Hfe Mutations and Iron Overload in Patients With Alcoholic Liver Disease

Abstract

-Context -Alcoholic liver disease (ALD) is generally associated with iron overload, which may contribute to its pathogenesis, through increased oxidative stress and cellular damage. There are conflicting reports in literature about hemochromatosis (HFE) gene mutations and the severity of liver disease in alcoholic patients. Objectives -To compare the prevalence of mutations in the hemochromatosis (HFE) gene between patients with ALD and healthy controls; to assess the relation of HFE mutations with liver iron stores and liver disease severity. Methods -Liver biopsy specimens were obtained from 63 ALD patients (during routine treatment) and 52 healthy controls (during elective cholecystectomy). All individuals underwent routine liver function tests and HFE genotyping (to detect wild-type sequences and C282Y, H63D, S65C, E168Q, E168X, V59M, H63H, P160delC, Q127H, Q283P, V53M and W164X mutations). Associations between HFE mutations and risk of excessive liver iron stores, abnormal serum ferritin, liver fibrosis, or necroinflammatory activity were assessed by multivariate logistic regression analysis. Results -ALD patients had significantly higher serum ferritin and transferrin saturation than controls (both P<0.05), but the distribution of HFE mutations was similar between the two groups. For ALD patients, the odds ratio for having at least one HFE mutation and excessive liver iron stores was 17.23 (95% confidence interval (CI): 2.09-142.34, P = 0.008). However, the presence of at least one HFE mutation was not associated with an increased risk of liver fibrosis or necroinflammatory activity. Active alcohol ingestion showed the strongest association to increased serum ferritin (OR = 8.87, 95% CI: 2.11-34.78, P = 0.003). Conclusions -ALD patients do not present with a differential profile of HFE mutations from healthy controls. In ALD patients, however, the presence of at least one HFE mutation increases the risk of having excessive liver iron stores but has no detectable effects on liver disease activity or severity. HEADINGS -Alcoholic liver disease. Membrane proteins. Iron. Hemochromatosis.

Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

“…A HFE mutation has been detected more frequently in patients with ALD and hepatic iron accumulation than in patients with ALD and no hepatic iron accumulation (odds ratio, 17.23; 95% CI: 2.09‐142.34; P = 0.008), but the HFE mutation has not been associated with increased hepatic fibrosis, disease severity, or inflammatory activity . Other studies have demonstrated that the occurrence of a single HFE mutation in ALD has not increased the hepatic iron content, frequency of fibrosis, or predisposition for severe ALD .…”

“…Serum ferritin levels and transferrin saturations are increased in 63% and 29% of patients with alcoholic liver disease (ALD), and the results are significantly higher than in healthy individuals ( P < 0.05) (Table ) . Stainable hepatic iron in parenchymal and reticuloendothelial cells has been demonstrated in 52% of patients with ALD, and severe (grade 3‐4) iron deposition has been present in 22% of liver explants .…”

HFE gene variants and iron-induced oxygen radical generation in idiopathic pulmonary fibrosis

“…The H63D variant, which we found most frequently associated with pulmonary fibrosis in the current study patients, is associated with disease with very low penetrance, even when homozygous, when compared with the C282Y allele, which is the more commonly causative allele of the autosomal recessive type 1 hereditary haemochromatosis. However, both the C282Y and the H63D variants are associated with increased susceptibility to liver cirrhosis in alcohol liver disease and viral hepatitis [20,21]. Is the carriage of HFE gene variants a cause of dysregulated cellular iron levels in IPF?…”

“…C282Y and H63D are common allelic variants of HFE, with allele frequencies of 3.8±0.7% and 13.6±1.3%, respectively, in Europe, and lower frequencies for C282Y in southern Europe and Italy [19]. Importantly, they have been reported, albeit not univocally, to confer greater susceptibility to liver iron overload and cirrhosis upon heterozygous carriers exposed to chronic inflammation, such as in viral hepatitis or alcohol-related liver disease [20,21]. With this as a background, and with the knowledge that a number of exposures have been implicated as possible risk factors for IPF [22,23], we hypothesised a role as susceptibility factors to HFE allelic variants, due to their potential for dysregulated iron accumulation and exaggerated generation of oxygen radicals.…”

Hfe-associated steatohepatitis: expression profiling and identifying the molecular basis of liver injury

“…The hepatic iron loading observed is generally modest, with infrequent cases of severe iron loading (193,194). The iron accumulation in ALD appears to be independent of HFE and other genetic mutations (195).…”