Hemochromatosis: An endocrine liver disease

Abstract

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

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

“…In general they are obese; have diabetes, with stigmata of the metabolic syndrome (MetS) and/or nonalcoholic fatty liver disease (NAFLD); and have no major genetic mutations among identifiable genetic hemochromatosis-related defects. HH genetic defects involve the hepcidin gene itself (HAMP) or the hepcidin regulators (such as HFE, TfR2, hemojuvelin, and ferroportin-1 [FPN1]) (8). The term for this disease was "insulin resistance-hepatic iron overload syndrome" (9).…”

RGMa and RGMb expression pattern during chicken development suggest unexpected roles for these repulsive guidance molecules in notochord formation, somitogenesis, and myogenesis

“…RGMc is expressed in skeletal muscle, heart, liver, bone, and cartilage (Samad et al, 2004;Niederkofler et al, 2004;Papanikolaou et al, 2004;Rodriguez et al, 2007;Kanomata et al, 2009), but its function in these tissues remains largely unknown. Nevertheless, mutations of RGMc have been linked with Hereditary Hemochromatosis, a heterogeneous group of autosomal recessive diseases that cause increased intestine absorption and deposition of iron in heart, liver, endocrine glands, joints, and skin (revised by Pietrangelo, 2007). For this reason, RGMc is also known as Hemojuvelin (HJV) or HFE2.…”

Iron chelation beyond transfusion iron overload

“…Iron accumulation essentially results from either increased cell iron influx or decreased efflux, or, as we are just now beginning to recognize, altered subcellular iron traffic ( Fig. 1) [1]. When considering iron distribution, specific pathologic states in humans result from systemic iron overload (e.g., hemochromatosis, posttransfusion siderosis, etc.).…”

“…When considering iron distribution, specific pathologic states in humans result from systemic iron overload (e.g., hemochromatosis, posttransfusion siderosis, etc.). Other disorders are associated instead with ''regional'' accumulation of iron in subcellular compartments (e.g., mitochondria in Friedreich's ataxia) or with certain cell types (e.g., macrophages in anemia of chronic disease and classic ferroportin disease) or organs (the liver in viral hepatitis or the brain in some neurodegenerative disorders) [1]. In strict terms, the latter disorders may not all qualify as true iron overload states, as total body iron content may not be increased.…”