Current approach to hemochromatosis.

Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.

The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis.

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common worldwide clinical and major public health problem affecting both adults and children in developed nations. Increased hepatic iron stores are observed in about one-third of adult NAFLD patients. Iron deposition may occur in parenchymal and/or non-parenchymal cells of the reticuloendothelial system (RES). Similar patterns of iron deposition have been associated with increased severity of other chronic liver diseases including HCV infection and dysmetabolic iron overload, suggesting there may be a common mechanism for hepatic iron deposition in these diseases. In NAFLD, iron may potentiate the onset and progression of disease by increasing oxidative stress and altering insulin signaling and lipid metabolism. The impact of iron in these processes may depend upon the sub-cellular location of iron deposition in hepatocytes or RES cells. Iron depletion therapy has shown efficacy at reducing serum aminotransferase levels and improving insulin sensitivity in subjects with NAFLD.

Iron Metabolism in Nonalcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is not a single disease entity, rather it describes a spectrum of liver conditions that range from fatty liver (steatosis) to more severe steatosis coupled with marked inflammation and fibrosis [non-alcoholic steatohepatitis (NASH)] to severe liver disease such as cirrhosis and possibly hepatocellular carcinoma. Obesity, notably abdominal obesity, is a common risk factor for NAFLD. The pathogenesis from steatosis to NASH is poorly understood, and the 'two hit' model, as suggested nearly two decades ago, provides a feasible starting point for characterization of underlying mechanisms. This review will examine the oxidative stress factors ('triggers') which have been implicated as a 'second hit' in the development of primary NASH. It would be reasonable to assume that multiple, rather than single, pro-oxidative intracellular and extracellular triggers act in conjunction promoting oxidative stress that drives the development of NASH. It is likely that the common denominator of these pro-oxidative triggers is mitochondrial dysfunction. Understanding the contribution of each of these 'triggers' is an essential step in starting to understand and elucidate the mechanisms responsible for progression from steatosis to NASH, thus enabling the development of therapeutic targeting to prevent NASH development and progression.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/liv.12523

Are oxidative stress mechanisms the common denominator in the progression from hepatic steatosis towards non‐alcoholic steatohepatitis (NASH)?

HFE gene: Structure, function, mutations, and associated iron abnormalities.

Frequency of primary iron overload and HFE gene mutations (C282Y, H63D and S65C) in chronic liver disease patients in north India

Frequency of primary iron overload and HFE gene mutations (C282Y, H63D and S65C) in chronic liver disease patients in north India.

The common C282Y mutation (HFE gene) in hereditary haemochromatosis (HH) patients of European origin is absent in Indians. The frequency of the second common missense H63D (187C→G) mutation of HFE gene ranges from 9.1–13.9% in the general population. In this study we investigated the haplotypes associated with H63D mutation in north Indians. Allele and haplotype frequencies were counted, and haplotypes were generated based on expectation– maximization (EM) algorithm using Haploview software (http://www.broad.mit.edu/mpg/haploview/). HH affects predominantly people of northern European origin and is often described as a ‘Celtic mutation’ that originated in a Celtic population in central Europe and spread west and north by population movement. There are suggestions that Viking migrations were largely responsible for the distribution of the disease (Lucotte 1998). The common form of HH is caused by the Cys282Tyr mutation (C282Y; 845G-A) of the HFE gene which occurred in mainland Europe before 4000 BC (Distante et al. 2004). The second common missense mutation in the HFE gene is a C to G transversion (187C-G) which causes a histidine to aspartic acid substitution at amino acid position 63 in the unprocessed protein (H63D) (Feder et al. 1996). Coinheritance of H63D mutation with the C282Y mutation is a known risk factor for iron overload (Pointon et al. 2000) The H63D mutation is widely distributed in nearly all populations examined with a variable allele frequency and is believed to have occurred earlier than the C282Y mutation (Merryweather-Clarke et al. 1997; Rochette et al. 1999). The allele frequency for H63D in most European countries varies between 10 and 20%, with

H63D mutation in HFE gene is common in Indians and is associated with the European haplotype.

Hereditary hemochromatosis (HH) is a rare disorder in Indians and is not associated with the common mutation Cys282Tyr in HFE gene found in Caucasians. Non-HFE HH can be associated with mutations in HJV, HAMP, TFR2 and SLC40A1 genes. Nineteen unrelated north Indian HH patients were detected after screening 258 chronic liver disease patients on the basis of increased transferrin saturation, ferritin levels >1000 ng/L and siderosis by Perl's stain on liver biopsy wherever available. Automated DNA sequencing was performed for the promoters and entire coding exons for HFE, HJV, HAMP, TFR2 and SLC40A1. A novel homozygous mutation at position p.Gly336Ter (c.1006 G>T) in exon 4 in HJV was identified in four adult unrelated patients. We encountered compound heterozygosity for p.Thr217Ile (c.650C>T) and p.His63Asp (c.187C>G) mutation of HFE gene in one patient. Two patients were compound heterozygous for two novel polymorphisms at c.−358 (G>A) and c.−36 (G>A) in 5′UTR of HJV gene. Our study shows a novel HJV gene mutation p.Gly336Ter as a recurrent mutation associated with HH in north Indians. Low index of suspicion, underlying nutritional iron deficiency and protective effect of menstrual blood loss may account for the late clinical presentation of juvenile HH.

Barjinderjit Kaur Dhillon

Papers

Frequency of primary iron overload and HFE gene mutations (C282Y, H63D and S65C) in chronic liver disease patients in north India.

H63D mutation in HFE gene is common in Indians and is associated with the European haplotype.

Adult onset hereditary hemochromatosis is associated with a novel recurrent Hemojuvelin (HJV) gene mutation in north Indians