Testing and Management of Hemochromatosis
The diagnosis of hemochromatosis requires a combination of transferrin saturation and serum ferritin tests, followed by genetic testing for HFE mutations in patients with elevated iron parameters, with liver biopsy reserved for specific clinical scenarios. 1
Diagnostic Algorithm
Initial Testing
- First-line tests: Transferrin saturation (TS) and serum ferritin should be measured simultaneously 1, 2
- TS ≥45% has high sensitivity for detecting C282Y homozygotes
- Confirm elevated TS with a second determination (preferably fasting)
- Normal values: TS 20-50%, ferritin 20-200 μg/L (men) and 15-150 μg/L (women)
Genetic Testing
- When to perform: If TS ≥45% or ferritin is above upper limit of normal 1
- What to test: HFE gene mutations (C282Y and H63D)
- Interpretation:
- C282Y homozygosity is the most common genotype causing hemochromatosis
- C282Y/H63D compound heterozygosity occasionally causes iron overload
- H63D homozygotes rarely develop significant iron overload 1
Liver Biopsy Indications
- Serum ferritin >1000 μg/L
- Elevated liver enzymes
- Age >40 years with clinical evidence of liver disease
- To assess presence of cirrhosis or rule out other liver diseases 1, 2
Family Screening
- First-degree relatives of patients with hemochromatosis should undergo screening 1
- For children of a proband, test the other parent first:
- If normal, child is an obligate heterozygote and needs no further testing
- If abnormal, test the child with both genotype (HFE) and phenotype (ferritin and TS) 1
Management Based on Test Results
C282Y Homozygotes or C282Y/H63D Compound Heterozygotes
- With elevated ferritin: Initiate therapeutic phlebotomy 1
- With normal ferritin: Annual follow-up with iron studies 1
C282Y Heterozygotes or H63D Heterozygotes
- Generally not at risk for progressive iron overload
- May have minor abnormalities in iron parameters
- No specific treatment needed unless other liver diseases are present 1
Non-HFE Genotypes with Iron Overload
- Consider liver biopsy for hepatic iron concentration and histopathology 1
- Exclude other liver or hematologic diseases
Treatment Protocol
Therapeutic Phlebotomy
- Initial phase: Remove 450-500 mL of blood weekly until serum ferritin is 10-20 μg/L 3
- Maintenance phase: Periodic phlebotomy to maintain ferritin ≤50 μg/L 3
- Monitoring: Check ferritin monthly during initial phase, then every 3-6 months 1
Dietary Recommendations
- Avoid medicinal iron and mineral supplements
- Limit excess vitamin C intake
- Avoid uncooked seafoods (risk of Vibrio infection) 3
Clinical Pitfalls to Avoid
- Delayed diagnosis: Average delay of 10 years from symptom onset to diagnosis 4
- Misinterpreting elevated ferritin: Can be increased in inflammatory conditions, alcoholic liver disease, viral hepatitis, and non-alcoholic fatty liver disease 2
- Relying solely on genetic testing: ~20% of clinical hemochromatosis cases have no identifiable disease-associated genotype 5
- Missing comorbid conditions: HFE mutations can be cofactors in other liver diseases like porphyria cutanea tarda, hepatitis C, alcoholic liver disease, or NAFLD 1
- Inadequate family screening: Family studies show many homozygous relatives have biochemical evidence of disease 1
Special Considerations
Patients unable to undergo phlebotomy: Consider iron chelation therapy with deferasirox 6, 7
- Initial dose: 14 mg/kg daily for patients with eGFR >60 mL/min/1.73m²
- Monitor serum ferritin monthly and adjust dose every 3-6 months
- Discontinue if ferritin falls below 500 μg/L 6
Monitoring for complications: Patients with hemochromatosis should be evaluated for:
Early diagnosis and treatment with phlebotomy can prevent complications of iron overload, significantly improving morbidity, mortality, and quality of life in patients with hemochromatosis 2.