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Francesca CARUBBI

Professore Associato
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Medicina, Endocrinologia, Metabolismo e Geriatria

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Pubblicazioni

2024 - Long-term outcome of a cohort of Italian patients affected with alpha-Mannosidosis [Articolo su rivista]
Bertolini, A.; Rigoldi, M.; Cianflone, A.; Mariani, R.; Piperno, A.; Canonico, F.; Cefalo, G.; Carubbi, F.; Simonati, A.; Urban, M. L.; Beccari, T.; Parini, R.
abstract

Alpha-mannosidosis (MIM #248500) is an ultra-rare autosomal recessive lysosomal storage disease with multi-system involvement and a wide phenotypic spectrum. Information on long-term outcomes remains poor. We present the long-term outcomes (median, 19 years) of nine patients with alpha-mannosidosis, three females and six males, followed at a single center. The findings of the nine patients were collected from medical records and reported as mean ± SD or median, and range. The age of onset of the first symptoms ranged from 0-1 to 10 years. The diagnostic delay ranged from 2 to 22 years (median= 11 years). Coarse face, hearing, heart valves, joints, gait, language, dysarthria, psychiatric symptoms, I.Q., MRI, walking disabilities, orthopedic disturbances and surgeries showed a slow worsening over the decades. Our patients showed a slowly worsening progressive outcome over the decades. Psychiatric symptoms were present in 100% of our population and improved with the appropriate pharmacological intervention. This aspect requires attention when following up on these patients. Our description of the long-term evolution of alpha-mannosidosis patients may provide basic knowledge for understanding the effects of specific treatments.

2023 - Acid sphingomyelinase deficiency (ASMD): addressing knowledge gaps in unmet needs and patient journey in Italy-a Delphi consensus [Articolo su rivista]
Scarpa, Maurizio; Barbato, Antonio; Bisconti, Annalisa; Burlina, Alberto; Concolino, Daniela; Deodato, Federica; Di Rocco, Maja; Dionisi-Vici, Carlo; Donati, Maria Alice; Fecarotta, Simona; Fiumara, Agata; Galeone, Carlotta; Giona, Fiorina; Giuffrida, Gaetano; Manna, Raffaele; Mariani, Paolo; Pession, Andrea; Scopinaro, Annalisa; Spada, Marco; Spandonaro, Federico; Trifirò, Gianluca; Carubbi, Francesca; Cappellini, Maria Domenica
abstract

Acid sphingomyelinase deficiency (ASMD) is an ultra-rare disease, and several gaps of knowledge on various issues remain, particularly at a regional/national level. Expert opinions collected through well-defined consensus methodologies are increasingly used to make available reliable information in the context of rare/ultra-rare diseases. With the aim to provide indications on infantile neurovisceral ASMD (also formerly known as Niemann-Pick disease type A), chronic neurovisceral ASMD (formerly known as Niemann-Pick disease type A/B) and chronic visceral ASMD (formerly known as Niemann-Pick disease type B) in Italy, we conducted a Delphi consensus of experts focused on five main areas: (i) patients and disease characteristics; (ii) unmet needs and quality of life; (iii) diagnostic issues; (iv) treatment-related aspects; and (v) patient journey. Pre-specified, objective criteria were used to outline the multidisciplinary panel, based on 19 Italian experts in ASMD in paediatric and adult patients from different Italian Regions, including both clinicians (n = 16) and ASMD patients' advocacy or payors with expertise in rare diseases (n = 3). During two Delphi rounds, a high ratio of agreement was found on several topics related to ASMD characteristics, diagnosis, management and disease burden. Our findings may provide valuable indications for management of ASMD at a public health level in Italy.

2023 - How to overcome barriers to the implementation of prevention and management strategies of atherosclerotic cardiovascular disease through lipid-lowering therapy [Articolo su rivista]
Arca, M.; Averna, M.; Borghi, C.; Lettino, M.; Filardi, P. P.; Alberti, A.; Bilato, C.; Calabrò, P.; Carubbi, F.; Ciccone, M. M.; Cipollone, F.; Citroni, N.; De Luca, L.; Giaccari, A.; Iannuzzo, G.; Maloberti, A.; Marcucci, R.; Spinazzola, P. P.; Pirro, M.; Pisciotta, L.; Sarullo, F.; Sciacqua, A.; Suppressa, P.; Varbella, F.; Werba, J. P.; Zambon, A.
abstract

: Atherosclerotic cardiovascular diseases remain the main cause of mortality worldwide, due to a poor control of modifiable risk factors for atherosclerosis. High levels of low-density lipoprotein cholesterol represent the most relevant actor in the development of atherosclerotic cardiovascular diseases, as well as the main target of prevention strategies. Although lipid-lowering treatments were shown to be effective for cardiovascular prevention, several barriers (e.g. clinician reluctance to prescribe an intensive treatment, poor adherence of patients to therapy, high pharmacotherapy burden of high-risk patients and the fear for adverse events potentially associated with statins) still prevent therapy optimization. Such issues will be addressed in this review article, taking into account possible strategies for their solution, through an integrated approach including both management interventions and a larger use of the available pharmacologic options.

2023 - Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia [Articolo su rivista]
Olmastroni, Elena; Gazzotti, Marta; Averna, Maurizio; Arca, Marcello; Tarugi, Patrizia; Calandra, Sebastiano; Bertolini, Stefano; Catapano, Alberico L; Casula, Manuela; Marcello, Arca; Laura, D'Erasmo; Maurizio, Averna; Angelo Baldassare Cefalù, ; Andrea, Bartuli; Paola Sabrina Buonuomo, ; Andrea, Benso; Guglielmo, Beccuti; Giacomo, Biasucci; Maria Elena Capra, ; Gianni, Biolo; Pierandrea, Vinci; Luca, Bonanni; Claudio, Borghi; Sergio, D'Addato; Antonio Carlo Bossi, ; Giancarla, Meregalli; Adriana, Branchi; Paolo, Calabrò; Carubbi, Francesca; Nascimbeni, Fabio; Francesco, Cipollone; Marco, Bucci; Nadia, Citroni; Maria Del Ben, ; Francesco, Baratta; Massimo, Federici; Martina, Montagna; Claudio, Ferri; Serena, Notargiacomo; Anna Maria Fiorenza, ; Emanuela, Colombo; Giuliana, Fortunato; Maria Donata Di Taranto, ; Andrea, Giaccari; Simona, Moffa; Francesco, Giorgino; Sergio Di Molfetta, ; Ornella, Guardamagna; Luisa De Sanctis, ; Arcangelo, Iannuzzi; Raimondo, Cavallaro; Gabriella, Iannuzzo; Marco, Gentile; Iughetti, Lorenzo; Bruzzi, Patrizia; Salvatore, Lia; Alessandro, Lupi; Giuseppe, Mandraffino; Arianna, Toscano; Rossella, Marcucci; Martina, Berteotti; Lorenzo, Maroni; Fabiana, Locatelli; Tiziana, Montalcini; Giuliana, Mombelli; Sandro, Muntoni; Davide, Baldera; Gianfranco, Parati; Angelina, Passaro; Valerio, Pecchioli; Cristina, Pederiva; Giuseppe, Banderali; Antonio, Pipolo; Debora, D'Elia; Matteo, Pirro; Vanessa, Bianconi; Livia, Pisciotta; Elena, Formisano; Francesco, Purrello; Roberto, Scicali; Elena, Repetti; Elena, Cantino; Elisabetta, Rinaldi; Elena, Sani; Riccardo, Sarzani; Francesco, Spannella; Francesco, Sbrana; Beatrice Dal Pino, ; Patrizia, Suppressa; Cocco, VERONICA MARGHERITA; Chiara, Trenti; Emanuele Alberto Negri, ; Josè Pablo Werba, ; Alessandra, Romandini; Sabina, Zambon; Alberto, Zambon; Maria Grazia Zenti, ; Giulia, Fainelli; Fabio, Pellegatta; Liliana, Grigore; Katia, Bonomo; Eleonora, Capatti; Ada, Cutolo; Fabio, Fimiani; Simonetta, Genovesi; Sandro, Inchiostro; Chiara, Pavanello; Roberta, Pujia; Alon, Schaffer; Stefano, Bertolini; CALANDRA BUONAURA, Sebastiano; Alberico Luigi Catapano, ; Manuela, Casula; Elena, Olmastroni; Tarugi, Patrizia Maria; Marta, Gazzotti; Federica, Galimberti
abstract

BackgroundEvidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and ResultsAn lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score >= 1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups <0.0001); however, subjects with FH/M- and lp(a) score >= 1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level >= 190 mg/dL (or from 68% to 50%, considering a more conservative formula). ConclusionsOur study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH.

2023 - Long-term bone outcomes in Italian patients with Gaucher disease type 1 or type 3 treated with imiglucerase: A sub-study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry [Articolo su rivista]
Cappellini, M. D.; Carubbi, F.; Di Rocco, M.; Giona, F.; Giuffrida, G.
abstract

Background: Gaucher disease (GD) is a lysosomal storage disorder. We evaluated the “real-world” effectiveness of first-line imiglucerase on long-term bone outcomes in Italian patients in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. Methods: Patients treated with imiglucerase for ≥2 years and with bone assessments at baseline and during follow-up were selected. Data on bone pain, bone crises, marrow infiltration, avascular necrosis, infarction, lytic lesions, Erlenmeyer flask deformity, bone fractures, mineral density, and imiglucerase dosage were evaluated. Results: Data on bone manifestations were available for 73 of 229 patients (31.9 %). Bone crises frequency decreased significantly from baseline to the most recent follow-up (p < 0.001), with some improvement observed in bone pain prevalence. Bone pain and bone crises prevalence decreased significantly from baseline at 2 to <4 and 4 to <6 years (all p < 0.05). A low median (25th, 75th percentile) baseline imiglucerase dosage was identified in patients reporting bone pain or bone crises (15.0 [13.7, 30.0] and 22.8 [17.5, 36.0] U/kg once every 2 weeks, respectively). Conclusion: Our study suggests that the management of GD in Italy, with regards to imiglucerase dosage, is suboptimal and confirms the need for clinicians to monitor and correctly treat bone disease according to best practice guidelines.

2023 - Refinement of the diagnostic approach for the identification of children and adolescents affected by familial hypercholesterolemia: Evidence from the LIPIGEN study [Articolo su rivista]
Casula, M.; Gazzotti, M.; Capra, M. E.; Olmastroni, E.; Galimberti, F.; Catapano, A. L.; Pederiva, C.; Anesi, A.; Arca, M.; Auricchio, R.; Averna, M.; Baldera, D.; Banderali, G.; Beccuti, G.; Benso, A.; Berteotti, M.; Bertolini, S.; Bianconi, V.; Biasucci, G.; Biolo, G.; Bonanni, L.; Borghi, C.; Bossi, A. C.; Branchi, A.; Bruzzi, P.; Bucci, M.; Buonuomo, P. S.; Calabro, P.; Calandra, S.; Carubbi, F.; Cavallaro, R.; Cefalu, A. B.; Cesaro, A.; Cipollone, F.; Citroni, N.; Colombo, E.; Coppola, C.; D'Addato, S.; Dal Pino, B.; Dalla Nora, E.; De Corrado, G.; Del Ben, M.; Di Molfetta, S.; Di Taranto, M. D.; Fainelli, G.; Federici, M.; Ferri, C.; Fiorenza, A. M.; Formisano, E.; Fortunato, G.; Giaccari, A.; Giorgino, F.; Grigore, L.; Guardamagna, O.; Iannuzzi, A.; Iannuzzo, G.; Iughetti, L.; Lia, S.; Longo, S.; Lupi, A.; Mandraffino, G.; Marcucci, R.; Maroni, L.; Massini, G.; Mazza, E.; Melchioda, E.; Meregalli, G.; Minicocci, I.; Moffa, S.; Mombelli, G.; Muntoni, S.; Nascimbeni, F.; Negri, E. A.; Notargiacomo, S.; Panfili, F. M.; Parati, G.; Passaro, A.; Pavanello, C.; Pecchioli, V.; Pecchioli, L.; Pellegatta, F.; Perla, F. M.; Pipolo, A.; Piro, S.; Pirro, M.; Pisciotta, L.; Pujia, R.; Putotto, C.; Repetti, E.; Rinaldi, E.; Romandini, A.; Sani, E.; Sarnari, S.; Sarzani, R.; Sbrana, F.; Scicali, R.; Scuruchi, M.; Suppressa, P.; Tarugi, P.; Trenti, C.; Vinci, P.; Werba, J. P.; Zambon, S.; Zambon, A.; Zenti, M. G.
abstract

Background and aims: We aimed to describe the limitations of familiar hypercholesterolemia (FH) diagnosis in childhood based on the presence of the typical features of FH, such as physical sings of cholesterol accumulation and personal or family history of premature cardiovascular disease or hypercholesterolemia, comparing their prevalence in the adult and paediatric FH population, and to illustrate how additional information can lead to a more effective diagnosis of FH at a younger age. Methods: From the Italian LIPIGEN cohort, we selected 1188 (≥18 years) and 708 (<18 years) genetically-confirmed heterozygous FH, with no missing personal FH features. The prevalence of personal and familial FH features was compared between the two groups. For a sub-group of the paediatric cohort (N = 374), data about premature coronary heart disease (CHD) in second-degree family members were also included in the evaluation. Results: The lower prevalence of typical FH features in children/adolescents vs adults was confirmed: the prevalence of tendon xanthoma was 2.1% vs 13.1%, and arcus cornealis was present in 1.6% vs 11.2% of the cohorts, respectively. No children presented clinical history of premature CHD or cerebral/peripheral vascular disease compared to 8.8% and 5.6% of adults, respectively. The prevalence of premature CHD in first-degree relatives was significantly higher in adults compared to children/adolescents (38.9% vs 19.7%). In the sub-cohort analysis, a premature CHD event in parents was reported in 63 out of 374 subjects (16.8%), but the percentage increased to 54.0% extending the evaluation also to second-degree relatives. Conclusions: In children, the typical FH features are clearly less informative than in adults. A more thorough data collection, adding information about second-degree relatives, could improve the diagnosis of FH at younger age.

2023 - Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study [Articolo su rivista]
Hirschfield, Gideon M; Shiffman, Mitchell L; Gulamhusein, Aliya; Kowdley, Kris V; Vierling, John M; Levy, Cynthia; Kremer, Andreas E; Zigmond, Ehud; Andreone, Pietro; Gordon, Stuart C; Bowlus, Christopher L; Lawitz, Eric J; Aspinall, Richard J; Pratt, Daniel S; Raikhelson, Karina; Gonzalez-Huezo, Maria S; Heneghan, Michael A; Jeong, Sook-Hyang; Ladrón de Guevara, Alma L; Mayo, Marlyn J; Dalekos, George N; Drenth, Joost P H; Janczewska, Ewa; Leggett, Barbara A; Nevens, Frederik; Vargas, Victor; Zuckerman, Eli; Corpechot, Christophe; Fassio, Eduardo; Hinrichsen, Holger; Invernizzi, Pietro; Trivedi, Palak J; Forman, Lisa; Jones, David E J; Ryder, Stephen D; Swain, Mark G; Steinberg, Alexandra; Boudes, Pol F; Choi, Yun-Jung; Mcwherter, Charles A; Carubbi, F
abstract

Background and Aims: ENHANCEwas a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).Approach and Results: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n= 89), 10 mg (n= 89), placebo (n= 87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67xupper limit of normal (ULN), >= 15% ALP decrease from baseline, and total bilirubin <= ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score >= 4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10mg: 78.2%) versus placebo (12.5%) (p < 0.0001). ALP normalization occurred in 5.4% (p= 0.08) and 27.3% (p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 (p= 0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% (p= 0.0008); 10 mg: 16.7% (p= 0.03); placebo: 4%]. There were no serious treatment-related adverse events.Conclusions: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

2023 - Similarities and differences between Gaucher disease and acid sphingomyelinase deficiency: An algorithm to support the diagnosis [Articolo su rivista]
Cappellini, M. D.; Motta, I.; Barbato, A.; Giuffrida, G.; Manna, R.; Carubbi, F.; Giona, F.
abstract

Lysosomal storage disorders are a group of inborn errors of metabolism due to defects in proteins crucial for lysosomal function. Gaucher disease is the most common autosomal recessive lysosomal storage disorder due to mutations in the GBA1 gene, resulting in the lysosomal deficiency of glucocerebrosidase activity. Gaucher disease is characterized by the toxic accumulation of glucosylceramide in the reticuloendothelial system. Acid sphingomyelinase deficiency (ASMD), previously known as Niemann Pick A/B disease, is also an autosomal recessive lysosomal storage disorder due to mutations in the SMPD1 gene, which result in acid sphingomyelinase deficiency and the accumulation of sphingomyelin in mononuclear phagocytic system and hepatocytes. The phenotypic expression of Gaucher disease type 1 (GD1), the most common type, and chronic visceral ASMD may overlap for several signs or symptoms. Splenomegaly is detectable in approximately 90% of the patients in both conditions; however, since GD1 is more frequent than ASMD, clinicians are more prone to suspect it, often neglecting the diagnosis of ASMD. Based on previous experience, a group of experts in the clinical and laboratory diagnosis, management, and treatment of lysosomal storage disorders developed an algorithm for both GD1 and ASMD to support physicians, including primary care providers, internists, and specialists (e.g., hepatologists, hematologists, and pulmonologists) to suspect and differentiate GD1 and ASMD and to provide the appropriate referral.

2022 - Effects of bariatric and metabolic surgical procedures on dyslipidemia: a retrospective, observational analysis. [Articolo su rivista]
Greco, Carla; Passerini, Francesca; Coluccia, Silvia; Bondi, Mario; Mecheri, Fouzia; Trapani, Vincenzo; Volpe, Alessandro; Toschi, PATRIZIA FEDERICA; Carubbi, Francesca; Simoni, Manuela; Santi, Daniele
abstract

Aim: Obesity and co-existing metabolic comorbidities are associated with increased cardiovascular (CV) morbidity and mortality risks, generally clustered to risk factors such as dyslipidemia. The aim of this study was to evaluate the lipid profile changes in subjects with severe obesity undergoing different procedures of bariatric and metabolic surgery (BMS), sleeve gastrectomy (SG), and Roux-en-Y gastric bypass (RYGB) in a real-world, clinical setting. Methods: A single-center, retrospective, observational clinical study was performed enrolling patients undergoing BMS. The primary outcome was the change in total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol, and triglycerides. Results: In total, 123 patients were enrolled (males 25.2% and females 74.8%) with a mean age of 48.2 ± 7.9 years and a mean BMI of 47.0 ± 9.1 kg/m2. All patients were evaluated until 16.9 ± 8.1 months after surgery. Total and HDL cholesterol did not change after surgery, while a significant reduction in triglyceride levels was recorded. Moreover, a rapid decline of both LDL and non-HDL cholesterol among follow-up visits was observed. In particular, significant inverse correlations were found between total cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides and the number of months elapsed after bariatric surgery. Similarly, a direct correlation was found considering HDL cholesterol. Moreover, total cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides significantly changed among visits after RYGB, while no changes were observed in the SG group. Finally, considering lipid-lowering therapies, the improvement in lipid asset was detected only in non-treated patients. Conclusion: This study corroborates the knowledge of the improvement in lipid profile with BMS in clinical practice. Together with sustained weight loss, the BMS approach efficiently corrects dyslipidemia, contributing to decreasing the CV risk.

2022 - Global multi-stakeholder endorsement of the MAFLD definition [Articolo su rivista]
Mendez-Sanchez, N.; Bugianesi, E.; Gish, R. G.; Lammert, F.; Tilg, H.; Nguyen, M. H.; Sarin, S. K.; Fabrellas, N.; Zelber-Sagi, S.; Fan, J. -G.; Shiha, G.; Targher, G.; Zheng, M. -H.; Chan, W. -K.; Vinker, S.; Kawaguchi, T.; Castera, L.; Yilmaz, Y.; Korenjak, M.; Spearman, C. W.; Ungan, M.; Palmer, M.; El-Shabrawi, M.; Gruss, H. -J.; Dufour, J. -F.; Dhawan, A.; Wedemeyer, H.; George, J.; Valenti, L.; Fouad, Y.; Romero-Gomez, M.; Eslam, M.; Abate, M. L.; Abbas, B.; Abbassy, A. A.; Abd El Ghany, W.; Abd Elkhalek, A.; Abd ElMajeed, E.; Abdalgaber, M.; Abdallah, M.; Abdallah, M.; Abdallah, N.; Abdelaleem, S.; Abdelghani, Y.; Abdelghany, W.; Abdelhalim, S. M.; Abdelhamid, W.; Abdelhamid, N.; Abdelkader, N. A.; Abdelkreem, E.; Abdelmohsen, A. M.; Abdelrahman, A. A.; Abd-elsalam, S. M.; Abdeltawab, D.; Abduh, A.; Abdulhakam, N.; Abdulla, M.; Abedpoor, N.; Abenavoli, L.; Aberg, F.; Ablack, O.; Abo elftouh, M.; Abo-Amer, Y. E. -E.; Aboubkr, A.; Aboud, A.; Abouelnaga, A. M.; Aboufarrag, G. A.; Aboutaleb, A.; Abundis, L.; Adali, G.; Adames, E.; Adams, L.; Adda, D.; Adel, N.; Adel, N.; Adel Sayed, M.; Afaa, T. J.; Afredj, N.; Aghayeva, G.; Aghemo, A.; Aguilar-Salinas, C. A.; Ahlenstiel, G.; Ahmady, W.; Ahmed, W.; MOHAMED IBRAHIM HELAL, Ahmed; Ahmed, S. N.; Ahmed, H. M.; Ahmed, R.; Aigner, E.; Akarsu, M.; Akroush, M.; Akyuz, U.; Al Mahtab, M.; Al Qadiri, T.; Al Rawahi, Y.; AL rubaee, R.; Al Saffar, M.; Alam, S.; Al-Ani, Z.; Albillos, A.; Alboraie, M.; Al-Busafi, S.; Al-Emam, M.; Alharthi, J.; Ali, K.; Ali, B. A.; Ali, M.; Ali, R. A. R.; Alisi, A.; AL-Khafaji, A. R.; Alkhatry, M.; Aller, R.; Almansoury, Y.; Al-Naamani, K.; Alnakeeb, A.; Alonso, A.; Alqahtani, S. A.; Alrabadi, L.; Alswat, K.; Altaher, M.; Altamimi, T.; Altamirano, J.; Alvares-da-Silva, M. R.; Aly, E. A. M.; Alzahaby, A.; Alzamzamy, A.; Amano, K.; Amer, M. A.; Amin, M. A.; Amin, S. A.; Amir, A. A.; Ampuero, J.; Anas, N.; Andreone, P.; Andriamandimby, S. F.; Anees, M.; Angela, P.; Antonios, M.; Arafat, W.; Araya, J. M.; Armendariz-Borunda, J.; Armstrong, M. J.; Ashktorab, H.; Aspichueta, P.; Assal, F.; Atef, M.; Attia, D.; Atwa, H.; Awad, R.; Awad, M. A. E.; Awny, S.; Awolowo, O.; Awuku, Y. A.; Ayada, I.; Aye, T. T.; Ayman, S.; Ayman, H.; Ayoub, H.; Azmy, H. M.; Babaran, R. P.; Badreldin, O.; Badry, A.; Bahcecioglu, I. H.; Bahour, A.; Bai, J.; Balaban, Y.; Balasubramanyam, M.; Bamakhrama, K.; Banales, J. M.; Bangaru, B.; Bao, J.; Barahona, J. S.; Barakat, S.; Barbalho, S. M.; Barbra, B.; Barranco, B.; Barrera, F.; Baumann, U.; Bazeed, S.; Bech, E.; Benayad, A.; Benesic, A.; Bernstein, D.; Bessone, F.; Birney, S.; Bisseye, C.; Blake, M.; Bobat, B.; Bonfrate, L.; Bordin, D. S.; Bosques-Padilla, F.; Boursier, J.; Boushab, B. M.; Bowen, D.; Bravo, P. M.; Brennan, P. N.; Bright, B.; Broekaert, I.; Buque, X.; Burgos-Santamaria, D.; Burman, J.; Busetto, L.; Byrne, C. D.; Cabral-Prodigalidad, P. A. I.; Cabrera-Alvarez, G.; Cai, W.; Cainelli, F.; Caliskan, A. R.; Canbay, A.; Cano-Contreras, A.; Cao, H. -X.; Cao, Z.; Carrion, A.; Carubbi, F.; Casanovas, T.; Castellanos Fernandez, M. I.; Chai, J.; Chan, S. P.; Charatcharoenwitthaya, P.; Chavez-Tapia, N.; Chayama, K.; Chen, J.; Chen, L.; Chen, Z. -W.; Chen, H.; Chen, S. -D.; Chen, Q.; Chen, Y.; Chen, G.; Chen, E. -Q.; Chen, F.; Chen, P. -J.; Cheng, R.; Cheng, W.; Chieh, J. T. W.; Chokr, I.; Cholongitas, E.; Choudhury, A.; Chowdhury, A.; Chukwudike, E. S.; Ciardullo, S.; Clayton, M.; Clement, K.; Cloa, M. M.; Coccia, C.; Collazos, C.; Colombo, M.; Cosar, A. M.; Cotrim, H. P.; Couillerot, J.; Coulibaly, A.; Crespo, G.; Crespo, J.; Cruells, M.; Cua, I. H. Y.; Dabbous, H. K.; Dalekos, G. N.; D'Alia, P.; Dan, L.; Dao, V. H.; Darwish, M.; Datz, C.; Davalos-Moscol, M. B.; Dawoud, H.; de Careaga, B. O.; de Knegt, R.; de Ledinghen, V.; de Silva, J.; Debzi, N.; Decraecker, M.; Del Pozo, E.; Delgado, T. C.; Delgado-Blanco, M.; Dembinski, L.; Depina, A.; Derbala, M.; Desalegn, H.; Desbois-Mouthon, C.; Desoky, M.; Dev, A.; Di Ciaula, A.; Diago, M.; Di
abstract

2022 - Trabecular complexity as an early marker of cardiac involvement in Fabry disease [Articolo su rivista]
Camporeale, A.; Moroni, F.; Lazzeroni, D.; Garibaldi, S.; Pieroni, M.; Pieruzzi, F.; Lusardi, P.; Spada, M.; Mignani, R.; Burlina, A.; Carubbi, F.; Econimo, L.; Battaglia, Y.; Graziani, F.; Pica, S.; Chow, K.; Camici, P. G.; Lombardi, M.
abstract

AIMS: Fabry cardiomyopathy is characterized by glycosphingolipid storage and increased myocardial trabeculation has also been demonstrated. This study aimed to explore by cardiac magnetic resonance whether myocardial trabecular complexity, quantified by endocardial border fractal analysis, tracks phenotype evolution in Fabry cardiomyopathy. METHODS AND RESULTS: Study population included 20 healthy controls (12 males, age 32±9) and 45 Fabry patients divided into three groups: 15 left ventricular hypertrophy (LVH)-negative patients with normal T1 (5 males, age 28±13; Group 1); 15 LVH-negative patients with low T1 (9 males, age 33±9.6; Group 2); 15 LVH-positive patients (11 males, age 53.5±9.6; Group 3). Trabecular fractal dimensions (Dfs) (total, basal, mid-ventricular, and apical) were evaluated on cine images. Total Df was higher in all Fabry groups compared to controls, gradually increasing from controls to Group 3 (1.27±0.02 controls vs. 1.29±0.02 Group 1 vs. 1.30±0.02 Group 2 vs. 1.34±0.02 Group 3; P<0.001). Group 3 showed significantly higher values of all Dfs compared to the other Groups. Both basal and total Dfs were significantly higher in Group 1 compared with controls (basal: 1.30±0.03 vs. 1.26±0.04, P =0.010; total: 1.29±0.02 vs. 1.27±0.02, P=0.044). Total Df showed significant correlations with: (i) T1 value (r=-0.569; P<0.001); (ii) LV mass (r=0.664, P<0.001); (iii) trabecular mass (r=0.676; P <0.001); (iv) Mainz Severity Score Index (r=0.638; P<0.001). CONCLUSION: Fabry cardiomyopathy is characterized by a progressive increase in Df of endocardial trabeculae together with shortening of T1 values. Myocardial trabeculation is increased before the presence of detectable sphingolipid storage, thus representing an early sign of cardiac involvement.

2021 - A case of statin-induced liver injury with positive rechallenge with a second statin. Is there a class effect? [Articolo su rivista]
Onfiani, G.; Nascimbeni, F.; Carubbi, F.
abstract

Statins have proved to reduce cardiovascular morbidity and mortality in high-risk population and are generally well tolerated, although adverse events can occur. Up to 3% of patients develop aminotransferases elevation, which usually normalizes with continued treatment and hardly is associated with clinical symptoms. Serious statin-related liver injury is exceedingly rare. Furthermore, literature regarding rechallenge with a second statin is extremely poor. Some authors caution that re-exposure to these drugs is associated with a more serious liver injury but safe switching to a second statin after drug-induced liver injury (DILI) is also reported. We describe a case of a middle-aged woman who developed hepatocellular liver injury after simvastatin dose escalation; a rechallenge with low dose rosuvastatin caused rapid recurrence of DILI. In our opinion, clinicians should be very cautious upon rechallenge and closely follow-up patients who experienced statin-induced liver injury when trying re-exposure to another statin.

2021 - Association of nonalcoholic fatty liver disease (Nafld) with peripheral diabetic polyneuropathy: A systematic review and meta-analysis [Articolo su rivista]
Greco, C.; Nascimbeni, F.; Carubbi, F.; Andreone, P.; Simoni, M.; Santi, D.
abstract

Aims. The relationship between nonalcoholic fatty liver disease (NAFLD) and diabetic polyneuropathy (DPN) has been demonstrated in many studies, although results were conflicting. This meta-analysis aims to summarize available data and to estimate the DPN risk among NAFLD patients. Materials and methods. We performed a comprehensive literature review until 4 June 2021. Clinical trials analyzing the association between NAFLD and DPN were included. Results. Thirteen studies (9614 participants) were included. DPN prevalence was significantly higher in patients with NALFD, compared to patients without NAFLD (OR (95%CI) 2.48 (1.42–4.34), p = 0.001; I2 96%). This finding was confirmed in type 2 diabetes (OR (95%CI) 2.51 (1.33–4.74), p = 0.005; I2 97%), but not in type 1 diabetes (OR (95%CI) 2.44 (0.85–6.99), p = 0.100; I2 77%). Also, body mass index and diabetes duration were higher in NAFLD subjects compared to those without NAFLD (p < 0.001), considering both type 2 and type 1 diabetes. Conclusion. Despite a high heterogeneity among studies, a significantly increased DPN prevalence among type 2 diabetes subjects with NAFLD was observed. This result was not found in type 1 diabetes, probably due to the longer duration of disease. Physicians should pay more attention to the early detection of DPN, especially in patients with NAFLD.

2021 - Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC) [Articolo su rivista]
Vallejo-Vaz, A. J.; Stevens, C. A. T.; Lyons, A. R. M.; Dharmayat, K. I.; Freiberger, T.; Hovingh, G. K.; Mata, P.; Raal, F. J.; Santos, R. D.; Soran, H.; Watts, G. F.; Abifadel, M.; Aguilar-Salinas, C. A.; Alhabib, K. F.; Alkhnifsawi, M.; Almahmeed, W.; Alnouri, F.; Alonso, R.; Al-Rasadi, K.; Al-Sarraf, A.; Al-Sayed, N.; Araujo, F.; Ashavaid, T. F.; Banach, M.; Beliard, S.; Benn, M.; Binder, C. J.; Bogsrud, M. P.; Bourbon, M.; Chlebus, K.; Corral, P.; Davletov, K.; Descamps, O. S.; Durst, R.; Ezhov, M.; Gaita, D.; Genest, J.; Groselj, U.; Harada-Shiba, M.; Holven, K. B.; Kayikcioglu, M.; Khovidhunkit, W.; Lalic, K.; Latkovskis, G.; Laufs, U.; Liberopoulos, E.; Lima-Martinez, M. M.; Lin, J.; Maher, V.; Marais, A. D.; Marz, W.; Mirrakhimov, E.; Miserez, A. R.; Mitchenko, O.; Nawawi, H.; Nordestgaard, B. G.; Panayiotou, A. G.; Paragh, G.; Petrulioniene, Z.; Pojskic, B.; Postadzhiyan, A.; Raslova, K.; Reda, A.; Reiner, ; Sadiq, F.; Sadoh, W. E.; Schunkert, H.; Shek, A. B.; Stoll, M.; Stroes, E.; Su, T. -C.; Subramaniam, T.; Susekov, A. V.; Tilney, M.; Tomlinson, B.; Truong, T. H.; Tselepis, A. D.; Tybjaerg-Hansen, A.; Vazquez Cardenas, A.; Viigimaa, M.; Wang, L.; Yamashita, S.; Kastelein, J. J. P.; Bruckert, E.; Vohnout, B.; Schreier, L.; Pang, J.; Ebenbichler, C.; Dieplinger, H.; Innerhofer, R.; Winhofer-Stockl, Y.; Greber-Platzer, S.; Krychtiuk, K.; Speidl, W.; Toplak, H.; Widhalm, K.; Stulnig, T.; Huber, K.; Hollerl, F.; Rega-Kaun, G.; Kleemann, L.; Maser, M.; Scholl-Burgi, S.; Saly, C.; Mayer, F. J.; Sablon, G.; Tarantino, E.; Nzeyimana, C.; Pojskic, L.; Sisic, I.; Nalbantic, A. D.; Jannes, C. E.; Pereira, A. C.; Krieger, J. E.; Petrov, I.; Goudev, A.; Nikolov, F.; Tisheva, S.; Yotov, Y.; Tzvetkov, I.; Baass, A.; Bergeron, J.; Bernard, S.; Brisson, D.; Brunham, L. R.; Cermakova, L.; Couture, P.; Francis, G. A.; Gaudet, D.; Hegele, R. A.; Khoury, E.; Mancini, G. B. J.; Mccrindle, B. W.; Paquette, M.; Ruel, I.; Cuevas, A.; Asenjo, S.; Wang, X.; Meng, K.; Song, X.; Yong, Q.; Jiang, T.; Liu, Z.; Duan, Y.; Hong, J.; Ye, P.; Chen, Y.; Qi, J.; Liu, Z.; Li, Y.; Zhang, C.; Peng, J.; Yang, Y.; Yu, W.; Wang, Q.; Yuan, H.; Cheng, S.; Jiang, L.; Chong, M.; Jiao, J.; Wu, Y.; Wen, W.; Xu, L.; Zhang, R.; Qu, Y.; He, J.; Fan, X.; Wang, Z.; Chow, E.; Pecin, I.; Perica, D.; Symeonides, P.; Vrablik, M.; Ceska, R.; Soska, V.; Tichy, L.; Adamkova, V.; Franekova, J.; Cifkova, R.; Kraml, P.; Vonaskova, K.; Cepova, J.; Dusejovska, M.; Pavlickova, L.; Blaha, V.; Rosolova, H.; Nussbaumerova, B.; Cibulka, R.; Vaverkova, H.; Cibickova, L.; Krejsova, Z.; Rehouskova, K.; Malina, P.; Budikova, M.; Palanova, V.; Solcova, L.; Lubasova, A.; Podzimkova, H.; Bujdak, J.; Vesely, J.; Jordanova, M.; Salek, T.; Urbanek, R.; Zemek, S.; Lacko, J.; Halamkova, H.; Machacova, S.; Mala, S.; Cubova, E.; Valoskova, K.; Burda, L.; Bendary, A.; Daoud, I.; Emil, S.; Elbahry, A.; Rafla, S.; Sanad, O.; Kazamel, G.; Ashraf, M.; Sobhy, M.; El-Hadidy, A.; Shafy, M. A.; Kamal, S.; Bendary, M.; Talviste, G.; Angoulvant, D.; Boccara, F.; Cariou, B.; Carreau, V.; Carrie, A.; Charrieres, S.; Cottin, Y.; Di-Fillipo, M.; Ducluzeau, P. H.; Dulong, S.; Durlach, V.; Farnier, M.; Ferrari, E.; Ferrieres, D.; Ferrieres, J.; Gallo, A.; Hankard, R.; Inamo, J.; Lemale, J.; Moulin, P.; Paillard, F.; Peretti, N.; Perrin, A.; Pradignac, A.; Rabes, J. P.; Rigalleau, V.; Sultan, A.; Schiele, F.; Tounian, P.; Valero, R.; Verges, B.; Yelnik, C.; Ziegler, O.; Haack, I. A.; Schmidt, N.; Dressel, A.; Klein, I.; Christmann, J.; Sonntag, A.; Stumpp, C.; Boger, D.; Biedermann, D.; Usme, M. M. N.; Beil, F. U.; Klose, G.; Konig, C.; Gouni-Berthold, I.; Otte, B.; Boll, G.; Kirschbaum, A.; Merke, J.; Scholl, J.; Segiet, T.; Gebauer, M.; Predica, F.; Mayer, M.; Leistikow, F.; Fullgraf-Horst, S.; Muller, C.; Schuler, M.; Wiener, J.; Hein, K.; Baumgartner, P.; Kopf, S.; Busch, R.; Schomig, M.; Matthias, S.; Allendorf-Ostwald, N.; Fink, B.; Bohm, D.; Jakel, A.; Koschker, A. -C.; Schweizer, R.; Vogt, A.; Parhofer, K.;
abstract

Background: The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods: Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings: Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53·6%] women) from 56 countries were included in the study. Of these, 31 798 (75·4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84·2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46·2 years (IQR 34·3–58·0); median age at diagnosis of familial hypercholesterolaemia was 44·4 years (32·5–56·5), with 40·2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17·4% (2·1% for stroke and 5·2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81·1%) were receiving statins and 3691 (21·2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5·43 mmol/L (IQR 4·32–6·72) among patients not taking lipid-lowering medications and 4·23 mmol/L (3·20–5·66) among those taking them. Among patients taking lipid-lowering medications, 2·7% had LDL cholesterol lower than 1·8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin–kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1·8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p<0·001). Interpretation: Familial hypercholesterolaemia is diagnosed late. Guideline-recommended LDL cholesterol concentrations are infrequently achieved with single-drug therapy. Cardiovascular risk factors and presence of coronary disease were lower among non-index cases, who were diagnosed earlier. Earlier detection and greater use of combination therapies are required to reduce the global burden of familial hypercholesterolaemia. Funding: Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron.

2021 - Nutrition in adult patients with selected lysosomal storage diseases [Articolo su rivista]
Carubbi, Francesca; Barbato, Antonio; Burlina, Alberto B.; Francini, Francesco; Mignani, Renzo; Pegoraro, Elena; Landini, Linda; De Danieli, Gianluca; Bruni, Stefano; Strazzullo, Pasquale; Landini, Linda; Barbato, Antonio; Carubbi, Francesca; Francini, Francesco; Strazzullo, Pasquale
abstract

Lysosomal storage disorders (LSDs) are a group of clinically heterogeneous disorders affecting the function of lysosomes and are characterized by an accumulation of undigested substrates within several cell types. In recent years there have been substantial advances in supportive care and drug treatment for some LSDs, leading to improved patient survival, as seen in Gaucher, Pompe and Fabry disease and some Mucopolysaccharidoses; however, many symptoms still persist. Thus it is now even more important to improve patients’ quality of life and reduce symptoms and comorbidities. One potential way of achieving this goal is through adjunct nutritional therapy, which is challenging as patients may be overweight with associated consequences, or malnourished, or underweight. Furthermore, drugs used to treat LSDs can modify the metabolic status and needs of patients. There are currently not enough data to make specific dietary recommendations for individual LSDs; however, suggestions can be made for managing clinical manifestations of the diseases, as well as treatment-associated adverse events. The metabolic and nutritional status of adult patients must be regularly assessed and individualized dietary plans may be created to cater to a patient’s specific needs. Damage to the autophagic process is a common feature in LSDs that is potentially sensitive to dietary manipulation and needs to be assessed in clinical studies.

2021 - The time has come to look for metabolic dysfunction-associated fatty liver disease in adult patients with type 1 Gaucher disease [Articolo su rivista]
Nascimbeni, F.; Lugari, S.; Andreone, P.; Carubbi, F.
abstract

MAFLD is highly prevalent in Gaucher type 1 adult patients as well as in the general population and may worsen liver disease progression. Hepatic complications should be followed up. A healthy lifestyle and therapies of cardiometabolic risk factors should be recommended in Gaucher disease patients.

2020 - Atrial Dysfunction Assessed by Cardiac Magnetic Resonance as an Early Marker of Fabry Cardiomyopathy [Articolo su rivista]
Bernardini, A.; Camporeale, A.; Pieroni, M.; Pieruzzi, F.; Figliozzi, S.; Lusardi, P.; Spada, M.; Mignani, R.; Burlina, A.; Carubbi, F.; Battaglia, Y.; Graziani, F.; Pica, S.; Tondi, L.; Chow, K.; Boveri, S.; Olivotto, I.; Lombardi, M.
abstract

In this retrospective, observational study, 45 patients with Anderson-Fabry disease (AFD) underwent CMR with T1 mapping using shortened modified Look-Locker inversion recovery sequences, 2-dimensional echocardiography and quantification of Mainz Severity Score Index (MSSI). LA total strain showed very good correlation with native septal T1, LV maximum wall thickness, atrial volumes, and global or cardiovascular MSSI. A good correlation was found with native T1 values, which in pre-hypertrophic patients with AFD had been shown to provide prognostic information. This study contributes to the characterization of the pre-hypertrophic phenotype of AFD, introducing LA total strain as a potential novel indicator of early cardiac involvement and a possible tool to personalize management decisions in Fabry disease patients.

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 - Liver involvement in Gaucher disease: A practical review for the hepatologist and the gastroenterologist [Articolo su rivista]
Carubbi, F.; Cappellini, M. D.; Fargion, S.; Fracanzani, A. L.; Nascimbeni, F.
abstract

Gaucher disease (GD), a rare lysosomal storage disorder caused by deficient glucocerebrosidase activity and consequent accumulation of glycosphingolipids in the mononuclear phagocyte system, may progress to disabling and potentially life-threatening complications when left undiagnosed and untreated. Unfortunately, because of non-specific signs and symptoms and lack of awareness, patients with type 1 GD, the most common non-neuropathic variant, frequently experience diagnostic delays. Since splenomegaly and thrombocytopenia are the dominant clinical features in many GD patients leading to first medical contact, the hepatologist and the gastroenterologist need to be aware of this condition. Liver involvement has been reported in the majority of GD patients, and comprises hepatomegaly, with or without liver enzymes alteration, fibrosis/cirrhosis, portal hypertension, focal liver lesions, and cholelithiasis. Moreover, GD is associated with several biochemical alterations of potential interest for the hepatologist and the gastroenterologist, including hypergammaglobulinemia, hyperferritinemia and metabolic abnormalities, that may lead to misdiagnoses with chronic liver diseases of common etiology, such as primary hemochromatosis, autoimmune liver diseases or nonalcoholic fatty liver disease. This comprehensive review, based on the collaborative experience of physicians managing patients with GD, provides practical information on the clinical, histological and radiological hepatic manifestations of GD aiming at facilitating the diagnosis of GD for the hepatologist and the gastroenterologist.

2020 - Liver steatosis is highly prevalent and is associated with metabolic risk factors and liver fibrosis in adult patients with type 1 Gaucher disease [Articolo su rivista]
Nascimbeni, F.; Lugari, S.; Cassinerio, E.; Motta, I.; Cavicchioli, A.; Dalla Salda, A.; Bursi, S.; Donatiello, S.; Spina, V.; Cappellini, M. D.; Andreone, P.; Carubbi, F.
abstract

Background and Aims: Gaucher disease (GD) is associated with peculiar metabolic abnormalities (ie hypermetabolic state, peripheral insulin resistance, dyslipidaemia), partially reverted by enzyme replacement therapy (ERT) at the expense of weight gain. Such metabolic alterations together with an unhealthy lifestyle acquired by an ageing GD population may favour the development of liver steatosis. We aimed at evaluating the prevalence of significant liver steatosis and at identifying the factors associated with liver steatosis in a cohort of patients with type 1 GD. Methods: Twenty adult type 1 GD patients from an Italian academic referral centre were prospectively submitted to vibration-controlled transient elastography (Fibroscan®) with controlled attenuation parameter (CAP); significant steatosis was defined as CAP values ≥250 dB/min. Results: Median CAP values were 234 [165-358] dB/min and 8 patients (40%) had significant steatosis. Significant steatosis was associated with indices of adiposity (weight, BMI and waist circumference), high blood pressure, insulin resistance and metabolic syndrome. GD-related variables and dose and duration of ERT were not associated with significant steatosis. In the subgroup of 16 patients on stable ERT for at least 24 months, CAP resulted significantly and positively associated with liver stiffness (rho 0.559, P =.024). Conclusions: Significant steatosis is highly prevalent in adult type 1 GD patients and is strongly associated with a worse metabolic profile, featuring metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD may determine liver fibrosis progression in GD patients on stable ERT and may be a risk factor for long-term liver-related complications.

2020 - Parkinson's disease in Gaucher disease patients: What's changing in the counseling and management of patients and their relatives? [Articolo su rivista]
Di Rocco, M.; Di Fonzo, A.; Barbato, A.; Cappellini, M. D.; Carubbi, F.; Giona, F.; Giuffrida, G.; Linari, S.; Pession, A.; Quarta, A.; Scarpa, M.; Spada, M.; Strisciuglio, P.; Andria, G.
abstract

Background: How to address the counseling of lifetime risk of developing Parkinson's disease in patients with Gaucher disease and their family members carrying a single variant of the GBA1 gene is not yet clearly defined. In addition, there is no set way of managing Gaucher disease patients, taking into account the possibility that they may show features of Parkinson's disease. Methods: Starting from an overview on what has recently changed in our knowledge on this issue and grouping the experiences of healthcare providers of Gaucher disease patients, we outline a path of counseling and management of Parkinson's disease risk in Gaucher disease patients and their relatives. Conclusion: The approach proposed here will help healthcare providers to communicate Parkinson's disease risk to their patients and will reduce the possibility of patients receiving inaccurate information from inadequate sources. Furthermore, this resource will help to empower healthcare providers to identify early signs and/or symptoms of Parkinson's disease and decide when to refer these patients to the neurologist for appropriate specific therapy and follow-up.

2019 - Gaucher Disease in Bone: From Pathophysiology to Practice [Articolo su rivista]
Hughes, D.; Mikosch, P.; Belmatoug, N.; Carubbi, F.; Cox, T.; Goker-Alpan, O.; Kindmark, A.; Mistry, P.; Poll, L.; Weinreb, N.; Deegan, P.
abstract

Gaucher disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the most prevalent aspects of GD and a major cause of pain, disability, and reduced quality of life. Uniform recommendations for contemporary evaluation and management are needed. To develop practical clinical recommendations, an international group of experienced physicians conducted a comprehensive review of 20 years’ of the literature, defining terms according to pathophysiological understanding and pointing out best practice and unmet needs related to the skeletal features of this disorder. Abnormalities of bone modeling, reduced bone density, bone infarction, and plasma cell dyscrasias accompany the displacement of healthy adipocytes in adult marrow. Exposure to excess bioactive glycosphingolipids appears to affect hematopoiesis and the balance of osteoblast and osteoclast numbers and activity. Imbalance between bone formation and breakdown induces disordered trabecular and cortical bone modeling, cortical bone thinning, fragility fractures, and osteolytic lesions. Regular assessment of bone mineral density, marrow infiltration, the axial skeleton and searching for potential malignancy are recommended. MRI is valuable for monitoring skeletal involvement: It provides semiquantitative assessment of marrow infiltration and the degree of bone infarction. When MRI is not available, monitoring of painful acute bone crises and osteonecrosis by plain X-ray has limited value. In adult patients, we recommend DXA of the lumbar spine and left and right hips, with careful protocols designed to exclude focal disease; serial follow-up should be done using the same standardized instrument. Skeletal health may be improved by common measures, including adequate calcium and vitamin D and management of pain and orthopedic complications. Prompt initiation of specific therapy for GD is crucial to optimizing outcomes and preventing irreversible skeletal complications. Investing in safe, clinically useful, and better predictive methods for determining bone integrity and fracture risk remains a need. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

2019 - Statins and nonalcoholic fatty liver disease in the era of precision medicine: More friends than foes [Articolo su rivista]
Nascimbeni, Fabio; Pellegrini, Elisa; Lugari, Simonetta; Mondelli, Alberto; Bursi, Serena; Onfiani, Giovanna; Carubbi, Francesca; Lonardo, Amedeo
abstract

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of alcohol-like hepatic histological changes, which occur in the absence of any competing causes of chronic liver disease, notably including significant alcohol consumption. A close and bi-directional relationship links NAFLD with the metabolic syndrome (MetS), and concurrent MetS will hasten the progression to more severe forms of NAFLD, including cirrhosis and hepatocellular carcinoma (HCC). Patients with NAFLD will typically exhibit atherogenic dyslipidemia and increased cardiovascular risk (CVR). Statins are among the most widely prescribed lipid-lowering drugs. Their use has historically been hampered, in individuals with liver disease, owing to the fear of hepatotoxicity. However, studies suggest that statins are not only effective in reducing cardiovascular events, but may also exert multiple beneficial effects on the liver. CVR in those with NAFLD has extensively been covered by our group and others. This updated clinical narrative review will critically examine the effects of statins on the pathogenesis of NAFLD, including the key elementary pathological lesions of NAFLD, i.e. steatosis, inflammation and fibrosis, and its liver-related complications, i.e. cirrhosis, portal hypertension and HCC.

2018 - Energy balance, glucose and lipid metabolism, cardiovascular risk and liver disease burden in adult patients with type 1 Gaucher disease [Articolo su rivista]
Nascimbeni, Fabio; Dalla Salda, Annalisa; Carubbi, Francesca
abstract

Gaucher disease (GD), the most prevalent lysosomal storage disease, is characterized by systemic accumulation of macrophages engorged with glycosphingolipid-laden lysosomes. Even though both lysosomes and sphingolipids play a pivotal role in metabolic homeostasis, little is known on metabolic abnormalities associated with GD. In this review, we discuss the peculiarity of energy balance and glucose and lipid metabolism in adult type 1 GD patients. Moreover, we evaluate the potential relationship between these metabolic derangements, cardiovascular risk and chronic liver disease. The limited data available show that adult type 1 GD is characterized by a hypermetabolic state, peripheral insulin resistance and hypolipidemia with markedly reduced HDL-cholesterol levels, partially reverted by enzyme replacement therapy (ERT) or substrate reduction therapy (SRT). Although this unfavorable metabolic profile has not been associated with increased incidence of type 2 diabetes and premature atherosclerosis, a natural history study has shown that cardio-cerebrovascular events and malignancy are the leading causes of death in treated type 1 GD patients. Hepatomegaly is frequently observed in GD and ERT/SRT are highly effective in reducing liver volume. Nevertheless, patients with GD may be at increased risk of long-term liver complications including cirrhosis and hepatocellular carcinoma. The role that ERT/SRT and/or lifestyle habits may have on such metabolic features of GD patients, and subsequently on long-term prognosis, deserves further investigations. To gain more insights into the peculiarity of GD metabolism may serve both surveillance and treatment purposes by helping to identify new markers of disease severity and define an updated natural history of GD.

2018 - Evaluation of the performance of Dutch Lipid Clinic Network score in an Italian FH population: The LIPIGEN study [Articolo su rivista]
Casula, Manuela; Olmastroni, Elena; Pirillo, Angela; Catapano, Alberico Luigi; Arca, Marcello; Averna, Maurizio; Bertolini, Stefano; Calandra, Sebastiano; Tarugi, Patrizia; Pellegatta, Fabio; Angelico, Francesco; Bartuli, Andrea; Biasucci, Giacomo; Biolo, Gianni; Bonanni, Luca; Bonomo, Katia; Borghi, Claudio; Bossi, Antonio Carlo; Branchi, Adriana; Carubbi, Francesca; Cipollone, Francesco; Citroni, Nadia; Federici, Massimo; Ferri, Claudio; Fiorenza, Anna Maria; Giaccari, Andrea; Giorgino, Francesco; Guardamagna, Ornella; Iannuzzi, Arcangelo; Iughetti, Lorenzo; Lupattelli, Graziana; Lupi, Alessandro; Mandraffino, Giuseppe; Marcucci, Rossella; Maroni, Lorenzo; Miccoli, Roberto; Mombelli, Giuliana; Muntoni, Sandro; Pecchioli, Valerio; Pederiva, Cristina; Pipolo, Antonio; Pisciotta, Livia; Pujia, Arturo; Purrello, Francesco; Repetti, Elena; Rubba, Paolo; Sabbà, Carlo; Sampietro, Tiziana; Sarzani, Riccardo; Tagliabue, Milena Paola; Trenti, Chiara; Vigna, Giovanni Battista; Werba, Josè Pablo; Zambon, Sabina; Zenti, Maria Grazia; Minicocci, Ilenia; Noto, Davide; Fortunato, Giuliana; Banderali, Giuseppe; Benso, Andrea; Bigolin, Paola; Bonora, Enzo; Bruzzi, Patrizia; Bucci, Marco; Buonuomo, Paola Sabrina; Capra, Maria Elena; Cardolini, Iris; Cefalù, Baldassarre; Cervelli, Nazzareno; Chiariello, Giuseppe; Cocci, Guido; Colombo, Emanuela; Cremonini, Anna Laura; D'addato, Sergio; D'erasmo, Laura; Dal Pino, Beatrice; De Sanctis, Luisa; De Vita, Emanuele; Del Ben, Maria; Di Costanzo, Alessia; Di Taranto, Maria Donata; Fasano, Tommaso; Gentile, Luigi; Gentile, Marco; Ghirardello, Omar; Grigore, Liliana; Lussu, Milena; Meregalli, Giancarla; Moffa, Simona; Montalcini, Tiziana; Morgia, Valeria; Nascimbeni, Fabio; Pasta, Andrea; Pavanello, Chiara; Saitta, Antonino; Scicali, Roberto; Siepi, Donatella; Spagnolli, Walter; Spina, Rossella; Sticchi, Elena; Suppressa, Patrizia; Vigo, Lorenzo; Vinci, Pierandrea; Manzato, Enzo; Tragni, Elena; Zampoleri, Veronica
abstract

Background and aims: Familial hypercholesterolemia (FH) is an inherited disorder characterized by high levels of blood cholesterol from birth and premature coronary heart disease. Thus, the identification of FH patients is crucial to prevent or delay the onset of cardiovascular events, and the availability of a tool helping with the diagnosis in the setting of general medicine is essential to improve FH patient identification. Methods: This study evaluated the performance of the Dutch Lipid Clinic Network (DLCN) score in FH patients enrolled in the LIPIGEN study, an Italian integrated network aimed at improving the identification of patients with genetic dyslipidaemias, including FH. Results: The DLCN score was applied on a sample of 1377 adults (mean age 42.9 ± 14.2 years) with genetic diagnosis of FH, resulting in 28.5% of the sample classified as probable FH and 37.9% as classified definite FH. Among these subjects, 43.4% had at least one missing data out of 8, and about 10.0% had 4 missing data or more. When analyzed based on the type of missing data, a higher percentage of subjects with at least 1 missing data in the clinical history or physical examination was classified as possible FH (DLCN score 3–5). We also found that using real or estimated pre-treatment LDL-C levels may significantly modify the DLCN score. Conclusions: Although the DLCN score is a useful tool for physicians in the diagnosis of FH, it may be limited by the complexity to retrieve all the essential information, suggesting a crucial role of the clinical judgement in the identification of FH subjects.

2018 - Prevalence and predictors of liver fibrosis evaluated by vibration controlled transient elastography in type 1 Gaucher disease [Articolo su rivista]
Nascimbeni, Fabio; Cassinerio, Elena; Dalla Salda, Annalisa; Motta, Irene; Bursi, Serena; Donatiello, Salvatore; Spina, Vincenzo; Cappellini, Maria Domenica; Carubbi, Francesca
abstract

Background & aims: Long-term liver-related complications of Gaucher disease (GD) include cirrhosis, portal hypertension and hepatocellular carcinoma. Although liver fibrosis is the main determinant of adverse liver-related clinical outcomes, it has rarely been evaluated in previously published cohorts of GD patients. We aimed at: assessing the prevalence of significant liver fibrosis in a cohort of patients with type 1 GD; identifying its predictors among GD-related variables, enzyme replacement therapy (ERT) and metabolic features. Methods: 37 adult type 1 GD patients from two Italian academic referral centers were prospectively submitted to vibration controlled transient elastography (Fibroscan®); significant fibrosis was defined as liver stiffness ≥7 kPa. Results: Median liver stiffness was 4.6 [3–15.1] kPa and 7 patients (19%) had significant fibrosis. Significant fibrosis was associated with splenectomy (p =.046) and with scores (DS3: p =.002; SSI: p =.026) and biomarkers (ACE: p =.016; HDL cholesterol: p =.004) of GD severity. Length of ERT was significantly lower in GD patients with significant fibrosis. In the subgroup of 29 patients who were on stable ERT for at least 24 months, further to splenectomy, GD severity and non-N370S GBA1 genotypes, also diastolic blood pressure, BMI and the number of metabolic syndrome (MetS) components emerged as factors significantly associated with significant fibrosis. Conclusions: Significant fibrosis is present in a remarkable proportion of adult type 1 GD patients. Splenectomy, GD severity and GBA1 genotypes are major GD-related predictors of liver fibrosis. Length of ERT is inversely correlated with liver disease in GD patients, suggesting a beneficial effect of ERT on liver fibrosis. However, GD patients on stable ERT should be monitored for metabolic complications, since MetS features may enhance liver disease progression despite optimal GD control.

2018 - The association of Mediterranean diet and exercise modifications with anthropometric parameters in a psychiatric community population: A pilot study [Articolo su rivista]
DI LORENZO, Rosaria; Pedretti, Jessica; Grossi, Letizia; Cuoghi, Benedetta; Varni, Cinzia; Landi, Giulia; Spattini, Ludovica; Visentini, Chiara; Ferri, Paola; Carubbi, Francesca
abstract

Weight gain and related metabolic syndrome (MS) are major current issues in public health. MS consists of abdominal fat, atherogenic dyslipidemia, hypertension, hyperglycemia, insulin resistance, pro-inflammatory and pro-thrombotic state, and accounts for both cardiovascular diseases and type II diabetes mellitus risk factors. Patients affected by psychiatric illness present a prevalence of 35–40% of MS. Many studies have shown that Mediterranean diet is associated with the reduction of mortality due to cardiovascular and malignant diseases, potentially preventing both obesity and type II diabetes mellitus. Our pilot study explores the effects of a 12- month healthy lifestyle program (Mediterranean diet and mild physical activity) on metabolic and anthropometric parameters of patients affected by chronic psychiatric disorders who live in a psychiatric community facility. A Mediterranean diet was provided by a senior nutritional clinician and adapted by two dieticians, according to the needs and preferences of the community population. Concomitantly, a program of moderate physical activity, consisting in 30-min walks on level ground 4 days a week, and psycho-educational group sessions with educational and therapeutic purposes were implemented. The metabolic and anthropometric parameters of our patients improved after both 6 (T6) and 12 (T12) months. Body Max Index was statistically significantly reduced at T6 and T12, with patients perceiving good quality of life. These positive outcomes suggest that a low-cost healthy lifestyle program can produce good adherence and feasibility even among patients with chronic psychiatric diseases, reducing their risk for MS, cardiovascular diseases and other complications.

2017 - Familial hypercholesterolemia: The Italian Atherosclerosis Society Network (LIPIGEN) [Articolo su rivista]
Averna, Maurizio; Cefalã¹, Angelo B.; Casula, Manuela; Noto, Davide; Arca, Marcello; Bertolini, Stefano; Calandra, Sebastiano; Catapano, Alberico L.; Tarugi, Patrizia; Arca, Marcello; Averna, Maurizio; Bertolini, Stefano; Calandra, Sebastiano; Catapano, Alberico Luigi; Tarugi, Patrizia; Pellegatta, Fabio; Angelico, Francesco; Arca, Marcello; Averna, Maurizio; Bartuli, Andrea; Biasucci, Giacomo; Biolo, Gianni; Bonanni, Luca; Bonomo, Katia; Borghi, Claudio; Bossi, Antonio Carlo; Branchi, Adriana; Carubbi, Francesca; Cipollone, Francesco; Citroni, Nadia; Federici, Massimo; Ferri, Claudio; Fiorenza, Anna Maria; Giaccari, Andrea; Giorgino, Francesco; Guardamagna, Ornella; Iannuzzi, Arcangelo; Iughetti, Lorenzo; Lupattelli, Graziana; Mandraffino, Giuseppe; Marcucci, Rossella; Mombelli, Giuliana; Muntoni, Sandro; Pecchioli, Valerio; Pederiva, Cristina; Pipolo, Antonio; Pisciotta, Livia; Pujia, Arturo; Purrello, Francesco; Repetti, Elena; Rubba, Paolo; Sabbã , Carlo; Sampietro, Tiziana; Sarzani, Riccardo; Tagliabue, Milena Paola; Trenti, Chiara; Vigna, Giovanni Battista; Werba, Josà Pablo; Zambon, Sabina; Zenti, Maria Grazia; Montali, Anna; Noto, Davide; Bertolini, Stefano; Calandra, Sebastiano; Fortunato, Giuliana; Grigore, Liliana; Del Ben, Maria; Maranghi, Marianna; Cefalã¹, Angelo B.; Barbagallo, Carlo M.; Buonuomo, Paola Sabrina; Capra, Maria Elena; Vinci, Pierandrea; D'Addato, Sergio; Galbiati, Stella; Nascimbeni, Fabio; Bucci, Marco; Spagnoli, Walter; Cardolini, Iris; Cervelli, Nazzareno; Emanuela, Colombo; Vinsin, A. Sun; Laviola, Luigi; Bello, Francesca; Chiariello, Giuseppe; Predieri, Barbara; Siepi, Donatella; Saitta, Antonino; Giusti, Betti; Pavanello, Chiara; Lussu, Milena; Prati, Lucia; Banderali, Giuseppe; Balleari, Giulia; Montalcini, Tiziana; Scicali, Roberto; Gentile, Luigi; Gentile, Marco; Suppressa, Patrizia; Sbrana, Francesco; Cocci, Guido; Benso, Andrea; Negri, Emanuele Alberto; Ghirardello, Omar; Lorenzo, Vigo; Zambon, Alberto; Enzo, Bonora; Minicocci, Ilenia; Spina, Rossella; Orlando, Camilla; Tarugi, Patrizia; Di Taranto, Maria Donata; Catapano, Alberico Luigi; Casula, Manuela; Chiodo, Lorenzo; Garlaschelli, Katia; Manzato, Enzo; Tragni, Elena
abstract

Background and aims Primary dyslipidemias are a heterogeneous group of disorders characterized by abnormal levels of circulating lipoproteins. Among them, familial hypercholesterolemia is the most common lipid disorder that predisposes for premature cardiovascular disease. We set up an Italian nationwide network aimed at facilitating the clinical and genetic diagnosis of genetic dyslipidemias named LIPIGEN (LIpid TransPort Disorders Italian GEnetic Network). Methods Observational, multicenter, retrospective and prospective study involving about 40 Italian clinical centers. Genetic testing of the appropriate candidate genes at one of six molecular diagnostic laboratories serving as nationwide DNA diagnostic centers. Results and conclusions From 2012 to October 2016, available biochemical and clinical information of 3480 subjects with familial hypercholesterolemia identified according to the Dutch Lipid Clinic Network (DLCN) score were included in the database and genetic analysis was performed in 97.8% of subjects, with a mutation detection rate of 92.0% in patients with DLCN score ≥6. The establishment of the LIPIGEN network will have important effects on clinical management and it will improve the overall identification and treatment of primary dyslipidemias in Italy.

2017 - Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study [Articolo su rivista]
Pirillo, Angela; Garlaschelli, Katia; Arca, Marcello; Averna, Maurizio; Bertolini, Stefano; Calandra, Sebastiano; Tarugi, Patrizia; Catapano, Alberico L.; Arca, Marcello; Averna, Maurizio; Bertolini, Stefano; Calandra, Sebastiano; Catapano, Alberico Luigi; Tarugi, Patrizia; Pellegatta, Fabio; Angelico, Francesco; Arca, Marcello; Averna, Maurizio; Bartuli, Andrea; Biasucci, Giacomo; Biolo, Gianni; Bonanni, Luca; Bonomo, Katia; Borghi, Claudio; Bossi, Antonio Carlo; Branchi, Adriana; Carubbi, Francesca; Cipollone, Francesco; Citroni, Nadia; Federici, Massimo; Ferri, Claudio; Fiorenza, Anna Maria; Giaccari, Andrea; Giorgino, Francesco; Guardamagna, Ornella; Iannuzzi, Arcangelo; Iughetti, Lorenzo; Lupattelli, Graziana; Mandraffino, Giuseppe; Marcucci, Rossella; Mombelli, Giuliana; Muntoni, Sandro; Pecchioli, Valerio; Pederiva, Cristina; Pipolo, Antonio; Pisciotta, Livia; Pujia, Arturo; Purrello, Francesco; Repetti, Elena; Rubba, Paolo; Sabbà, Carlo; Sampietro, Tiziana; Sarzani, Riccardo; Tagliabue, Milena Paola; Trenti, Chiara; Vigna, Giovanni Battista; Werba, Josà Pablo; Zambon, Sabina; Zenti, Maria Grazia; Montali, Anna; Noto, Davide; Bertolini, Stefano; Calandra, Sebastiano; Fortunato, Giuliana; Grigore, Liliana; Del Ben, Maria; Maranghi, Marianna; Cefalù, A. Baldassarre; Buonuomo, Paola Sabrina; Capra, Maria Elena; Vinci, Pierandrea; D'Addato, Sergio; Galbiati, Stella; Nascimbeni, Fabio; Bucci, Marco; Spagnoli, Walter; Cardolini, Iris; Cervelli, Nazzareno; Emanuela, Colombo; Sun, Vinsin A.; Laviola, Luigi; Bello, Francesca; Chiariello, Giuseppe; Predieri, Barbara; Siepi, Donatella; Saitta, Antonino; Giusti, Betti; Pavanello, Chiara; Lussu, Milena; Prati, Lucia; Banderali, Giuseppe; Balleari, Giulia; Montalcini, Tiziana; Scicali, Roberto; Gentile, Luigi; Gentile, Marco; Suppressa, Patrizia; Sbrana, Francesco; Cocci, Guido; Benso, Andrea; Negri, Emanuele Alberto; Ghirardello, Omar; Lorenzo, Vigo; Zambon, Alberto; Enzo, Bonora; Minicocci, Ilenia; Spina, Rossella; Orlando, Camilla; Tarugi, Patrizia; Di Taranto, Maria Donata; Catapano, Alberico Luigi; Casula, Manuela; Chiodo, Lorenzo; Garlaschelli, Katia; Manzato, Enzo; Tragni, Elena
abstract

Background Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDL-cholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality. Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study). Methods We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major candidate genes for monogenic hypercholesterolemia (LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1). Results A total of 213 variants were detected in 1076 subjects. About 90% of them had a pathogenic or likely pathogenic variants. More than 94% of patients carried pathogenic variants in LDLR gene, 27 of which were novel. Pathogenic variants in APOB and PCSK9 were exceedingly rare. We found 4 true homozygotes and 5 putative compound heterozygotes for pathogenic variants in LDLR gene, as well as 5 double heterozygotes for LDLR/APOB pathogenic variants. Two patients were homozygous for pathogenic variants in LDLRAP1 gene resulting in autosomal recessive hypercholesterolemia. One patient was found to be heterozygous for the ApoE variant p.(Leu167del), known to confer an FH phenotype. Conclusions This study shows the molecular characteristics of the FH patients identified in Italy over the last two years. Full phenotypic characterization of these patients and cascade screening of family members is now in progress.

2015 - Erratum to: Management of Bone Disease in Gaucher Disease Type 1: Clinical Practice [Articolo su rivista]
Giuffrida, Gaetano; Cappellini, Maria Domenica; Carubbi, Francesca; Di Rocco, Maja; Iolascon, Giovanni
abstract

Erratum and supplementary material. Supplementary material at doi : 10.1007/s12325-015-0196-2

2014 - Cardiovascular risk, lipidemic phenotype and steatosis. A comparative analysis of cirrhotic and non-cirrhotic liver disease due to varying etiology. [Articolo su rivista]
Loria, Paola; Marchesini, G; Nascimbeni, Fabio; Ballestri, S; Maurantonio, M; Carubbi, Francesca; Ratziu, V; Lonardo, A.
abstract

BACKGROUND: Liver regulates lipid metabolism in health and disease states. Nevertheless, the entity of cardiovascular risk (CVR) resulting from dysregulation of lipid metabolism secondary to liver disease is poorly characterized. AIM AND METHODS: To review, based on a PubMed literature search, the features and the determinants of serum lipid phenotype and its correlation with hepatic steatosis, insulin resistance (IR) and CVR across the wide spectrum of the most common chronic liver diseases due to different etiologies. RESULTS: Alcoholic liver disease (ALD) is associated with steatosis, IR and a typical lipid profile. The relationship between alcohol intake, incident type 2 diabetes (T2D) and CVR describes a J-shaped curve. Non-alcoholic fatty liver disease (NAFLD), and probably nonalcoholic steatohepatitis (NASH) in particular, is associated with IR, atherogenic dyslipidemia and increased CVR independent of traditional risk factors. Moreover, NASH-cirrhosis and T2D contribute to increasing CVR in liver transplant recipients. HBV infection is generally free from IR, steatosis and CVR. HCV-associated dysmetabolic syndrome, featuring steatosis, hypocholesterolemia and IR, appears to be associated with substantially increased CVR. Hyperlipidemia is an almost universal finding in primary biliary cirrhosis, a condition typically spared from steatosis and associated with neither subclinical atherosclerosis nor excess CVR. Finally, little is known on CVR in patients with hepatocellular carcinoma. CONCLUSIONS: CVR is increased in ALD, NAFLD and chronic HCV infection, all conditions featuring IR and steatosis. Therefore, irrespective of serum lipid phenotype, hepatic steatosis and IR may be major shared determinants in amplifying CVR in common liver disease due to varying etiology

2014 - Management of bone disease in Gaucher disease type 1: clinical practice [Articolo su rivista]
Giuffrida, Gaetano; Cappellini, Maria Domenica; Carubbi, Francesca; Di Rocco, Maja; Iolascon, Giovanni
abstract

Gaucher disease is a rare autosomal recessive disorder of glycosphingolipid metabolism resulting from deficient activity of the lysosomal enzyme beta-glucocerebrosidase that causes accumulation of glucosylceramide in tissue macrophage with damage to hematological, visceral, and skeletal organ systems. Severity and progression may vary independently among these domains, necessitating individualized therapy. Skeletal involvement is highly prevalent and often associated with intense pain, impaired mobility, and reduced quality of life. Enzyme replacement therapy improves parameters in all affected domains, but skeletal involvement requires longer treatment and higher dosages to obtain significant results. Despite numerous papers on bone complications in patients with Gaucher disease, there are no specific indications on how to assess properly bone involvement in such condition, the frequency of assessment, the use of markers for osteoblast and osteoclast activity, or the administration of bisphosphonates or other symptomatic drugs in adult and pediatric patients. Starting from a re-evaluation of cases with bone involvement, we have identified some common errors in the diagnostic approach and management. The aim of this paper was to propose a methodological and critical approach to the diagnosis, follow-up and treatment of bone disease in patients with Gaucher disease type 1.

2014 - Quality of life in adult patients with glycogen storage disease type i: Results of a multicenter Italian study [Articolo su rivista]
Sechi, A.; Deroma, L.; Paci, S.; Lapolla, A.; Carubbi, F.; Burlina, A.; Rigoldi, M.; Di Rocco, M.
abstract

Background: Glycogen storage disease type I (GSD I) is a chronic metabolic disease that requires a lifelong strict dietetic treatment to avoid hypoglycemia and can lead to severe complications during adult age. Impaired quality of life (QoL) has been reported in affected children, but this aspect has not been previously investigated in adults. Objective: To assess QoL in adult patients with GSD I. Patients and Methods: Italian patients with GSD type Ia and Ib, who were 16 years or older, were asked to complete the SF-36 questionnaire, assessing their QoL. Data on demographic characteristics and clinical history were collected from clinical records and interviews. Results: Thirty-eight patients (22 females, 16 males; 27 with GSD Ia, 11 with GSD Ib, median age 26.5 years) completed the SF-36 questionnaire. Overall, when compared to normal values, patients with GSD I had lower median scores in general health perception and social functioning, but better median scores for bodily pain and mental health. Patients with GSD Ib had a lower Z-score than GSD Ia patients for emotional health problems. Male patients showed better Z-scores in physical functioning, general health perception, and social functioning when compared to females. Emotional health problems Z-score was lower in nephropathic patients. Conclusion: QoL can be impaired in adult patients with GSD I. The results of this study show that patients with GSD type Ib, women, and those with renal complications are more likely to experience a poorer QoL.

2013 - Fertility and pregnancy in women affected by glycogen storage disease type I, results of a multicenter Italian study [Articolo su rivista]
Sechi, Annalisa; Deroma, Laura; Lapolla, Annunziata; Paci, Sabrina; Melis, Daniela; Burlina, Alberto; Carubbi, Francesca; Rigoldi, Miriam; Di Rocco, Maja
abstract

Life expectancy of patients with glycogen storage disease (GSD) type I has improved considerably, opening new problems correlated with adult age. In females polycystic ovaries (PCOs) has been described as frequently associated with the disease, however successful pregnancies have been reported. Whether or not GSD I is associated with impaired reproductive function is still unclear.

2013 - Short-term multidisciplinary non-pharmacological intervention is effective in reducing liver fat content assessed non-invasively in patients with nonalcoholic fatty liver disease (NAFLD) [Articolo su rivista]
Scaglioni, Federica; Marino, Mariano; Ciccia, Stefania; Procaccini, Alessia; Busacchi, Marcello; Loria, Paola; Lonardo, Amedeo; Malavolti, Marcella; Battistini, Nino Carlo; Pellegrini, Massimo; Carubbi, Francesca; Bellentani, Stefano
abstract

Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to steatohepatitis, and cirrhosis in patients with alcohol intake less than 20 g/day, and is usually associated with insulin resistance (IR). We tested the efficacy of a non-pharmacological multidisciplinary intervention based on a personalized diet, physical activity and behavior therapy. In this open non-randomized study, personalized diet, physical exercise and behaviour therapy for 3 months were prescribed in 12 consecutive patients with NAFLD. Data show that the multidisciplinary intervention produced a significant reduction of total caloric intake, a 8% reduction in body weight, a modest increase in daily physical activity, a significant (P<0.001) reduction of aminotransferases and a decrease of total hepatic fat content.

2012 - Effects of bile duct ligation and cholic acid treatment on fatty liver in two rat models of non-alcoholic fatty liver disease [Articolo su rivista]
Gabbi, Chiara; Bertolotti, Marco; Anzivino, Claudia; Macchioni, Daria; Del Puppo, Marina; Ricchi, Matteo; Carubbi, Francesca; Tagliafico, Enrico; Romagnoli, Dante; Odoardi, Maria Rosaria; Loria, Paola; Losi, Luisa; Carulli, Nicola
abstract

Non-alcoholic fatty liver disease, one of the most prevalent liver disorders in Western countries, is characterized by hepatic accumulation of triglycerides. Bile acids have long been known to affect triglyceride homeostasis through a not completely understood mechanism.

2012 - Fabry disease: raising awareness of the disease among physicians [Articolo su rivista]
Carubbi, Francesca; Bonilauri, Lisa
abstract

Fabry disease is an X-linked inherited lysosomal disorder due to dysfunctions of the lysosomal enzyme alpha-galactosidase A, causing insufficient breakdown of glycolipids, which are stored in the eyes, kidneys, autonomic nervous system, skin, vessels and cardiovascular system. Manifestations of Fabry disease include progressive renal and cardiac insufficiency, neuropathic pain, stroke and cerebral disease, skin and gastrointestinal symptoms. Clinical onset usually occurs in childhood, but many severe patients are diagnosed in adulthood. Females may be severely affected as males and both may die prematurely due to stroke, heart disease and renal failure. Enzyme replacement therapy can stabilize or reduce the progression of the disease. There is a need to improve the knowledge of Fabry disease, as an early therapy may prevent complications of the disease. This brief overview aims to raise awareness of the signs and symptoms of Fabry disease and to summarize the effects of treatments.

2012 - Minimal disease activity in Gaucher disease: criteria for definition [Articolo su rivista]
Di Rocco, Maja; Andria, Generoso; Bembi, Bruno; Carubbi, Francesca; Giona, Fiorina; Giuffrida, Gaetano; Linari, Silvia; Sibilio, Michelina; Spina, Vincenzo; Cappellini, Maria Domenica
abstract

Gaucher disease type I is a metabolic disorder caused by a genetic deficiency of lysosomal β-glucocerebrosidase that leads to accumulation of glucocerebroside in macrophages, thus causing damage in different organ systems. Enzyme replacement therapy with imiglucerase improves organ impairment and clinical manifestations, but patients differ in response to treatment. While clinical remission is the most desirable therapeutic outcome, a more realistic goal in patients with high disease burden is reasonably good clinical status despite persistence of residual biochemical or imaging abnormalities. Therefore, the concept of minimal disease activity--used in certain haematological or rheumatologic conditions--needs to be introduced in Gaucher disease, with a level of disease activity that patients and physicians consider a useful treatment target. In this paper, we propose specific parameters and criteria for defining minimal disease activity in Gaucher disease and its stability over time, based on three major systemic domains typically involved: haematological, visceral, and skeletal. Biomarker parameters were not included as criteria, because currently they do not adequately reflect disease evolution in individual patients. Neurological and respiratory domains were also excluded, as their involvement per se indicates severe disease unlikely to respond to enzyme replacement therapy and achieve minimal disease status. Our goal in defining minimal disease activity and stability is to identify a tool to facilitate treatment decisions in clinical practice.

2012 - New motor outcome function measures in evaluation of late-onset Pompe disease before and after enzyme replacement therapy [Articolo su rivista]
Angelini, Corrado; Semplicini, Claudio; Ravaglia, Sabrina; Moggio, Maurizio; Comi, Giacomo P; Musumeci, Olimpia; Pegoraro, Elena; Tonin, Paola; Filosto, Massimiliano; Servidei, Serenella; Morandi, Lucia; Crescimanno, Grazia; Marrosu, Giovanni; Siciliano, Gabriele; Mongini, Tiziana; Toscano, Antonio; Carubbi, Francesca
abstract

The clinical course of late-onset Pompe disease is heterogeneous, and new clinical outcome measures are needed to evaluate enzyme replacement therapy (ERT).

2012 - Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4 years [Articolo su rivista]
Angelini, C; Semplicini, C; Ravaglia, S; Bembi, B; Servidei, S; Pegoraro, E; Moggio, M; Filosto, M; Sette, E; Crescimanno, G; Tonin, P; Parini, R; Morandi, L; Marrosu, G; Greco, G; Musumeci, O; Di Iorio, G; Siciliano, G; Donati, M. A; Carubbi, Francesca; Ermani, M; Mongini, T; Toscano, A.
abstract

The objective of this study was to describe a large Italian cohort of patients with late-onset glycogen storage disease type 2 (GSDII) at various stages of disease progression and to evaluate the clinical effectiveness of alglucosidase alpha enzyme replacement therapy (ERT). Previous studies showed in late-onset patients ERT efficacy against placebo and variable response in uncontrolled studies. Seventy-four juvenile or adult GSDII patients were treated with ERT in a multicenter open label, non-randomized study, from 12 months up to 54 months. Recombinant human alpha glucosidase (rh-GAA) was injected by intravenous route at 20 mg/kg every second week. Patients were divided into three groups according to ERT duration: Group A received treatment for 12-23 months (n = 16), Group B for 24-35 months (n = 14), and Group C for more than 36 months (n = 44). Clinical assessment included a 6-min walk test (6MWT), forced vital capacity (FVC), the Walton and Gardner-Medwin score, the number of hours of ventilation, body mass index, echocardiography and blood creatine kinase (CK). Included in our cohort were 33 males and 41 females (M:F = 0.8:1), with a mean age at first symptoms of 28.3 years (range 2-55 years) and a mean age of 43 years at study entry (range 7-72 years). Seven wheelchair bound patients, as well as 27 patients requiring ventilation support, were included. After treatment we could observe an increase in distance walked on the 6MWT in the large majority of patients (48/58; 83%), with an overall mean increase of 63 m (from 320 ± 161 to 383 ± 178 m). After treatment in the majority of patients FVC was improved or unchanged (45/69; 65%). In ventilated patients we observed an improvement in average number of hours off the ventilator (from 15.6 to 12.1 h). Six patients stopped mechanical ventilation and two others started it. The effect of therapy was not related to ERT duration. Nine of 64 patients (13%) that underwent to echocardiography showed a variable degree of cardiac hypertrophy (left ventriculum or septum), and a positive effect was observed after 36 months of ERT in one adult case. Discontinuation of treatment occurred in four patients: one drop-off case, one patient died for a sepsis after 34 months of treatment and two patients stopped ERT for worsening of general clinical condition. Mild adverse effects were observed in four cases (5%). This study represents the largest cohort of late-onset GSDII patients treated with ERT, and confirm a positive effect of treatment. These results, obtained in a large case series on therapy, indicate a favourable effect of ERT therapy, even in more advanced stage of the disease.

2008 - A new severity score index for phenotypic classification and evaluation of responses to treatment in type I Gaucher disease [Articolo su rivista]
Di Rocco, Maja; Giona, Fiorina; Carubbi, Francesca; Linari, Silvia; Minichilli, Fabrizio; Brady, Roscoe O; Mariani, Giuliano; Cappellini, Maria Domenica
abstract

Gaucher disease is the first lysosomal storage disease for which specific therapy became available. Over 4800 patients have been treated with enzyme replacement therapy. Analysis of Gaucher disease registry data has outlined the clinical heterogeneity of the disease and the different responses to treatment from patient to patient, and for different organs. This variability in clinical response justifies the development of a severity score index to assess disease activity, stage and prognosis, and to quantify the effects of treatment.The “Gaucher Disease Severity Score Index Type I”(GauSSI-I), is based on the clinical experience of the authors and an extensive literature review, including data from the International Gaucher Registry. In particular for skeletal disease, all the available scoring systems have been reviewed and compared in order to provide a skeletal scoring system that allows use of any of the different methods. Siix specific domains, in which different items were scored according to their impact on morbidity, were characterized. GauSSI-I was evaluated in 53 type I Gaucher patients treated with imiglucerase, and it was compared to the Zimran score, the only severity index score so far available. It is a reliable method for staging the severity of adult type I Gaucher disease, and it is more sensitive than the Zimran score for monitoring the response to treatment.

2008 - Hypertriglyceridaemia and low plasma HDL in a patient with apolipoprotein A-V deficiency due to a novel mutation in the APOA5 gene [Articolo su rivista]
PRIORE OLIVA, Claudio; Carubbi, Francesca; Schaap, F. G; Bertolini, S; CALANDRA BUONAURA, Sebastiano
abstract

APOA5 encodes a novel apolipoprotein (apo A-V) which appears to be a modulator of plasma triglyceride (TG). In apoA5 knock out mice plasma TG level increases almost fourfold, whereas in human APOA5 transgenic mice it decreases by 70%. Some SNPs in the APOA5 gene have been associated with variations in plasma TG in humans. In addition, hypertriglyceridaemic (HTG) patients have been identified who carried rare nonsense mutations in the APOA5 gene (Q139X and Q148X), predicted to result in apo A-V deficiency. In this study we report a 17-year-old male with high TG and low high density lipoprotein cholesterol (HDL-C), who at the age of two had been found to have severe HTG and eruptive xanthomas suggesting a chylomicronaemia syndrome. Plasma postheparin LPL activity, however, was normal and no mutations were found in LPL and APOC2 genes. The sequence of APOA5 gene revealed that the patient was homozygous for a point mutation (c.289 C&gt;T) in exon 4, converting glutamine codon at position 97 into a termination codon (Q97X). Apo A-V was not detected in patient's plasma, indicating that he had complete apo A-V deficiency. The administration of a low-fat and low-oligosaccharide diet, either alone or supplemented with ω-3 fatty acids, started early in life, reduced plasma TG to a great extent but had a negligible effect on plasma HDL-C. Loss of function mutations of APOA5 gene may be the cause of severe HTG in patients without mutations in LPL and APOC2 genes.

2008 - Nonalcoholic fatty liver disease induced by leuprorelin acetate [Articolo su rivista]
Gabbi, C.; Carubbi, Francesca; Losi, L.; Loria, Paola; Costantini, M.; Bertolotti, Marco; Carulli, N.
abstract

Leuprorelin acetate is an agonist of gonadotropinreleasinghormone, used as a first choice treatment in patientswith prostate carcinoma. The impact of leuprorelin therapy inliver function and metabolism is largely unknown. We reportabout a patient who had been treated for 32 months withleuprorelin acetate, who developed a nonalcoholic fatty liverdisease (NAFLD), associated with a focal lesion at the IVhepatic segment where histologic features appeared to be moresevere. The patient, in addition to NAFLD, presented a markediatrogenic hypotestosteronemia and full-criteria meeting thediagnosis of metabolic syndrome, including insulin resistance.The radiologic and clinical findings, the histopathologicfeatures, and the absence of any hepatic abnormalities beforetreatment, support a causal role of leuprorelin in inducingmetabolic derangement that, most likely secondary to androgendeprivation, were, in turn, responsible for the development of NAFLD. This is the first case report of NAFLDwith focal fatty liver associated with leuprorelin therapy.Patients in leuprorelin should be carefully monitored for thedevelopment of liver disease.

2006 - MOLECULAR REGULATION OF STEROL METABOLISM BY BILE ACIDS IN CULTURED HUMAN HEPATOCYTES [Abstract in Rivista]
Anzivino, Claudia; Bertolotti, Marco; C., Gabbi; M., Ricchi; Tagliafico, Enrico; Tenedini, Elena; Carulli, Lucia; Carubbi, Francesca; Loria, Paola; Carulli, Nicola
abstract

Disruption of hepatic cholesterol homeostasis may predispose to important clinical conditions such as cholelithiasis and atherosclerosis. The regulatory role of nuclear receptors has recently been underlined but the integration of the different metabolic pathways is largely unknown. AIM of the present study is to analyze the expression of a number of genes involved in cholesterol and bile acid metabolism in cultured human hepatocytes. METHODS. HepG2 cells were incubated with 100 micromol concentrations of different bile acids (DCA, CDCA, UDCA) for 24 hr. mRNA levels of cholesterol 7alpha-hydroxylase (CYP7A1), LDL-receptor, HMG-CoA reductase and a number of nuclear receptors and coactivators involved in sterol metabolism were assayed by real-time RT-PCR. RESULTS. A significant effect of bile acid treatment, detected by ANOVA, was shown on the expression of CYP7A1 and SHP, which were respectively reduced and increased by treatment with the hydrophobic bile acids DCA and CDCA, but not with UDCA; expression of SREBP-2 and LDL-receptor were also significantly increased by hydrophobic bile acids. CONCLUSIONS. Hydrophobic, but not hydrophilic bile acids suppress CYP7A1 expression, possibly via increased expression of SHP. Surprisingly, the same bile acids seem to enhance the expression of SREBP-2 and of genes involved in LDL uptake, mimicking a condition of cholesterol depletion. Knowledge of the subtle relationships linking bile acid and cholesterol metabolism might provide useful information for the management of cholesterol accumulation conditions.

2006 - Tenofovir treatment in HIV-related lipodystrophy syndrome. Retrospective observational forty-eight weeks follow-up study [Articolo su rivista]
Guaraldi, Giovanni; Orlando, Gabriella; Roverato, A.; DE SANTIS, Giorgio; Pedone, A.; Spaggiari, A.; Baccarani, A.; De Fazio, D.; Vandelli, M.; Bertucelli, C.; Beghetto, Barbara; Nardini, Giulia; Borghi, V.; Grisendi, C.; Bertolotti, Marco; Carubbi, Francesca; Zini, I.; Esposito, Roberto
abstract

Efficacy and safety of morphological and metabolic alterations treatment in HIV related lipodystrophy syndrome have never been evaluated outside clinical trials and progression of lipodystrophy remains uncertain. This is a 48 weeks follow up observational retrospective study over consecutive patients attending the Metabolic Clinic of the University of Modena and Reggio Emilia in whom a biochemical, antropometric with DEXA and psychometric evaluation was available. The aim of this research was to assess efficacy and safety of switching to tenofovir (TDF) in the context of the multidisciplinary interventions offered in the Metabolic Clinic comprehensive of: dietary counseling, physical activities, surgical treatment for facial lipoatrophy or fat hypertrophy and psychological support. In a cohort of 189 people with lipodystrophy, TDF was part of the antiretroviral regimen in 125 individuals (82 males e 43 females). TDF-control group was made of 64 individuals (38 males e 26 females). The two study groups were homogeneous for metabolic, morphologic and psychometric profile at baseline. In the follow up period a significant improvement was observed in TDF+ group with regard of blood glucose, insuline, triglyceride. Non significant change in morphologic alterations evaluated with DEXA was observed in the two study groups. With regards of psychometric evaluations, a striking improvement was observed in aesthetic satisfaction of the face, of the body, of body image and depression. In the cohort, no progressions of HIV disease nor serious adverse events were observed. We conclude that switching to tenofovir in the context of the multidisciplinary interventions offered in the Metabolic Clinic is efficacious and safe in the management of LD

2004 - Dietary evaluation and metabolic alterations in HIV-related lipodystrophy [Abstract in Rivista]
Orlando, Gabriella; Guaraldi, Giovanni; Giuricin, F; Grisendi, G; Carubbi, Francesca; Zini, Isabella; Borghi, V; Esposito, Roberto; Galetti, S.
abstract

not available

2004 - Dislipidemie.In Teodori 2004. Trattato italiano di medicina interna [Monografia/Trattato scientifico]
Carulli, Nicola; Carubbi, Francesca; Bertolotti, Marco
abstract

le dislipidemie. Fisiopatologia, diagnosi e terapia.

2002 - Comparative cytotoxic and cytoprotective effects of taurohyodeoxycholic acid (THDCA) and tauroursodeoxycholic acid (TUDCA) in HepG2 cell line. [Articolo su rivista]
Carubbi, Francesca; Me, Guicciardi; M., Concari; Loria, Paola; Bertolotti, Marco; Carulli, Nicola
abstract

This study was performed to compare the effects of two hydrophilic bile acids, taurohyodeoxycholic acid (THDCA) and tauroursodeoxycholic acid (TUDCA), on HepG2 cells. Cytotoxicity was evaluated at different times of exposure by incubating cells with increasing concentrations (50-800 micromol/l) of either bile acid, while their cytoprotective effect was tested in comparison with deoxycholic acid (DCA) (350 micromol/l and 750 micromol/l)-induced cytotoxicity. Culture media, harvested at the end of each incubation period, were analyzed to evaluate aspartate transaminase (AST), alanine transaminase and gamma-glutamyltranspeptidase release. In addition, the hemolytic effect of THDCA and TUDCA on human red blood cells was also determined. At 24 h of incubation neither THDCA nor TUDCA was cytotoxic at concentrations up to 200 and 400 micromol/l. At 800 micromol/l both THDCA and TUDCA induced a slight increase in AST release. At this concentration and with time of exposure prolonged up to 72 h, THDCA and TUDCA induced a progressive increase of AST release significantly (P<0.05) higher than that of controls being AST values for THDCA (2.97+/-0.88 time control value (tcv) at 48 h and 4.50+/-1.13 tcv at 72 h) significantly greater than those of TUDCA (1.50+/-0.20 tcv at 48 h and 1.80+/-0.43 tcv at 72 h) (P<0.01). In cytoprotection experiments, the addition of 50 micromol/l THDCA decreased only slightly (-5%) AST release induced by 350 micromol/l DCA, while the addition of 50 micromol/l TUDCA was significantly effective (-23%; P<0.05). Higher doses of THDCA or TUDCA did not reduce toxicity induced by 350 micromol/l DCA, but were much less toxic than an equimolar dose of DCA alone. At the concentration used in this experimental model neither THDCA nor TUDCA was hemolytic; however at a very high concentration (6 mmol/l) both bile acids induced 5-8% hemolysis. We conclude that bile acid molecules with a similar degree of hydrophilicity may show different cytotoxic and cytoprotective prope

2001 - Suppression of bile acid synthesis, but not of hepatic cholesterol 7alpha-hydroxylase expression, by obstructive cholestasis in humans [Articolo su rivista]
Bertolotti, Marco; Carulli, Lucia; Concari, M; Martella, P; Loria, Paola; Tagliafico, Enrico; Ferrari, S; Del Puppo, M; Amati, B; De Fabiani, E; Crestani, M; Amorotti, Claudio; Manenti, A; Carubbi, Francesca; Pinetti, A; Carulli, N.
abstract

Regulation of bile acid synthesis, a key determinant of cholesterol homeostasis, is still incompletely understood. To elucidate the feedback control exerted on bile acid biosynthesis in humans with obstructive cholestasis, 16 patients with bile duct obstruction were studied. In vivo 7alpha-hydroxylation, reflecting bile acid synthesis, was assayed in 13 of them by tritium release analysis. Serum 27-hydroxycholesterol was determined by gas chromatography-mass spectrometry. In a subgroup, hepatic cholesterol 7alpha-hydroxylase mRNA was assayed by real-time polymerase chain reaction (PCR), enzyme activity was determined by isotope incorporation, and microsomal cholesterol content was assayed by gas chromatography-mass spectrometry. Age-matched control subjects were studied in parallel. Hydroxylation rates were lower in cholestatic patients (108 +/- 33 mg of cholesterol per day, mean +/- SEM; controls: 297 +/- 40 mg/d; P &lt;.01). The reduction was proportional to the severity of cholestasis, and synthetic rates were normalized in 4 subjects restudied after resolution of biliary obstruction. Consistent findings were obtained by analysis of serum 7alpha-hydroxycholesterol levels. On the other hand, hepatic cholesterol 7alpha-hydroxylase mRNA, microsomal enzyme activity, and cholesterol content tended to be increased in cholestasis. Finally, serum 27-hydroxycholesterol levels were slightly reduced in cholestatic subjects and were not related with the severity of the disease. Suppression of in vivo bile acid synthesis with no corresponding reduction in tissue 7alpha-hydroxylase expression and activity is consistent with nontranscriptional, posttranslational levels of regulation; these may play a role in the feedback control of bile acid synthesis in particular conditions. Alteration of the alternate biosynthetic pathway seems unlikely according to the present data.

2000 - Nuove prospettive terapeutiche con acidi biliari. [Capitolo/Saggio]
Carulli, Nicola; Loria, Paola; Carubbi, Francesca; Bertolotti, Marco; Concari, M.
abstract

Eds. Paolo Gentilini, Editore Scientific Press

2000 - Review article: effect of bile salt pool composition on hepatic and biliary functions [Articolo su rivista]
Carulli, N; Bertolotti, Marco; Carubbi, Francesca; Concari, M; Martella, P; Carulli, Lucia; Loria, P.
abstract

The enterohepatic recirculation of bile salts exerts important regulatory effects on many hepatic, biliary and intestinal functions: such regulation is likely to depend, to a large extent, on the physical-chemical property of hydrophobicity of the recirculating pool. The present review summarizes the main experimental evidence carried out by our research group over the past two decades, in the attempt to investigate systematically the relationships between structural properties and biological effects of bile acids in humans. Hydrophobic bile acids (chenodeoxycholic acid, deoxycholic acid), but not hydrophilic acids (ursodeoxycholic acid), significantly suppressed hepatic activity of HMG-CoA reductase, the limiting step of cholesterol synthesis, and in vivo cholesterol 7alpha-hydroxylation, the limiting step of bile acid synthesis. The output of biliary cholesterol and phospholipid was also directly related to the hydrophobicity of the bile acid pool. Finally, treatment with chenodeoxycholic acid, but not with ursodeoxycholic acid, significantly decreased gall-bladder emptying rates. When turning to the in vitro model of HepG2 cells, hydrophobic bile acids were found to induce greater cytotoxic and pro-apoptotic effects. From this series of studies, we conclude that the regulatory effects of bile acids on the liver and biliary tract are largely dependent on the hydrophobic-hydrophilic balance of the recirculating bile acid pool.

1999 - Bile acid and hepatocyte death [Monografia/Trattato scientifico]
M. E., Guicciardi; Carubbi, Francesca; M., Concari; P., Martella; Loria, Paola; Carulli, Nicola
abstract

we demonstrated that liver injury and hepatocyte death depend on the biliary bile acid composition. The effect of diferent bile acids on AST release has been shown in Hep G 2 cells. Deoxycholic and other hydrophobic bile acid toxicity can be reduced by addition of UDCA to the cell medium.

1999 - Herpesvirus DNA is frequently detected in liver tissue from hepatitis C patients [Articolo su rivista]
Cermelli, Claudio; M., Concari; P., Pietrosemoli; M., Meacci; Sabbatini, Anna Maria Teresa; A., Divincenzo; Carubbi, Francesca; Loria, Paola; A., Bagni; Carulli, Nicola; Portolani, Marinella
abstract

Background and aims: Herpesviruses infect the liver and cause minor hepatitis. Our aim is to verify the presence of herpesviruses in the liver from hepatitis C patients and the possible influence of these viruses in the liver disease. Methods: We searched for herpesvirus DNA in liver biopsies from patients with hepatitis C and from a control group without hepatitis by means of nested polymerase chain reaction. Serological investigations were carried out as well. Results: Thirty-four liver specimens from hepatitis C patients were examined, 12 of which (35.3%) were positive for at least one herpesvirus DNA, whereas among the 19 control specimens only two were positive (10.5%; P = 0.049). Liver biopsies from seven patients, three with acute hepatitis of unknown origin, three with non-alcoholic steatohepatitis and one with autoimmune hepatitis were also investigated and three positive samples were found. Conclusions: The prevalence of herpesvirus DNA was found higher in patients with hepatitis C than in individuals without hepatitis. The influence of herpesviruses on the clinical course of hepatitis C is considered. (C) 1999 Elsevier Science B.V. All rights reserved.

1999 - Inquadramento delle sindromi colestatiche. [Capitolo/Saggio]
N., Carulli; Bertolotti, Marco; Carubbi, Francesca; P., Loria
abstract

le sindromi colestatiche nell'uomo: inquadramento nosologico, etiopatogenesi e terapia

1999 - LA SECREZIONE LIPIDICA BILIARE [Capitolo/Saggio]
P., Loria; Bertolotti, Marco; Carubbi, Francesca; P., Martella; M., Concari; N. C. A. R. U. L. L. I., Masson; Milano, P. P.
abstract

biliary lipid sceretion in humans: pathophysiology

1999 - MECCANISMI DI CITOTOSSICITÀ DEGLI ACIDI BILIARI. [Capitolo/Saggio]
Carubbi, Francesca; M. E., Guicciardi; M., Concari; N. CARULLI, .
abstract

liver damage, cholestasis, UDCA, TUDCA, bile ACIDS, LIVER TOXICITY

1997 - Effect of liver cirrhosis on the systemic availability of naltrexone in humans [Articolo su rivista]
Bertolotti, Marco; Ferrari, Anna; Vitale, Giovanni; Stefani, M; Trenti, T; Loria, Paola; Carubbi, Francesca; Carulli, Nicola; Sternieri, Emilio
abstract

Naltrexone is a competitive opiate antagonist with high hepatic extraction. It is used for detoxification treatment for heroin addicts and has been proposed as a possible treatment of pruritus in cholestasis. Such patients are likely to have impaired liver function, underscoring the need to understand the pharmacokinetic behavior of naltrexone in liver disease. These studies were undertaken to evaluate the effect of liver cirrhosis on the plasma time-course of naltrexone. METHODS: A total of 18 patients were investigated: seven migraine patients with normal liver function regarded as controls and 11 patients with liver cirrhosis (six with decompensated disease and five with preserved liver function). A bolus of 100 mg of naltrexone was administered orally in the morning, after an overnight fast. Blood samples were taken in basal conditions and at fixed intervals, up to 24 h after administration. Serum levels of naltrexone and of its major active metabolite, 6 beta-naltrexol, were assayed by reversed-phase HPLC analysis. RESULTS: In control subjects, circulating concentrations of naltrexone were always much lower than those of 6 beta-naltrexol (area under the curve: naltrexone, 200 +/- 97 ng/ml x 24 h; 6 beta-naltrexol, 2467 +/- 730 ng/ml x 24 h, p < 0.01). In severe cirrhosis serum levels of 6 beta-naltrexol increased more slowly, so that circulating levels of naltrexone during the first 2-4 h after drug intake were higher than those of 6 beta-naltrexol (6 beta-naltrexol/naltrexone ratio at 2 h: controls, 10.91 +/- 4.80; cirrhosis, 0.39 +/- 0.18, p < 0.01). The area under the curve for naltrexone (1610 +/- 629 ng/ml x 24 h) was significantly greater than in controls, whereas that for 6 beta-naltrexol (2021 +/- 955 ng/ml x 24 h) was not significantly different. Patients with compensated cirrhosis showed an intermediate pattern. No differences in elimination half-life of the two drugs were detected among the groups. CONCLUSIONS: Our data suggest the occurrence of important changes in the systemic availability of naltrexone and 6 beta-naltrexol in liver cirrhosis; such alterations are consistent with lesser reduction of naltrexone to 6 beta-naltrexol and appear to be related to the severity of liver disease. This must be considered when administering naltrexone in conditions of liver insufficiency.

1997 - Effect of taurohyodeoxycholic acid on biliary lipid secretion in humans [Articolo su rivista]
Loria, Paola; M., Bozzoli; M., Concari; M. E., Guicciardi; Carubbi, Francesca; Bertolotti, Marco; D., Piani; A., Nistri; M., Angelico; M., Romani; Carulli, Nicola
abstract

This study aimed to determine the effect in humans of taurohyodeoxycholic acid, a 6 alpha-hydroxylated bile acid with hydrophilic properties, on bile lipid secretion, Four cholecystectomized patients who had gallstones and an interrupted enterohepatic circulation were intraduodenally infused with taurohyodeoxycholic and tauroursodeoxycholic acids on separate occasions at a dose of 0.8 to 1 g/h for 3 hours, In hourly bile samples collected for 8 hours after the beginning of the infusion, biliary bile acid composition (by high-performance liquid chromatography), biliary lipid concentrations (by standard methods), and distribution of biliary carriers (by gel chromatography) were evaluated, Blood liver function tests were performed before and after the infusions. Taurohyodeoxycholic and tauroursodeoxycholic acids became the predominant biliary bile acids in all patients except for one infused with taurohyodeoxycholic acid. Taurohyodeoxycholic acid stimulated significantly greater (P<.05) cholesterol and phospholipid secretion per unit of secreted bile acid (0.098 and 0.451 mu mol/mu mol, respectively) compared with tauroursodeoxycholic acid (0.061 mu mol/mu mol for cholesterol and 0.275 mu mol/mu mol for phospholipids). The secretory ratio between phospholipid and cholesterol was significantly higher after infusion of taurohyodeoxycholic acid (3.88 mu mol/mu mol) compared with taroursodeoxycholic acid (3.09 mu mol/pmol) (P<.05). Biliary enrichment with taurohyodeoxycholic acid was positively related with percent concentration of phospholipids but not with that of cholesterol, The opposite trend was observed in tauroursodeoxycholic acid-enriched biles. In both tauroursodeoxycholic acid- and tauroursodeoxycholic acid-rich bile, 80% to 90% of cholesterol was carried in a gel-chromatographic fraction corresponding to an apparent molecular weight of 80 to 200 kd. No alteration in liver function test results was observed after taurohyodeoxycholic acid infusion, In conclusion, taurohyodeoxycholic acid stimulates greater cholesterol and phospholipid secretion than tauroursodeoxycholic acid, but with a higher phospholipid/cholesterol secretory ratio. In bile enriched with both bile acids, biliary cholesterol is transported in nonmicellar aggregates, Finally, in the conditions of our study, taurohyodeoxycholic acid was not hepatotoxic.

1996 - Bile acid structure and regulation of biliary protein secretion and composition in man [Articolo su rivista]
M., Bozzoli; Loria, Paola; Carubbi, Francesca; M., Concari; M. E., Guicciardi; Bertolotti, Marco; Tagliafico, Enrico; Carulli, Nicola
abstract

To evaluate the effect of bile acid structure on total protein secretion and composition, 4 different bile acids, deoxycholic acid, chenodeoxycholic acid, cholic acid and ursodeoxycholic acid, in order of decreasing hydrophobicity, were infused intraduodenally in 5 cholecystectomized T-tube patients with interrupted enterohepatic circulation, Concentration and composition of biliary proteins were evaluated before and after acute substitution of the endogenous bile acid pool with each bile acid, Total biliary protein concentration and secretion increased progressively with increasing hydrophobicity of the infused bile acid and was highest for deoxycholic acid, followed by chenodeoxycholic acid, cholic acid and ursodeoxycholic acid, A significant increase in the 120 and 150 kDa protein bands on gel-electrophoresis was found after infusion with the more hydrophobic bile acids (deoxycholic acid and chenodeoxycholic acid), Quantitative and qualitative changes in biliary proteins, associated with the administration of bile acids that have different physico-chemical structures, may be relevant to the process of cholesterol crystal nucleation and the:pathogenesis of gallstone formation.

1996 - Effect of taurohyodeoxycholic acid on biliary lipid secretion in man: preliminary report. [Articolo su rivista]
Loria, Paola; M., Bozzoli; M., Angelico; Bertolotti, Marco; Carubbi, Francesca; M., Concari; L., Baiocchi; A., Nistri; P., Della Guardia; M., Romani; Carulli, Nicola
abstract

Taurohyodeoxycholic acid and tauroursodeoxycholic acid were infused intraduodenally at a rate of 0.8 gk for three hours in 3 cholecystectomized T-tube patients, Biliary lipid secretion and bile acid composition were evaluated before and after replacement of the endogenous bile acid pool with the two bile acids. As compared to basal values (2.78+/-1.67 mM/l), taurohyodeoxycholic acid induced a greater increase in the biliary concentration of phospholipids (4.12+/-1.23 mM/l) as compared to tauroursodeoxycholic acid (3.14+/-0.98 mM/l). Biliary cholesterol concentration after taurohyodeoxycholic acid (1.89+/-0.63 mM/l) was unchanged as compared to the pretreatment period (1.98+/-0.58 mM/l), while it decreased significantly after tauroursodeoxycholic acid (0.85+/-0.08 mM/l). Biliary cholesterol secreted per unit of bile acid was greater during taurohyodeoxycholic acid than during tauroursodeoxycholic acid, while the opposite was observed for the secretion of phospholipids.

1996 - Effectiveness of dietetic counselling in lowering plasma cholesterol of children affected by hypercholesterolemia [Articolo su rivista]
Balli, Fiorella; Leoni, S; Marastoni, E; Carubbi, Francesca; Guicciardi, Me; Concari, M.
abstract

We assessed the effectiveness of the dietetic counselling provided by a paediatrician in order to obtain a reduction in plasma cholesterol levels of children affected by hypercholesterolemia (HC). Twenty one children were enrolled into the study on the basis of plasma cholesterol levels exceeding 180 mg/dl. After their parents had been? adequately instructed by the paediatrician the children were invited to follow some simple dietetic advice. This advice, focusing primarily on the quality of the ingested foods, was based on the recommendations of the Italian Society of Paediatrics. Weight, height, blood pressure, total plasma cholesterol (C) and triglycerides as well their fraction bounded to VLDL, LDL and HDL, were measured al the rime of the diagnosis and 3 to 6 and 6 to 12 months after dietetic counselling had been provided Plasma cholesterol levels were significantly reduced at 6-12 months with respect to their baseline values (205.0 +/- 49.0 vs 240.0 +/- 48.1, p < .05). This reduction appeared to be due to a decrease in LDL-C (139.0 +/- 44.4 vs 158.4 +/- 42.0, p < .05), VLDL-C (17.6 +/- 7.3 vs 23.8 +/- 10.0, p < .05) and HDL-C (48.5 +/- 7.9 vs 58.6 +/- 9.7, p < .05) levels. However, the latter were still within the recommended values. According to these preliminary results, it appears that the dietetic counselling provided by a well trained paediatrician may represent a simple and feasible way to achieve a reduction of plasma cholesterol levels in children affected by HC.

1996 - Growth of human herpesvirus 6 in HepG2 cells [Articolo su rivista]
Cermelli, Claudio; M., Concari; Carubbi, Francesca; Fabio, Giuliana; Sabbatini, Anna Maria Teresa; M., Pecorari; P., Pietrosemoli; M., Meacci; E., Guicciardi; Carulli, Nicola; Portolani, Marinella
abstract

HepG2 cells, a well differentiated liver cell line, were shown to be permissive for both human herpesvirus 6 (HHV-6) A and B strains by three independent methods of analysis: detection of viral antigens, viral DNA sequences and infectious virus. HepG2 cell infection with HHV-6 resulted in functional damage as shown by the increased release in the culture medium of some hepatocyte markers. Cells surviving the acute infection were serially passaged without showing cytopathic effect, but, some months later, HHV-6 DNA was still present in the cells and virus induction with a phorbol ester was successful. A possible pathogenetic role of HHV-6 in liver diseases is discussed. Experiments of HepG2 infection with human herpesvirus 7 (HHV-7) were also carried out. The lack of an efficient virus replication suggested a difficulty for HHV-7 to infect hepatic cells.

1996 - Liver metastases from carcinoid tumor: Imaging patterns [Articolo su rivista]
De Santis, M.; Santini, D.; Alborino, S.; Carubbi, F.; Romagnoli, R.
abstract

Our study was aimed at describing the diagnostic imaging patterns of carcinoid liver metastases. Six patients with liver metastases secondary to carcinoid tumor were examined. The metastases were histologically proved in each patient. All patients were examined with ultrasonography (US), Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and Digital Subtraction Angiography (DSA). All patients were treated with transcatheter embolization of liver metastases. Diagnostic imaging methods showed ten to many dozen metastases in each patient. Tumor size ranged 0.5 to 14 cm. US showed hypoechoic, hyperechoic and isoechoic carcinoid liver metastases with a hypoechoic halo. Large lesions had anechoic central areas due to colliquative necrosis. Hypoechoic patterns were the most frequent ones. Precontrast CT showed hypodense metastases; very small lesions were isodense relative to surrounding liver. CT during contrast agent injection showed that the metastases were hyperdense in the arterial phase; contrast enhancement was poorer in the portal phase. Large lesions showed a hypodense central area due to necrosis which remained hypodense in the late phase. The metastases were hypointense on T1-weighted and hyperintense on T2-weighted MR images. Gradient echo dynamic imaging with Gd-DTPA showed high-signal metastases in the arterial phase and lower signal intensity in the portal phase. DSA, an essential exam before embolization, showed tortuous and elongated intra- and extrahepatic arteries and tumor neovascularization with no malignant abnormalities. In the capillary phase, tumor uptake and inhomogeneous hypervascular patterns were shown. Portal veins were only displaced and compressed, but never infiltrated by the metastases. All the techniques we used contributed to assess liver involvement by carcinoid metastases. DSA must be used only before treatment; both CT and MRI showed the hypervascular patterns of the metastases, but no technique could predict their nature.

1995 - Regulation of bile acid synthesis in humans: studies on cholesterol 7alpha-hydroxylation 'in vivo' [Articolo su rivista]
Bertolotti, Marco; N., Abate; Loria, Paola; M., Concari; M. E., Guicciardi; M. A., Dilengite; M., Bozzoli; Carubbi, Francesca; Carulli, Nicola
abstract

Over the last few years important progress has been made on the quantitation of cholesterol 7 alpha-hydroxylation, the rate-limiting step of bile acid synthesis. The use of a technique based on the determination of body water tritium enrichment after i.v. administration of [7 alpha-H-3] cholesterol has allowed in vivo investigation of this step in humans in different experimental conditions, The cholesterol 7 alpha-hydroxylation rate was not affected by the administration of the hydrophilic bile acid ursodeoxycholic acid (UDCA) whereas it was significantly reduced by the more hydrophobic chenodeoxycholic acid (CDCA) and even more so by the strongly hydrophobic deoxycholic acid (DCA). The administration of cholestyramine induced a significant dose-related increase of 7 alpha-hydroxylation along with a correspondent decrease in plasma cholesterol, The administration of simvastatin exerted no effect on cholesterol 7 alpha-hydroxylation despite a marked decrease in serum cholesterol, Treatment with fibrates reduced plasma lipid levels and 7 alpha-hydroxylation rates, Hydroxylation rates were unchanged in familial hypercholesterolaemia and increased in familial combined hyperlipidaemia. These data suggest that in humans bile acid synthesis can be affected by quantitative and qualitative alterations of the enterohepatic circulation of bile acids. Changes in cholesterol 7 alpha-hydroxylation rates may be associated with alterations in plasma lipid levels, bat such a relationship is ill-defined and seems to vary with the different experimental models.

1995 - Rupture d'un anevrysme de l'aorte infecté par salmonelle. [Articolo su rivista]
Maleti, O.; Collura, M.; Farinetti, Alberto; Lugli, M.; Zauli Sajani, M.; Carubbi, Francesca
abstract

Salmonella acute enteric infection caused the rupture of an aortic aneurysm

1994 - Anatomia e fisiologia delle vie biliari [Articolo su rivista]
Loria, Paola; Bozzoli, M; Bertolotti, Marco; Carubbi, Francesca; Carulli, N; Bagni, A.
abstract

No Abstract

1994 - EFFECT OF CHENODEOXYCHOLIC ACID AND URSODEOXYCHOLIC ACID ADMINISTRATION ON ACYL-COA - CHOLESTEROL ACYLTRANSFERASE ACTIVITY IN HUMAN LIVER [Articolo su rivista]
Abate, N; Carubbi, Francesca; Bozzoli, M; Bertolotti, Marco; Farah, I; Rosi, A; Carulli, Nicola
abstract

In order to investigate the relationship between bile acid pool composition and hepatic cholesterol metabolism in humans, we studied the effect of chronic feeding of chenodeoxycholic (CDCA) or ursodeoxycholic acid (UDCA) on the hepatic activity of acyl-CoA: cholesterol acyltransferase (ACAT) evaluated ''in vitro''. Twenty-eight gallstone patients were admitted to the study: 15 were untreated subjects, 8 were treated with UDCA (10 mg/kg/day for 15-20 days) and 5 were treated with CDCA (15 mg/kg/day for 15-20 days). A liver specimen and a bile sample were obtained during laparotomy for elective cholecystectomy. Untreated subjects had bile supersaturated with cholesterol (mean saturation index: 1.35 +/- 0.31) whereas subjects treated with either UDCA or CDCA had bile unsaturated with cholesterol (mean saturation index: 0.66 +/- 0.1 and 0.75 +/- 0.06 respectively). In all treated subjects the bile acid administered became predominant in bile. ACAT activity was 14% lower in subjects treated with UDCA and 16% lower in those treated with CDCA compared to controls; the differences did not achieve statistical significance. Microsomal cholesterol content did not differ between the groups (75.4 +/- 7.2 nmol/mg protein in control group; 86.5 +/- 7.0 nmol/mg protein in CDCA treated group; 83.4 +/- 7.0 nmol/mg protein in UDCA treated group). Our data show that the cholesterol esterifying activity of human liver is not affected by changes in bile acid pool composition.

1994 - Effect of Chenodeoxycholic acid and Ursodeoxycholic acid administration on acyl-CoA: cholesterol acyl tranferase activity in human liver. [Articolo su rivista]
Abate, N.; Carubbi, Francesca; Bozzoli, M.; Bertolotti, Marco; Farah, I.; Rosi, A.; Carulli, N.
abstract

Chenodeoxycholic acid and Ursodeoxycholic acid administration on acyl-CoA: cholesterol acyl tranferase activity in human liver.

1994 - Effect of diabetic autonomic neuropathy on gallbladder kinetics in insulin dependent diabetic patients [Articolo su rivista]
Dilengite, Ma; Loria, Paola; Menozzi, D; Tripodi, A; Giucciardi, L; Digrisolo, A; Bertolotti, Marco; Bozzoli, M; Carubbi, Francesca; Carulli, Nicola
abstract

Objective: To evaluate the relationship between autonomic nervous system involvement and gall bladder contraction in insulin-dependent diabetic patients. Patients and methods: Fasting gall bladder volume and gall bladder emptying in response to a standard liquid meal were evaluated using ultrasonography in 10 normal subjects and in 35 patients with insulin-dependent diabetes: 10 without, 15 with asymptomatic and 10 with symptomatic autonomic neuropathy (AN). Gall bladder volumes were calculated from ultrasonographic images, taken during fasting and at regular intervals after a standard meal, using the sum of cylinders method. Evaluation of the presence and degree of AN was based on standard tests and clinical history. Results: In controls, the mean fasting gall bladder volume was 1 7.6 +/- 3.7 ml, while respective values for residual volume, per cent emptying and emptying rate were: 3.63 +/- 1.69 ml, 77.3 +/- 10.7% and 0.0356 +/- 0.0121 min-1. Compared with controls, diabetic patients had a slightly higher fasting gall bladder volume (19.1 +/- 5.6 ml), while values for residual volume, per cent emptying and emptying rate were significantly altered at: 9.79 +/- 5.90 ml, 50.7 +/- 18.2% and 0.0155 +/- 0.0070 min-1, respectively (P<0.01). When diabetic patients were grouped according to the degree of AN, values for fasting gall bladder volume were significantly higher in those with symptomatic AN (22.0 +/- 7.7 ml) compared with controls (P<0.05). When compared with controls, patients without AN had a significantly (P<0.01) higher residual volume (5.58 +/- 1.96 ml), a significantly lower value for per cent emptying (65.3 +/- 11.3%) and a prolonged emptying rate (0.0213 +/- 0.0055 min-1). Gall bladder motility deteriorated progressively in diabetic patients with asymptomatic and symptomatic neuropathy. In the latter group, gall bladder emptying was greatly compromised, with a residual volume of 15.22 +/- 8.10 ml, and per cent emptying and emptying rate of 32.8 +/- 19.8% and 0.0060 +/- 0.0030 min-1, respectively (P<0.01 versus controls and diabetic patients with and without asymptomatic AN). Conclusions: Impairment of gall bladder contraction in diabetic patients seems to be dependent on the presence of AN. However, the presence of an alteration in gall bladder motility in those without neuropathy suggests that other factors could also play a role in gall bladder contraction in diabetic patients.

1994 - Malattie delle vie biliari [Articolo su rivista]
Carulli, Nicola; Loria, Paola; Carubbi, Francesca; Bozzoli, M; Rigo, G; Piani, D; Martella, P; Balli, Fiorella; Bagni, A; Gibertini, G.
abstract

No abstract

1994 - Patogenesi della colelitiasi [Articolo su rivista]
Loria, Paola; Bozzoli, M; Concari, M; Giucciardi, Me; Dilengite, Ma; Carubbi, Francesca; Carulli, Nicola; Tagliafico, Enrico
abstract

No abstract

1994 - Prevalence rates of gallstone disease in Italy: the Chianciano population study [Articolo su rivista]
Loria, Paola; Ma, Dilengite; M., Bozzoli; Carubbi, Francesca; R., Messora; R., Sassatelli; Bertolotti, Marco; A., Tampieri; Pl, Tartoni; M., Cassinadri; M., Dellaciana; M., Contemori; N., Save; B., Sordi; G., Alimenti; F., Fabrizi; A., Buciuni; Carulli, Nicola
abstract

The prevalence of gallstone disease and associated factors in the entire population of subjects aged 15-65 years born and resident in Chianciano Terme (Siena - Tuscany) was examined in the years 1985 and 1986. The investigation included gallbladder ultrasonography, administration of a questionnaire on personal and family history, physical examination and blood chemistry. A total of 1809 subjects (attendance rate 87.7%) participated in the study. Personal history and physical examination showed that Chianciano inhabitants have a low prevalence of obesity (4.3%) and only 4.4% of the female population had more than two pregnancies. Overall prevalence of gallstone disease (cholecystectomy + cholelithiasis) was 5.9% (3.7% for males and 8.4% for females). Age standardized relative risk of gallstone disease for females was 2.25 (95% confidence limits = 1.68-2.68). Prevalence of cholelithiasis was 3.5% (2.7% for males and 4.2% for females). Prevalence of gallstone disease increased with increasing age in both sexes, being extremely low in the age interval of 15-29 years (0.25%). The overall gallstones/cholecystectomy ratio was found to be lower(l:l) in females than in males (2.7:1). Although subjects with gallstones reported more frequently biliary colics and nonspecific dyspeptic symptoms, the diagnostic power of all symptoms in identifying cholelithiasis was very poor due to low sensitivity. Only one third of subjects with gallstones was aware of having the disease. Age, obesity and number of pregnancies were positively associated with gallstone disease in univariate analyses. The association with obesity and parity disappeared in multivariate analysis. Blood lipids and glucose were not associated with the disease both in univariate and multivariate analyses. Our data show that the prevalence of gallbladder disease in Chianciano is lower than that previously reported in italy. This difference could be related to a lower prevalence of obesity and to a smaller number of pregnancies or to the effect of environmental and genetic factors.

1994 - Regulation of bile acid synthesis in humans [Relazione in Atti di Convegno]
Bertolotti, Marco; Abate, N.; Loria, Paola; Dilengite, M.; Carubbi, Francesca; Bozzoli, M.; Carulli, N.
abstract

regulation of bile acid synthesis is studied by determination of 7 alpha hydroxylase activity in vivo in humans

1994 - Short-term effects of simvastatin on bile acid synthesis and biliary lipid secretion in human subjects. [Articolo su rivista]
Loria, Paola; Bertolotti, Marco; Cassinadri, M. T.; Dilengite, M. A.; Bozzoli, M.; Carubbi, Francesca; Concari, M.; Guicciardi, M. E.; Carulli, N. .
abstract

To test whether de novo synthesis of cholesterol is a limiting factor for bile acid synthesis, we studied the acute effect of simvastatin, an inhibitor of HMG-coenzyme A reductase (the limiting step of cholesterol synthesis) on bile acid synthesis and biliary lipid secretion in subjects with interrupted enterohepatic circulation. In these conditions bile acid synthesis is derepressed and is assumed to equal biliary bile acid secretion. Five cholecystectomized patients fitted with T-tubes were studied. All subjects were administered simvastatin (80 mg as a single dose) 5 days after surgery. Bile was collected in 3-hr intervals for 15 hr before and 30 hr after the administration of the drug. During the experiment we kept the enterohepatic circulation of bile acid interrupted by inflating an occludable balloon inserted, during cholecystectomy, in the common bile duct. Simvastatin induced significant decreases of plasma total and low density lipoprotein cholesterol concentrations, from 163 +/- 29 mg/dl and 97 +/- 24 mg/dl of the pretreatment value to 144 +/- 30 mg/dl and 82 +/- 22 mg/dl 18 hr after simvastatin administration, respectively. Bile flow tended to increase after simvastatin, and the mean values from the third to the 15th hour after simvastatin administration (22.1 +/- 1.9 ml/hr) were significantly greater than the mean values of the pretreatment period (19.9 +/- 2.8 ml/hr). Concomitantly biliary bile acid, cholesterol and phospholipid concentrations fell from basal values of 15.9 +/- 5.1, 2.3 +/- 0.3 and 5.5 +/- 0.3 mmol/L to mean values, after treatment, of 9.0 +/- 3.5, 1.9 +/- 0.5 and 3.0 +/- 0.9 mmol/L, respectively

1993 - Effect of aging on cholesterol 7 alpha-hydroxylation in humans [Articolo su rivista]
Bertolotti, Marco; N., Abate; S., Bertolotti; Loria, Paola; M., Concari; R., Messora; Carubbi, Francesca; A., Pinetti; Carulli, Nicola
abstract

In order to investigate the alterations of bile acid synthesis in aging, we studied the rates of cholesterol 7 alpha-hydroxylation, the rate-limiting step, in 28 patients of different ages (34-83 years old, 14 below and 14 above the age of 65) of both sexes. Hydroxylation rates were determined by tritium release assay after an intravenous bolus of [7 alpha-3H]cholesterol. Cholesterol 7 alpha-hydroxylation was significantly decreased in the older age group, compared to middle-aged subjects, both in males and females; moreover, a significant inverse correlation between hydroxylation rates and age was found in the whole sample (r = -0.56; P &lt; 0.01) and in females, but not in males. The percent concentration of deoxycholic acid in plasma (determined by gas-liquid chromatography) was increased in older subjects. Plasma cholesterol and triglyceride levels were not related with age even though triglyceride concentrations tended to be lower in the older age group. Triglyceride, but not cholesterol levels, were directly correlated with hydroxylation rates (r = 0.45, P &lt; 0.05). After cholestyramine treatment (8-12 g/day for 4 weeks) a sharp increase in 7 alpha-hydroxylation rates was observed in three elderly patients, accompanied by reduced levels of dihydroxylated bile acids. Our data are consistent with a reduced rate of conversion of cholesterol to bile acids with aging, particularly in females, and suggest a coordinate reduction of triglyceride production. Alterations of the quantitative and/or qualitative pattern of the bile acid pool recirculating to the liver may be responsible, at least in part, for the changes observed.

1992 - Transport of sulfobromophthalein and taurocholate in the HepG2 cell line in relation to the expression of membrane carrier proteins [Articolo su rivista]
P., Marchegiano; Carubbi, Francesca; C., Tiribelli; S., Amarri; M., Stebel; Gc, Lunazzi; D., Levy; S., Bellentani
abstract

The transport of two different classes of organic anions (cholephilic dyes; the sulfobromophthalein, BSP, and bile acids; taurocholate, TC) was investigated in the HepG2 cell line. At 37 degrees C, BSP uptake was found to be biphasic with an apparent saturative curve in the concentration range between 0-6 microM followed by a linear component up to 18 microM. Kinetic constant determination showed an apparent Km of 26.6 +/- 3.1 microM and a Vmax of 5.64 +/- 0.82 nmol BSP.min-1.mg prot-1. At 4 degrees C, uptake was linear. By subtracting this latter component from the total uptake, a saturable, carrier mediated uptake was found with an apparent Km of 3.6 +/- 1.0 microM BSP and a Vmax of 0.37 +/- 0.04 nmol BSP.min-1.mg prot-1 (m +/- SEM, n = 6). These values were fully comparable with those found in freshly isolated male hepatocyte. Immunoblot analysis of HepG2 cell plasma membrane revealed the presence of bilitranslocase when tested against a monospecific antibody against this carrier molecule. On the contrary, TC uptake was linear up to concentration of 100 microM TC. No difference was observed in the presence or absence of Na+. Immunoprecipitation analysis showed the absence of the putative carrier of TC. These data indicate that the HepG2 cell line expresses a functioning bilitranslocase-mediated system. Conversely, carrier mediated bile acid uptake is absent in line with the lack of expression of the carrier protein.

1991 - Regulation of bile acid synthesis in humans: effect of treatment with bile acids, cholestyramine or simvastatin on cholesterol 7 alpha-hydroxylation rates in vivo. [Articolo su rivista]
Bertolotti, Marco; N., Abate; Loria, Paola; M., Dilengite; Carubbi, Francesca; Pinetti, Adriano; A., Digrisolo; Carulli, Nicola
abstract

The rates of cholesterol 7-alpha-hydroxylation (the first and rate-limiting step of bile acid synthesis from cholesterol) were evaluated in vivo in patients administered bile acids with different structural properties, cholestyramine or simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Twenty-three subjects, with normal hepatic and intestinal functions, were studied in basal conditions and after one of the following treatment schedules, lasting 4 to 6 weeks: cholestyramine, 4 and 12 gm/day (four patients); ursodeoxycholic acid, 9 to 11 mg/kg/day (four patients); chenodeoxycholic acid, 12 to 15 mg/kg/day (five patients); deoxycholic acid, 8 to 10 mg/kg/day (four patients); and simvastatin, 40 mg/day (six patients). 7-alpha-Hydroxylation of cholesterol was assayed by measuring the increase in body water tritium after intravenous bolus of cholesterol tritiated at the 7-alpha position. Plasma bile acid composition, evaluated by gas-liquid chromatography, revealed a substantial enrichment of the recirculating pool by the administered bile acid, whereas treatment with cholestyramine decreased the content of dihydroxylated bile acids. Cholesterol 7-alpha-hydroxylation increased in a dose-related manner after cholestyramine, in parallel with a decrease of cholesterol in total plasma and low-density lipoproteins (1.006 to 1.063 gm/ml). Hydroxylation rates decreased by an average of 47% with chenodeoxycholic acid and by an average of 78% with deoxycholic acid; ursodeoxycholic acid treatment did not affect 7-alpha-hydroxylation significantly. Simvastatin markedly reduced plasma total and low-density lipoprotein-cholesterol but exerted no change on 7-alpha-hydroxylation rates. Our results support the existence of a feedback inhibition exerted on cholesterol 7-alpha-hydroxylation (and consequently on bile acid synthesis) by hydrophobic bile acids returning to the liver through the enterohepatic circulation. The finding emphasizes the importance of the physicochemical properties of bile acids in the regulation of hepatic cholesterol balance. Under these experimental conditions, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and presumably reduced availability of newly synthesized cholesterol are not critical for bile acid synthesis.

1990 - Effects of bile acid pool composition on hepatic metabolism of cholesterol in man [Articolo su rivista]
Carulli, Nicola; Loria, Paola; Bertolotti, Marco; Carubbi, Francesca; A., Tripodi; N., Abate; M., Dilengite
abstract

This work reviews the evidence concerning the role of the bile acid pool composition in the regulation of the overall hepatic metabolism of cholesterol in man. It has been known that bile acids regulate bile secretion, biliary lipid transport and hepatic cholesterol metabolism. However, the intimate mechanisms of these regulatory functions are not well understood. Current thinking attributes most of this regulation to the size of the bile acid pool. A typical example is represented by the negative feed-back mechanism by which bile acids returning to the liver control their own synthesis. Recent evidence however tend to suggest that not only the size but also the composition contributes to the regulatory activity of the bile acid pool. Specifically the hydrophobic-hydrophilic balance of the pool, as resulting from the characteristics and the proportions of the individual bile acids present within the pool, seems to dictate most of the effects of bile acids on hepatic cholesterol metabolism. Thus abundance within the pool of hydrophobic bile acids, such as deoxycholic or chenodeoxycholic acid, seems to induce a greater biliary lipid secretion and to exert inhibition of cholesterol and bile acid synthesis whereas hydrophilic bile acids such as ursodeoxycholic acid seem to be uneffective. It follows that by changing the composition of the bile acid pool it is possible to influence the hepatic metabolism of cholesterol

1989 - "Assay of HMG-CoA reductase activity in the evaluation of cholesterol synthesis in man". [Articolo su rivista]
Carulli, Nicola; A., Tripodi; Carubbi, Francesca
abstract

Assay of HMG-CoA reductase activity is useful in the evaluation of cholesterol synthesis in humans

1989 - Patogenesi della colelitiasi. I. Colelitiasi colesterinica. [Articolo su rivista]
Loria, Paola; Tripodi, A; Bertolotti, Marco; Carubbi, Francesca; Medici, G; Dilengite, Ma; Carulli, N.
abstract

no abstract

1987 - Il pool degli acidi biliari quale regolatore del metabolismo epatico del colesterolo: sintesi degli acidi biliari. [Articolo su rivista]
Carulli, N; Bertolotti, Marco; Menozzi, D; Loria, Paola; Tripodi, A; Carubbi, Francesca
abstract

Supplemento "Progressi in Epatologia".

1986 - "Bile acid synthesis: metabolism of 3B-OH-5-cholenoic acid to chenodeoxycholic acid" [Articolo su rivista]
Nb, Javitt; E., Kok; Carubbi, Francesca; T. B. L. I. Z. Z. A. R. D., J. B. I. O. L. C. H. E. M.
abstract

metabolism of 3B-OH-5-cholenoic acid to chenodeoxycholic acid was demonstrated in experimental animals. the intermediate can cause cholestasis and hepatocellular damage.

1986 - Effect of small doses of deoxycholic acid on bile cholesterol saturation in patients with liver cirrhosis [Articolo su rivista]
P., DI DONATO; Carubbi, Francesca; PONZ DE LEON, Maurizio; Carulli, Nicola
abstract

To test the hypothesis that the detergent power of each individual bile acid--that is, its separate capacity to solubilize cholesterol and to induce biliary cholesterol secretion, present in the biliary bile acid mixture might be one of the determinant factors of biliary cholesterol saturation, we studied the effect of feeding small doses of deoxycholic acid on biliary cholesterol saturation in patients with liver cirrhosis and low deoxycholic acid pool. Eleven hospitalised patients with cirrhosis of various degree of severity were put on a standard solid diet. Fasting bile rich duodenal fluid was obtained at the beginning of the study, after a three to four weeks treatment with deoxycholic acid (3 mg/kg/day, in two doses) and one month after discontinuing bile acid ingestion. Before treatment the fraction of deoxycholic acid was 5.3 +/- 4.9% (mean +/- SD); after treatment the fraction rose to 43.9 +/- 12.0 of total bile acids, but returned to the basal values after stopping bile acids. Bile cholesterol saturation increased significantly from a mean of 0.92 +/- 0.26 (before treatment) to a mean of 1.34 +/- 0.34 after deoxycholic acid feeding (p less than 0.005). One month after treatment, bile saturation was not significantly different from the basal values (0.91 +/- 0.44). We conclude that feeding low doses of deoxycholic acid to patients with liver cirrhosis induces a significant increase of the fraction of this bile acid in the total pool and this is followed by a sharp increase of bile cholesterol saturation. These data are compatible with the hypothesis that the detergent capacity of individual bile acids is one of the main determinants of bile cholesterol saturation.

1985 - Cholesterol Esterase Activity of human intestinal mucosa [Capitolo/Saggio]
Carubbi, Francesca; PONZ DE LEON, Maurizio; P., Di Donato; N., Carulli
abstract

Not applicable

1985 - Cholesterol esterase activity of human intestinal mucosa [Articolo su rivista]
PONZ DE LEON, Maurizio; Carubbi, Francesca; P., di Donato; N., Carulli
abstract

Abstract It has been suggested that cholesterol absorption in humans is dependent on bile acid pool composition and that expansion of the cholic acid pool size is followed by an increase of the absorption values. Similar observations were reported in rats, where the increase of cholesterol absorption, after trihydroxy bile acid feeding, seems to be due to the stimulatory effect of cholic acid on the intestinal cholesterol esterase. In the present study, therefore, we investigated some general properties of human intestinal cholesterol esterase, with particular emphasis to the effect of bile acids on this enzymatic activity. Twenty-nine segments of small intestine were taken during operations; the enzymatic activity was studied by using mucosal homogenate as a source of enzyme and oleic acid, cholesterol, and14C-labeled cholesterol as substrates. The time-activity relationship was linear within the first two hours; optimal pH for esterification ranged between 5 and 6.2. There was little difference between the esterifying activity of the jejunal and ileal mucosa. Esterification of cholesterol was observed with all the investigated fatty acids but was maximal with oleic acid. Bile acids did not affect cholesterol esterase activity when present in the incubation mixture at 0.1 and 1.0 mM; the enzymatic activity, however, was significantly inhibited when bile acids were added at 20 mM. In conclusion, this study has shown that the human intestinal mucosa possesses a cholesterol esterase activity; at variance with the rat, however, the human enzyme does not seem to be stimulated by trihydroxy bile acids. Thus, the stimulatory effect of cholic acid on cholesterol absorption induced by the administration of this bile acid does not seem to be simply due to changes of cholesterol esterase activity of the small bowel mucosa.Parts of this work have been presented at the 43rd Annual Meeting of the British Society of Gastroenterology (Leeds, September 22–24, 1982); at the 3rd Italian Week of Digestive Diseases (Bari, May 27-June 1, 1983); and at the 18th Meeting of the European Association for the Study of the Liver, (Southhampton, U.K., September 1–3, 1983).This work was supported by the grant 60%, a.a. 81/82 of the University of Modena and the Ministero della Pubblica Istruzione.Thanks are due to the surgical staff of the University of Modena and Policlinic for giving us the surgical specimens of small intestine.

1985 - Effect of feeding small doses of deoxycholic acid on bile lipid composition in patients with liver cirrhosis [Abstract in Atti di Convegno]
Carubbi, Francesca; P., Di Donato; PONZ DE LEON, Maurizio; N., Carulli
abstract

Not applicable

1985 - Incidence of colorectal cancer and polyps in a health care district: experience at 1 year of registration [Articolo su rivista]
Carubbi, Francesca; P., Di Donato; PONZ DE LEON, Maurizio; N., Carulli
abstract

not applicable

1984 - Cholesterol esterase activity in the small bowel of humans [Capitolo/Saggio]
P., Di Donato; Carubbi, Francesca; PONZ DE LEON, Maurizio; N., Carulli; G., Barberini; C., Pezcoller
abstract

Not applicable

1984 - Cholesterol esterase activity of human intestinal mucosa [Abstract in Atti di Convegno]
PONZ DE LEON, Maurizio; P., Di Donato; Carubbi, Francesca; N., Carulli
abstract

Not applicable

1984 - Deoxycholic acid (DCA) feeding induces significant changes of biliary lipid composition in cirrhotic patients [Abstract in Atti di Convegno]
Carubbi, Francesca; PONZ DE LEON, Maurizio; P., Di Donato; N., Carulli
abstract

not applicable

1984 - Fattori di rischio della litiasi biliare: importanza dell'alimentazione [Capitolo/Saggio]
PONZ DE LEON, Maurizio; Carubbi, Francesca; P., Di Donato; N., Carulli
abstract

Not applicable

1984 - Regulation of cholesterol absorption in humans [Capitolo/Saggio]
PONZ DE LEON, Maurizio; Carulli, N.; Loria, P.; Iori, R.; Di Donato, P.; Carubbi, Francesca; Manenti, A.; Pezcoller, C.; Zanni, C.; Barbolini, G.; Zaniol, P.; Motta, R.
abstract

Not applicable

1983 - Pancreatic cholesterol esterase of intestinal mucosa: characterization of enzymatic activity in humans [Abstract in Atti di Convegno]
P., Di Donato; PONZ DE LEON, Maurizio; Carubbi, Francesca; C., Pezcoller; N., Carulli
abstract

Not applicable