caucasians with normal iron status and 25 Caucasians with non-HFE iron overload. The hemoglobin concentration was significantly lower in the African community controls with the Q248H mutation than in those without it. We conclude that the Q248H mutation is a common polymorphism in the ferroportin 1 gene in African populations that may be associated with mild anemia and a tendency to iron loading.


2003 - Iron transporter ferroportin FPN1 [Capitolo/Saggio]
Pietrangelo, Antonello
abstract

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2003 - Iron-induced oxidant stress in alcoholic liver fibrogenesis [Articolo su rivista]
Pietrangelo, Antonello
abstract

Iron is an essential micronutrient. However, because human beings have no means to control iron excretion, excess iron, regardless of the route of entry, accumulates in parenchymal organs and threatens cell viability. Indeed, when iron-buffering capability is overwhelmed, oxidative stress-induced cell damage and fibrogenesis may arise, mainly in the liver, the main storage site for iron in the body. Results of recent studies have clearly shown that these pathologic events are induced by iron-generated reactive oxygen species and lipid peroxidation by-products. Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix components in the liver, is a dynamic process, from chronic liver damage to end-stage liver cirrhosis. Iron-induced oxidant stress is involved in this process (1) as the primary cause of parenchymal cell necrosis or (2) as activator of cells that are effectors [e.g., hepatic stellate cells, (myo)fibroblasts] or key mediators (e.g., Kupffer cells) of hepatic fibrogenesis (or through both mechanisms). Beyond their effect as direct cytotoxic agents, iron and free radicals may trigger increased synthesis of collagen in myofibroblast-like cells as well as activate granulocytes and Kupffer cells, resulting in an increased formation of cytokines and eicosanoids and further reactive oxygen species. This may constitute a cascade of amplifying loops, which perpetuate the fibrogenic process. The fibrogenic potential of iron is even more dramatic when iron acts in concert with other hepatotoxins such as alcohol. In this instance, even if tissue iron levels are only slightly elevated, the toxic effect of alcohol or its metabolites may be amplified and propagated with rapid acceleration of the liver disease. At the molecular level, the presence of catalytically active free iron may (1) contribute directly to the hepatotoxicity of alcohol or (2) enhance the generation of cytokine and fibrogenic mediators from resident Kupffer cells (or be involved in both ways). A challenge for future research is to develop therapeutic tools able to block redox-active free iron in the cell.


2003 - Parametri predittivi e risposta sostenuta alla terapia antivirale combinata nell'epatite cronica attivva HCV correlata (ECA HCV) [Abstract in Atti di Convegno]
P., Ballesini; E., Boldrini; A., Borghi; G., Cioni; Corradini, Elena; A., Cristani; F., Ferrara; Gandolfo, Marco; Pietrangelo, Antonello; M., Pipino; S., Polidoro; C., Rosa; C., Sardini; Vandelli, Carmen; E., Ventura; Ventura, Paolo; I., Venturini; M. L., Zeneroli
abstract

Introduzione: benché siano codificate le migliori terapie per l’ECA da HCV, rimangono relativamente controverse le scelte su quando cominciare la terapia e in quali pazienti. Il presente studio è una analisi retrospettiva che prende in considerazione la risposta virologica, i parametri istologici ed alcune altre caratteristiche (anagrafiche…) rilevanti dei pazienti.Soggetti e metodi: Abbiamo considerato 127 pazienti (età 47 ± 11, 47 f) con diagnosi istologica di ECA HCV-correlata; tutti i pazienti, trattati con associazione di IFN2b (di cui 37 nella forma pegilata) e ribavirina, sono stati valutati per genotipo virale (sfavorevole : 1 e 4; favorevole: 2 e 3), grading e staging istologici (sia considerando i valori continui che a due classi: per lo staging da 0 a 2 e da 3 a 6; per il grading da 0 a 4 e da 5 a 18) secondo Ishak et al., stato di naive o relapser e risposta alla terapia (sustained responders, SR: risposta sostenuta a oltre 6 mesi dal termine della terapia; non sustained responders, NSR: risposta assente o interruzione terapia per intolleranza o altro).Risultati: I due gruppi di pazienti, SR (n=63) e NSR (n=64) non differivano in modo significativo per età (45±11 vs. 48±10) [erano tuttavia più frequenti i soggetti di età uguale o inferiore a 40 anni : 28/63 (44.4%) vs. 15/64 (23.4%), p=0.012 ] e sesso ( m/f : 37/26 vs. 43/21), mentre nel gruppo SR erano più frequenti i naives [47/63 (74.6%) vs. 36/64 (56.2%), p= 0.024], i genotipi favorevoli [29/63 (46 %) vs. 19/64 (29.7 %), p= 0.001], i pazienti con basso valore di necro-infiammazione (grading=0-4) [36/63 (57.1%) vs. 17/64 (26.5%), p= 0.058] e fibrosi (staging=0-2) [47/63 (74.6%) vs. 37/64 (57.8%), p= 0.046]. L’associazione tra risposta favorevole e i suddetti parametri, misurata in termini di Odds Ratio è risultata significativa per la presenza di genotipo favorevole (OR= 2.15, IC 95%= 1.35÷3.4, p=0.000), stato naive (OR=1.34, IC 95%= 1.04÷1.74, p= 0.019), età giovane (OR= 1.9, IC 95% = 1.12 ÷ 3.19, p=0.001), basso valore di staging (OR= 1.29, IC 95%= 1.01÷ 1.66, p= 0.035), basso valore di grading (OR= 1.55, IC 95% = 0.977÷ 2.46, p=0.043). La tabella evidenzia il risultato dell’analisi di regressione logistica che considera come variabile dipendente il tipo di risposta (SR o NSR) alla terapia e come covariate la presenza di un’età maggiore o minore di 40 anni, il genotipo (favorevole o sfavorevole), la condizione naive o relapser, la presenza di bassi o alti livelli di necro-infiammazione (grading) o fibrosi (staging), parametri che nella nostra casistica hanno dimostrato singolarmente una associazione significativa con la risposta alla terapia. ParametroBE.S.WaldSig.Exp(B)Naive-,630,4202,246,134,533Genotipo 1,125,4067,699,0063,081Grading-,411,434,896,344,663Staging-,510,4381,352,245,601Età-,451,4331,086,297,637R2= 0.196Discussione: Come noto, la risposta alla terapia antivirale combinata per l’ECA HCV correlata dipende da numerosi fattori. I nostri dati confermano differenze significative nella risposta sostenuta per età inferiore a 40 anni, genotipo favorevole, basso grado di fibrosi e di necro-infiammazione; nessuno di tali parametri dimostra tuttavia un livello di associazione tale da guidare la scelta terapeutica nel singolo paziente. Il tentativo di costruire con tali parametri un modello predittivo della risposta mediante analisi di regressione logistica risulta insoddisfacente (solo circa il 20% di accuratezza predittiva).


2003 - Solving hemochromatosis with knock-out mice [Articolo su rivista]
Pietrangelo, Antonello
abstract

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2003 - The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression [Articolo su rivista]
A., Lymboussaki; Pignatti, Elisa; Montosi, Giuliana; Garuti, Cinzia; Dj, Haile; Pietrangelo, Antonello
abstract

Background/Aims: MTP1/Ferroportin1/IREG1, the product of the SLC40A1 gene, is a main iron export protein in mammals. However, the way this gene is regulated by iron is still unclear. The aim of this study was to investigate the functional role of genomic SLC40A1 elements in response to iron. Methods: Vectors containing either similar to 2.6 kb 5' flanking region or deletion constructs, including one devoid of an iron responsive element (SLC40A1-DeltaIRE-Luc), were analyzed by luciferase reporter gene in transfected HepG2, CaCO2 and U937 cells. Expression of iron genes and activity of the iron regulatory protein were also studied. Results: Iron increased and desferrioxamine decreased luciferase activity in all the cell types using both the full-length construct and the promoter deletion constructs, in the absence of changes in SLC40A1 or luciferase mRNA levels. To test the role of the SLC40A1 5' untranslated region, we first demonstrated that wild type and not SLC40A1-DeltaIRE-Luc could bind iron regulatory protein. Then, in cells transfected with SLC40A1-DIRE-Luc, we found that, in spite of iron regulatory protein activation, the response to iron manipulation was lost. Conclusions: We demonstrate that the iron responsive element in the SLC40A1 gene is functional and that it controls gene expression through the cytoplasmic iron regulatory protein system. (C) 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


2002 - Design, synthesis, and physicochemical and biological characterization of a new iron chelator of the family of hydroxychromenes [Articolo su rivista]
Ferrali, M; Bambagioni, S; Ceccanti, A; Donati, D; Giorgi, G; Fontani, M; Laschi, F; Zanello, P; Casolaro, M; Pietrangelo, Antonello
abstract

Increasing evidence suggests that iron plays an important role in tissue damage both during chronic iron overload diseases (i.e., hemochromatosis) and when, in the absence of actual tissue iron overload, iron is delocalized from specific carriers or intracellular sites (inflammation, neurodegenerative diseases, postischaemic reperfusion, xenobiotic intoxications, etc.), In the present work we appropriately modified an iron chelator of the hydroxychromene family in, order to obtain a tridentate chelator that would inactivate the iron redox cycle after its complexation, with a view to using this molecule in human therapy and/or in disease prevention. We synthesized such a chelator for the first time and show, by different physticochemical analysis, its tridentate nature and, importantly, its capacity to chelate iron with enough strength to inhibit both iron-dependent H2O2 generation and lipid peroxidation in in vitro biological systems.


2002 - Frequency of the S65C mutation of HFE and iron overload in 309 subjects heterozygous for C282Y [Articolo su rivista]
Wallace, Df; Walker, Ap; Pietrangelo, Antonello; Clare, M; Bomford, Ab; Dixon, Jl; Powell, Lw; Subramaniam, Vn; Dooley, Js
abstract

Background/Aims: HFE-related haemochromatosis is a common disorder of iron metabolism. Most affected individuals are homozygous for the C282Y mutation of HFE. Some are compound heterozygotes for C282Y/H63D. A small proportion have neither of these genotypes. We have investigated the phenotype of compound heterozygotes for C282Y and another missense mutation S65C. Methods: Genotype for the S65C mutation was determined in 309 subjects Heterozygous for C282Y and negative for H63D, referred because of increased serum iron indices or family screening. A control sample comprising 315 individuals was also studied. Results: Twelve individuals were compound heterozygotes for C282Y and S65C. Seven, referred for family screening, had normal serum iron indices. Five subjects had elevated serum iron indices; three of these had elevated hepatic iron and have received treatment for iron overload. Transferrin saturation was significantly elevated in C282Y/S65C compound heterozygotes compared with simple C282Y heterozygotes. Conclusions: Some C282Y/S65C compound heterozygotes have elevated serum iron indices and iron overload. The penetrance of this genotype is low and other genetic and environmental factors may influence the expression of iron loading. Screening for S65C may be useful in individuals with iron overload who are not homozygous for C282Y or compound heterozygous for C282Y/H63D. (C) 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.


2002 - Iron-induced oxidant stress in nonparenchymal liver cells: Mitochondrial derangement and fibrosis in acutely iron-dosed gerbils and its prevention by silybin [Articolo su rivista]
Pietrangelo, Antonello; Montosi, Giuliana; Garuti, Cinzia; Contri, Miranda; F., Giovannini; D., Ceccarelli; A., Masini
abstract

Hepatic fibrosis due to iron overload is mediated by oxidant stress. The basic mechanisms underlying this process in vivo are still little understood. Acutely iron-dosed gerbils were assayed for lobular accumulation of hepatic lipid peroxidation by-products, oxidant-stress gene response, mitochondrial energy-dependent functions, and fibrogenesis. Iron overload in nonparenchymal cells caused an activation of hepatic stellate cells and fibrogenesis. Oxidant-stress gene response and accumulation of malondialdehyde-protein adducts were restricted to iron-filled nonparenchymal cells, sparing nearby hepatocytes. Concomitantly, a significant rise in the mitochondrial desferrioxamine-chelatable iron pool associated with the impairment of mitochondrial oxidative metabolism and the hepatic ATP decrease, was detected. Ultrastructural mitochondrial alterations were observed only in nonparenchymal cells. All biochemical and functional derangements were hindered by in vivo silybin administration which blocked completely fibrogenesis. Iron-induced oxidant stress in nonparenchymal cells appeared to bring about irreversible mitochondrial derangement associated with the onset of hepatic fibrosis.


2002 - Mechanism of iron toxicity [Capitolo/Saggio]
Pietrangelo, Antonello
abstract

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2002 - Physiology of iron transport and the hemochromatosis gene [Articolo su rivista]
Pietrangelo, Antonello
abstract

Iron is essential for fundamental cell functions but is also a catalyst for chemical reactions involving free radical formation, potentially leading to oxidative stress and cell damage. Cellular iron levels are therefore carefully regulated to maintain an adequate substrate while also minimizing the pool of potentially toxic "free iron." The main control of body iron homeostasis in higher organisms is placed in the duodenum, where dietary iron is absorbed, whereas no controlled means of eliminating unwanted iron have evolved in mammals. Hereditary hemochromatosis, the prototype of deregulated iron homeostasis in humans, is due to inappropriately increased iron absorption and is commonly associated to a mutated HFE gene. The HFE protein is homologous to major histocompatibility complex class I proteins but is not an iron carrier, whereas biochemical and cell biological studies have shown that the transferrin receptor, the main protein devoted to cellular uptake of transferrin iron, interacts with HFE. This review focuses on recent advances in iron research and presents a model of HFE function in iron metabolism.


2002 - Response of young, aged and osteoarthritic human articular chondrocytes to inflammatory cytokines: molecular and cellular aspects [Articolo su rivista]
Dozin, B; Malpeli, M; Camardella, L; Cancedda, R; Pietrangelo, Antonello
abstract

The aim of this study was to investigate the metabolic properties of human articular chondrocytes derived from young, aged and osteoarthritic subjects and their genetic adaptation to a catabolic challenge (i.e. the inflammatory cytokines interleukin-1alpha and tumor necrosis factor-alpha), in the absence or presence of diacerein, a drug potentially useful in osteoarthritis. Chondrocytes in primary culture were analyzed for newly secreted proteins, metalloproteinase synthesis and activity, and production of nitric oxide by-products. Results show that chondrocytes from normal but aged subjects present biochemical properties closer to osteoarthritic-derived cartilage than to normal young cartilage, as indicated by cell morphology, cell proliferation rate and pattern of protein secretion (in particular stromelysin-1 and interstitial collagenase). According to patient age and cartilage physiopathology, chondrocytes secrete increasing amounts of a protein identified by micro-sequencing as chitinase-like protein. Upon exposure to the inflammatory cytokines, chondrocytes, regardless the age or the status of the donor, significantly enhance their production of stromelysin-1, interstitial collagenase, interleukin-6 and interleukin-8. By contrast, the chitinase-like protein is not modulated by the cytokines. The pattern of protein secretion and metal loproteinase activity in chondrocytes from aged subjects appeared to be different from that of young patients, but was highly expressed in osteoarthritic chondrocytes. Diacerein, at therapeutically useful concentrations, consistently counteracts the stimulatory effect of cytokines on newly secreted proteins, metal loproteinase activity and nitric oxide production, whereas a selective nitric oxide blocker alone is ineffective. These data demonstrate that a specific gene program is turned on in cytokine-stimulated chondrocytes, which involves production of proteins engaged in remodeling and destruction of cartilage matrix. Part of these mechanisms appears to be operative also in unstimulated aged chondrocytes. Diacerein largely prevents the metabolic alterations caused by cytokine exposure in human chondrocytes, possibly through its ability to block early intracellular mediators after cytokine stimulation, such as oxygen radicals. (C) 2002 Elsevier Science B.V./International Society of Matrix Biology. Published by Elsevier Science B.V. All rights reserved.


2002 - The iron regulatory proteins: Targets and modulators of free radical reactions and oxidative damage [Articolo su rivista]
G., Cairo; S., Recalcati; Pietrangelo, Antonello; G., Minotti
abstract

Iron acquisition is a fundamental requirement for many aspects of life, but excess iron may result in formation of free radicals that damage cellular constituents. For this reason, the amount of iron within the cell is carefully regulated in order to provide an adequate level of a micronutrient while preventing its accumulation and toxicity. A major mechanism for the regulation of iron homeostasis relies on the post-transcriptional control of ferritin and transferrin receptor mRNAs, which are recognized by two cytoplasmic iron regulatory proteins (IRP-1 and IRP-2) that modulate their translation and stability, respectively. IRP-1 can function as a mRNA binding protein or as an aconitase, depending on whether it disassembles or assembles an iron-sulfur cluster in response to iron deficiency or abundancy, respectively. IRP-2 is structurally and functionally similar to IRP-1, but does not assemble a cluster nor exhibits aconitase activity. Here we briefly review the role of IRP in iron-mediated damage induced by oxygen radicals, nitrogen-centered reactive species, and xenobiotics of pharmacological and clinical interest.


2001 - 3-hydroxy-(4H)-benzopyran-4-ones as potential iron chelating agents in vivo [Articolo su rivista]
Ferrali, M; Donati, D; Bambagioni, S; Fontani, M; Giorgi, G; Pietrangelo, Antonello
abstract

Increasing evidence suggests that iron plays an important role in tissue damage both during chronic iron overload diseases (i.e., hemochromatosis) and when, in the absence of actual tissue iron overload, iron is delocalised from specific carriers or intracellular sites (inflammation, neurodegenerative diseases, post-ischaemic reperfusion, etc.). In order to be used for therapeutical purposes in vivo, a reliable iron chelator should be capable of preventing the undesired effects that follow the electrochemical activation of iron (see below). Bearing in mind the molecular structure of some flavonols that are able to chelate iron, we synthesised a new oral iron-chelator, 2-methyl-3-hydroxy-4H-benzopyran-4-one (MCOH). We demonstrate that MCOH chelates iron in a 2:1 ratio showing a stability constant of similar to 10(10). MCOH is able to cross cell membranes (erythrocytes, ascite tumour cells) in both directions. Following intraperitoneal administration to rats, it is quickly taken up by the liver and excreted in the urine within 24 h. A similar behaviour has been documented after oral administration. We propose that MCOH may represent the prototype of a new class of iron chelating agents to be developed for iron-removal therapy in vivo with the goal of preventing tissue damage caused by the iron redox cycle. (C) 2001 Elsevier Science Ltd. All rights reserved.


2001 - Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene [Articolo su rivista]
Montosi, Giuliana; Donovan, A.; Totaro, Antonella; Garuti, Cinzia; Pignatti, Elisa; Cassanelli, S.; Trenor, C. C.; Gasparini, P.; Andrews, N. C.; Pietrangelo, Antonello
abstract

Hemochromatosis is a progressive iron overload disorder that is prevalent among individuals of European descent. It is usually inherited in an autosomal-recessive pattern and associated with missense mutations in HFE, an atypical major histocompatibility class I gene. Recently, we described a large family with autosomal-dominant hemochromatosis not linked to HFE and distinguished by early iron accumulation in reticuloendothelial cells. Through analysis of a large pedigree, we have determined that this disease maps to 2q32. The gene encoding ferroportin (SLC11A3), a transmembrane iron export protein, lies within a candidate interval defined by highly significant lod scores. We show that the iron-loading phenotype in autosomal-dominant hemochromatosis is associated with a nonconservative missense mutation in the ferroportin gene. This missense mutation, converting alanine to aspartic acid at residue 77 (A77D), was not seen in samples from 100 unaffected control individuals. We propose that partial loss of ferroportin function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation.


2001 - Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload [Articolo su rivista]
Zoller, H; Koch, R; Theurl, I; Obrist, P; Pietrangelo, Antonello; Montosi, Giuliana; Haile, D; Vogel, W; Weiss, G.
abstract

Background & AIMS: Imbalances of iron homeostasis are accompanied by alterations of intestinal iron absorption. The identification of divalent-metal transporter 1 (DMT1) and ferroportin 1 (FP1) has improved our understanding of transmembrane iron trafficking. To gain insight into the regulatory properties of these transporters in the duodenum, we studied their expression in patients with hereditary hemochromatosis (HFE-associated and non-HFE-associated), secondary iron overload, and iron deficiency. Methods: DMT1, FP1 messenger RNA (mRNA), and protein expression were analyzed in duodenal biopsy specimens from patients by means of TaqMan real-time polymerase chain reaction, Western blotting technique, and immunohistochemistry. Results: DMT1 and FP1 mRNA levels are positively correlated with each other in all patient groups (P < 0.001), Moreover, DMT1 and FP1 mRNA levels were significantly increased in patients with iron deficiency, HFE and non-HFE hemochromatosis, whereas they were unchanged in patients with secondary iron overload. Alterations in DMT1 and FP1 mRNA levels were paralleled by comparable changes in the duodenal expression of these proteins. In patients with normal iron status or iron deficiency, significant negative correlations between DMT1, FP1 tnRNA, and serum iron parameters were found, which were absent in subjects with primary hemochromatosis, Conclusions: DMT1 and FP1 are centrally involved in iron uptake/transfer in the duodenum and in the adaptive changes of iron homeostasis to iron deficiency and overload.


2001 - Frequency and biochemical expression of C282Y/H63D hemochromatosis (HFE) gene mutations in the healthy adult population in Italy [Articolo su rivista]
Cassanelli, S; Pignatti, Elisa; Montosi, Giuliana; Garuti, Cinzia; Mariano, M; Campioli, D; Carbonieri, A; Baldini, Enrica; Pietrangelo, Antonello
abstract

Background/Aims: The actual prevalence of the main hemochromatosis (HFE) mutations in the Italian adult population and their phenotypic expression have not yet been established. This information is key to advocate a mass-screening program. Methods: Two thousand one hundred adults were tested for the C282Y/H63D HFE gene mutations by an automated genotyping assay as well as transferrin saturation (TS) and serum ferritin levels. Results: No homozygotes for the C282Y mutation were found. Heterozygosity for the C282Y mutation was 3.1%, while heterozygosity and homozygosity for the H63D mutation were 21.5% and 2.5%, respectively. TS was significantly higher in C282Y heterozygotes and H63D homozygotes as compared to wild-type individuals (P < 0.01). Interestingly, of the HFE wild-type subjects 5.9% had a TS value above the 45% threshold. Conclusions: This study shows that (i) the predicted prevalence for C282Y homozygosity in Italy is 1:3900; (ii) the C282Y/H63D wild-type population has an increased baseline of iron parameters possibly due to genetic factors not linked to the C282Y/H63D mutations; (iii) since in the latter population the actual tissue iron burden cannot be assessed, phenotypic (TS) screening in Italy is not recommended until the true prevalence of all mutations in the HFE gene and in other hemochromatosis genes will be established. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.


2001 - Hereditary hemochromatosis masquerading as rheumatoid arthritis [Articolo su rivista]
Lonardo, A; Neri, P; Mascia, Maria Teresa; Pietrangelo, Antonello
abstract

Early erroneous diagnosis of rheumatic disease is common in subjects with arthropathy due to hereditary hemochromatosis. A 71-year-old male with chronic obstructive pulmonary disease and monoclonal gammopathy underwent hip replacement and was referred to our Department because of altered liver function tests. Test results were negative for hepatitis B surface antigen and hepatitis C virus, and positive for rheumatoid factor. A diagnosis of rheumatoid arthritis had been made on the basis of compatible joint involvement and laboratory data and steroid treatment prescribed. Since his serum ferritin was 3249 ng/mL, genetic testing for hereditary hemochromatosis was carried out and revealed homozygosity for Cys282Tyr mutation in the HFE gene. Liver biopsy disclosed cirrhosis compatible with hemochromatosis. Following a review of the patients' radiographs, the diagnosis of hemochromatosis arthropathy was made. Phlebotomies and family screening for hereditary hemochromatosis were done. The most logical explanation for the positive rheumatoid factor result in this subject are his age and the presence of two chronic diseases involving long-standing antigenic stimulation and monoclonal gammopathy of uncertain significance. It is important to distinguish rheumatoid arthritis from hemochromatosis arthropathy for several reasons: patients with hereditary hemochromatosis do not require corticosteroid treatment; in case of erroneous diagnosis of rheumatoid arthritis, phlebotomy is not started early, and familial genetic counseling is not considered. In male subjects with positive rheumatoid factor and joint and liver disease, hereditary hemochromatosis should be considered. More liberal use of genetic testing is justified in such cases.


2001 - Ursodeoxycholic acid complexation with 2-hydroxypropyl-beta-cyclodextrin increases ursodeoxycholic acid biliary excretion after single oral administration in rats [Articolo su rivista]
Ventura, Paolo; R., Panini; G., Montosi; C., Garuti; Vandelli, Maria Angela; G., Brunetti; Hd, Tauschel; Pietrangelo, Antonello; Salvioli, Gianfranco
abstract

Complexation of ursodeoxycholic acid (UDCA) with 2-hydroxypropyl-beta -cyclodextrin (HP beta CD) improves the water solubility and the dissolution rate of UDCA and may therefore increase its bioavailability. We compared the amount and the rate of biliary excretion of UDCA and biliary lipid secretion after a single oral administration of UDCA in 3 different pharmaceutical formulations [UDCA-HP beta CD (´urso-beta -cyclodextrin´), UDCA suspension and UDCA capsule] at 3 different dosages each, in 11 groups (2 control groups) of bile fistula rats. UDCA excretion increased with an increase in dose, biliary UDCA recovery and peak secretion were significantly higher after administration of UDCA-HP beta CD than after UDCA in suspension or capsule. This enhancement of biliary excretion may achieve greater UDCA enrichment in the bile acid pool than conventional pharmaceutical UDCA formulations, this giving to UDCA-HP beta CD a considerable therapeutical potential, Copyright


2000 - EASL International Consensus Conference on Haemochromatosis [Articolo su rivista]
Pietrangelo, Antonello
abstract

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2000 - Iron regulatory proteins in pathobiology [Articolo su rivista]
Cairo, G; Pietrangelo, Antonello
abstract

The capacity of readily exchanging electrons makes iron not only essential for fundamental cell functions, but also a potential catalyst for chemical reactions involving free-radical formation and subsequent oxidative stress and cell damage. Cellular iron levels are therefore carefully regulated in order to maintain an adequate substrate while also minimizing the pool of potentially toxic 'free iron'. Iron homoeostasis is controlled through several genes, an increasing number of which have been found to contain non-coding sequences [i.e. the iron-responsive elements (IREs)] which are recognized at the mRNA level by two cytoplasmic iron-regulatory proteins (IRP-1 and IRP-2). The IRPs belong to the aconitase superfamily. By means of an Fe-S-cluster-dependent switch, IRP-1 can function as an mRNA-binding protein or as an enzyme that converts citrate into isocitrate. Although structurally and functionally similar to IRP-1, IRP-2 does not seem to assemble a cluster nor to possess aconitase activity; moreover, it has a distinct pattern of tissue expression and is modulated by means of proteasome-mediated degradation. In response to fluctuations in the level of the 'labile iron pool', IRPs act as key regulators of cellular iron homoeostasis as a result of the translational control of the expression of a number of iron metabolism-related genes. Conversely, various agents and conditions may affect IRP activity, thereby modulating iron and oxygen radical levels in different pathobiological settings. As the number of mRNAs regulated through IRE-IRP interactions keeps growing, the definition of IRPs as iron-regulatory proteins may in the near future become limiting as their role expands to other essential metabolic pathways.


2000 - Iron, friend or foe? "Freedom" makes the difference [Articolo su rivista]
Pietrangelo, Antonello
abstract

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2000 - Iron-induced oxidant stress leads to irreversible mitochondrial dysfunctions and fibrosis in the liver of chronic iron-dosed gerbils. The effect of silybin [Articolo su rivista]
A., Masini; D., Ceccarelli; F., Giovannini; Montosi, Giuliana; Garuti, Cinzia; Pietrangelo, Antonello
abstract

Hepatic iron toxicity because of iron overload seems to be mediated by lipid peroxidation of biological membranes and the associated organelle dysfunctions. However, the basic mechanisms underlying this process in vivo are still little understood. Gerbils were dosed with weekly injections of iron-dextran alone or in combination with sylibin, a well-known antioxidant, by gavage for 8 weeks. A strict correlation was found between lipid peroxidation and the level of desferrioxamine chelatable iron pool. A consequent derangement in the mitochondrial energy-transducin capability, resulting from a reduction in the respiratory chain enzyme activities, occurred. These irreversible oxidative anomalies brought about a dramatic drop in tissue ATP level, The mitochondrial oxidative derangement was associated with the development of fibrosis in the hepatic tissue. Silybin administration significantly reduced both functional anomalies and the fibrotic process by chelating desferrioxamine chelatable iron.


2000 - Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis [Articolo su rivista]
Montosi, Giuliana; P., Paglia; Garuti, Cinzia; Ca, Guzman; Jm, Bastin; Mp, Colombo; Pietrangelo, Antonello
abstract

Hereditary hemochromatosis (HC) is one of the most common single-gene hereditary diseases. A phenotypic hallmark of HC is low iron in reticuloendothelial cells in spite of body iron overload. Most patients with HC have the same mutation, a change of cysteine at position 282 to tyrosine (C282Y) in the HFE protein. The role of HFE in iron metabolism and the basis for the phenotypic abnormalities of HC are not understood. To clarify the role of HFE in the phenotypic expression of HC, we stud led monocytes-macrophages from subjects carrying the C282Y mutation in the HFE protein and clinically expressing HC and transfected them with wild-type HFE by using an attenuated Salmonella typhimurium strain as a gene carrier. The Salmonella system allowed us to deliver genes of interest specifically to monocytes-macrophages with high transduction efficiency. The accumulation of Fe-55 delivered by Fe-55-Tf was significantly lower in macrophages from patients with HC than from controls expressing wild-type HFE. Transfection of HC macrophages with the HFE gene resulted in a high level of expression of HFE protein at the cell surface, The accumulation of Fe-55 delivered by 55Fe-Tf was raised by 40% to 60%, and this was reflected by an increase in the Fe-55-ferritin pool within the HFE-transfected cells. These results suggest that the Iron-deficient phenotype of HC macrophages is a direct effect of the HFE mutation, and they demonstrate a role for HFE in the accumulation of iron in these cells.


1999 - Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosis [Articolo su rivista]
H., Zoller; Pietrangelo, Antonello; W., Vogel; G., Weiss
abstract

Background Although the gene for hereditary haemochromatosis has been cloned, the mechanism by which iron uptake is inappropriately increased in this disorder is unclear. Iron absorption is regulated by the duodenal metal transporter, DMT-1, also called NRAMP-2. We investigated the expression of NRAMP-2 in patients with hereditary haemochromatosis. Methods Duodenal biopsy samples were taken from 20 patients with haemochromatosis homozygous for the C282Y mutation and from ten controls. NRAMP-2 expression was assessed by northern blotting and competitive PCR, NRAMP-2 mRNA was sequenced in seven patients and two controls. Findings Duodenal NRAMP-2 mRNA concentrations were increased in patients as estimated by Northern blotting. Accordingly, competitive PCR showed significantly higher NRAMP-2 cDNA concentrations in patients than in controls (mean 3.43 [SD 0.61] vs 1.11 [0.74] log ng competitorx10(4); p<0.001). No mutations were found within the NRAMP-2 mRNA. Duodenal NRAMP-2 mRNA expression was correlated with serum ferritin in controls (r=-0.94, p=0.001) but not in patients (r=-0.18, p=0.8). Interpretation Increased NRAMP-2 mRNA expression in duodenal mucosa of patients with hereditary haemochromatosis may promote duodenal iron uptake and lead to iron overload.


1999 - Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene [Articolo su rivista]
Pietrangelo, Antonello; Montosi, Giuliana; A., Totaro; Garuti, Cinzia; D., Conte; Cassanelli, Stefano; M., Fraquelli; C., Sardini; F., Vasta; P., Gasparini
abstract

Background and Methods Hereditary hemochromatosis in adults is usually characterized by mutations in the hemochromatosis (HFE) gene on the short arm of chromosome 6. Most patients have a substitution of tyrosine for cysteine at position 282 (C282Y). We studied a large family from Italy that includes persons who have a hereditary iron-overload condition indistinguishable from hemochromatosis but without apparent pathogenic mutations in the HFE gene. We performed biochemical, histologic, and genetic studies of 53 living members of the family, including microsatellite analysis of chromosome 6 and direct sequencing of the HFE gene, Results Of the 53 family members, 15 had abnormal serum ferritin levels, values for transferrin saturation that were higher than 50 percent, or both. Thirteen of the 15 had elevated body iron levels, diagnosed on the basis of the clinical evaluation and liver biopsy, and underwent iron-removal therapy. The other two, both children, did not undergo liver biopsy or iron-removal therapy. None of the 15 members had the C282Y mutation of the HFE gene; 5 of the 15 (as well as 5 healthy relatives) had another mutation of this gene, a substitution of aspartate for histidine at position 63, but none were homozygous for it. No other mutations were found after sequencing of the entire HFE gene for all family members. Microsatellite analysis showed no linkage of the hemochromatosis phenotype with the short arm of chromosome 6, the site of the HFE gene. Conclusions Hereditary hemochromatosis can occur in adults who do not have pathogenic mutations in the hemochromatosis gene. (N Engl J Med 1999;341:725-32,) (C)1999, Massachusetts Medical Society.


1998 - Diacerhein blocks iron regulatory protein activation in inflamed human monocytes [Articolo su rivista]
Pietrangelo, Antonello; Montosi, Giuliana; Recalcati, S; Garuti, Cinzia; Cairo, G.
abstract

Iron Regulatory Proteins (IRPs), by modulating expression of ferritin, which stores excess iron in a non toxic form, and transferrin receptor, which controls iron uptake, are the main controller of cellular iron metabolism. During inflammation, modification of IRP activity may affect iron availability, free radical generation and cytokine gene response in inflammatory cells. In the present study we tested the effect of inflammatory stimuli on IRP function in a human monocytic-macrophagic cell line and the possibility of interfering with these pathways by using an antiinflammatory compound, diacerhein (DAR). IRP activity was enhanced by interferon gamma/lipopolysaccarhide (IFN/LPS), and this effect was consistently counteracted by increasing concentrations of DAR. No direct effect of DAR on IRP activity was found in vitro. However, in vivo, similar IRP activation was achieved by exposing cells to nitric oxide (NO) donors and the LPS/IFN-induced activation of IRP was reversed by NO inhibitors. Interestingly, NO-induced IRP activation was efficiently blocked by DAR. These data show for the first time that a clinically useful antiinflammatory compound, DAR, interferes with IRP activation by NO in inflammed human cells.


1998 - Hemochromatosis 1998: is one gene enough? [Articolo su rivista]
Pietrangelo, Antonello
abstract

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1998 - Hepatic stellate cells are not subjected to oxidant stress during iron-induced fibrogenesis in rodents [Articolo su rivista]
Montosi, Giuliana; Garuti, Cinzia; S., Martinelli; Pietrangelo, Antonello
abstract

Oxidant stress plays a key role in hepatic fibrogenesis. This study was undertaken to assess whether, during iron overload-associated liver fibrosis in vivo, oxidant stress occurs in hepatic stellate cells (HSC) during active fibrogenesis. Gerbils were treated with iron-dextran, and, after hepatic fibrosis developed, livers were subjected to various combination of in situ hybridization and immunocytochemistry analyses. In iron-treated animals, no specific accumulation of ferritin protein was found in collagen mRNA-expressing cells. Moreover, the activity of the iron regulatory protein, the main sensor of cellular iron status, was unchanged in HSC from iron-treated animals. Although a significant amount of malondialdehyde-protein adducts was detected in gerbil liver during fibrogenesis, accumulation of these lipid peroxidation by-products was restricted to iron-laden cells adjacent to activated HSC. In cultured gerbil HSC, iron, aldehydes, and other pro-oxidants were able to enhance the expression of an oxidant stress-responsive gene, heme oxygenase (HO), with no change in collagen mRNA accumulation. In keeping with these findings, we found that, in vivo, activation of HO gene was present in iron-filled nonparenchymal cell aggregates, but absent in HSC. In conclusion, the data indicate that during iron overload-associated fibrogenesis, HSC are not directly subjected to oxidant stress, but are likely to be activated by paracrine signals arising in neighboring cells.


1998 - Heterogeneity of hemochromatosis in Italy [Articolo su rivista]
Piperno, A; Sampietro, M; Pietrangelo, Antonello; Arosio, C; Lupica, L; Montosi, Giuliana; Vergani, A; Fraquelli, M; Girelli, D; Pasquero, P; Roetto, A; Gasparini, P; Fargion, Silvia; Conte, Daniele; Camaschella, C.
abstract

Background & Aims: Patients with hemochromatosis show variable phenotype expression. We evaluated the frequency of hemochromatosis gene (HFE) mutations and the contribution of HFE genotype, ancestral haplotype, ethnic background, and additional factors (alcohol intake, hepatitis viruses, and beta-thalassemia trait) to the severity of iron overload in a large series of Italian patients with a hemochromatosis phenotype. Methods: HFE genotype was studied in 188 patients. Phenotype evaluation was available in 153 men and 20 women and was based mainly on iron removed. HFE genotype was determined by a polymerase chain reaction restriction assay and ancestral haplotype through D6S265 and D6S105 microsatellite analysis. Results: The frequency of C282Y homozygotes was 64%, with a decreasing gradient from north to south. C282Y homozygotes showed more severe iron overload than the other HFE genotypes. In the same group, ancestral haplotype was associated with a more severe phenotype. Additional factors may favor the development of a relatively mild hemochromatosis phenotype in patients nonhomozygous for the C282Y mutation. Conclusions: Hemochromatosis in Italy is a nonhomogenous disorder in which genetic and acquired factors are involved. In patients with a single or no HFE mutation, further studies will enable a differentiation between true genetic disorders and interactions between genetic and acquired factors.


1998 - Iron, oxidative stress and liver fibrogenesis. [Articolo su rivista]
Pietrangelo, Antonello
abstract

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1998 - Lack of coordinate control of ferritin and transferrin receptor expression during rat liver regeneration [Articolo su rivista]
Cairo, G; Tacchini, L; Pietrangelo, Antonello
abstract

Transferrin receptor (TfR) and ferritin, key proteins of cellular iron metabolism, are coordinately and divergently controlled by cytoplasmic proteins (iron regulatory proteins, IRP-1 and IRP-2) that bind to conserved mRNA motifs called iron-responsive elements (IRE). IRP, in response to specific stimuli (low iron levels, growth and stress signals) are activated and prevent TfR mRNA degradation and ferritin mRNA translation by hindering ferritin mRNA binding to polysomes. We previously found that, in regenerating liver, IRP activation was accompanied by increased TfR mRNA levels, but not by reduced ferritin expression. The basis for this unexpected behavior was investigated in the present study. Liver regeneration triggered by carbon tetrachloride (CCl4) stimulated by four- to fivefold the synthesis of both L and H ferritin chains. This increase was accompanied with a transcriptionally regulated twofold rise in the amount of ferritin mRNAs. Moreover, polysome-associated ferritin transcripts were fourfold higher in CCl4-treated animals than in control animals. Because RNA bandshift assays showed a fourfold increase in IRP-2 binding activity after CCl4 administration, activated IRP in regenerating liver seemed unable to prevent ferritin mRNAs binding to polysomes. This was confirmed by direct demonstration in the wheat germ translation system that the efficiency of IRP as a translational repressor of a mRNA bearing an IRE motif in front of a reporter transcript is impaired in CCl4-treated rats in spite of an enhanced IRE-binding capacity. In conclusion, we show for the first time that the paradigm of coordinate and opposite control of ferritin and TfR by IRP is contradicted in liver regeneration. Under these circumstances, growth-dependent signals may activate ferritin gene transcription and at the same time hamper the;ability of activated IRP-2 to repress translation of ferritin mRNAs, thus preserving for growing liver cells an essential iron-storage compartment.


1998 - Molecular genetics and control of iron metabolism in hemochromatosis [Articolo su rivista]
Pietrangelo, Antonello; Camaschella, C.
abstract

Background and Objectives. Hereditary hemochromatosis (HC) is an inborn error of iron metabolism that leads to progressive iron overload. Considerable advances in the knowledge of molecular events in iron metabolism have been recently obtained. These molecular findings, the cloning of the gene responsible for HC (HFE gene) and the results of preliminary studies on the HFE protein prompted us to review this topic. information Sources. The material examined in this review article includes papers and abstracts published in the Journals covered by the Science Citation Index(C) and Medline(C). The authors have been working in the field of HC for several years and have contributed eleven of the quoted papers. State of Art and Perspective. HC is now recognized as the genetic disease characterized by the homozygosity for the Cys --&gt; Tyr substitution at position 282 (C282Y) of the HFE protein. The mutation abolishes the association of the HFE protein with beta(2)-microglobulin (beta(2)M), making the complex unable to gain the cell surface. Thus HC is an example of abnormal trafficking of the corresponding proteins. It Is clear by the analysis of its structure that HFE protein is not an iron transporter itself, but has a regulatory role in iron metabolism. Its peculiar localization in the crypt cells of the small intestine suggests an important role in iron trafficking at this level. However, other proteins are involved in iron uptake, as the recently cloned Nramp2, the first iron transporter discovered in mammalians. Nramp2 has a recognized role both in the intestinal iron uptake and in the iron transport within the erythroblast. The relationships between HFE and Nramp2 are still unexplored. The recent association of HFE gene with transferrin receptor (TfR) in trophoblast cells opens new possibilities on its role in cellular iron uptake. The existence of other forms of genetic iron overload suggests that the scenario of iron proteins is not yet fully defined. Further studies in this field will contribute to our knowledge of iron metabolism regulation in humans. (C)1998, Ferrata Storti Foundation.


1998 - No HFE, no HLA, no 6p-linked adult hemochromatosis: A new genetic iron overload condition [Abstract in Atti di Convegno]
Pietrangelo, Antonello; Montosi, Giuliana; Garuti, Cinzia; Conte, D; Fraquelli, M; Gasparini, P.
abstract

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1998 - Oxidant stress: cell signalling and gene response in the liver: the iron-oxygen connection. [Relazione in Atti di Convegno]
Pietrangelo, Antonello; Montosi, Giuliana; Garuti, Cinzia; S., Martinelli
abstract

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1998 - Spatial and temporal dynamics of hepatic stellate cell activation during oxidant-stress-induced fibrogenesis [Articolo su rivista]
Montosi, Giuliana; Garuti, Cinzia; Iannone, Anna; Pietrangelo, Antonello
abstract

In vitro and in vivo studies indicate that oxidant stress is implicated in Liver fibrogenesis, However, it is still unknown whether, in vivo, oxidant stress directly affects the hepatic cells responsible for fibrogenesis, ie, the hepatic stellate cells (HSCs), This study was aimed at answering this question by assessing the temporal and spatial relationships between oxidant stress and activation of HSCs in an in vivo model of oxidant-stress-associated fibrogenesis, To this purpose, rats were treated with carbon tetrachloride (CCl4) and livers subjected to in situ perfusion with nitroblue tetrazolium, which, in the presence of superoxide ions, is reduced to an insoluble blue-colored formazan derivative and is readily detectable in the tissue by Light microscopy, Moreover, various combinations of in situ hybridization and immunocytochemical analyses were performed. An acute dose of CCl4 caused a transient production of superoxide radicals at 24 hours into pericentral necrotic areas, whereas HSC appearance and expression of collagen mRNA were detectable only at 48 and 72 hours. After chronic CCl4 intoxication, higher levels of oxygen radical production in necrotic areas were detectable along with dramatic and sustained activation of HSCs, However, maximal HSC activation was still delayed as compared with superoxide production. Expression of heme oxygenase, a gene responsive to a variety of oxidant stress mediators, was strongly enhanced by chronic CCl4 administration but remained unchanged in HSCs, both in situ and after isolation of pure HSC fractions from control and CCl4-treated animals. In conclusion, during postnecrotic fibrogenesis, oxidant stress anticipates HSC activation. HSCs do not directly face an oxidant stress while engaged in active fibrogenesis.


1998 - Ursodeoxycholic acid complexation with 2-hydroxypropyl-beta-cyclodextrin increases ursodeoxycholic acid biliary excretion after single oral administration in rats [Abstract in Rivista]
Ventura, Paolo; Panini, Rossana; Montosi, Giuliana; Garuti, Cinzia; Vandelli, Maria Angela; G., Brunetti; Pietrangelo, Antonello; Salvioli, Gianfranco
abstract

Complexation of ursodeoxycholic acid (UDCA) with 2-hydroxypropyl-beta-cyclodextrin (HPbCD) (1:1 molar ratio) improves the water solubility and dissolution rate of UDCA and hence its bioavailability. We compared UDCA bile recovery (percentage of administered UDCA dose excreted in bile) after single oral (gavage) administration of UDCA in three different pharmaceutical forms in a bile fistula rat model. Male Sprague-Dawley rats were randomly assigned to 11 groups (6 rats per groups); the bile duct was cannulated after gavage to collect 4-h bile samples. Groups 1, 2 and 3 (fed 5, 10 and 50 mg/kg body weight UDCA/HPbCD complex, respectively) showed (mean values ± SD) 39.2 ± 5.9%, 25.7 ± 4.1% and 9.4 ± 3.1% UDCA bile recovery, respectively; in groups 4, 5 and 6 (fed UDCA suspension formulation containing 5, 10 and 50 mg/kg body weight, respectively) UDCA bile recovery was 33.2 ± 3.6%, 16.9 ± 4.7% and 6.3 ± 0.8%, respectively; groups 7, 8 and 9 (fed UDCA capsule formulation containing 5, 10 and 50 mg/kg body weight, respectively) showed 30.6 ± 9.0%, 21.7 ± 6.4% and 4.7 ± 1.8% UDCA recovery. Groups 10 and 11 (controls) were fed with HPbCD and saline, respectively. Results indicate a significantly (p<0.05) higher bile UDCA recovery in rats fed UDCA-HPbCD complex than in those fed UDCA suspension or UDCA capsule formulations at the same dose. In this model, oral UDCA/HPbCD complex increased UDCA biliary excretion making for greater UDCA enrichment of the bile acid pool than identical doses of common pharmaceutical formulations.


1997 - HLA-H mutations in Italian patients with genetic hemochromatosis: Evidence of genetic heterogeneity [Relazione in Atti di Convegno]
Piperno, A; Sampietro, M; Arosio, C; Lupica, L; Vergani, A; Pietrangelo, Antonello; Conte, D; Pasquero, P; Nicoli, C; Montosi, Giuliana
abstract

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1997 - Inappropriately high iron regulatory protein activity in monocytes of patients with genetic hemochromatosis [Articolo su rivista]
Cairo, G; Recalcati, S; Montosi, Giuliana; Castrusini, E; Conte, D; Pietrangelo, Antonello
abstract

In genetic hemochromatosis (GH), excess iron is deposited in parenchymal cells, whereas little iron is found in reticuloendothelial (RE) cells until the later stages of the disease. As iron absorption is inversely related to RE cells stores, a failure of RE to retain iron has been proposed as the basic defect in GH. In RE cells of GH subjects, we examined the activity of iron regulatory protein (IRP), a reliable indicator of the elusive regulatory labile iron pool, which modulates cellular iron homeostasis through control of ferritin (Ft) and transferrin receptor gene expression. RNA-bandshift assays showed a significant increase in IRP activity in monocytes from 16 patients with untreated GH compared with 28 control subjects (1.5-fold) and five patients with secondary hemochromatosis (SH) with similar iron burden (fourfold). In 17 phlebotomy-treated GH patients, IRP activity did not differ from that of control subjects, In both GH and SH monocyte-macrophages, Ft content increased by twofold and the L subunit-rich isoferritin profile was unchanged as compared with controls. IRP activity was still upregulated in vitro in monocyte-derived macrophages of GH subjects but, following manipulations of iron levels, was modulated normally. Therefore, the sustained activity of monocyte IRP found in vivo in monocytes of GH patients is not due to an inherent defect of its control, but is rather the expression of a critical abnormality of iron metabolism, eg, a paradoxical contraction of the regulatory iron pool. By preventing Ft mRNA translation, high IRP activity in monocytes may represent a molecular mechanism contributing to the inadequate Ft accumulation and insufficient RE iron storage in GH.


1996 - C/EBP-beta/LAP controls down-regulation of albumin gene transcription during liver regeneration [Articolo su rivista]
Trautwein, C; Rakemann, T; Pietrangelo, Antonello; Plumpe, J; Montosi, Giuliana; Mann, Mp
abstract

Expression of the albumin gene in the liver is controlled by several liver-enriched transcription factors. However, the mechanisms which contribute to its regulation during pathophysiological states, such as liver regeneration, are still little understood. In the present study we found that during liver regeneration downregulation of albumin mRNA expression is transcriptionally controlled through a minimal element (nucleotide -170 to +22) of the albumin promoter and is observed mainly during the G(1) phase of the cell cycle, while high levels of albumin expression are preserved at later time points, Decreased albumin mRNA levels correlate with a dramatic increase in nuclear expression of C/EBP-beta/LAP, a protein known to bind to the D site of the albumin promoter and also to be involved in cell cycle control. In contrast, nuclear expression of other factors such as HNF-1 or C/EBP-alpha, which also have been shown to transcriptionally control albumin expression, is either unchanged or slightly decreased. We show that pre- and post-translational mechanisms are involved in the higher nuclear expression of C/EBP-beta/LAP as early as 1 h after hepatectomy, which also leads to ifs increased binding toward the D site of the albumin promoter. Finally, in vitro transcription assays with liver nuclear extracts and recombinant C/EBP-beta/LAP demonstrate that C/EBP-beta/LAP can directly down-regulate transcription mediated by the minimal element of the albumin promoter. Additionally the inhibitory role of C/EBP-beta/LAP on the albumin minimal promoter could be confirmed by transfection experiments in hepatoma cells. These results indicate that C/EBP-beta/LAP, while enhancing transcription of cell cycle-related genes and controlling G(1)/S phase checkpoint, down-regulates a major liver function, i.e. albumin synthesis, to prepare the hepatocyte for entry into the cell cycle.


1996 - Defective control or iron metabolism in pre-neoplastic liver nodules during experimental carcinogenesis [Abstract in Atti di Convegno]
Pietrangelo, Antonello; Montosi, Giuliana; Garuti, Cinzia; Stal, P; Eriksson, L.
abstract

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1996 - Expression of messenger RNA for liver functions following 70% and 90% hepatectomy [Articolo su rivista]
Tygstrup, N; Jensen, Sa; Krog, B; Pietrangelo, Antonello; Shafritz, Da
abstract

Aims/Methods: The effect of moderate and severe reduction of the functional liver mass on gene expression for liver functions was studied in rats following 70% and 90% hepatectomy. At intervals up to 24 h after operation rats were killed and RNA was extracted from the remaining liver tissue. By slot-blot hybridization mRNA steady-state levels were determined for enzymes involved in metabolic 'liver-specific' functions, acute phase proteins, 'house-keeping', and growth-related proteins. Results were expressed as per cent of levels in a pool from fed control rats of the same gender and age. Results: Among 'liver-specific' metabolic functions only expression of gluconeogenesis, represented by phosphoenol carboxykinase mRNA, was augmented initially, followed by a fall to very low values after 90% hepatectomy. The drug metabolizing system represented by CYP2B1/2 mRNA was reduced to half of the control values. Expression of urea synthesis, as reflected by carbamoylphosphate synthetase mRNA, showed a gradual decline after 90% hepatectomy, in contrast to rising levels of argininosuccinate lyase and arginase mRNA, possibly serving polyamine rather than urea synthesis. The mRNA level of the acute phase protein al-acid glycoprotein showed a smaller and later rise in 90% than in 70% hepatectomized rats, whereas that of alpha 2-macroglobulin only increased after 90% hepatectomy like the 'housekeeping' beta-actin mRNA. A rise in histone 3, which coincides with mitosis, was only seen after 70% hepatectomy, indicating that after 90% hepatectomy the response to growth-stimulating factors is weak or delayed, supported by a delayed rise in cyclin d and low levels of growth hormone receptor mRNA. Conclusions: It is concluded that attempts by gene regulation to adapt liver functions to a reduction of the liver mass depend on the amount of liver tissue lost. When the loss is nearly fatal, compensation for normal metabolic functions may be abandoned for efforts to regenerate, which, however, may be delayed or after all be too weak.


1996 - Metals, oxidative stress, and hepatic fibrogenesis [Articolo su rivista]
Pietrangelo, Antonello
abstract

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1995 - Antioxidant activity of silybin in vivo during long-term iron overload in rats [Articolo su rivista]
Pietrangelo, Antonello; F., Borella; Casalgrandi, Giovanna; Montosi, Giuliana; D., Ceccarelli; D., Gallesi; F., Giovannini; A., Gasparetto; Masini, Alberto
abstract

Background &amp; Aims: Hepatic iron toxicity may be mediated by free radical species and lipid peroxidation of biological membranes. The antioxidant property of silybin, a main constituent of natural flavonoids, was investigated in vivo during experimental iron overload. Methods: Rats were fed a 2.5% carbonyl-iron diet and 100 mg . kg body wt(-1). day(-1) silybin for 4 months and were assayed for accumulation of hepatic lipid peroxidation by-products by immunocytochemistry, mitochondrial energy-dependent functions, and mitochondrial malondialdehyde content. Results: Iron overload caused a dramatic accumulation of malondialdehyde-protein adducts into iron-filled periportal hepatocytes that was decreased appreciably by silybin treatment. The same beneficial effect of silybin was found on the iron-induced accumulation of malondialdehyde in mitochondria. As to the liver functional efficiency, mitochondrial energy wasting and tissue adenosine triphosphate depletion induced by iron overload were successfully counteracted by silybin. Conclusions:Oral administration of silybin protects against iron-induced hepatic toxicity in vivo. This effect seems to be caused by the prominent antioxidant activity of this compound.


1995 - Basal promoter of the rat connexin 32 gene: Identification and characterization of an essential element and its DNA-binding protein [Articolo su rivista]
Bai, S.; A., Schoenfeld; Pietrangelo, Antonello; R. D., Burk
abstract

The connexin 32 (Cx32) gene, a member of a multigene family, is expressed preferentially in the liver. The basal promoter complex of the rat Cx32 gene was previously localized to a 146-bp region (map positions [mp] -179 to -34) immediately upstream of the first exon. To investigate the biochemical factors contributing to the basal promoter activity, nuclear protein-DNA complexes within this region (mp -177 to -106) were investigated by using a DNA mobility shift assay. Three DNA-protein binding activities, termed Cx32-B1, Cx32-B2, and Cx32-B3, were identified with nuclear protein extracts from hepatoma cell lines, HuH7 and FAO-1. However, only Cx32-B2 binding activity was detected in nuclear protein extract from normal rat liver tissue. This activity was significantly more abundant in rat liver tissue than in hepatoma cell lines and tissues from various other organs. By using methylation interference footprinting, the Cx32-B2 complex was localized to the region between mp -152 and -127 and a DNA probe containing this region bound to a 60-kDa protein in rat liver nuclear extracts. Mutation of two nucleotides in the Cx32-B2 binding site abrogated the formation of the Cx32-B2 protein-DNA complex and significantly reduced the transcriptional activity of the Cx32 promoter. These results indicate that the Cx32-B2 complex is an essential component of the rat Cx32 basal promoter and is likely a major factor in the preferential expression of this gene in the liver.


1995 - Duodenal ferritin synthesis in genetic hemochromatosis [Articolo su rivista]
Pietrangelo, Antonello; Casalgrandi, Giovanna; Quaglino, Daniela; R., Gualdi; D., Conte; S., Milani; Montosi, Giuliana; Ventura, Ezio; L., Cesarini; G., Cairo
abstract

Background/Aims: The molecular defect of genetic hemochromatosis (GH) is unknown. It is believed that low expression of duodenal ferritin in GH is caused by tissue or cell specific defect of ferritin synthesis. Our study was designed to ascertain whether the control of duodenal ferritin synthesis in GH was defective. Methods: Expression at the single cell level of H and L ferritin messenger RNAs and protein and activity of the iron regulatory factor, which controls the translation of ferritin messenger RNA, were assessed in 43 duodenal biopsy specimens from individuals with GH, secondary hemochromatosis (SH), anemia, or normal iron balance. Results: Signal for ferritin H and L subunit messenger RNAs was detected in both absorptive and nonabsorptive cells by in situ hybridization, but in 10 of 14 patients with untreated GH, the signal was lower than in patients with SH or normal subjects. However, immunostaining for ferritin protein documented a diffuse/cytoplasmic pattern, whereas a supranuclear/granular staining was found in normal subjects or patients with SH. The spontaneous activity of duodenal iron regulatory factor was consistently higher in patients with GH than in normal subjects or subjects with anemia or SH. Conclusions: In patients with GH, ferritin gene transcription is preserved in both absorptive and nonabsorptive intestinal cells. Low accumulation of ferritin is not caused by a defective control of ferritin synthesis but by low expression of ferritin messenger RNA and sustained activity of iron regulatory factor.


1995 - Erratum: Duodenal ferritin synthesis in genetic hemochromatosis (Gastroenterology (1995) 108 (208-207)) [Articolo su rivista]
Pietrangelo, A.; Casalgrand, G.; Quaglino, D.; Gualdi, R.; Conte, D.; Milani, S.; Montosi, G.; Cesarini, L.; Ventura, E.; Cairo, G.
abstract


1995 - Gene expression of urea cycle enzymes following two-thirds partial hepatectomy in the rat. [Articolo su rivista]
Tygstrup, N; Bak, S; Krog, B; Pietrangelo, Antonello; Shafritz, Da
abstract

The effect of reduction of functional liver mass on the expression of enzyme systems for hepatic urea synthesis was assessed in rats following two-thirds partial hepatectomy. Results were related to normal, fed rats and to sham-operated rats, with identical timing for surgery and feeding.Among the five urea cycle enzymes the mRNA steady-state level was higher in hepatectomized than in sham-operated rats for carbamoyl phosphate synthetase and arginino-succinate lyase, The level for albumin mRNA remained close to that of the controls. Relative transcription rates were found to be increased for carbamoyl phosphate synthetase, arginino-succinate synthase and arginase, For albumin the transcription rate was drastically reduced initially, but recovered gradually during the experimental period.The data indicate that the expression of urea cycle enzymes, in particular that of carbamoyl phosphate synthetase which is the rate-limiting step, is up-regulated by partial hepatectomy, This helps to maintain urea synthesis rate at a normal or near normal level during the period of reduced liver mass, confirming metabolic studies. In contrast, the transcription for albumin was reduced.The immediate increase in urea cycle enzyme expression during the period of acute hepatocyte loss is consistent with the view that it is vitally important that urea synthesis, in contrast to e.g. albumin synthesis, remains intact when the metabolic capacity of the liver is reduced.


1995 - MOLECULAR AND CELLULAR ASPECTS OF IRON-INDUCED HEPATIC CIRRHOSIS IN RODENTS [Articolo su rivista]
Pietrangelo, Antonello; Gualdi, Rossana; Casalgrandi, Giovanna; Montosi, Giuliana; Ventura, Ezio
abstract

Hepatic fibrosis and cirrhosis are common findings in humans with hemochromatosis, In this study we investigated the molecular pathways of iron-induced hepatic fibrosis and evaluated the anti-fibrogenic effect of vitamin E. Male gerbils were treated with iron-dextran and fed a standard diet or a alpha-tocopherol enriched diet (250 mg/Kg diet), In gerbils on the standard diet at 6 wk after dosing with iron, in situ hybridization analysis documented a dramatic increase of signal for collagen mRNA around iron foci onto liver fat storing cells (FSC), as identified by immunocytochemistry with desmin antibody, After 4 mo, micronodular cirrhosis developed in these animals, with nonparenchymal cells surrounding hepatocyte nodules and expressing high level of TGF beta mRNA, In this group, in vivo labeling with [H-3]thymidine showed a marked proliferation of nonparenchymal cells, including FSC, In iron-dosed gerbils on the vitamin E-enriched diet for 4 mo, in spite of a severe liver iron burden, a normal lobular architecture was found, with a dramatic decrease of collagen mRNA accumulation and collagen deposition. At the molecular level, a total suppression of nonparenchymal cell proliferation was appreciable, although expression of collagen and TGF beta mRNAs was still present into microscopic iron-filled nonparenchymal cell aggregates scattered throughout the hepatic lobule, In conclusion, our study shows that anti-oxidant treatment during experimental hepatic fibrosis arrests fibrogenesis and completely prevents iron induced hepatic cirrhosis mainly through inhibition of nonparenchymal cell proliferation induced by iron.


1995 - MOLECULAR AND CELLULAR ASPECTS OF LIVER-DISEASE IN GENETIC HEMOCHROMATOSIS [Abstract in Atti di Convegno]
Pietrangelo, Antonello; Montosi, Giuliana; Garuti, Cinzia; Stal, P; Hultcrantz, R.
abstract

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1995 - Nitric-oxide-mediated activation of iron-regulatory protein controls hepatic iron metabolism during acute inflammation. [Articolo su rivista]
Cairo, G; Pietrangelo, Antonello
abstract

The molecular regulation of intracellular iron metabolism has been studied in the livers of rats undergoing an acute inflammatory reaction following turpentine injection. Treatment induced an increase in the steady-state level of the transferrin receptor (TfR) mRNA, peaking 18 h after treatment and returning to control levels 24 h after treatment, with no change in TfR gene transcription. RNA band-shift assays documented an activation of the cytoplasmic RNA-binding protein called the iron-regulatory protein (IRP), in parallel with a rise in the amount of TfR transcripts. A 2-3-fold increase in the amount of H and L ferritin subunit mRNAs was found 12-18 h after turpentine treatment. Surprisingly, higher accumulation of ferritin mRNAs did not result in appreciable differences in the liver ferritin content. This might be due to the concomitant rise of IRP activity, which is known to prevent ferritin mRNA translation. The absence of significant changes in the total iron and ferritin contents prompted us to investigate the role of nitric oxide (NO), an inflammatory mediator which is also known to modulate the activity of IRP. Northern-blot analysis showed a marked enhancement in the expression of the inducible form of nitric oxide synthase mRNA in turpentine-treated rats. Furthermore, the activation of IRP and the increase of the TfR mRNA content that occur in turpentine-treated rats were abolished by treatment with N5-nitro-L-arginine, a specific nitric oxide synthase inhibitor. The present data suggest that NO-mediated activation of IRP regulates alterations of hepatic iron homeostasis that occur in acute inflammation.


1994 - Enhanced hepatic collagen type I mRNA expression into fat-storing cells in a rodent model of hemochromatosis. [Articolo su rivista]
Pietrangelo, Antonello; Gualdi, R; Casalgrandi, Giovanna; Geerts, A; DE BLESER, P; Montosi, Giuliana; Ventura, Ezio
abstract

recent years, identifying the hepatic cell type responsible for collagen synthesis in experimental models of postnecrotic or inflammatory fibrosis has been the subject of active investigation. In primary iron overload states, however, hepatic fibrosis and cirrhosis occur without accompanying necroinflammatory phenomena. In this study, we combined morphological, immunological, cell isolation and purification and molecular biological techniques to identify the hepatic cell responsible for enhanced collagen type I gene expression during chronic enteral iron overload in the rat. Ultrastructural analysis of liver tissue sections from iron-loaded rats specifically revealed an altered appearance of fat-storing cells, which showed few if any fat droplets left and increased rough endoplasmic reticulum. In situ hybridization analysis with specific complementary RNA probes identified enhanced signal for collagen type I into nonparenchymal cells in zones 1 and 2, without signal over the background onto iron-laden hepatocytes. Immunocytochemistry with desmin antibodies combined with in situ hybridization on the same tissue sections identified the cells expressing high level of collagen type I transcripts as fat-storing cells. Northern-blot analysis on RNA extracted from various purified cell isolates, confirmed the presence of collagen type I mRNA signal only into the fat-storing cells isolate. Our study shows that in an experimental model of metabolic fibrosis in which the hepatotoxin selectively accumulates into parenchymal cells, fat-storing cells are the main source of enhanced collagen type I gene expression.


1994 - Excess iron into hepatocytes is required for activation of collagen type I gene during experimental siderosis [Articolo su rivista]
R., Gualdi; Casalgrandi, Giovanna; Montosi, Giuliana; Ventura, Ezio; Pietrangelo, Antonello
abstract

Background/Aims: Liver fibrosis and cirrhosis represent common pathological findings in humans with iron overload. This study was undertaken to assess whether in vivo targeting of iron to liver parenchymal or nonparenchymal cells would differently affect collagen gene activity. Methods: Rats were treated with an iron diet or intramuscular injections of iron dextran, and in situ hybridization analyses on liver samples were performed. Results: These iron treatments determined parenchymal or reticuloendothelial cell iron overload, respectively. The typical distribution of iron into different liver cells was documented by histochemistry and confirmed by in situ hybridization analysis with a ferritin L complementary RNA probe. In iron-fed rats, in situ hybridization analysis identified a signal for collagen type I messenger RNA into nonparenchymal cells in zones I and ii. In rats with nonparenchymal cell iron overload, no activation of collagen gene expression was detected into or near iron-laden nonparenchymal cells. These findings were also confirmed by quantitative Northern blot analysis. Conclusions: The results of this study indicate that, regardless of the total hepatic iron burden, selective localization of iron into liver cells (i.e., parenchymal cells) is required for the activation of collagen gene during long-term iron overload in rodents.


1994 - Homeostatic regulation of hepatocyte nuclear transcription factor 1 expression in cultured hepatoma cells [Articolo su rivista]
Pietrangelo, Antonello; D. A., Shafritz
abstract

Serum colloid osmotic pressure is believed to control the hepatic output of plasma proteins, including albumin. The present study was aimed at identifying the molecular basis for feedback control of albumin gene expression in highly differentiated hepatoma cells. The steady-state level of albumin mRNA and the activity of a 282-bp albumin promoter-chloramphenicol acetyltransferase reporter gene in cells incubated in the presence of increasing amounts of serum albumin or dextran were significantly and selectively decreased. When nuclear extracts from cells exposed to 5% (wt/vol) serum albumin were tested in a gel-retardation assay with six oligonucleotide probes containing DNA elements of the albumin promoter, only the element B-retarded band, which contains the nucleotide recognition sequence for hepatocyte nuclear transcription factor 1alpha (HNF-1alpha), was consistently decreased as compared to nuclear extract from cells not exposed to serum albumin. Moreover, the activity of a reporter gene with a basal TATA-promoter driven by multiple HNF-1alpha recognition elements was selectively inhibited in cells incubated in the presence of 5% serum albumin. A reduction of HNF-1alpha mRNA appears to be responsible for this response to a change in the level of macromolecules in the incubation medium. These results indicate that activity of a dominant liver transcription factor, HNF-1alpha, controlling the transcription of several liver-specific genes, is modulated by a fluctuation in the level of oncotically active macromolecules.


1994 - IRON IS A MITOGENIC AND PROFIBROGENIC FACTOR IN EXPERIMENTAL LIVER FIBROSIS DUE TO IRON OVERLOAD [Abstract in Atti di Convegno]
Pietrangelo, Antonello; Gualdi, Rossana; Casalgrandi, Giovanna; Montosi, Giuliana; Ventura, Ezio
abstract

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1994 - Iron overload in rodents leads to hepatic cirrhosis through enhancement of collagen gene expression into non-parenchymal cells. [Capitolo/Saggio]
Pietrangelo, Antonello; Gualdi, Rossana; G., Casalgrandi; Montosi, Giuliana; Ventura, Ezio
abstract

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1994 - Transferrin receptor gene expression during rat liver regeneration. Evidence for post-transcriptional regulation by iron regulatory factorB, a second iron-responsive element-binding protein. [Articolo su rivista]
Cairo, G; Pietrangelo, Antonello
abstract

Transferrin receptor (TfR) expression is regulated by iron at the level of mRNA stability through a factor (IRF/ IRE-BP) which binds to specific iron-responsive elements (IRE). On the other hand, growth-dependent regulation of TfR expression is generally believed to be transcriptionally controlled. We analyzed the molecular mechanisms that control TfR gene expression at the onset of cell proliferation in vivo during liver regeneration after partial hepatectomy. The amount of TfR mRNA increased considerably after partial hepatectomy while run-on assays did not show significant changes in TfR gene transcription. RNA band-shift assays documented a significant activation of IRF/IRE-BP specific for the faster migrating IRE-protein complex (IRF(B)). These changes occurred in the absence of modifications of total liver iron concentration but together with a significant decrease of ferritin content. Moreover, when extreme variations of liver iron content were achieved by either chronic iron overload or severe iron deficiency, liver regeneration was unable to influence IRE-binding activity. We conclude that IRF/IRE-BP-mediated post-transcriptional control can fully account for TfR mRNA induction during liver cell proliferation in vivo. IRF/ IRE-RE activation in the absence of changes in total tissue iron content might depend either on a drop of iron levels into the regulatory pool or on a relatively iron-independent mechanism specific for the faster migrating complex.


1993 - The role of Ito cells in the biosynthesis of HGF-SF in the liver. [Capitolo/Saggio]
Schirmacher, P; Geerts, A; Jung, W; Pietrangelo, Antonello; Rogler, Ce; Dienes, Hp
abstract

Hepatocyte Growth Factor-Scatter Factor (HGF-SF) is produced by sinusoidal cells in normal rat liver. Analysis of isolated cells has proven that Ito cells (fat-storing cells, hepatic lipocytes) are the source of hepatic HGF. In diseased liver the HGF-expression pattern is more complex. In acute liver injury HGF is expressed by an increased number of resident liver cells, which may be due to recruitment of other nonparenchymal liver cells as well as an increased number of Ito cells due to cell division. In cirrhotic rat liver tissue, the number of HGF-expressing cells is decreased. This may be explained by the complete loss of HGF-expression in myofibroblast-like cells derived from Ito cells. Quiescent Ito cells seem to be in a strategic position to control parenchymal cell proliferation. Activation of Ito cells, which occurs in chronic fibrotic liver disease, may lead to the loss of this control function.


1993 - VITAMIN-E SUPPLEMENTATION PREVENTS HEPATIC CIRRHOSIS DUE TO IRON OVERLOAD IN RODENTS [Abstract in Atti di Convegno]
Pietrangelo, Antonello; Gualdi, Rossana; Casalgrandi, Giovanna; Montosi, Giuliana; Ventura, Ezio
abstract

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1992 - Albumin gene expression is down-regulated by albumin or macromolecule infusion in the rat. [Articolo su rivista]
Pietrangelo, Antonello; Panduro, A; Chowdhury, Jr; Shafritz, Da
abstract

A novel feedback regulatory mechanism operating on transcription of the albumin gene is described in the rat. In 1946, it was proposed that circulating colloids, including serum albumin, may affect the synthesis and/or secretion of albumin in the liver. The molecular basis for this proposed regulation has now been investigated by adding oncotically active macromolecules to the circulation of normal or genetically albumin-deficient Nagase analbuminemic rats (NAR) and analyzing the hepatic expression of genes, including albumin after 24 h. The transcription rate of the albumin gene was higher in NAR than in normal rats and was dramatically reduced by raising serum albumin to 1.6 g/dl. Intravenous infusion of albumin into normal rats also decreased transcriptional activity of the albumin gene by 50-60%, and this decrease correlated with changes in serum colloid osmotic pressure after albumin infusion. Inhibition of albumin gene transcription was also observed upon intravenous infusion of other protein or nonprotein macromolecules, such as gamma-globulin and dextran. This down-regulation appears to control the steady-state level of albumin mRNA in the liver. Aside from a concomitant decrease in apo E gene transcription after albumin or macromolecule infusion, there was no change in the transcription rate of other genes, including those exhibiting liver-preferred or -specific expression (e.g., tyrosine aminotransferase, cytochrome P450, alpha-1-antitrypsin, apolipoproteins A-I and B, and transferrin) or general cellular expression (e.g., alpha-tubulin, pro alpha-2-collagen, and beta-actin). Feedback regulation of albumin gene expression by serum colloids may serve as a specific homeostatic mechanism to maintain the steady-state level of total protein in the circulation.


1992 - Enhanced hepatic collagen gene expression in a rodent model of haemochromatosis [Capitolo/Saggio]
Pietrangelo, Antonello; Quaglino, Daniela; Gualdi, Rossana; G., Casalgrandi; G., Cairo; Ventura, Ezio
abstract

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1992 - Hepatocyte growth factor/hepatopoietin A is expressed in fat-storing cells from rat liver but not myofibroblast-like cells derived from fat-storing cells. [Articolo su rivista]
Schirmacher, P; Geerts, A; Pietrangelo, Antonello; Dienes, Hp; Rogler, Ce
abstract

Hepatocyte growth factor/hepatopoietin A is a complete mitogen for parenchymal liver cells, and its expression is increased as an early response to acute liver injury. To identify the liver cell population responsible for hepatocyte growth factor gene expression, we investigated tissue sections and isolated and purified cell fractions from normal rat liver by in situ and Northern blot hybridization. Hepatocyte growth factor transcripts were present in sinusoidal liver cells, which were preferentially located in the periportal parenchyma. Northern hybridization analysis of RNA isolated from purified liver cell fractions demonstrated that HGF messenger RNA is present only in fat-storing cells. No specific hepatocyte growth factor gene expression was detected in parenchymal cells, endothelial cells and Kupffer cells. Myofibroblast-like transition of fat-storing cells, which is linked to fibrogenesis in chronic liver disease, results in the loss of hepatocyte growth factor expression. Hepatocyte growth factor gene expression in the normal liver, a new function of fat-storing cells, suggests that this growth factor may play a role in the physiological balance between cell death and replacement in the liver and that hepatocyte growth factor may also act in a paracrine manner. Furthermore, loss of hepatocyte growth factor expression in myofibroblast-like cells derived from fat-storing cells may be responsible for reduced parenchymal cell regeneration in chronic liver disease.


1992 - Regulation of transferrin, transferrin receptor, and ferritin genes in human duodenum [Articolo su rivista]
Pietrangelo, Antonello; Rocchi, Emilio; G., Casalgrandi; G., Rigo; Ferrari, Alberto; M., Perini; Ventura, Ezio; G., Cairo
abstract

To gain insights at the molecular level into the expression of iron-regulated genes [transferrin (Tf), transferrin receptor (TfR), and ferritin H and L subunits] in human intestinal areas relevant to iron absorption, the steady-state levels of specific messenger RNAs (mRNAs) were analyzed in gastric and duodenal samples obtained from 6 normal subjects, or 10 patients with anemia, 14 patients with untreated iron overload, and 8 patients with various gastrointestinal disorders. No Tf mRNA was detected in human gastroduodenal tissue, confirming earlier findings in the rat. In normal subjects, although higher levels of ferritin H- and L-subunit mRNAs were consistently found in duodenal than in gastric samples, no differences in the content of TfR transcripts were detected. However, a dramatic increase in TfR mRNA levels was specifically found in duodenal samples from subjects with mild iron deficiency but severe anemia. This response of the TfR gene is presumably secondary to decreased cellular iron content due to its accelerated transfer into the bloodstream, as also indicated by the low levels of ferritin subunit mRNAs found in the same tissue samples, and is not linked to faster growth rate of mucosal cells because no changes in duodenal expression of histone, a growth-related gene, were detected. In patients with secondary iron overload, a down-regulation of duodenal TfR gene expression and a concomitant increase in ferritin mRNA content were documented. On the contrary, a lack of TfR gene down-regulation and an abnormally low accumulation of ferritin H- and L-subunit mRNAs were detected in the duodenums of subjects with idiopathic hemochromatosis. Whether these molecular abnormalities in idiopathic hemochromatosis are relevant to the metabolic defect(s) of the disease is presently unknown.


1991 - REGULATION OF HEPATIC IRON AND COLLAGEN GENES DURING EXPERIMENTAL AND HUMAN SIDEROSIS [Articolo su rivista]
Pietrangelo, Antonello; Cairo, G; Gualdi, R; Ventura, E.
abstract


1991 - Regulation of hepatic transferrin, transferrin receptors and ferritin genes in human siderosis. [Articolo su rivista]
Pietrangelo, Antonello; Rocchi, Emilio; Ferrari, Alberto; Ventura, Ezio; G., Cairo
abstract

Although many studies have examined the regulation of transferrin, transferrin receptor and ferritin subunit gene expression in experimental systems, no molecular biological data in humans have been documented to date. In this study we simultaneously analyzed the hepatic content of transferrin, transferrin receptor and heavy and light ferritin subunit messenger RNAs in tissue samples obtained from subjects with normal iron balance and patients with primary or secondary iron overload. Steady-state levels of transferrin messenger RNA were not depressed by iron overload. On the contrary, they were increased (p < 0.001) in patients with severe hepatic siderosis (liver iron content > 200-mu-mol/gm dry wt) as compared with the control group. This indicates that, as already suggested by our previous data in experimental siderosis, iron maintains the ability to induce transferrin gene activity even when cellular iron content is significantly increased. Transferrin receptor gene expression was found to respond in the same manner to any cause of iron-tissue load, regardless of the cause. In fact, a lower signal for transferrin receptor messenger RNA was consistently detected in iron-overloaded patients vs. control subjects, particularly in patients with thalassemia major and idiopathic hemochromatosis (p < 0.001). Ferritin light-subunit messenger RNA accumulation was significantly increased in those patients with severe siderosis (idiopathic hemochromatosis and thalassemia major = liver iron between 200 and 600-mu-mol/gm dry wt). The fact that no significant change in hepatic ferritin heavy-subunit gene expression was detected in iron-loaded patients confirms preferential production of light-subunit-enriched ferritins in long-term iron overload. In addition, our data indicate that, in conditions where liver-specific abnormalities of iron-regulated proteins have been suggested (i.e., idiopathic hemochromatosis and sporadic porphyria cutanea tarda), the hepatic control of human iron metabolism, as inferred by the activity of transferrin, transferrin receptor and ferritin genes, is normal.


1990 - Diagnosis of digestive diseases. [Articolo su rivista]
Coppo, M; Gibertini, P; Pietrangelo, Antonello
abstract

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1990 - Lipid composition and fluidity of liver mitochondria, microsomes and plasma membrane of rats with chronic dietary iron overload. [Articolo su rivista]
Pietrangelo, Antonello; Grandi, R; Tripodi, A; Tomasi, Aldo; Ceccarelli, D; Ventura, E; Masini, A.
abstract

The effect of chronic dietary iron overload on the lipid composition and physical state of rat liver mitochondria, microsomes and plasma membranes was investigated. After 9 weeks of iron treatment, a significant decrease of polyunsaturated and a parallel increase of saturated fatty acids was observed in mitochondrial and plasma membrane phospholipids. By contrast, no appreciable modification of the fatty acid composition of microsomal membranes was detected. The cholesterol/phospholipid molar ratio as well as the lipid/protein ratio, did not reveal any significant difference in any of the fractions studies. Finally, no change in the molecular order of the various membranes, as assessed by electron spin resonance spectrometry, was observed following iron intoxication. These data indicate that, although in vivo chronic hepatic iron overload induces a modification of fatty acid profile in cellular structures consistent with the in vivo occurrence of lipid peroxidation, these changes do not bring about appreciable modifications of other physico-chemical parameters relevant to membrane integrity and cell viability.


1990 - Liver gene expression during chronic dietary iron overload in rats [Articolo su rivista]
Pietrangelo, Antonello; Rocchi, Emilio; L., Schiaffonati; E., Ventura; G., Cairo
abstract

To clarify the pathogenesis of hepatic iron toxicity, we investigated the effect of chronic dietary iron overload on the expression of several genes in rat liver. After 10 wk of iron treatment, when only minor histological features of liver damage were appreciable, the level of pro-alpha 2(I)-collagen mRNA was already higher than in control liver and increased further at 30 wk of treatment. Also, the relative amount of L ferritin subunit mRNA was enhanced early by iron load and was even more elevated at the latest time point considered, whereas neither H ferritin subunit nor transferrin mRNA levels were affected by iron treatment. In contrast, after chronic iron treatment, no variations were found in the steady-state level of mRNAs transcribed from liver-specific and preferentially expressed genes (albumin, alpha-fetoprotein, apolipoprotein A-1), growth-related genes (c-myc, c-Ha-ras and c-fos) and stress-induced genes (heat shock protein 70). These results suggest that chronic dietary iron overload in rats can specifically activate target genes in the liver (i.e., L ferritin and procollagen) in the absence of either histological signs of severe liver damage or alterations in differentiated liver functions.


1989 - Effect of heparin-like compounds on the in vitro proliferation and protein synthesis of various cell types. [Articolo su rivista]
Tiozzo, Roberta; Cingi, Mr; Pietrangelo, Antonello; Albertazzi, L; Calandra, S; Milani, Mr
abstract

Previous studies have shown that heparin and heparin-like compounds inhibit the proliferation of arterial smooth muscle cells (SMC) both in vivo and in vitro. This anti-proliferative effect seems to be exerted almost exclusively on arterial SMC and related cell types. In the present study the effect of heparin (HTh) is compared with that of two sulfated glycosaminoglycans with low anticoagulant activity, sulodexide (SDX) and low molecular weight heparin (OP/LMWH) on cell proliferation and protein synthesis of 3 cell types: human arterial smooth muscle cells (SMC), fibroblast-like cells (BHK-21) and epithelial cells (rat hepatoma cells, FAO). HTh, SDX and OP/LMWH (5-100 micrograms/ml) are equally effective in reducing the proliferation of human arterial SMC. This inhibition is dose dependent and reversible. BHK-21 and FAO cells are even more sensitive than SMC to heparin-like compounds. For example 1 microgram/ml of heparin-like compounds is sufficient to produce 40-60% inhibition of FAO cell proliferation. In all types of cells HTh, SDX and OP/LMWH do not reduce the incorporation of 35S-methionine into cellular and medium proteins; they increase the radioactivity incorporated into some proteins secreted into the medium. In the case of SMC this effect is dependent on the concentration and the length of exposure to heparin-like compounds. These findings demonstrate that several cell types are sensitive to the anti-proliferative effect of heparin-like compounds.


1989 - Lipid composition and fluidity of liver plasma membranes from rats with chronic dietary iron overload. [Articolo su rivista]
Pietrangelo, Antonello; Tripodi, A; Carulli, N; Tomasi, Aldo; Ceccarelli, D; Ventura, Ezio; Masini, A.
abstract

Liver plasma membranes isolated from rats with chronic dietary iron overload showed a large modification of their phospholipid fatty acid composition. Specifically, a significant decrease in polyunsaturated fatty acids and a parallel increase in saturated fatty acids was observed. This pattern was consistent with the in vivo occurrence of lipoperoxidative reactions in the liver plasma membranes. However, neither change in the cholesterol/phospholipid molar ratio nor in the lipid/protein ratio was detected. Direct measurement of the plasma membrane fluidity state by electron spin resonance spectrometry did not reveal any difference between control and iron-treated rats. These findings indicate that chronic dietary iron overload can induce lipid peroxidation of rat liver plasma membranes, but this event does not bring about modification in the physical state of the membrane.


1989 - Translational regulation of ferritin synthesis in rat liver. Effects of chronic dietary iron overload. [Articolo su rivista]
Cairo, G; Tacchini, L; Schiaffonati, L; Rappocciolo, E; Ventura, Ezio; Pietrangelo, Antonello
abstract

In rats with chronic dietary iron overload, a higher amount of liver ferritin L-subunit mRNA was found mainly engaged on polysomes, whereas in control rats ferritin L-subunit mRNA molecules were largely stored in ribonucleoprotein particles. On the other hand, ferritin H-subunit mRNA was unchanged by chronic iron load and remained in the inactive cytoplasmic pool. In agreement with previous reports, in rats acutely treated with parenteral iron, only the ferritin L-subunit mRNA increased in amount, whereas both ferritin subunit mRNAs shifted to polysomes. This may indicate that, whereas in acute iron overload the hepatocyte operates a translation shift of both ferritin mRNAs to confront rapidly the abrupt entry of iron into the cell, during chronic iron overload it responds to the slow iron influx by translating a greater amount of L-subunit mRNA to synthesize isoferritins more suitable for long-term iron storage.


1988 - DNA repair in lymphocytes from humans and rats with chronic iron overload. [Articolo su rivista]
Pietrangelo, Antonello; Cossarizza, Andrea; Monti, D; Ventura, Ezio; Franceschi, C.
abstract

A marked reduction of the proliferative capability after a mitogenic stimulus and a dramatic decrease of the capacity to repair DNA damages were found in lymphocytes from iron overloaded rats. These immunological parameters were not significantly different from controls in peripheral blood lymphocytes from patients with primary iron overload: hereditary hemochromatosis and porphyria cutanea tarda. This discrepancy could be due to the accelerated modality of iron overload in the rat model and to the fact that rat lymphocytes were obtained from an highly iron repleted microenvironment (i.e. spleen). Our data indicate that iron overload can affect the structure and/or the function of cellular DNA thus offering new insights on the close association of iron overload conditions and cancer.


1988 - Modulation of the synthesis of apolipoproteins in rat hepatoma cells. [Articolo su rivista]
Pietrangelo, Antonello; Tiozzo, Roberta; Ghisellini, Margherita; Cingi, Mr; Albertazzi, L; Ventura, E; CALANDRA BUONAURA, Sebastiano
abstract

The present study was designed to investigate whether plasma lipoproteins and albumin can affect the basal synthetic rate of apolipoproteins in differentiated rat hepatoma cells (Fao) incubated in serum-free medium. The synthesis of apolipoproteins was measured by the incorporation of [35S]methionine into medium lipoproteins isolated by density gradient ultracentrifugation. Under all the experimental conditions used, Fao cells synthesized almost exclusively apolipoprotein E. When cells were incubated in the presence of 5-10% rat plasma the synthesis of apolipoprotein E increased 2-3-fold; lipoprotein-deficient serum had a negligible effect. Fatty acid-poor bovine serum albumin (BSA), which had been found to reduce very-low-density lipoprotein secretion in isolated rat hepatocytes, did not modify the synthesis of apolipoprotein E. When Fao cells were incubated in medium containing rat plasma lipoprotein fractions, the synthesis of apolipoprotein E increased. The d less than 1.090 g/ml plasma lipoprotein fraction had the major stimulatory effect. Increased apolipoprotein E synthesis was observed when cells were incubated in the presence of lipids extracted from rat plasma lipoproteins. These results suggest that the intracellular accumulation of lipoprotein-lipids plays an important role in regulating apolipoprotein E synthesis in Fao cells.


1987 - Internal medicine evaluation of the surgical risk in cirrhosis patients. [Articolo su rivista]
Gibertini, P; Pietrangelo, Antonello; Coppo, M.
abstract

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1987 - Intravenous fat and glucose in liver cirrhosis [Articolo su rivista]
Pietrangelo, Antonello
abstract

Little is known about lipids recently introduced (with other nutrients) in the parenteral feeding of hepatic encephalopathy, for conflicting results. For this reason 5 cirrhotic patients and 5 healthy controls were infused with 0.8-1.0 g/kg of a commercially available fat emulsion (Intralipid (R) 10%) in combination with 1.6-2.0 g/kg of glucose as 20% intravenous solution during an 8 hr period. Timed blood samples (before and every 4hrs for 24hrs) were obtained for the assay of glucose, insulin, glucagon, free fatty acids (FFA), free and total tryptophan (TRP), the last using a high performance chromatographic method developed in our laboratory. The results confirm a poor glucose tolerance and insulin-resistance in cirrhotic patients, who presented also high base levels of glucagon which normalized during the infusion. The triglycerides were and remained higher in controls but their percent variation resulted greater in patients. From a pathologically augmented basal level (0.73 ± 0.11 VS 0.39 ± 0.12 mVal/l, mean ± SEM), FFA fall progressively during infusion in cirrhotic patients (0.40 ± 0.08), but then rise and remain high in the second half of the study (1.01 ± 0.10), a pattern that is quite different from that seen for the controls. Free TRP is significantly higher in cirrhotic patients (17.7 ± 2.6 vs 11.04 ± 0.8 μmol/l, p&lt;0.01) and remains unchanged throughout the study, as well as the ratio of free to total TRP. The delayed and persistent increase of FFA confirms a reduced clearance of intravenous lipids in cirrhotic patients and accounts for a displacement of TRP from albumin-binding sites. It is concluded that a combined fat and glucose load determines a long-lasting increased availability of TRP to peripheral tissues (brain included) and this might interfere with neurotransmission through an increased serotonin synthesis.


1986 - Hepatitis B virus infection in porphyria cutanea tarda [Articolo su rivista]
Rocchi, Emilio; Gibertini, P.; Cassanelli, M.; Pietrangelo, Antonello; Jensen, J.; Ventura, Ezio
abstract

Serum markers of hepatitis B virus (HBV) infection were determined in 82 patients with porphyria cutanea tarda (PCT). Pathogenetic factors (alcohol, thalassemia minor, drugs) and clinical and histologic findings of PCT were taken into account. The prevalence of HBV infection was very high (70.7%). Hepatitis B surface antigen (HBsAg) was positive in 14 patients (17%). Eight patients had HBV infection as the only documented acquired factor. The clinical picture and histologic findings were aggravated by HBV infection; primary hepatic carcinoma occurred in four patients with HBV infection. Liver siderosis was histologically documented in 82.6% of cases, serum ferritin was pathologically increased in 91%, confirming the role of iron overload in PCT. A correlation (p less than 0.02; chi-squared method) was found between increased serum ferritin levels and HBV infection, suggesting a possible relationship between liver siderosis and HBV clearance. HBV infection appears to be a relevant additional factor in the pathogenesis of PCT liver disease.


1986 - Iron removal therapy in porphyria cutanea tarda: phlebotomy versus slow subcutaneous desferrioxamine infusion [Articolo su rivista]
Rocchi, Emilio; Gibertini, P.; Cassanelli, M.; Pietrangelo, Antonello; Borghi, A.; Pantaleoni, M.; Jensen, J.; Ventura, Ezio
abstract

Twenty-five patients with overt clinical and biochemical findings of porphyria cutanea tarda took part in a study comparing intensive phlebotomy with slow subcutaneous desferrioxamine treatment. Fifteen male patients (Group A) had intensive venesection therapy. Ten patients (Group B) with associated diseases (minor thalassemia, cardiovascular impairment, pulmonary tuberculosis or severe liver cirrhosis) received 1.5 g of desferrioxamine by slow subcutaneous infusion using an automatic syringe pump 5 days a week. No patient complained of appreciable side effects. Serum iron, ferritin and uroporphyrins were normalized in all subjects by the end of treatment. The mean time necessary for complete recovery was 13.8 months (range 9-19) and 11.2 months (range 6-14) in Groups A and B, respectively. Liver function significantly improved during and after the treatments in both groups. We conclude that recovery from porphyria cutanea tarda can be achieved equally well using phlebotomy or desferrioxamine subcutaneous infusion. Phlebotomy is easily performed and remains the treatment of choice; slow subcutaneous desferrioxamine treatment, although expensive, is recommended when severe associated diseases contra-indicate venesection.


1986 - Serum ferritin in the assessment of liver iron overload and iron removal therapy in porphyria cutanea tarda [Articolo su rivista]
Rocchi, Emilio; Gibertini, P.; Cassanelli, M.; Pietrangelo, Antonello; Borghi, A.; Ventura, Ezio
abstract

Serum ferritin, an index of iron stores, was studied in 60 patients with porphyria cutanea tarda (PCT), in 21 patients who had other liver diseases without siderosis (cirrhosis [LC] and chronic active hepatitis [CAH]), and in 32 patients with associated liver siderosis (alcoholic LC, LC and CAH in minor thalassemia). Ferritin levels were higher in patients with porphyria than in healthy controls and patients without liver siderosis (P less than 0.001), whereas no statistical difference was observed between patients with porphyria and those with liver siderosis. Because iron removal is considered the treatment of choice for PCT, some patients with PCT underwent phlebotomy and others received chelating therapy with subcutaneous infusion of deferoxamine. Follow-up of the patients showed a correlation between serum ferritin level and urinary porphyrin excretion; when the clinical and biochemical syndrome became normal, serum iron and ferritin had fallen to normal values (t test pair data analysis before and after: P less than 0.001 in each group). No appreciable difference was found between controls and patients with PCT whose conditions had been normalized, irrespective of the chronic liver damage always present in PCT. Our results suggest that serum ferritin increase in PCT is related more to liver iron overload than to liver damage, and ferritin follow-up is recommended to indicate the exhaustion of hepatic iron stores during iron depletion therapy, as well as to detect an early replenishment after remission.


1985 - SALIVARY TYPE HYPERAMYLASEMIA IN CHRONIC LIVER-DISEASE [Articolo su rivista]
Gibertini, P; Pietrangelo, Antonello; Coppo, M.
abstract

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1985 - Standard or branched-chain amino acid infusions as short-term nutritional support in liver cirrhosis? [Articolo su rivista]
Rocchi, Emilio; Cassanelli, M; Gibertini, P; Pietrangelo, Antonello; Casalgrandi, Giovanna; Ventura, Ezio
abstract

The metabolic effects of selected and branched-chain amino acid (BCAA)-enriched parenteral solutions were studied in liver cirrhosis. After 3 days of an oral protein-free diet with balanced amino acid (AA) infusion, 36 cirrhotic patients without encephalopathy were randomly divided into four groups. Groups A and B were infused for 5 days with BCAA (valine, leucine, isoleucine) at doses of 0.5 and 1.0 g/kg/day, respectively, as the only nitrogen source. Group C received 0.8 g/kg of essential and nonessential AA solution with a prevalence of BCAA; the last group (D) continued the basic standard diet, as control. Routine chemistry, urinary nitrogen losses, nitrogen balance, and the whole plasma AA pattern were detected before and after the treatment period. BCAA alone led to an impressive and significant improvement in the basic AA pattern in both the A and B groups. The same results were obtained in group C for plasma AA. In particular, the ratio of BCAA to aromatic amino acids in groups A, B, and C was significantly increased (p less than 0.01, less than 0.02, less than 0.02, respectively). In group D the AA pattern and the BCAA/aromatic amino acid ratio remained unchanged. The negative nitrogen balance of the base state remained unchanged after 0.5 g of BCAA (A); it improved significantly and became positive during and after the infusions of a double dose of BCAA (B), as it did in the case of selective solutions (C), although to a lesser extent; the negative nitrogen balance of the control group showed only a slight improvement.


1984 - ADVANCES IN THE TREATMENT OF PORPHYRIA CUTANEA-TARDA - EFFECTIVENESS OF SLOW SUBCUTANEOUS DESFERRIOXAMINE INFUSION [Articolo su rivista]
Gibertini, P; Rocchi, Emilio; Cassanelli, M; Pietrangelo, Antonello; Ventura, E.
abstract

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1984 - Coproporphyrin excretion in healthy newborn babies [Articolo su rivista]
Rocchi, Emilio; Balli, F.; Gibertini, G.; Trenti, T.; Pietrangelo, Antonello; Cassanelli, M.; Frigeri, G.; Ventura, Ezio
abstract

The urinary and fecal coproporphyrins (CP) undergo significant changes in cholestatic diseases of both adults and infants and their determination may provide a diagnostic tool. Little is known about CP excretion in the first days of life. The authors have studied the daily urinary and fecal excretion of CP as well as the I and III isomer distribution in 10 healthy newborn babies from 1 to 10 days old. CP were determined by the solvent partition method and the isomer distribution by thin-layer chromatographic technique. Preliminary studies on urinary porphyrin pattern were performed using a personal high-performance liquid chromatographic method. CP excretion was almost 10 times higher on the 1st day than on the 10th, when expressed by adult standards. The isomer I accounted for almost 80% of the total amount on the first days, whereas at the end of the study, both the CP total amount and isomer distribution overlapped the infant and adult pattern. The authors propose a personal interpretation based on a possible transient enzymatic defect in the metabolic chain of heme synthesis.


1984 - Determination of serum ferritin in porphyria cutanea tarda. A reliable sign of hepatic siderosis [Articolo su rivista]
P., Gibertini; Rocchi, Emilio; Pietrangelo, Antonello; Coppini, Maurizio; E., Ventura; Cassanelli, M
abstract

Some parameters of iron metabolism in 26 patients with porphyria cutanea tarda (PCT) which is often associated with mild iron overload and hepatic siderosis, are studied. Serum iron, percent transferrin saturation and ferritin were pathologically increased. Statistical comparisons were performed between PCT patients and healthy controls, liver disease patients (cirrhosis, chronic active hepatitis) and patients with associated liver siderosis (alcoholic cirrhosis, cirrhosis and chronic active hepatitis in thalassemia). Ferritin levels are higher in patients with porphyria than in healthy controls (p less than 0,001) and in patients without liver siderosis (p less than 0,001). No statistical difference is observed between patients with porphyria and patients with siderosis. A significant decrease in ferritin levels is registered after venesection therapy. The conclusion is drawn that serum ferritin increase in PCT is related to hepatic iron store amounts rather than hepatic necrosis. It is assumed that ferritin follow-up during phlebotomy therapy and also during remission is useful to indicate the exhaustion or an early replenishment of hepatic iron stores.


1984 - Hereditary coproporphyria. A familial study [Articolo su rivista]
Rocchi, Emilio; Pietrangelo, Antonello; Gibertini, P; Cassanelli, M; Trenti, T; Borghi, A; Silingardi, M; Jensen, J; Ventura, Ezio
abstract

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1984 - Porphyria cutanea tarda in beta-thalassemia trait carriers. [Articolo su rivista]
Gibertini, P; Rocchi, Emilio; Cassanelli, M; Pietrangelo, Antonello; Ventura, Ezio
abstract

The authors report 5 cases of porphyria cutanea tarda (PCT) occurring in carriers of the beta-thalassemia trait. This hematologic condition may be responsible for the development of liver damage resulting in siderosis, higher susceptibility to hepatitis B virus infection, and the earlier appearance of clinical features of PCT. Consequently, the authors propose chelation therapy with long-term subcutaneous desferioxamine infusions.