Iron and liver diseases.

A mild to moderate iron excess is found in patients with liver diseases apparently unrelated to genetic hemochromatosis. Iron appears to affect the natural history of hepatitis C virus-related chronic liver diseases, alcoholic liver disease and nonalcoholic steatohepatitis by leading to a more severe fibrosis and thus aiding the evolution to cirrhosis.Ahigher frequency of mutations of the HFE gene, the gene responsible for hereditary hemochromatosis, is found in patients with liver diseases and increased liver iron than in normal patients. Patients with excess iron are potentially at a higher risk of developing hepatocellular carcinoma. Iron depletion therapy could interfere with fibrosis development and possibly reduce the risk of liver cancer occurrence

Iron in fatty liver and in the metabolic syndrome: A promising therapeutic target

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The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies.

AIMS: Non-alcoholic fatty liver disease (NAFLD) is a complex disease trait where genetic variations and environment interact to determine disease progression. The association of PNPLA3 with advanced disease has been consistently demonstrated but many other modifier genes remain unidentified. In NAFLD, increased fatty acid oxidation produces high levels of reactive oxygen species. Manganese-dependent superoxide dismutase (MnSOD), encoded by the SOD2 gene, plays an important role in protecting cells from oxidative stress. A common non-synonymous polymorphism in SOD2 (C47T; rs4880) is associated with decreased MnSOD mitochondrial targeting and activity making it a good candidate modifier of NAFLD severity. METHODS: The relevance of the SOD2 C47T polymorphism to fibrotic NAFLD was assessed by two complementary approaches: we sought preferential transmission of alleles from parents to affected children in 71 family trios and adopted a case-control approach to compare genotype frequencies in a cohort of 502 European NAFLD patients. RESULTS: In the family study, 55 families were informative. The T allele was transmitted on 47/76 (62%) possible occasions whereas the C allele was transmitted on only 29/76 (38%) occasions, p=0.038. In the case control study, the presence of advanced fibrosis (stage>1) increased with the number of T alleles, p=0.008 for trend. Multivariate analysis showed susceptibility to advanced fibrotic disease was determined by SOD2 genotype (OR 1.56 (95% CI 1.09-2.25), p=0.014), PNPLA3 genotype (p=0.041), type 2 diabetes mellitus (p=0.009) and histological severity of NASH (p=2.0×10(-16)). CONCLUSIONS: Carriage of the SOD2 C47T polymorphism is associated with more advanced fibrosis in NASH

Mir-101-3p downregulation promotes fibrogenesis by facilitating hepatic stellate cell transdifferentiation during insulin resistance

Insulin resistance (IR) and microRNAs (miRNAs), which regulate cell-to-cell communication between hepatocytes and hepatic stellate cells (HSCs), may intertwine in nonalcoholic fatty liver disease (NAFLD) pathogenesis. The aim of this study was to evaluate whether epigenetics and environmental factors interact to promote progressive NAFLD during IR. We examined the miRNA signature in insulin receptor haploinsufficient (InsR+/ 12) and wild-type (wt) HSCs by RNAseq (n = 4 per group). Then, we evaluated their impact in an IR-NASH (nonalcoholic steatohepatitis) model (InsR+/ 12 mice fed standard or methionine choline deficient (MCD) diet, n = 10 per group) and in vitro. InsR+/ 12 HSCs displayed 36 differentially expressed miRNAs (p < 0.05 vs. wt), whose expression was then analyzed in the liver of InsR+/ 12 mice fed an MCD diet. We found that miR-101-3p negatively associated with both InsR+/ 12 genotype and MCD (p < 0.05) and the histological spectrum of liver damage (p < 0.01). miR-101-3p was reduced in InsR+/ 12 hepatocytes and HSCs and even more in InsR+/ 12 cells exposed to insulin (0.33 \ub5M) and fatty acids (0.25 mM), resembling the IR-NASH model. Conversely, insulin induced miR-101-3p expression in wt cells but not in InsR+/ 12 ones (p < 0.05). In conclusion, IR combined with diet-induced liver injury favors miR-101-3p downregulation, which may promote progressive NAFLD through HSC and hepatocyte transdifferentiation and proliferation

Vascular damage in patients with nonalcoholic fatty liver disease : Possible role of iron and ferritin

Non Alcoholic Fatty Liver Disease (NAFLD) is the most common chronic liver disease in Western countries. Recent data indicated that NAFLD is a risk factor by itself contributing to the development of cardiovascular disease independently of classical known risk factors. Hyperferritinemia and mild increased iron stores are frequently observed in patients with NAFLD and several mechanisms have been proposed to explain the role of iron, through oxidative stress and interaction with insulin metabolism, in the development of vascular damage. Moreover, iron depletion has been shown to decrease atherogenesis in experimental models and in humans. This review presents the recent evidence on epidemiology, pathogenesis, and the possible explanation of the role of iron and ferritin in the development of cardiovascular damage in patients with NAFLD, and discusses the possible interplay between metabolic disorders associated with NAFLD and iron in the development of cardiovascular disease

Juvenile hemochromatosis associated with heterozygosity for novel hemojuvelin mutations and with unknown cofactors

Background & Aims. Juvenile hemochromatosis (JH) is a rare autosomal recessive disorder characterized by severe early-onset iron overload, caused by mutations in hemojuvelin (HJV), hepcidin (HAMP), or a combination of genes regulating iron metabolism. Here we describe two JH cases associated with simple heterozygosity for novel HJV mutations and unknown genetic factors. Case 1: A 12 year-old male from Central Italy with beta-thalassemia trait, increased aminotransferases, ferritin 9035 ng/ml and transferrin saturation 84%, massive hepatocellular siderosis and hepatic bridging fibrosis. Case 2: A 12 year-old female from Northern Italy with ferritin 467 ng/ml, transferrin saturation 87-95%, and moderate hepatic iron overload. Material and methods. Direct sequencing of hemochromatosis genes (HFE-TfR2-HJV-HAMP-FPN-1) was performed in the children and siblings. Results. In case 1, we detected heterozygosity for a novel HJV mutation (g.3659_3660insG), which was inherited together with the beta thalassemia trait from the father, who (as well as the mother) had normal iron parameters. In case 2, we detected another novel HJV mutation (g.2297delC) in heterozygosity, which was inherited from the mother, affected by mild iron deficiency. The father had normal iron stores. Both mutations are frameshifts determining premature stop codons. No other disease causing variant was detected. Conclusion. Although beta-thalassemia trait was a possible cofactor of iron overload in case 1, iron overload cannot be explained by simple heterozygosity for HJV mutations in both cases. Other genetic factors should be investigated, and further studies are needed to understand genotype-phenotype correlations in JH

MiRNA signature in NAFLD: A turning point for a non-invasive diagnosis

Nonalcoholic fatty liver disease (NAFLD) defines a wide pathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may predispose to liver cirrhosis and hepatocellular carcinoma. It represents the leading cause of hepatic damage worldwide. Diagnosis of NASH still requires liver biopsy but due to the high prevalence of NAFLD, this procedure, which is invasive, is not practicable for mass screening. Thus, it is crucial to non-invasively identify NAFLD patients at higher risk of progression to NASH and fibrosis. It has been demonstrated that hepatic fat content and progressive liver damage have a strong heritable component. Therefore, genetic variants associated with NAFLD have been proposed as non-invasive markers to be used in clinical practice. However, genetic variability is not completely explained by these common variants and it is possible that many of the phenotypic differences result from gene-environment interactions. Indeed, NAFLD development and progression is also modulated by epigenetic factors, in particular microRNAs (miRNAs), which control at post-transcriptional level many complementary target mRNAs and whose dysregulation has been shown to have high prognostic and predictive value in NAFLD. The premise of the current review is to discuss the role of miRNAs as pathogenic factors, risk predictors and therapeutic targets in NAFLD