Hemochromatosis is a disorder of iron storage that results in increased intestinal iron absorption with Fe deposition and damage to many tissues. The classic clinical constellation of hemochromatosis is a pt presenting with bronze skin, liver disease, diabetes, arthropathy, cardiac conduction abnormalities, and hypogonadism. Two major causes of hemochromatosis exist: hereditary (due to inheritance of mutant HFE genes) and secondary iron overload (usually the result of ineffective erythropoiesis, such as thalassemia or sideroblastic anemia). HFE encodes a protein that is involved in cellular iron sensing and in regulating intestinal iron absorption. HFE mutations are very common in populations of Northern European origin (1 in 10 is a carrier). Heterozygotes are asymptomatic; homozygotes show a disease penetrance of ∼30%. There is progressive iron overload, with clinical manifestations appearing after age 30–40, typically earlier in men than in women. Alcoholic liver disease and chronic excessive Fe ingestion may also be associated with a moderate increase in hepatic Fe and elevated body Fe stores.
Early symptoms include weakness, lassitude, weight loss, a bronze pigmentation or darkening of skin, abdominal pain, and loss of libido. Hepatomegaly occurs in 95% of pts, sometimes in the presence of normal LFTs. If untreated, liver disease progresses to cirrhosis, and further to hepatocellular carcinoma in ∼30% of pts with cirrhosis. Other manifestations include skin pigmentation (bronzing), diabetes mellitus (65% of pts), arthropathy (25–59%), cardiac arrhythmias and CHF (15%), and hypogonadotropic hypogonadism. Diabetes mellitus is more common in pts with a family history of diabetes, and hypogonadism may be an isolated early manifestation. Typical signs of portal hypertension and decompensated hepatic cirrhosis may appear late in the clinical course. Adrenal insufficiency, hypothyroidism, and hypoparathyroidism rarely occur.
Serum Fe, percent transferrin saturation, and serum ferritin levels are increased. In an otherwise-healthy person, a fasting serum transferrin saturation >50% is abnormal and suggests homozygosity for hemochromatosis. In most untreated pts with hemochromatosis, the serum ferritin level is also greatly increased. If either the percent transferrin saturation or the serum ferritin level is abnormal, genetic testing for hemochromatosis should be performed. All first-degree relatives of pts with hemochromatosis should be tested for the C282Y and H63D mutations in HFE. Liver biopsy may be required in affected individuals to evaluate possible cirrhosis and to quantify tissue iron. An algorithm for evaluating pts with possible hemochromatosis is shown in Fig. 182-1. Death in untreated pts results from cardiac failure (30%), cirrhosis (25%), and hepatocellular carcinoma (30%); the latter may develop despite adequate Fe removal.
Algorithm for screening for HFE-associated hemochromatosis. HH, hereditary hemochromatosis, homozygous subject (C282Y +/+); LFT, liver function tests; SF, serum ferritin concentration; TS, transferrin saturation. (From EJ Eijkelkamp et al: Can J Gastroenterol 14:2, 2000; with permission.)