Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 16-13: Hemochromatosis + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Usually suspected because of elevated iron saturation or serum ferritin or a family history Most patients are asymptomatic Hepatic abnormalities and cirrhosis, heart failure, hypogonadism, and arthritis The disease is rarely recognized clinically before the fifth decade HFE gene mutation (usually C282Y/C282Y) is found in most cases +++ General Considerations ++ Increased accumulation of iron as hemosiderin in the liver, pancreas, heart, adrenals, testes, pituitary, and kidneys Cirrhosis is more likely to develop in affected persons who drink alcohol excessively or have obesity-related hepatic steatosis Autosomal recessive disease About 85% of persons with well-established hemochromatosis are homozygous for the C282Y mutation Population studies have shown an increased prevalence of liver disease but not of diabetes, arthritis, or heart disease in C282Y homozygotes Hemochromatosis develops in 1–2% of C282Y/H63D compound heterozygotes Heterozygotes do not develop cirrhosis in the absence of associated disorders such as viral hepatitis or nonalcoholic fatty liver disease +++ Demographics ++ The frequency of the gene mutation Averages 7% in Northern European and North American white populations, resulting in a 0.5% frequency of homozygotes (iron overload will develop in 38–50% but clinical symptoms will develop in only 28% of men and 1% of women) Uncommon in blacks and Asian-American populations Risk factors for advanced fibrosis Male sex Excess alcohol consumption Diabetes mellitus + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ The onset is usually after age 50—earlier in men than in women Early symptoms are nonspecific (eg, fatigue, arthralgia) +++ Later clinical manifestations ++ Symmetrical arthropathy that is similar to osteoarthritis and calcium pyrophosphate deposition disease (and the need for joint replacement surgery), hepatomegaly, and evidence of hepatic dysfunction Skin pigmentation (combination of slate gray due to iron and brown due to melanin, sometimes resulting in a bronze color) Cardiac enlargement with or without heart failure or conduction defects, diabetes mellitus with its complications, and erectile dysfunction in men Bleeding from esophageal varices +++ Differential Diagnosis ++ Hepatomegaly due to other causes, eg, fatty liver Diabetes mellitus due to other causes, eg, Cushing syndrome Cardiac infiltrative disease due to other causes, eg, amyloidosis, sarcoidosis Arthritis due to other causes, eg, rheumatoid arthritis, pseudogout Hyperpigmentation due to other causes, eg, hyperbilirubinemia Cirrhosis due to other causes + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ Mildly abnormal liver chemistries (aspartate aminotransferase [AST], alkaline phosphatase) An elevated plasma iron with > 45% transferrin saturation A low unsaturated iron-binding capacity An elevated serum ferritin (although a normal iron saturation or a normal ferritin does not exclude the diagnosis) Affected men are more likely than affected women to have an elevated ferritin level Testing for HFE mutations is indicated in any patient with evidence of iron overload +++ Imaging Studies ++ CT and MRI may show changes consistent with iron overload of the liver MRI can quantitate hepatic iron stores and help assess the degree of hepatic fibrosis +++ Diagnostic Procedures ++ The liver biopsy characteristically shows Extensive iron deposition in hepatocytes and in bile ducts Hepatic iron index—hepatic iron content per gram of liver converted to micromoles and divided by the patient's age—generally > 1.9 In patients who are homozygous for C282Y, liver biopsy is often indicated to determine whether cirrhosis is present (found in 5% of patients with hemochromatosis identified by screening in a primary care setting) However, biopsy can be deferred when patients Are younger than 40 years Have serum ferritin level < 1000 mcg/L Have normal serum AST level Do not have hepatomegaly Likelihood of cirrhosis is low in these individuals Liver biopsy is also indicated when iron overload is suspected even though the patient is not homozygous for C282Y or a C282Y/H63D compound heterozygote + Treatment Download Section PDF Listen +++ +++ Medications ++ The chelating agent deferoxamine Indicated for patients with hemochromatosis and anemia or for those with secondary iron overload due to thalassemia who cannot tolerate phlebotomies Administer intravenously or subcutaneously in a dose of 20–40 mg/kg/day infused over 24 h Treatment is painful and time consuming Can mobilize 30 mg of iron per day Deferasirox, 20 mg/kg once daily orally, and deferiprone, 25 mg/kg three times daily orally Used to treat iron overload due to blood transfusions However, these agents have many side effects and drug-drug interactions +++ Surgery ++ Liver transplantation for advanced cirrhosis Associated with severe iron overload, including hemochromatosis Has been reported to lead to survival rates that are lower than those for other types of liver disease because of cardiac complications and an increased risk of infections Following liver transplantation, serum iron studies and hepcidin levels are normal, and phlebotomy is not required +++ Therapeutic Procedures ++ Early diagnosis and treatment in the precirrhotic phase are of great importance Avoid foods rich in iron (such as red meat), alcohol, vitamin C, raw shellfish, and supplemental iron, although dietary restrictions may not be necessary in those undergoing phlebotomy Phlebotomies Initially, weekly 1 or 2 units of blood (each containing about 250 mg of iron) Continue for up to 2–3 years to achieve depletion of iron stores Process is monitored by hematocrit and serum iron determinations When iron store depletion is achieved (iron saturation < 50% and serum ferritin level 50–100 mcg/L), phlebotomies (every 2–4 months) to maintain serum ferritin levels between 50 mcg/L and 100 mcg/L are continued Complications of hemochromatosis—arthropathy, diabetes, heart disease, portal hypertension, and hypopituitarism—also require treatment + Outcome Download Section PDF Listen +++ +++ Complications ++ Patients are at increased risk for infection with Vibrio vulnificus, Listeria monocytogenes, Yersinia enterocolitica, and other siderophilic organisms Arthropathy, diabetes, heart disease, portal hypertension, and hypopituitarism In patients in whom cirrhosis develops, there is a 15–20% incidence of hepatocellular carcinoma +++ Prognosis ++ The course of the disease is favorably altered by phlebotomy therapy In precirrhotic patients, cirrhosis may be prevented Cardiac conduction defects improve with treatment In patients with cirrhosis, varices may reverse, and the risk of variceal bleeding declines However, cirrhotic patients must be monitored for the development of hepatocellular carcinoma +++ Prevention ++ Genetic testing is recommended for all first-degree family members of the proband Children of an affected person (C282Y homozygote) need to be screened only if the patient's spouse carries the C282Y or H63D mutation General population screening is not recommended because the clinical penetrance of C282Y homozygosity and morbidity and mortality from hemochromatosis are low Screening is recommended for patients with chondrocalcinosis, erectile dysfunction, and type 1 diabetes mellitus (especially late-onset) +++ When to Refer ++ For liver biopsy For initiation of therapy + References Download Section PDF Listen +++ + +Barton JC et al. Cirrhosis in hemochromatosis: independent risk factors in 368 HFE p.C282Y homozygotes. Ann Hepatol. 2018 Aug 24;17(5):871–9. [PubMed: 30145563] + +Brissot P et al. Pathophysiology and classification of iron overload diseases; update 2018. Transfus Clin Biol. 2019 Feb;26(1):80–88. [PubMed: 30173950] + +Kowdley KV et al. ACG Clinical Guideline: hereditary hemochromatosis. Am J Gastroenterol. 2019 Aug;114(8):1202–18. [PubMed: 31335359] + +Radford-Smith DE et al. Haemochromatosis: a clinical update for the practising physician. Intern Med J. 2018 May;48(5):509–16. [PubMed: 29722188] + +Vanclooster A et al. Proton pump inhibitors decrease phlebotomy need in HFE hemochromatosis: double-blind randomized placebo-controlled trial. Gastroenterology. 2017 Sep;153(3):678–80. [PubMed: 28624580]