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.
Clinical Features
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.
Diagnosis
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. Algorithm for Screening for HFE-Associated Hemochromatosis. Death in untreated pts results from cardiac failure (30%), cirrhosis (25%), and hepatocellular carcinoma (30%); the latter may develop despite adequate Fe removal.
| TREATMENT | ||
HemochromatosisTherapy involves removal of excess body Fe, usually by intermittent phlebotomy, and supportive treatment of damaged organs. Since 1 unit of blood contains ∼250 mg Fe, and since up to 25 g of Fe must be removed, phlebotomy is performed weekly for 1-2 years. Less frequent phlebotomy is then used to maintain serum Fe at 9-18 µmol/L (50-100 µg/dL). Chelating agents such as deferoxamine (infused subcutaneously using a portable pump) remove 10-20 mg iron per day, a fraction of that mobilized by weekly phlebotomy. An effective oral iron chelating agent, deferasirox (Exjade), is effective in thalassemia and secondary iron overload, but it is expensive and carries the risk of significant side effects. Chelation therapy is indicated, however, when phlebotomy is inappropriate, such as with anemia or hypoproteinemia. Alcohol consumption should be eliminated. End-stage liver disease may require liver transplantation. |
Section 13. Endocrinology and Metabolism