Hepcidin Is Down‐regulated in Alcoholic Liver Injury: Implications for the Pathogenesis of Alcoholic Liver Disease

Bridle, Kim R.; Cheung, Ting-Kin; Murphy, Tamara C.; Walters, Margaret M.; Anderson, Gregory J.; Crawford, Darrell; Fletcher, Linda M.

doi:10.1111/j.1530-0277.2006.00002.x

Cited by 147 publications

(114 citation statements)

References 41 publications

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“…10,11 As for the contribution of nongenetic factors, ethanol abuse (long associated with iron overload) is now believed to inhibit hepcidin transcription. 12,13 Similar effects can be produced by toxic and viral insults (for example, the hepatitis C virus may inhibit hepcidin expression 14 ). The unexplained hepatic iron overload associated with acute liver failure and chronic end-stage liver disease, which closely resembles that of hemochromatosis, 15 may be a manifestation of diminished hepcidin output due to a markedly reduced functional hepatic mass.…”

Section: Disruption Of Homeostasis: Insulin and Diabetes Hepcidin Anmentioning

confidence: 98%

Hemochromatosis

2007

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This review acknowledges the recent and dramatic advancement in the field of hemochromatosis and highlights the surprising analogies with a prototypic endocrine disease, diabetes. The term hemochromatosis should refer to a unique clinicopathologic subset of ironoverload syndromes that currently includes the disorder related to the C282Y homozygote mutation of the hemochromatosis protein HFE (by far the most common form of hemochromatosis) and the rare disorders more recently attributed to the loss of transferrin receptor 2, HAMP (hepcidin antimicrobial peptide), or hemojuvelin or to certain ferroportin mutations. The defining characteristic of this subset is failure to prevent unneeded iron from entering the circulatory pool as a result of genetic changes compromising the synthesis or activity of hepcidin, the iron hormone. Like diabetes, hemochromatosis results from the complex, nonlinear interaction between genetic and acquired factors. Depending on the underlying mutation, the coinheritance of modifier genes, the presence of nongenetic hepcidin inhibitors, and other host-related factors, the clinical manifestation may vary from simple biochemical abnormalities to severe multiorgan disease. The recognition of the endocrine nature of hemochromatosis suggests intriguing possibilities for new and more effective approaches to diagnosis and treatment. (HEPATOLOGY 2007;46:1291-1301

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Section: Disruption Of Homeostasis: Insulin and Diabetes Hepcidin Anmentioning

confidence: 98%

Hemochromatosis

2007

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“…Recently, it has been shown that alcohol down-regulates hepcidin transcription, which leads to increased duodenal iron absorption via a divalent metal transporter-1 (with enhanced luminal import) and ferroportin protein expression (with enhanced basolateral translocation to the circulation) [7,8] . Furthermore, it has been shown that alcohol abolishes the iron-induced upregulation of both liver hepcidin transcription and the DNA-binding activity of C/EBP alpha [9] , thus negating the protective effect of hepcidin.…”

Section: Introductionmentioning

confidence: 99%

Iron homeostasis and H63D mutations in alcoholics with and without liver disease

Machado¹,

Ravasco²,

Martins³

et al. 2009

WJG

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AIM:To evaluate the prevalence of HFE gene mutation and indices of disturbed iron homeostasis in alcoholics with and without liver disease. METHODS:One hundred and fifty-three heavy drinkers (defined as alcohol consumption > 80 g/d for at least 5 years) were included in the study. These comprised 78 patients with liver disease [liver disease alcoholics (LDA)] in whom the presence of liver disease was confirmed by liver biopsy or clinical evidence of hepatic decompensation, and 75 subjects with no evidence of liver disease, determined by normal liver tests on two occasions [non-liver disease alcoholics (NLDA)], were consecutively enrolled. Serum markers of iron status and HFE C282Y and H63D mutations were determined. HFE genotyping was compared with data obtained in healthy blood donors from the same geographical area. RESULTS:Gender ratio was similar in both study groups. LDA patients were older than NLDA patients (52 ± 10 years vs 48 ± 11 years, P = 0.03). One third and one fifth of the study population had serum transferrin saturation (TS) greater than 45% and 60% respectively. Serum iron levels were similar in both groups. However, LDA patients had higher TS (51 ± 27 vs 36 ± 13, P < 0.001) and ferritin levels (559 ± 607 ng/mL vs 159 ± 122 ng/mL, P < 0.001), and lower total iron binding capacity (TIBC) (241 ± 88 µg/dL vs 279 ± 40 µg/dL, P = 0.001). The odds ratio for having liver disease with TS greater than 45% was 2.20 (95% confidence interval (CI): 1.37-3.54). There was no difference in C282Y allelic frequency between the two groups. However, H63D was more frequent in LDA patients (0.25 vs 0.16, P = 0.03). LDA patients had a greater probability of carrying at least one HFE mutation than NLDA patients (49.5% vs 31.6%, P = 0.02). The odds ratio for LDA in patients with H63D mutation was 1.57 (95% CI: 1.02-2.40). CONCLUSION:The present study confirms the presence of iron overload in alcoholics, which was more severe in the subset of subjects with liver disease, in parallel with an increased frequency of H63D HFE mutation.

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“…19 Oxidative stress in the liver secondary to alcohol or chronic viral hepatitis can lead to suppression of hepcidin, leading to excess iron accumulation and progression of underlying disease. 20,21 4. Correct Answers: A, D, and E Intrahepatic cholestasis of pregnancy (ICP) classically presents in the third trimester with pruritus, raised serum bile acids, and spontaneous resolution after delivery.…”

Section: Correct Answers: a B And Cmentioning

confidence: 99%