Clinical Pearls & Morning Reports
Published December 7, 2022
Hemochromatosis comprises a group of inherited disorders that can cause iron overload, which primarily affects the liver and joints and results from a failure in the regulation of the key liver-derived iron regulatory hormone hepcidin to respond to increasing iron stores. Read the NEJM Review Article here.
Q: What is the cause of most cases of hemochromatosis?
A: Hemochromatosis is caused by several genetic disorders, the majority of which result in loss-of-function mutations in regulatory components of hepcidin synthesis. The cause of 95% of cases of hemochromatosis is a homozygous mutation in HFE (hemostatic iron regulator; chromosome 6p22.2, exon 4, c.845G→A, rs1800562), which results in a p.C282Y substitution and is termed HFE hemochromatosis.
Q: Do the complications of hemochromatosis affect men and women equally?
A: Homozygosity for p.C282Y is associated with complications in up to 40% of men and 13% of women. The variable biochemical and clinical penetrance is most likely due to multiple genetic and environmental modifiers of iron bioavailability, transport, and loading. Men are likely to be at higher risk than women because of the absence of the protective effects of menstruation and pregnancy or hormone-related differences in iron absorption.
A: The most frequent clinical manifestations of hemochromatosis are liver disease (advanced liver fibrosis or cirrhosis and primary liver cancer) and arthritis. Oxidative stress–related tissue injury is responsible for the pathogenesis of the disease. Among men but not women, the risk of liver disease is significantly increased, by a factor of 4.3, for p.C282Y homozygotes as compared with men who do not have HFE variants; the risks of arthritis and colorectal cancer are doubled, and the risks of pneumonia and diabetes mellitus are increased by a factor of 1.5. Among women who are homozygous for p.C282Y, the risks of colorectal cancer and breast cancer are doubled and the risk of arthritis is increased by a factor of 1.3, as compared with women who do not have HFE variants. Although it is not clear whether the predispositions to colorectal and breast cancer are HFE- or iron-related, epidemiologic observations indicate that iron elevation is a risk factor for breast cancer.
A: Treatment has been shown to result in clinical improvement in persons with hemochromatosis who have elevated serum ferritin levels. The mainstay of treatment is phlebotomy; dietary restriction of iron intake offers little or no proven benefit in routine management. Treatment consists of weekly phlebotomy until a target serum ferritin level of 50 to 100 μg per liter is reached. Thereafter, maintenance therapy is undertaken to stabilize the target serum ferritin level. Most often, this requires phlebotomy three times a month, but the required frequency is highly variable and needs to be individualized. Treatment reduces fatigue, improves cognition, and reduces liver fibrosis. There is no clear evidence that phlebotomy therapy reduces the risk of primary liver cancer, alleviates established arthritis, or is effective in treating diabetes mellitus secondary to hemochromatosis, if cirrhosis persists. For persons for whom routine phlebotomy therapy is associated with unacceptable adverse events, several alternatives exist. Erythrocytapheresis selectively depletes the red-cell mass, and fewer episodes of treatment are required than with routine phlebotomy. Alternatively, chelation therapy may be considered.