Primary hemochromatosis: causes, symptoms, diagnosis, treatment

Primary hemochromatosis is a congenital disorder characterized by severe iron accumulation, causing tissue damage. The disease does not manifest clinically until organ damage has developed, often irreversibly. Symptoms include weakness, hepatomegaly, bronze skin pigmentation, loss of libido, arthralgia, manifestations of cirrhosis, diabetes, cardiomyopathy. Diagnosis is based on serum iron measurements and genetic testing. Treatment is a series of phlebotomies.

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Epidemiology

The disease is autosomal recessive, the frequency in Northern Europe of the homozygous form is 1:200, and the heterozygous form is 1:8. The disease is rare in Asia and Africa. Patients with clinical hemochromatosis are homozygotes in 83% of cases.

The disease usually does not manifest itself until middle age. In 80-90% of people, by the time symptoms develop, total iron stores are greater than 10%.

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Causes of primary hemochromatosis

Almost all primary hemochromatoses are caused by a mutation in the HFE gene. Primary hemochromatoses not associated with HFE are rare and include ferroportin disease, juvenile hemochromatosis, and the very rare neonatal hemochromatosis, hypotransferrinemia, and aceruloplasminemia. The clinical consequences of iron overload are similar in all types of disease.

More than 80% of HFE-related hemochromatosis are caused by the homozygous C282Y mutation or the combined heterozygous C282Y/H63D mutation. The mechanism of iron overload is increased iron absorption from the gastrointestinal tract. Hepcidin, a recently identified peptide synthesized by the liver, controls the iron absorption mechanism. Hepcidin with a normal HFE gene prevents excess absorption and accumulation of iron in healthy individuals.

The total iron content in the body in this pathology can reach 50 g compared to the normal level of about 2.5 g in women and 3.5 g in men. Iron deposition in organs catalyzes the generation of free reactive hydroxyl radicals.

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Symptoms of primary hemochromatosis

Since iron accumulates in many organs and tissues, symptoms may be multiorgan or systemic. In women, weakness and systemic symptoms develop early; in men, cirrhosis or diabetes are common initial manifestations of hemochromatosis. Hypogonadism is typical in both sexes and may cause various manifestations. Liver disease is the most common complication and usually progresses to cirrhosis, and in 20-30% of cases it transforms into hepatocellular carcinoma. Heart failure develops in 10-15% of untreated patients, severe skin pigmentation in 90%, diabetes and its potential complications (nephropathy, retinopathy, neuropathy) in 65%, and arthropathy in 25-50%.

Juvenile hemochromatosis

A rare autosomal recessive disorder caused by a mutation in the HJV gene that disrupts the transcription of the hemojuvelin protein. It occurs primarily in adolescents. Ferritin levels are greater than 1000, and transferrin saturation is greater than 90%. Symptoms and signs include progressive hepatomegaly and hypogonadotropic hypogonadism.

Diagnostics of primary hemochromatosis

Hemochromatosis is suspected in the presence of typical symptoms, especially in the presence of unexplained liver dysfunction, and in patients with a family history. Since symptoms develop only after tissue damage, diagnosis is desirable before symptoms develop (which is often difficult). If hemochromatosis is suspected, serum iron, serum transferrin saturation, serum ferritin are determined, and gene studies are performed.

Serum iron is elevated (>300 mg/dL). Serum transferrin saturation is usually >50% and often >90%. Serum ferritin is elevated. Genetic testing is the definitive diagnostic test. Other mechanisms of iron overload, such as congenital hemolysis (eg, sickle cell disease, thalassemia), must be excluded. Liver iron status can be measured by high-intensity MRI. Because the development of cirrhosis worsens the prognosis, liver biopsy is recommended in patients with unexplainedly high serum ferritin (eg, >1000), taking into account the age at which ferritin may increase and elevated liver enzymes that may lower ferritin. Liver iron status may confirm tissue iron deposition. First-degree relatives of patients with primary hemochromatosis should be examined. In more than 95% of cases, C282Y and H63D are determined.

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Treatment of primary hemochromatosis

Phlebotomy is a simple method of removing excess iron in most cases, prolonging survival but not preventing the development of hepatocellular carcinoma. Once the diagnosis is made, about 500 mL of blood (about 250 mg of iron) is exfused weekly until serum iron levels are normalized and transferrin saturation is less than 50%. Weekly phlebotomy may be necessary for several years. Once iron levels are normalized, further phlebotomies are performed to maintain transferrin saturation less than 30%. Treatment of diabetes, cardiac dysfunction, erectile dysfunction, and other secondary manifestations is indicated.