Hemochromatosis

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

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

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

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

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