Hemochromatosis: More Common Than You Think?

Rowen K. Zetterman, MD


October 22, 2012

In This Article

Hemochromatosis, Type 1

Type 1 HFE hemochromatosis, an autosomal recessive disorder, is the most common genetic disorder of white populations and has a worldwide distribution. The genetic predisposition for type 1 HFE hemochromatosis is lower in black and Hispanic populations, and lowest in Asian populations.[11]

Approximately 10% of white individuals are heterozygous for C282Y. Homozygous C282Y disease, which affects 1 in 250 persons of northern European ancestry, accounts for 85%-90% of cases of systemic iron overload.[11] Compound heterozygotes (C282Y/H63D) can also develop iron overload syndromes.[12] Alcohol consumption increases the risk for clinical disease.[13]

Hemochromatosis, a systemic disorder and phenotypic expression of iron accumulation, can result in injury to the liver, heart, endocrine system, joints, and bones. When clinical disease is present, total body iron often exceeds 20 g. Prevention of end-organ disease depends on early diagnosis and treatment to limit iron accumulation. The American Association for the Study of Liver Disease (AASLD) recently published a practice guideline for the diagnosis and management of hemochromatosis.[14]

Why don't I see more patients with the disease? The clinical status of patients with homozygous C282Y hemochromatosis ranges from genetic predisposition with no increase in body iron stores to excessive iron stores with end-stage organ disease. Approximately 10% of homozygous C282Y patients will develop end-organ injury from excessive iron overload.[15] However, women are much less likely than men to develop clinical manifestations of disease, with roughly 1% of women vs 28% of men developing end-stage disease.[1]

Signs and symptoms of end-organ disease usually begin after 40 years of age. We recently saw a veteran in his 20s who was initially diagnosed with homozygous C282Y hemochromatosis to account for his advanced liver disease.[16] Because of his young age, additional investigation was performed, which uncovered coexisting Wilson disease that responded clinically to reduction of total body copper.

Clinical Manifestations of Hemochromatosis

Common symptoms of hemochromatosis include fatigue, arthralgias, right upper quadrant abdominal pain, and hair loss.[5] Fatigue and lethargy occur in more than 60% of patients and are more common in women, younger patients,[17] and those with serum ferritin levels > 1000 µg/L.[1] Hyperpigmentation is an early sign that develops in both sun-exposed and non-sun-exposed areas of the skin. Porphyria cutanea tarda can also occur.

Arthritis of the hands and large joints from hemochromatosis is often symmetrical.[18] Arthralgias of the metacarpophalangeal joints, especially the second or third joints, are frequent.[1] Arthropathy may not be improved by iron depletion.[19] Endocrine manifestations include hypogonadism, testicular atrophy, and impotence. Moreover, up to 60% of symptomatic patients may have type 2 diabetes. Cardiac disease is an infrequent end-organ manifestation developing in 3%-10% of patients.[20] Cardiac manifestations include restrictive cardiomyopathy with arrhythmias and heart failure. Although heart failure, diabetes, and arrhythmias are less common in patients with HFE hemochromatosis, when present, they signify a poorer prognosis.[21]

Hepatomegaly, cirrhosis, and hepatocellular carcinoma develop as end-organ manifestations of hemochromatosis. Patients with suspected cirrhosis should be screened for esophageal varices and repetitively screened for hepatocellular carcinoma. The risk for hepatocellular carcinoma in untreated cirrhosis is 30%-50% and accounts for approximately one third of all deaths from hemochromatosis.[22]

Phlebotomy may improve some symptoms and signs of iron overload such as fatigue and malaise, abdominal pain, cardiac function, and insulin requirements.[14] Patients with advanced hepatic fibrosis may have some reduction in scarring with adequate treatment. Testicular atrophy and arthropathy, however, typically do not improve.