Elena Corradini1, Elena Buzzetti2, Paola Dongiovanni3, Stefania Scarlini4, Angela Caleffi4, Serena Pelusi5, Isabella Bernardis6, Paolo Ventura2, Raffaela Rametta3, Elena Tenedini6, Enrico Tagliafico6, Anna Ludovica Fracanzani7, Silvia Fargion3, Antonello Pietrangelo2, Luca Vittorio Valenti8. 1. Internal Medicine and Centre for Hemochromatosis and Heredometabolic Liver Diseases, ERN-EuroBloodNet Center for Iron Disorders, Azienda Ospedaliero-Universitaria di Modena - Policlinico, Modena, Italy; Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy. Electronic address: elena.corradini75@unimore.it. 2. Internal Medicine and Centre for Hemochromatosis and Heredometabolic Liver Diseases, ERN-EuroBloodNet Center for Iron Disorders, Azienda Ospedaliero-Universitaria di Modena - Policlinico, Modena, Italy; Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy. 3. General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milan, Italy. 4. Internal Medicine and Centre for Hemochromatosis and Heredometabolic Liver Diseases, ERN-EuroBloodNet Center for Iron Disorders, Azienda Ospedaliero-Universitaria di Modena - Policlinico, Modena, Italy. 5. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milan, Italy. 6. Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy; Center for Genome Research, Università degli Studi di Modena e Reggio Emilia, Modena, Italy. 7. General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. 8. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milan, Italy. Electronic address: luca.valenti@unimi.it.
Abstract
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disorder resulting from genetic and environmental factors. Hyperferritinemia has been associated with increased hepatic iron stores and worse outcomes in patients with NAFLD. The aim of this study was to evaluate the prevalence of variants of iron-related genes and their association with hyperferritinemia, hepatic iron stores and liver disease severity in patients with NAFLD. METHODS: From a cohort of 328 individuals with histological NAFLD, 23 patients with ferritin >750 ng/ml and positive iron staining, and 25 controls with normal ferritin and negative iron staining, were selected. Patients with increased transferrin saturation, anemia, inflammation, β-thalassemia trait, HFE genotype at risk of iron overload and ferroportin mutations were excluded. A panel of 32 iron genes was re-sequenced. Literature and in silico predictions were employed for prioritization of pathogenic mutations. RESULTS: Patients with hyperferritinemia had a higher prevalence of potentially pathogenic rare variants (73.9% vs. 20%, p = 0.0002) associated with higher iron stores and more severe liver fibrosis (p <0.05). Ceruloplasmin was the most mutated gene and its variants were independently associated with hyperferritinemia, hepatic siderosis, and more severe liver fibrosis (p <0.05). In the overall cohort, ceruloplasmin variants were independently associated with hyperferritinemia (adjusted odds ratio 5.99; 95% CI 1.83-19.60; p = 0.0009). CONCLUSIONS: Variants in non-HFE iron genes, particularly ceruloplasmin, are associated with hyperferritinemia and increased hepatic iron stores in patients with NAFLD. Carriers of such variants have more severe liver fibrosis, suggesting that genetic predisposition to hepatic iron deposition may translate into liver disease. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is a common disease which can progress to cirrhosis and liver cancer. Increased levels of serum ferritin are often detected in patients with NAFLD and have been associated with altered iron metabolism and worse patient outcomes. We found that variants of genes related to iron metabolism, particularly ceruloplasmin, are associated with high ferritin levels, hepatic iron deposition and more severe liver disease in an Italian cohort of patients with NAFLD.
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disorder resulting from genetic and environmental factors. Hyperferritinemia has been associated with increased hepatic iron stores and worse outcomes in patients with NAFLD. The aim of this study was to evaluate the prevalence of variants of iron-related genes and their association with hyperferritinemia, hepatic iron stores and liver disease severity in patients with NAFLD. METHODS: From a cohort of 328 individuals with histological NAFLD, 23 patients with ferritin >750 ng/ml and positive iron staining, and 25 controls with normal ferritin and negative iron staining, were selected. Patients with increased transferrin saturation, anemia, inflammation, β-thalassemia trait, HFE genotype at risk of iron overload and ferroportin mutations were excluded. A panel of 32 iron genes was re-sequenced. Literature and in silico predictions were employed for prioritization of pathogenic mutations. RESULTS: Patients with hyperferritinemia had a higher prevalence of potentially pathogenic rare variants (73.9% vs. 20%, p = 0.0002) associated with higher iron stores and more severe liver fibrosis (p <0.05). Ceruloplasmin was the most mutated gene and its variants were independently associated with hyperferritinemia, hepatic siderosis, and more severe liver fibrosis (p <0.05). In the overall cohort, ceruloplasmin variants were independently associated with hyperferritinemia (adjusted odds ratio 5.99; 95% CI 1.83-19.60; p = 0.0009). CONCLUSIONS: Variants in non-HFE iron genes, particularly ceruloplasmin, are associated with hyperferritinemia and increased hepatic iron stores in patients with NAFLD. Carriers of such variants have more severe liver fibrosis, suggesting that genetic predisposition to hepatic iron deposition may translate into liver disease. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is a common disease which can progress to cirrhosis and liver cancer. Increased levels of serum ferritin are often detected in patients with NAFLD and have been associated with altered iron metabolism and worse patient outcomes. We found that variants of genes related to iron metabolism, particularly ceruloplasmin, are associated with high ferritin levels, hepatic iron deposition and more severe liver disease in an Italian cohort of patients with NAFLD.
Authors: Hairong Yao; Xuan Yang; Man Yan; Xueqin Fang; Yange Wang; Hong Qi; Li Sun Journal: Comput Math Methods Med Date: 2022-09-30 Impact factor: 2.809