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

Abstract

Background: Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome. Aims:To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management Methods: English abstracts were identified in PubMed by multiple search terms.Full length articles were selected for review, and secondary and tertiary bibliographies were developed.Results: Hyperferritinemia is present in 4%-65% of patients with non-alcoholic fatty liver disease, autoimmune hepatitis, chronic viral hepatitis, or alcoholic liver disease, and hepatic iron content is increased in 11%-52%. Heterozygosity for the C282Y mutation is present in 17%-48%, but this has not uniformly distinguished patients with adverse outcomes. An inappropriately low serum hepcidin level has characterised most chronic liver diseases with the exception of non-alcoholic fatty liver disease, and the finding has been associated mainly with suppression of transcriptional activity of the hepcidin gene. Iron overload has been associated with oxidative stress, advanced fibrosis and decreased survival, and promising therapies beyond phlebotomy and oral iron chelation have included hepcidin agonists. Conclusions:Iron dysregulation is common in chronic liver diseases other than hereditary haemochromatosis, and has been associated with liver toxicity and poor prognosis. Further evaluation of iron overload as a co-morbid factor should identify the key pathogenic disturbances, establish the risk threshold for iron toxicity, and promote molecular interventions.

Letter: high ferritin to haemoglobin ratio is related to early mortality in patients with alcoholic hepatitis

“…Hyperferritinaemia is a feature of several chronic liver diseases apart from genetic haemochromatosis, 1 and anaemia is a frequent diseasenonspecific manifestation of chronic illness. 2,3 Hyperferritinaemia has been associated with laboratory tests of liver inflammation, increased early mortality in cirrhosis, and hepatic iron deposition, 1 and anaemia has been associated with increased mortality in several chronic nonliver diseases. 2 Hepatic iron overload displaces inactive ferric iron from storage complexes, and the released iron is reduced to the reactive ferrous state.…”

“…2 Hepatic iron overload displaces inactive ferric iron from storage complexes, and the released iron is reduced to the reactive ferrous state. 1,5 Ferrous iron in turn reacts with hydrogen peroxide, and reactive oxygen species induce hepatocyte injury and stimulate hepatic fibrosis. 1,6,7 Surrogate markers, such as serum ferritin, cytokine, and haemoglobin levels, can help recognise the iron-induced, liver damaging, oxidative stress and predict its consequences, but tests closer to the pathogenic mechanisms of the liver injury…”

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IL-1, TNF-alpha and oxidative stress have stimulatory effects on ferritin and serve as key inflammatory mediators in pathobiology of AH. 1,7 It is predictable therefore, that ferritin values are associated with severity of inflammation and consequently outcome in AH. As IL-1 plays an important role in the anaemia of inflammation, 9 the ferritin/Hb ratio, which takes into account both the levels of ferritin and the severity of anaemia, seems to perform particularly well as a prognostic score in AH.

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Letter: high ferritin to haemoglobin ratio is related to early mortality in patients with alcoholic hepatitis – author’s reply

“…Hyperferritinaemia is a feature of several chronic liver diseases apart from genetic haemochromatosis, 1 and anaemia is a frequent diseasenonspecific manifestation of chronic illness. 2,3 Hyperferritinaemia has been associated with laboratory tests of liver inflammation, increased early mortality in cirrhosis, and hepatic iron deposition, 1 and anaemia has been associated with increased mortality in several chronic nonliver diseases. 2 Hepcidin is a liver-derived acute phase reactant that inhibits ferroportin activity and reduces intestinal absorption of iron and its mobilisation from storage sites.…”

“…

IL-1, TNF-alpha and oxidative stress have stimulatory effects on ferritin and serve as key inflammatory mediators in pathobiology of AH. 1,7 It is predictable therefore, that ferritin values are associated with severity of inflammation and consequently outcome in AH. As IL-1 plays an important role in the anaemia of inflammation, 9 the ferritin/Hb ratio, which takes into account both the levels of ferritin and the severity of anaemia, seems to perform particularly well as a prognostic score in AH.

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