What are the implications of ordering genetic testing for hereditary hemochromatosis (HH) in the absence of iron overload evidence, with normal transferrin saturation and ferritin levels?

From the Guidelines

Genetic testing for hemochromatosis without evidence of iron overload (normal transferrin saturation and ferritin) is not recommended as a first-line approach. This is because the absence of biochemical iron overload, as indicated by normal transferrin saturation and ferritin levels, suggests that even if a genetic predisposition exists, it is not currently causing disease 1.

Key Considerations

• The American College of Physicians recommends that individuals should be made aware of the benefits and risks of genetic testing, including discussing available treatment and its efficacy, costs involved, and social issues such as impact of disease labeling, insurability, and psychological well-being 1.
• The lack of information on the natural history of the disease makes it difficult to manage patients with hereditary hemochromatosis, and there are no clearly defined criteria to risk-stratify patients into groups more or less likely to develop overt disease 1.
• Many people with hemochromatosis-associated genetic mutations, particularly heterozygotes or those with low-penetrance variants, never develop clinically significant iron overload.

Approach to Genetic Testing

• Iron studies should precede genetic testing in most cases, as they provide a more direct indication of iron overload and the potential for disease progression.
• If iron studies are normal, genetic testing has limited clinical utility, and the potential risks and costs of testing may outweigh the benefits.
• The exception to this approach would be in family screening scenarios, where testing first-degree relatives of individuals with confirmed hereditary hemochromatosis may be appropriate regardless of iron studies 1.

Counseling and Monitoring

• If genetic testing is pursued despite normal iron studies, patients should receive genetic counseling to understand that a positive result doesn't necessarily predict future disease development 1.
• Continued monitoring of iron levels would still be recommended for those with high-risk genotypes, as the absence of iron overload at the time of testing does not preclude the development of disease in the future.

From the Research

Implications of Ordering Genetic Testing in Hemochromatosis

• The decision to order genetic testing for hemochromatosis in individuals without evidence of iron overload (normal transferrin saturation and ferritin) is not straightforward, as expert societies recommend screening for asymptomatic and symptomatic individuals with hemochromatosis by obtaining transferrin saturation and further testing for the hemochromatosis gene if transferrin saturation is >45% with or without hyperferritinemia 2.
• In patients with features of iron overload and high serum ferritin levels, low or normal transferrin saturation should alert the physician to other primary and secondary causes of iron overload besides hemochromatosis 2, 3.
• Confirmatory homeostatic iron regulator (HFE) genetic testing for C282Y and H63D mutations should be pursued in the evaluation of hyperferritinemia, and a secondary cause for iron overload should be considered if HFE genetic testing is negative for the C282Y homozygous or C282Y/H63D compound heterozygous mutations 3.
• The deposition of excess iron into parenchymal cells can lead to cellular dysfunction and clinical manifestations of the disease, including liver, pancreas, joints, heart, skin, and pituitary gland involvement 4, 5.
• Genetic testing for the hereditary hemochromatosis genes should be offered after 18 years of age to first-degree relatives of patients with the condition, and individuals with hereditary hemochromatosis have an increased risk of hepatocellular carcinoma and colorectal and breast cancers 4, 5.

Diagnostic Approach

• Diagnosis of iron overload can be suspected on the basis of clinical data, high transferrin saturation and/or serum ferritin values, but several hyperferritinemic conditions are not related to iron overload 6.
• Liver biopsy is still very useful in the diagnostic approach to iron overload disorders, by defining the amount and the distribution of iron within the liver, and the analysis of HFE gene mutations (C282Y and H63D) is a simple and strong tool in the diagnostic work out of iron overload conditions 6.
• 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, and 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 4.