What is the diagnosis and treatment approach for hereditary hemochromatosis?

From the Guidelines

Hereditary hemochromatosis is diagnosed through a combination of blood tests showing elevated transferrin saturation (>45%) and serum ferritin levels, followed by genetic testing for HFE gene mutations (particularly C282Y homozygosity) 1. The primary treatment is therapeutic phlebotomy, which involves removing one unit (approximately 500 mL) of blood weekly until ferritin levels reach 50-100 ng/mL, followed by maintenance phlebotomies every 2-4 months to keep ferritin below 50-100 ng/mL. For patients who cannot tolerate phlebotomy, iron chelation therapy with medications like deferasirox (typical dose 20-30 mg/kg/day) or deferoxamine (20-40 mg/kg/day subcutaneously) may be used 1. Treatment should begin immediately upon diagnosis, even in asymptomatic patients, to prevent organ damage. Patients should also avoid iron supplements, vitamin C supplements with meals (which enhance iron absorption), and excessive alcohol consumption. Regular monitoring of ferritin levels, liver function, and cardiac function is essential. The treatment works by removing excess iron from the body, preventing the oxidative damage that occurs when iron accumulates in tissues, particularly the liver, heart, pancreas, and joints, which can lead to cirrhosis, heart failure, diabetes, and arthropathy if left untreated 1. Some key points to consider in the diagnosis and treatment of hereditary hemochromatosis include:

• The use of genetic testing to identify individuals at risk for hereditary hemochromatosis, particularly those with a family history of the disease 1
• The importance of early diagnosis and treatment to prevent organ damage and improve quality of life
• The need for regular monitoring of ferritin levels, liver function, and cardiac function to ensure effective treatment and prevent complications
• The potential benefits and risks of genetic testing, including the impact on disease labeling, insurability, and psychological well-being 1.

From the Research

Diagnosis of Hereditary Hemochromatosis

• Hereditary hemochromatosis is usually diagnosed in the 40s or 50s, with women often being diagnosed later than men due to menstrual blood loss 2
• There is no typical presentation or pathognomonic signs and symptoms of hereditary hemochromatosis, but a common initial presentation is an asymptomatic patient with mildly elevated liver enzymes who is subsequently found to have elevated serum ferritin and transferrin saturation 2
• Ferritin levels greater than 300 ng per mL for men and 200 ng per mL for women and transferrin saturations greater than 45% are highly suggestive of hereditary hemochromatosis 2
• Genetic testing for the hereditary hemochromatosis genes should be offered after 18 years of age to first-degree relatives of patients with the condition 2

Diagnostic Tests

• Serum ferritin measurement is the most useful prognostic indicator of disease severity 3
• Transferrin saturation is also an important diagnostic test, with levels greater than 45% being highly suggestive of hereditary hemochromatosis 2, 3
• Liver biopsy may be performed to stage the degree of fibrosis with severe ferritin elevation or transaminitis, or to diagnose nonclassical hereditary hemochromatosis in patients with other genetic defects 3
• Genetic testing for the HFE mutation can be performed in patients with elevated iron indices and a suspicion for hemochromatosis or liver disease 4

Treatment of Hereditary Hemochromatosis

• Phlebotomy is the mainstay of treatment and can help improve heart function, reduce abnormal skin pigmentation, and lessen the risk of liver complications 2, 4, 5
• The frequency of phlebotomy is guided by serial measurements of serum ferritin levels and transferrin saturation 3
• Iron depletion by phlebotomy is highly effective in preventing the complications of iron overload if instituted before the development of cirrhosis 5
• Dietary modification is generally unnecessary, but screening for hepatocellular carcinoma is reserved for those with hereditary hemochromatosis and cirrhosis 3

Screening and Prevention

• Universal screening for hereditary hemochromatosis is not recommended, but testing should be performed in first-degree relatives of patients with classical HFE-related hemochromatosis, those with evidence of active liver disease, and patients with abnormal iron study results 3, 5
• Genetic testing is currently not recommended for population screening because of low yield, as the majority of healthy, asymptomatic p.C282Y homozygotes do not develop clinically significant iron overload 5