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Elena CORRADINI
Professore Associato
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto
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Pubblicazioni
2024
- Haemochromatosis in children: A national retrospective cohort promoted by the A.I.E.O.P. (Associazione Italiana Emato-Oncologia Pediatrica) study group
[Articolo su rivista]
Corti, P.; Ferrari, G. M.; Faraguna, M. C.; Capitoli, G.; Longo, F.; Corradini, E.; Casini, T.; Boscarol, G.; Pinto, V. M.; Ghilardi, R.; Russo, G.; Colombatti, R.; Mariani, R.; Piperno, A.
abstract
: Haemochromatosis (HC) encompasses a range of genetic disorders. HFE-HC is by far the most common in adults, while non-HFE types are rare due to mutations of HJV, HAMP, TFR2 and gain-of-function mutations of SLC40A1. HC is often unknown to paediatricians as it is usually asymptomatic in childhood. We report clinical and biochemical data from 24 paediatric cases of HC (10 cases of HFE-, 5 TFR2-, 9 HJV-HC), with a median follow-up of 9.6 years. Unlike in the adult population, non-HFE-HC constitutes 58% (14/24) of the population in our series. Transferrin saturation was significantly higher in TFR2- and HJV-HC compared to HFE-HC, and serum ferritin and LIC were higher in HJV-HC compared to TFR2- and HFE-HC. Most HFE-HC subjects had relatively low ferritin and LIC at the time of diagnosis, so therapy could be postponed for most of them after the age of 18. Our results confirm that HJV-HC is a severe form already in childhood, emphasizing the importance of early diagnosis and treatment to avoid the development of organ damage and reduce morbidity and mortality. Although phlebotomies were tolerated by most patients, oral iron chelators could be a valid option in early-onset HC.
2024
- Prevalence and Characteristics of Metabolic Hyperferritinemia in a Population-Based Central-European Cohort
[Articolo su rivista]
Gensluckner, Sophie; Wernly, Bernhard; Koutny, Florian; Strebinger, Georg; Zandanell, Stephan; Stechemesser, Lars; Paulweber, Bernhard; Iglseder, Bernhard; Trinka, Eugen; Frey, Vanessa; Langthaler, Patrick; Semmler, Georg; Valenti, Luca; Corradini, Elena; Datz, Christian; Aigner, Elmar
abstract
Background: Hyperferritinemia (HF) is a common finding and can be considered as metabolic HF (MHF) in combination with metabolic diseases. The definition of MHF was heterogenous until a consensus statement was published recently. Our aim was to apply the definition of MHF to provide data on the prevalence and characteristics of MHF in a Central-European cohort. Methods: This study was a retrospective analysis of the Paracelsus 10,000 study, a population-based cohort study from the region of Salzburg, Austria. We included 8408 participants, aged 40-77. Participants with HF were divided into three categories according to their level of HF and evaluated for metabolic co-morbidities defined by the proposed criteria for MHF. Results: HF was present in 13% (n = 1111) with a clear male preponderance (n = 771, 69% of HF). Within the HF group, 81% (n = 901) of subjects fulfilled the metabolic criteria and were defined as MHF, of which 75% (n = 674) were characterized by a major criterion. In the remaining HF cohort, 52% (n = 227 of 437) of subjects were classified as MHF after application of the minor criteria. Conclusion: HF is a common finding in the general middle-aged population and the majority of cases are classified as MHF. The new classification provides useful criteria for defining MHF.
2023
- A Population-based and Clinical Cohort Validation of the Novel Consensus Definition of Metabolic Hyperferritinemia
[Articolo su rivista]
Liu, Wen-Yue; Lian, Li-You; Zhang, Huai; Chen, Sui-Dan; Jin, Xin-Zhe; Zhang, Ni; Ye, Chen-Hui; Chen, Wen-Ying; Bee, George Goh Boon; Wang, Fu-Di; Miele, Luca; Corradini, Elena; Valenti, Luca; Zheng, Ming-Hua
abstract
Background: There is limited data on the clinical significance of metabolic hyperferritinemia (MHF) based on the most recent consensus. We aimed to validate the clinical outcomes of MHF in general population and biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD) patients. Methods: NHANES database and PERSONS cohort were included. MHF was defined as elevated serum ferritin with metabolic dysfunction (MD) and stratified into different grades according to ferritin (grade 1: 200 [females]/300 [males] - 550 ng/ml; grade 2: 550 - 1000 ng/ml; grade 3: > 1000 ng/ml). The clinical outcomes, including all-cause death, comorbidities and liver histology were compared between non-MHF and MHF in adjusted models. Results: In NHANES, compared with non-MHF with MD, MHF was related to higher risks of advanced fibrosis (FIB-4, P = 0.036), elevated albumin-creatinine ratio (UACR, P = 0.001) and sarcopenia (P = 0.013). Although the association between all grades of MHF and mortality was insignificant (P = 0.122), grades 2/3 was associated with increased mortality (P = 0.029). While comparing with non-MHF without MD, the harmful effects of MHF were more significant in mortality (P < 0.001), elevated UACR (P < 0.001), cardiovascular disease (P = 0.028), and sarcopenia (P < 0.001). In PERSONS cohort, MHF was associated with more advanced grades of steatosis (P < 0.001), lobular inflammation (P < 0.001), advanced fibrosis (P = 0.017), and more severe hepatocellular iron deposition (P < 0.001). Conclusions: Both in general population and at-risk individuals with MAFLD, MHF was related with poorer clinical outcomes.
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.
abstract
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.
abstract
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
- Corrigendum to “EASL Clinical Practice Guidelines on haemochromatosis” [J Hepatol 2022 (77) 479–502](S0168827822002112)(10.1016/j.jhep.2022.03.033)
[Articolo su rivista]
Zoller, H.; Schaefer, B.; Vanclooster, A.; Griffiths, B.; Bardou-Jacquet, E.; Corradini, E.; Porto, G.; Ryan, J.; Cornberg, M.
abstract
CORRIGENDUM
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
abstract
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.
2023
- Role and challenges to digital technologies in community health promotion programs in Italy during the COVID-19 pandemic: a multiple embedded case study protocol
[Articolo su rivista]
Del Riccio, Marco; Costantini, Luigi; Guasconi, Massimo; Casella, Giovanna; Fanfani, Alice; Cosma, Claudia; Mindrican, Paula; Bonaccorsi, Guglielmo; Corradini, Elena; Artioli, Giovanna; Sarli, Leopoldo; Laverack, Glenn; Rondini, Ermanno; Martucci, Gianfranco
abstract
Background and aim: Due to the COVID-19 pandemics, The Italian League Against Cancer (LILT), a national federation of local associations promoting cancer prevention, had to face the challenge to find new ways and technologies to promote health in their territories. This study aims to explore how LILT associations led their health promotion interventions during the COVID-19 pandemic and to understand which interventions had a greater impact, for which population group, and why. Methods: In this descriptive multiple embedded case study, each case will focus on the activities of a local LILT association and their collaborators on the perception and experience of the use of digital technology for health promotion and prevention, through interviews, observations, and a study of products and artifacts. A general overview of each case study will be provided, along with an introduction of the unit(s) of more in-depth analysis. The logical models that emerge from the analysis of each case will be described by using realist analysis, producing a list of possible CMO configurations (Context; Mechanisms; Outcomes). The final report will consist of a cross-case analysis (a comparison between the different case studies). Discussion: This multiple case study will help generate a first "theory of the use of digital technology in health promotion in local LILT communities. The observation of what local LILT associations in Italy have done during COVID-19 will help identify new and useful health promotion strategies based on these technologies.
2023
- Use of digital technologies to support cancer screening in community health promotion interventions: scoping review
[Articolo su rivista]
Costantini, Luigi; Del Riccio, Marco; Piccoli, Elisa; Lavecchia, Vincenzo; Corradini, Elena; Bonaccorsi, Guglielmo; Martucci, Gianfranco; Lavserack, Glenn
abstract
: The scoping review investigated how digital technologies have helped to increase cancer screening uptake in communities including adolescents, adults and elderly people during the COVID-19 outbreak between January 2020 and June 2021. Thirteen studies were identified as being relevant, mostly addressing underserved or minority communities with the purpose to increase screening uptake, delivering health education or investigating social and cultural barriers to cancer screening. The interventions effectively used digital technologies such as mobile apps and messengers mobile apps, messaging and Web platforms. The limitations imposed by COVID-19 on social interaction can be supported with digital solutions to ensure the continuity of cancer screening programs. However, more research is needed to clarify the exact nature of effectiveness, especially in large-scale interventions.
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
- 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
- EASL Clinical Practice Guidelines on haemochromatosis
[Articolo su rivista]
Zoller, Heinz; Schaefer, Benedikt; Vanclooster, Annick; Griffiths, Bill; Bardou-Jacquet, Edouard; Corradini, Elena; Porto, Graça; Ryan, John; Cornberg, Markus
abstract
: Haemochromatosis is characterised by elevated transferrin saturation (TSAT) and progressive iron loading that mainly affects the liver. Early diagnosis and treatment by phlebotomy can prevent cirrhosis, hepatocellular carcinoma, diabetes, arthropathy and other complications. In patients homozygous for p.Cys282Tyr in HFE, provisional iron overload based on serum iron parameters (TSAT >45% and ferritin >200 μg/L in females and TSAT >50% and ferritin >300 μg/L in males and postmenopausal women) is sufficient to diagnose haemochromatosis. In patients with high TSAT and elevated ferritin but other HFE genotypes, diagnosis requires the presence of hepatic iron overload on MRI or liver biopsy. The stage of liver fibrosis and other end-organ damage should be carefully assessed at diagnosis because they determine disease management. Patients with advanced fibrosis should be included in a screening programme for hepatocellular carcinoma. Treatment targets for phlebotomy are ferritin <50 μg/L during the induction phase and <100 μg/L during the maintenance phase.
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
- Iron Metabolism in the Disorders of Heme Biosynthesis
[Articolo su rivista]
Ricci, Andrea; Di Betto, Giada; Bergamini, Elisa; Buzzetti, Elena; Corradini, Elena; Ventura, Paolo
abstract
Given its remarkable property to easily switch between different oxidative states, iron is
essential in countless cellular functions which involve redox reactions. At the same time, uncon-
trolled interactions between iron and its surrounding milieu may be damaging to cells and tissues.
Heme—the iron-chelated form of protoporphyrin IX—is a macrocyclic tetrapyrrole and a coordina-
tion complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen-
binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues.
The majority of the body production of heme is ultimately incorporated into hemoglobin within
mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis.
Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron-
dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main
pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital
sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors
accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different por-
phyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic
anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mito-
chondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with
the complexity of the processes involved, the role of iron in these conditions is then multifarious.
This review aims to summarise the most important lines of evidence concerning the interplay be-
tween iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron
in inherited conditions of altered heme biosynthesis.
2022
- Iron in Porphyrias: Friend or Foe?
[Articolo su rivista]
Buzzetti, Elena; Ventura, Paolo; Corradini, Elena
abstract
Iron is a trace element that is important for many vital processes, including oxygen
transport, oxidative metabolism, cellular proliferation, and catalytic reactions. Iron supports these
functions mainly as part of the heme molecule. Heme synthesis is an eight-step process which, when
defective at the level of one of the eight enzymes involved, can cause the development of a group
of diseases, either inherited or acquired, called porphyrias. Despite the strict link between iron and
heme, the role of iron in the different types of porphyrias, particularly as a risk factor for disease
development/progression or as a potential therapeutic target or molecule, is still being debated, since
contrasting results have emerged from clinical observations, in vitro studies and animal models. In
this review we aim to deepen such aspects by drawing attention to the current evidence on the role of
iron in porphyrias and its potential implication. Testing for iron status and its metabolic pathways
through blood tests, imaging techniques or genetic studies on patients affected by porphyrias can
provide additional diagnostic and prognostic value to the clinical care, leading to a more tailored and
effective management.
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.
2021
- Assistenza sanitaria primaria. Vol. 2: La formazione medica per il suo sviluppo
[Monografia/Trattato scientifico]
Becchi, Maria Angela; Corradini, Elena; Pignatti, Fabio
abstract
L’opera approfondisce l’ampia cultura dell’assistenza sanitaria primaria (Primary Health Care) nei suoi vari aspetti sanitari, sociali, relazionali, propone un nuovo approccio metodologico e culturale (approccio bio-psico-sociale) per i professionisti e gli operatori del sistema sanitario nazionale ed è strutturata in due volumi. Il secondo La formazione medica per il suo sviluppo ha un approccio prevalentemente didattico e permette ai diversi professionisti della salute di acquisire una formazione adeguata e orientata al modello bio-psico-sociale nell'ambito dei corsi pre-laurea, post-laurea e di educazione professionale continua (ECM) attivati nelle università, nelle aziende sanitarie e nelle regioni. Il materiale didattico è presentato in forma di tabelle e schede utili a elaborare interventi di formazione (di base, specialistica, continua) sia negli atenei che ancora non prevedono corsi dedicati all’area dell’assistenza sanitaria primaria, sia nelle aziende sanitarie che pianificano corsi ECM multiprofessionali in un settore emergente, per rispondere ai bisogni della popolazione.
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
- Reply to: “Ceruloplasmin variants might have different effects in different iron overload disorders”
[Articolo su rivista]
Corradini, E.; Valenti, L. V.
abstract
2020
- Assistenza sanitaria primaria. Aspetti culturali, metodi e strumenti per il suo sviluppo
[Monografia/Trattato scientifico]
Becchi, Maria Angela; Corradini, Elena; Pignatti, Fabio
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
- 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
- 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.
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
- 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
- Fegato, pancreas e vie biliari.
[Capitolo/Saggio]
Pietrangelo, Antonello; Abbati, Gianluca; Corradini, Elena; Ventura, Paolo
abstract
-
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
-
2017
- Iron overload disorders
[Abstract in Atti di Convegno]
Corradini, Elena
abstract
-
2017
- Subacute copper-deficiency myelopathy in a patient with occult celiac disease
[Articolo su rivista]
Cavallieri, Francesco; Fini, Nicola; Contardi, Sara; Fiorini, Massimo; Corradini, Elena; Valzania, Franco
abstract
Context: Acquired copper deficiency represents a rare cause of progressive myelopathy presenting with sensory ataxia and spastic gait. The time interval from neurological symptoms onset to diagnosis of myelopathy ranges from 2 months to several years in almost all cases, mimicking the clinical course of subacute combined degeneration due to vitamin B12 deficiency. Findings: A 60-year-old man, without any gastrointestinal symptoms, developed over the course of one week rapidly progressive gait imbalance, tingling and numbness in his feet and ascending lower limb weakness. Spine magnetic resonance imaging revealed hyperintensity involving cervical and dorsal posterior columns of spinal cord. Blood analysis revealed undetectable serum copper levels, low serum ceruloplasmin and positive serum Immunoglobulin A anti-tissue transglutaminase. Upper gastrointestinal endoscopy was performed revealing duodenal villous atrophy consistent with a malabsorption pattern. A gluten-free diet in association with intravenous then oral copper supplementation prompted sustained normalization of serum copper levels and progressive clinical improvement. Conclusion/Clinical Relevance: We report a rare case of myelopathy induced by copper deficiency secondary to undiagnosed celiac disease, peculiarly presenting with a subacute onset. This case expands the neurological presentation and clinical course of myelopathy due to acquired copper deficiency. We suggest investigation of copper deficiency in patients presenting with subacute or even acute sensory ataxia and spastic gait. Detection of hypocupremia in patients without a previous history of gastric surgery should lead to diagnostic testing for celiac disease even in the absence of any obvious gastrointestinal symptoms.
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
-
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
-
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
-
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
- 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
-
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
- 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
- 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
-
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.
2011
- Iron Regulation of Hepcidin Despite Attenuated Smad1,5,8 Signaling in Mice Without Transferrin Receptor 2 or Hfe.
[Articolo su rivista]
Corradini, Elena; Rozier, M; Meynard, D; Odhiambo, A; Lin, Hy; Feng, Q; Migas, Mc; Britton, Rs; Babitt, Jl; Fleming, R. E.
abstract
BACKGROUND & AIMS: HFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression. In murine Hfe and Tfr2 knockout models of hereditary hemochromatosis (HH), signal transduction to hepcidin via the bone morphogenetic protein 6 (Bmp6)/Smad1,5,8 pathway is attenuated. We examined the effect of dietary iron on regulation of hepcidin expression via the Bmp6/Smad1,5,8 pathway using mice with targeted disruption of Tfr2, Hfe, or both genes. METHODS: Hepatic iron concentrations and messenger RNA expression of Bmp6 and hepcidin were compared with wild-type mice in each of the HH models on standard or iron-loading diets. Liver phospho-Smad (P-Smad) 1,5,8 and Id1 messenger RNA levels were measured as markers of Bmp/Smad signaling. RESULTS: Whereas Bmp6 expression was increased, liver hepcidin and Id1 expression were decreased in each of the HH models compared with wild-type mice. Each of the HH models also showed attenuated P-Smad1,5,8 levels relative to liver iron status. Mice with combined Hfe/Tfr2 disruption were most affected. Dietary iron loading increased hepcidin and Id1 expression in each of the HH models. Compared with wild-type mice, HH mice demonstrated attenuated (Hfe knockout) or no increases in P-Smad1,5,8 levels in response to dietary iron loading. CONCLUSIONS: These observations show that Tfr2 and Hfe are each required for normal signaling of iron status to hepcidin via the Bmp6/Smad1,5,8 pathway. Mice with combined loss of Hfe and Tfr2 up-regulate hepcidin in response to dietary iron loading without increases in liver Bmp6 messenger RNA or steady-state P-Smad1,5,8 levels.
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
- Regulation of TMPRSS6 by BMP6 and iron in human cells and mice.
[Articolo su rivista]
Meynard, D; Vaja, V; Sun, Cc; Corradini, Elena; Chen, Sz; Lopez Otin, C; Grgurevic, L; Hong, Cc; Stirnberg, M; Gutschow, M; Vukicevic, S; Babitt, Jl; Lin, H. Y.
abstract
Mutations in transmembrane protease, serine 6 (TMPRSS6), encoding matriptase-2, are responsible for the familial anemia disorder iron-refractory iron deficiency anemia (IRIDA). Patients with IRIDA have inappropriately elevated levels of the iron regulatory hormone hepcidin, suggesting that TMPRSS6 is involved in negatively regulating hepcidin expression. Hepcidin is positively regulated by iron via the bone morphogenetic protein (BMP)-SMAD signaling pathway. In this study, we investigated whether BMP6 and iron also regulate TMPRSS6 expression. Here we demonstrate that, in vitro, treatment with BMP6 stimulates TMPRSS6 expression at the mRNA and protein levels and leads to an increase in matriptase-2 activity. Moreover, we identify that inhibitor of DNA binding 1 is the key element of the BMP-SMAD pathway to regulate TMPRSS6 expression in response to BMP6 treatment. Finally, we show that, in mice, Tmprss6 mRNA expression is stimulated by chronic iron treatment or BMP6 injection and is blocked by injection of neutralizing antibody against BMP6. Our results indicate that BMP6 and iron not only induce hepcidin expression but also induce TMPRSS6, a negative regulator of hepcidin expression. Modulation of TMPRSS6 expression could serve as a negative feedback inhibitor to avoid excessive hepcidin increases by iron to help maintain tight homeostatic balance of systemic iron levels.
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 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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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
- 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
- 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.
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
- 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
- The RGM/DRAGON family of BMP co-receptors.
[Articolo su rivista]
Corradini, Elena; Babitt, Jl; Lin, Hy
abstract
The BMP signaling pathway controls a number of cell processes during development and in adult tissues. At the cellular level, ligands of the BMP family act by binding a hetero-tetrameric signaling complex, composed of two type I and two type If receptors. BMP ligands make use of a limited number of receptors, which in turn activate a common signal transduction cascade at the intracellular level. A complex regulatory network is required in order to activate the signaling cascade at proper times and locations, and to generate specific downstream effects in the appropriate cellular context.
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
- Hereditary Hemochromatosis
[Capitolo/Saggio]
Corradini, Elena; Ferrara, Francesca; Pietrangelo, Antonello
abstract
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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 & 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
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.
[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
- 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.
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.
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
- 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.
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
- Metodologia per l’adozione di linee guida cliniche in Medicina Interna.
[Abstract in Atti di Convegno]
Ballesini, P; Borghi, A; Corradini, Elena; Cristani, A; Ferrara, F; Gandolfo, Marco; Pipino, M; Polidoro, S; Rosa, C; Sardini, C; Vandelli, Carmen; Ventura, Paolo; Venturini, I; Zeneroli, Ml
abstract
Le linee guida definiscono raccomandazioni, elaborate a partire da un'analisi multidisciplinare e sistematica della letteratura scientifica disponibile, con l'obiettivo di assitere i professionisti sanitari nelle decisioni cliniche, individuando le modalità assistenziali più appropriate in specifiche circostanze. Anche la migliore linea guida disponibile può fallire i suoi obiettivi se non passa attraverso fasi di adattamento locale e di implemenatzione
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 IFN2b (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).