Introduction

Hemochromatosis is one of the most common genetic diseases and may lead to iron accumulation in the liver (Figures 54.1 and 54.2), heart, pancreas, and endocrine organs. Early diagnosis and treatment are essential to prevent organ damage. Arthopathy (Figure 54.3) and pigmentation (Figure 54.4) are also clinical features of hemochromatosis.

Genetics

Since the discovery of the gene for hemochromatosis (HFE) in 1996, a simple genetic blood test has been developed, which can be done on a blood sample or stored tissue. The C282Y mutation on chromosome 6 of the HFE gene is present in 93–100% of homozygotes in pedigree studies. In less well‐defined patients with iron overload, the prevalence ranges from 60% to 80%. A second mutation, H63D, is less common and its relationship to hemochromatosis is less well defined. Other iron overload diseases have been associated with mutations in other iron‐related genes (transferrin receptor 2, hemojuvelin, hepcidin, ferroportin) (Box 54.1).

Use of the C282Y genetic test for hemochromatosis

The genetic test is most useful in a patient who is suspected clinically of having hemochromatosis (Box 54.2) or with an elevated transferrin saturation and/or serum ferritin (Figure 54.5, Box 54.3). It is also useful when investigating siblings and other family members of a C282Y homozygote. It has replaced HLA typing in pedigree studies.

There have been reports of a number of cases within hemochromatosis families that are homozygous for the C282Y mutation without iron overload. This may represent incomplete penetrance. The frequency of this phenomenon in the general population has been estimated to be 50% of women and 20% of men. Population studies in North America, Europe, and Australia suggest that, overall, the C282Y mutation is more common than the clinical disease. This may reflect a high degree of incomplete penetrance or underdiagnosis of the disease.

Treatment of hemochromatosis

Patients are initially treated by the weekly removal of 500 mL of blood. Patients attend an ambulatory care facility and the venesection is performed by a nurse using a kit containing a 16 gauge straight needle and collection bag. Blood is removed with the patient in the reclining position over 15–30 min. A hemoglobin test is done at the time of each venesection. If the hemoglobin decreases to less than 100 g/L, the venesection schedule is modified to 500 mL every other week. Serum ferritin is measured periodically (every 3 months in severe iron overload, monthly in mild iron overload) and weekly venesections are continued until the serum ferritin is approximately 50 μg/L. Transferrin saturation often remains elevated despite therapy.

After the initial iron depletion therapy, a serum ferritin is repeated 6 months later. If the ferritin is rising, patients may then begin maintenance venesections 3–4 times per year. Many patients will not need maintenance and the need for maintenance can be predicted based on the initial ferritin and the age at presentation. Iron reaccumulation is inconsistent and many patients will go for years without a rise in serum ferritin with no treatment. Chelation therapy is not used for the treatment of hemochromatosis.