Clinical Information

Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism with a carrier frequency of   approximately 1 in 10 individuals of Northern European ancestry.(1) The disease is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues (eg, liver, skin, heart, joints). Clinical symptoms of HFE hemochromatosis usually appear in men between age 40 and 60 years and after menopause in women, and they might be affected by other factors such as intake of iron and other mineral supplements, vitamin C, and alcohol consumption. Iron overload can     lead to hepatic cirrhosis, hepatocellular carcinoma, diabetes mellitus, arthropathy, and cardiomyopathy. Such complications may be prevented by phlebotomy, and patients may have a normal life expectancy when treated before organ damage occurs.(2) For individuals with clinical symptoms consistent with HH or biochemical evidence of iron overload, an HH diagnosis is typically based on the results of transferrin-iron saturation and serum ferritin concentration. Molecular testing can also be performed to confirm/establish the diagnosis.

The two most common variants in the HFE gene are C282Y and H63D. The majority of HH patients (approximately 85-90%) show homozygosity for the C282Y variant or compound heterozygosity for the C282Y and H63D variants.(1) Individuals with carrier status (heterozygotes) generally do not develop complications of iron overload but may have abnormal serum iron results.(1) Furthermore, clinically significant iron overload can also occur in the absence of known HFE variants. Therefore, a negative HFE test does not exclude other rare variants in the HFE gene or in other genes and, thus, does not exclude a diagnosis of iron overload or hemochromatosis.

The most common disease-causing variant identified in the HFE gene is C282Y (c.845G>A in exon 4). Individuals who are homozygous for the C282Y variant account for 60% to 90% of all HH cases, however clinical penetrance is incomplete.(3) Up to 50% of individuals homozygous for C282Y develop iron overload (elevated serum iron indices) and 10% to 33% (mainly men) develop hemochromatosis-related syndromes or end-organ damage symptoms.(2) Currently no test can predict whether an individual who is homozygous for C282Y will develop clinical symptoms. Additionally, 3% to 8% of individuals affected with HH are heterozygous for this variant. These frequencies show variability among different populations, with the highest frequency observed in individuals of Northern European ancestry.

The H63D (c.187C>G in exon 2) variant is also associated with HH; however, the presence of a single H63D variant is unlikely to be of clinical significance in the absence of other disease-causing variants. Additionally, homozygosity for H63D is insufficient to cause clinically significant iron overload in the absence of other modifying risk factors. Individuals who are compound heterozygous for C282Y/H63D have higher penetrance compared to those who are H63D homozygous and have been associated with increased hepatic iron concentrations. Approximately 0.5% to 2% of individuals with this genotype will develop clinical evidence of iron overload.(2) While individuals with this genotype may have increased iron indices, most will not develop clinical disease without comorbid factors (steatosis, diabetes, or excess alcohol consumption).(4)

The clinical significance of a third HFE variant, S65C (c.193A>T in exon 2), appears to be minimal. This rare variant displays a very low penetrance and is generally not associated with iron overload. Individuals who are heterozygous for S65C with either the wildtype or H63D allele do not seem to be at an increased risk for HH. Compound heterozygosity for C282Y and S65C may confer a low risk for mild HH.(1) Therefore, the C282Y/S65C genotype is reported when observed.

For more information see Hereditary Hemochromatosis Algorithm