Clinical Pearls & Morning Reports
Published August 18, 2021
Classic hereditary hemochromatosis is an iron-loading disorder caused by partial loss-of-function mutations (most often homozygous C282Y mutations) in the HFE gene, an upstream regulator of the master regulator of systemic iron homeostasis, hepcidin. Read the NEJM Case Records of the Massachusetts General Hospital here.
Q: Describe the basic pathophysiology of hereditary hemochromatosis.
A: Patients with hereditary hemochromatosis have low circulating levels of hepcidin and thus have unregulated expression and activity of ferroportin, which results in increased absorption of dietary iron. Binding sites of transferrin in plasma become saturated, and this leads to the appearance of redox-active non–transferrin-bound iron, which is rapidly cleared by the liver and other organs (e.g., pancreas, heart, and pituitary), where it can cause oxidant-mediated tissue damage.
Q: Is hereditary hemochromatosis prevalent?
A: Hereditary hemochromatosis is prevalent; more than 6% of the White population have one variant allele. However, it also has low penetrance; only 28% of homozygous men and 1.4% of homozygous women have clinical symptoms.
A: Hereditary hemochromatosis results in total body iron overload and iron deposition in the heart, liver, joints, and pancreas. Manifestations typically occur in the fourth or fifth decade of life in men. In part because of blood loss from menstruation, women with the C282Y–C282Y genotype often present with symptoms later in life than men with the same mutation. The liver is the organ most commonly affected, and excessive alcohol use is a risk factor for the development of liver disease in patients with hereditary hemochromatosis. Iron deposition in the pancreas can result in new-onset diabetes. Iron deposition in the pituitary can cause hypopituitarism and decreased libido. Small studies have shown an increased prevalence of the factor V Leiden mutation (associated with deep-vein thrombosis) among patients with a specific mutation of the HFE gene, but this correlation is not well established. An elevated ferritin level and an elevated transferrin saturation (serum iron level divided by total iron-binding capacity) would help to establish the diagnosis of hereditary hemochromatosis; however, the definitive test result would be detection of an HFE mutation.
A: Standard treatment for hereditary hemochromatosis is therapeutic phlebotomy, which normalizes total body iron stores, promotes iron use through hematopoiesis, and decreases iron-mediated free-radical damage. Guidelines for the initiation of treatment vary, although most experts recommend therapeutic phlebotomy in C282Y homozygotes when the ferritin level is elevated. Initial treatment involves removal of 500 ml of blood every 1 to 2 weeks. Once the ferritin level decreases to 50 to 100 μg per deciliter, maintenance phlebotomy is performed 4 to 6 times per year. Both hepatic fibrosis and cardiac dysfunction can abate with therapeutic phlebotomy in patients with hereditary hemochromatosis.