Hereditary hemochromatosis (HH) is the most common inherited genetic disorder in Whites, with a prevalence of 1 in 250 persons of northern European descent. Approximately 85% to 90% of patients with HH are homozygous for the C282Y mutation in the HFE gene; the remaining patients are typically compound heterozygotes for C282Y and the H63D or S65C mutations. Patients with isolated H63D or S65C mutations may not be at risk of iron overload injury. HFE mutations result in hepcidin deficiency and increased ferroportin expression on duodenal enterocytes, which results in increased iron absorption and eventual organ injury because no physiologic mechanism allows for excreting excess iron. Cirrhosis and cardiomyopathy are major causes of morbidity, small joint arthritis is common, and diabetes mellitus and other endocrinopathies may be seen.
Patients may be diagnosed late in the disease course through evaluation of decompensated liver disease or symptomatic cardiomyopathy, although liver and heart damage are largely irreversible at this late stage even if iron stores are actively reduced. The diagnosis may also be made earlier in the disease course through evaluation of abnormal aminotransferase levels that precede cirrhosis, characteristic arthropathy involving the second and third metacarpophalangeal joints (Figure 16), or endocrinopathy such as androgen insufficiency arising from pituitary or endocrine organ injury. Skin hyperpigmentation, accounting for the “bronze diabetes” terminology for HH, is likely caused by pituitary infiltration and excess melanin secretion. The diagnosis is also made through screening family members of patients with known hemochromatosis.
The diagnosis is suspected by finding an elevated transferrin saturation greater than 45% and an elevated serum ferritin level; diagnosis is confirmed through genetic testing. MRI with special software is used to noninvasively assess the extent of cardiac and liver iron overload and generally obviates the need to perform organ biopsy to quantitate iron deposits. Liver biopsy is used if it is also necessary to grade the degree of fibrosis or evaluate for other liver diseases.
First-degree relatives of patients with HH should be counseled about their risks and advised to undergo medical evaluation and screening. Asymptomatic family members of patients with hemochromatosis and a serum ferritin level less than 300 ng/mL (300 µg/L) (men) or 250 ng/mL (250 µg/L) (women) can be observed. Asymptomatic patients with genetic mutations whose initial ferritin levels are normal can be observed, with periodic assessment of aminotransferase and serum ferritin levels. Patients with HH confirmed by homozygous C282Y or compound C282Y/H63D mutations, ferritin above the target level, and iron saturation greater than 45% should be treated with phlebotomy. Symptomatic patients or those with signs of end-organ injury should also undergo therapeutic phlebotomy, the goal of which is to reduce total body iron stores; each unit (450-500 mL) of blood removed contains 200 to 250 mg iron, which unloads parenchymal deposition over time. Phlebotomy should be performed once or twice per week depending on the patient's hematocrit level. Iron stores in patients with HH may exceed 30 g, requiring phlebotomy over 2 to 3 years. The serum ferritin level should be evaluated every 3 months, with a target goal of 50 to 100 ng/mL (50-100 µg/L). When this goal is reached, maintenance phlebotomy should be instituted; schedules vary from 2 to 6 units of blood per year. Patients with HH without hepatic fibrosis or cardiomyopathy can expect a normal life expectancy with phlebotomy and judicious alcohol intake. Although advanced liver disease is not reversible with phlebotomy, patients benefit from screening for hepatocellular carcinoma and other secondary prevention as indicated for patients with cirrhosis. Similarly, phlebotomy is much less effective in patients who already manifest cardiac toxicity from iron overload.
Secondary iron overload occurs in patients who require chronic transfusion (most commonly in hereditary hemoglobinopathies such as thalassemia major); in subsets of patients with sickle cell anemia; or in acquired bone marrow failure conditions, such as myelodysplastic syndrome. End-organ involvement in secondary iron overload overlaps with that seen in HH, particularly regarding hepatic deposition, although endocrinopathy and cardiac effects are more common and arthropathy is less common. Therapeutic phlebotomy should not be performed, because these patients are anemic. The iron chelator deferoxamine has traditionally been the mainstay of therapy, but it requires continuous infusion, either intravenously or subcutaneously. Several oral iron chelators, including deferasirox and deferiprone, are available and may be more convenient. Monitoring is accomplished by serial serum ferritin measurements.
Porphyria cutanea tarda is a less common cause of secondary iron overload unrelated to chronic transfusion, but it is typically associated with acquired abnormalities in porphyrin metabolism and underlying liver disease, especially hepatitis C infection. Porphyria cutanea tarda is characterized by cutaneous blisters, often on the hands, and hypertrichosis; it responds well to phlebotomy.