Hemochromatosis: Pathophysiologic and Genetic Considerations

Abstract

The clinical, genetic, and pathologic findings, and the pertinent case histories in two families with idiopathic hemochromatosis are presented. These studies support the view that idiopathic hemochromatosis is a disease inherited in at least two ways. In one of these families, inheritance appeared to occur in an autosomal recessive manner, whereas in the other, autosomal dominant expression seemed evident. Evidence that an inability of the reticuloendothelial cells to handle iron may play a major role in the pathogenesis of hemochromatosis is presented. The early age of onset and poorer prognosis associated with the recessive inheritance suggest that the defect in reticuloendothelial cell function present in such cases is different from or more severe than those associated with dominant inheritance.

Adipocyte iron regulates leptin and food intake

“…Hfe -/-mice are a model of human hereditary hemochromatosis (HH), a disease of genetic iron overload wherein the gene most commonly mutated in HH has been deleted. HFE protein is required for normal regulation of a master iron regulatory hormone, hepcidin, which downregulates the iron export channel ferroportin (29,30 , herein referred to as aFpnKO) (25). Fpn mRNA was undetectable in adipocytes purified by collagenase digestion from aFpnKO mice.…”

Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man.

“…The parenchymal iron accumulation in the livers of[32m / mice resembles that of HH patients and contrasts with the histopathological findings in other iron storage disorders in man. The amount of demonstrable iron in macrophages in HH is minimal until the late stages of the disease (27,(39)(40)(41)(42). By contrast, iron accumulation in the overload diseases Bantu siderosis (in Africa) and Kaschin-Beck (in Asia) is prominent both in mononuclear phagocyte system cells and in hepatic parenchymal cells (43)(44)(45).…”

Organelle Pathology in Primary and Secondary Haemochromatosis with Special Reference to Lysosomal Changes

“…Inspection of the centrifugation data indicates a selective loss of the mitochondrial component which is reversed by iron depletion. Morphological studies both in human (Bessis & Caroli, 1959;Essner & Novikoff, 1960;Scheuer et a / , 1962;Ross et al, 1975) and expcrirnental (Bradford e t a / , 1969;Trump e t a / , 1973) hepatic iron overload have failed to demonstrate any accumulation of iron by mitochondria. The centrifugation studies indicate that the density distribution of the mitochondria is normal.…”