What is the role of HFE (Human Ferritin) testing in diagnosing Hereditary Hemochromatosis?

From the Guidelines

HFE gene testing is recommended for diagnosing hereditary hemochromatosis, particularly in individuals with elevated iron levels, family history of the condition, or symptoms suggesting iron overload. The most common test looks for C282Y and H63D mutations in the HFE gene, with C282Y homozygosity (having two copies) being responsible for most cases of hereditary hemochromatosis 1. Testing should begin with serum iron studies including transferrin saturation and ferritin levels; if these are elevated (typically transferrin saturation >45% and elevated ferritin), genetic testing is warranted.

Key Points to Consider

• The mutation of C282Y in the HFE gene on chromosome 6 is present in almost 90% of those affected 1.
• Most patients are homozygous, and mutation transmission is autosomal recessive 1.
• The H63D mutation may be associated with hereditary hemochromatosis, but the actual clinical effects of this mutation are uncertain 1.
• Although in a small proportion, compound heterozygotes (C282Y/H63D) can develop iron overload 1.
• Phenotypic markers of hereditary hemochromatosis may be used to identify the disease, including percentage of transferrin saturation and serum ferritin level 1.
• Liver biopsy to measure hepatic iron concentration by staining is considered the gold standard to test for hereditary hemochromatosis, but with the advent of genetic testing, liver biopsy is not widely used to confirm the diagnosis 1.

Treatment and Prevention

For diagnosed patients, treatment consists primarily of phlebotomy (blood removal) - initially weekly removal of 500ml of blood until ferritin levels normalize (usually <50-100 μg/L), followed by maintenance phlebotomies every 2-4 months as needed 1. Early diagnosis and treatment are crucial as they can prevent complications like liver cirrhosis, diabetes, heart problems, and joint damage. First-degree relatives of affected individuals should also be screened, as the condition has an autosomal recessive inheritance pattern. The HFE gene normally regulates iron absorption in the intestines, and mutations disrupt this control, leading to excessive iron absorption and subsequent deposition in organs, which causes the clinical manifestations of the disease 1.

From the Research

HFE Testing and Hereditary Haemochromatosis

• Hereditary haemochromatosis is a common inherited disorder of iron metabolism, characterized by the presence of two missense mutations (C282Y and H63D) in the HFE gene 2, 3.
• The C282Y mutation is found homozygous in 90-95% of subjects with typical hereditary haemochromatosis, while the H63D mutation is not associated with the same degree of iron overload 3.
• HFE genotyping for the C282Y and H63D mutations can contribute to the diagnosis of hemochromatosis and determine the prevalence of HFE mutations in patients with liver disease 2.
• The diagnosis of hereditary haemochromatosis can be confirmed by serum iron studies and genetic testing, and treatment typically involves phlebotomy to remove excess iron stores 3, 4.

Diagnosis and Management

• Early diagnosis is essential for patients with hereditary haemochromatosis to obtain good outcomes, and regular phlebotomy after diagnosis can improve symptoms and delay disease progression 5.
• Liver biopsy should still be considered in all patients with iron overload, except for C282Y homozygotes or compound heterozygotes diagnosed under the age of 40 years and with no biochemical or clinical evidence of liver disease 3.
• Screening of first-degree relatives should be based on genotype assessment and measurement of serum iron parameters to determine phenotypic expression of the disease 3.
• New treatments being studied include erythrocytapheresis and 'mini-hepcidins', and iron overload is being recognized to play a carcinogenic role in hepatocellular carcinoma and other cancers 6.

Genetic Testing

• Genetic testing for the HFE mutation can be performed in patients with elevated iron indices and a suspicion for hemochromatosis or liver disease 4.
• The HFE genotype can be used to identify patients with hereditary haemochromatosis, and to determine the risk of developing iron overload and related complications 2, 3.
• The presence of the C282Y or H63D mutation can be used to guide treatment and management of patients with hereditary haemochromatosis 3, 4.