Introduction
This topic covers two inherited disorders of metal metabolism: hereditary hemochromatosis, in which the body absorbs and stores too much iron, and Wilson-Konovalov disease (Wilson disease), in which copper accumulates in the liver, brain and other tissues. Both are autosomal recessive in their classic forms, both cause organ damage if untreated, and both are treatable when recognised early. For the exam, you should be able to explain the gene defect and the metabolic mechanism, describe the clinical picture, name the key laboratory and genetic tests, outline treatment, and describe genetic counselling for the family.
Hereditary hemochromatosis: genetics and mechanism
The classic form is caused mainly by mutations in the HFE gene on chromosome 6p. The most common variant is C282Y; homozygosity for it accounts for most cases in people of Northern European descent. The inheritance is autosomal recessive, but penetrance is incomplete, so many homozygotes never develop clinical disease, and iron overload is more common and severe in men than in women, who lose iron through menstruation and pregnancy.
The key pathogenic step is a relative deficiency of hepcidin, the liver hormone that normally blocks the iron exporter ferroportin. Without this control, the duodenum absorbs excess dietary iron and the iron is released into the blood without restraint. Iron is then deposited in parenchymal cells of the liver, pancreas, heart, pituitary, joints and skin, where it causes oxidative damage and fibrosis.
- Other genes that cause hemochromatosis are rarer: HJV (hemojuvelin, juvenile form with early and severe disease), HAMP (hepcidin), and TFR2.
- Ferroportin disease (SLC40A1) is autosomal dominant and differs: iron is trapped in macrophages, so transferrin saturation is low or normal while ferritin is high.