Treatment Recommendation for Heterozygous Hemochromatosis
Management of heterozygous hemochromatosis should be guided entirely by phenotypic presentation (iron overload status) rather than genotype alone, with phlebotomy reserved only for those with confirmed iron overload by MRI or liver biopsy after excluding other causes. 1
Key Principle: Genotype Does Not Drive Treatment
The most critical concept is that heterozygous genotypes (including C282Y/H63D compound heterozygotes and H63D homozygotes) are insufficient to cause hemochromatosis by themselves. 1 A meta-analysis confirms this genotype is inadequate to cause true hemochromatosis, though it represents a risk factor for mildly increased iron parameters. 1
Clinical Approach Based on Iron Overload Status
For Heterozygotes WITHOUT Iron Overload:
- No treatment is indicated—phlebotomy should not be performed based on genotype alone. 1
- Instruct patients to maintain a healthy lifestyle, as they may develop mild iron overload only in association with additional environmental risk factors (diabetes, fatty liver, obesity, alcohol consumption). 1
- Monitor serum iron parameters at intervals determined by age and risk profile, though specific intervals require clinical judgment. 1
- The risk of developing significant iron overload in asymptomatic compound heterozygotes is low. 1
For Heterozygotes WITH Confirmed Iron Overload:
- First, investigate for other causes of iron overload before attributing it to the heterozygous genotype. 1 This is a strong recommendation with consensus. 1
- Look specifically for disease-modifying factors: diabetes, fatty liver disease, obesity, alcohol consumption, chronic liver diseases, or hematologic disorders. 1
- Confirm true iron overload using MRI quantification of hepatic iron concentration or liver biopsy—do not rely solely on elevated ferritin. 1, 2
Phlebotomy Decision-Making
Phlebotomy may be considered for heterozygotes with confirmed iron overload, but this requires individualized clinical assessment weighing the unclear benefits. 1 This is a weak recommendation, reflecting that:
- Between 14-30% of patients referred for phlebotomy are compound heterozygotes, but the benefits are largely unclear. 1
- Management of additional environmental risk factors or associated liver diseases is crucial and may be more important than phlebotomy itself. 1
If Phlebotomy Is Pursued:
- Remove 500 mL of blood weekly or biweekly until serum ferritin falls below 50 ng/mL. 1
- Check hematocrit prior to each phlebotomy; allow hematocrit to fall by no more than 20% of prior level. 1
- Check serum ferritin every 10-12 phlebotomies. 1, 3
- Continue maintenance phlebotomy to keep ferritin between 25-50 ng/mL (or 50-100 μg/L per some protocols). 1, 3
- Avoid vitamin C supplements, as they accelerate iron mobilization. 1, 3
Common Pitfalls to Avoid
- Do not treat based on genotype alone—the 2022 EASL guidelines explicitly state management should be guided by phenotypic presentation and additional risk factors, not genotype. 1
- Do not assume elevated ferritin equals iron overload—dysmetabolic and inflammatory hyperferritinemia do not require phlebotomy. 2
- Do not overlook secondary causes—in heterozygotes with iron overload, coincidence of disease-modifying factors is higher than in C282Y homozygotes. 1
- Iron overload-related disease is rare in heterozygotes, particularly in females despite increasing ferritin with age. 1
Prognosis and Surveillance
- Large population studies show that while incident hemochromatosis diagnoses are more common in C282Y/H63D heterozygotes, excess morbidity becomes non-significant after correction for multiple testing. 1
- Serum iron indices in compound heterozygotes do not change during middle life in males. 1
- Weight loss through dietary modification and increased physical activity should be recommended for those with fatty liver disease. 1
- In patients with excessive alcohol consumption and elevated iron parameters, the risk of fibrosis and hepatocellular malignancy is increased. 1