Effect of alcohol on iron storage diseases of the liver

The consumption of excess alcohol in patients with liver iron storage diseases, in particular the iron-overload disease hereditary haemochromatosis (HH), has important clinical consequences. HH, a common genetic disorder amongst people of European descent, results in a slow, progressive accumulation of excess hepatic iron. If left untreated, the condition may lead to fibrosis, cirrhosis and primary hepatocellular carcinoma. The consumption of excess alcohol remains an important cause of hepatic cirrhosis and alcohol consumption itself may lead to altered iron homeostasis. Both alcohol and iron independently have been shown to result in increased oxidative stress causing lipid peroxidation and tissue damage. Therefore, the added effects of both toxins may exacerbate the pathogenesis of disease and impose an increased risk of cirrhosis. This review discusses the concomitant effects of alcohol and iron on the pathogenesis of liver disease. We also discuss the implications of co-existent alcohol and iron in end-stage liver disease.

Atteintes de la chevill et du tarse postérieur dans les maladies métaboliques

De nombreuses maladies métaboliques peuvent atteindre la cheville et le tarse postérieur. Dans la phase aiguë, la goutte peut toucher l'arrière-pied, la cheville, le médio-tarse ou le tendon calcanéen. Une rougeur intense des tissus souscutanés du dos du pied peut être en rapport avec une inflammation liée à des microtophus sous-cutanés. Un diagnostic de certitude se fait par la mise en évidence de cristaux d'urate de sodium dans le liquide de ponction articulaire ou dans les tissus. L'imagerie par tomodensitométrie ou par échographie peut orienter de façon pratiquement certaine le diagnostic. Le traitement de la goutte de l'arrière-pied fait appel aux antiinflammatoires, aux anti-inflammatoires non stéroïdiens (AINS) et à la colchicine. Dans la phase chronique, un traitement hypo-uricémiant au long terme est à instaurer. L'hémochromatose se manifeste principalement sous forme d'une arthrose, liée souvent à une chondrocalcinose de la cheville et du tarse postérieur. L'enthésopathie hyperostosante diffuse peut causer des talalgies ou des douleurs du fascia plantaire liées à des exostoses. L'hypercholestérolémie familiale provoque souvent des xanthomes tendineux des tendons calcanéens. Des calcifications apatitiques de la région du talon peuvent s'observer, notamment chez des patients en hémodialyse chronique. Numerous metabolic diseases can affect the ankle and the hind-foot. In the acute phase, gout can affect the rear of the foot, the ankle, the mid-foot and the calcaneal (Achilles) tendon. Intense redness of the subcutaneous tissue of the back of the foot can be present in conjunction with inflammation associated with subcutaneous micro-tophaceous deposits. A definitive diagnosis is made by confirming the existence of sodium urate crystals in joint puncture fluid or in tissue. CT scan or ultrasonography images can also be used to provide a fairly definitive diagnosis. Treatment of gout of the rear of the foot requires the use of anti-inflammatory medication, NSAIDs and colchicine. In the chronic phase, long-term hypouricemic therapy is to be used. Haemochromatosis mainly shows in the form of arthritis, often associated with chondrocalcinosis of the ankle and hind-foot. A diffuse hyperostosis enthesopathy can cause talalgia or pain to the plantar fascia associated with exostoses. Familial hypercholesterolaemia often leads to tendinous xanthoma on the calcaneal tendons. Apatitic calcifications to the heel can also be observed, especially undergoing chronic haemodialysis.

Hypofibrinogenemia and liver disease: a new case of Aguadilla fibrinogen and review of the literature.

INTRODUCTION Fibrinogen storage disease (FSD) is characterized by hypofibrinogenemia and hepatic inclusions due to impaired release of mutant fibrinogen which accumulates and aggregates in the hepatocellular endoplasmic reticulum. Liver disease is variable. AIM We studied a new Swiss family with fibrinogen Aguadilla. In order to understand the molecular peculiarity of FSD mutations, fibrinogen Aguadilla and the three other causative mutations, all located in the γD domain, were modelled. METHOD The proband is a Swiss girl aged 4 investigated because of fatigue and elevated liver enzymes. Protein structure models were prepared using the Swiss-PdbViewer and POV-Ray software. RESULTS The proband was found to be heterozygous for fibrinogen Aguadilla: FGG Arg375Trp. Familial screening revealed that her mother and maternal grandmother were also affected and, in addition, respectively heterozygous and homozygous for the hereditary haemochromatosis mutation HFE C282Y. Models of backbone and side-chain interactions for fibrinogen Aguadilla in a 10-angstrom region revealed the loss of five H-bonds and the gain of one H-bond between structurally important amino acids. The structure predicted for fibrinogen Angers showed a novel helical structure in place of hole 'a' on the outer edge of γD likely to have a negative impact on fibrinogen assembly and secretion. CONCLUSION The mechanism by which FSD mutations generate hepatic intracellular inclusions is still not clearly established although the promotion of aberrant intermolecular strand insertions is emerging as a likely cause. Reporting new cases is essential in the light of novel opportunities of treatment offered by increasing knowledge of the degradation pathway and autophagy.

Purification and partial characterisation of recombinant human hepcidin

Hepcidin is a liver-expressed antimicrobial and iron regulatory peptide. A number of studies have indicated that hepcidin is important for the correct regulation of body iron homeostasis. The aims of this study were to analyse the expression, trafficking and regulation of human hepcidin in an in vitro cell culture system. Human hepcidin was transfected into human embryonic kidney cells. Immunofluorescence and confocal microscopy analysis revealed that recombinant hepcidin localised to the Golgi complex. Recombinant hepcidin is secreted from the cell within 1 h of its synthesis. Recombinant hepcidin was purified from the cell culture medium using ion-exchange and metal-affinity chromatography and was active in antimicrobial assays. Amino-terminal sequence analysis of the secreted peptide revealed that it was the mature 25 amino acid form of hepcidin. Our results show that recombinant myc-His tagged human hepcidin was expressed, processed and secreted correctly and biologically active in antimicrobial assays. (C) 2005 Elsevier SAS. All rights reserved.