How should I manage a 64‑year‑old man with compound‑heterozygous HFE C282Y/H63D genotype and a hematocrit of 62%?

Management of a 64-Year-Old Man with C282Y/H63D Compound Heterozygosity and Hematocrit 62%

The hematocrit of 62% indicates polycythemia, not iron overload, and must be evaluated as a separate hematologic disorder; the C282Y/H63D genotype alone does not cause this degree of erythrocytosis and requires investigation for primary polycythemia vera or secondary causes. 1

Critical Initial Assessment

This patient presents with two distinct problems that must be addressed separately:

• The elevated hematocrit (62%) is abnormal and unrelated to the HFE genotype. Normal hematocrit ranges are 38.3–48.6% for men; a value of 62% represents significant polycythemia that requires urgent evaluation for myeloproliferative disorders (particularly polycythemia vera), hypoxic conditions, or other secondary causes. 1

• The C282Y/H63D compound heterozygous genotype is a low-penetrance variant that rarely causes clinically significant iron overload and does not produce erythrocytosis. 1

Immediate Workup for Polycythemia

Order the following tests to determine the cause of the elevated hematocrit:

• Complete blood count with differential, platelet count, and red blood cell indices 1
• Serum erythropoietin level (low in polycythemia vera, elevated in secondary causes) 1
• JAK2 V617F mutation testing (positive in >95% of polycythemia vera cases) 1
• Arterial oxygen saturation 1
• Renal ultrasound if secondary polycythemia is suspected 1

If JAK2 mutation is positive or erythropoietin is suppressed, refer to hematology immediately for bone marrow biopsy and management of polycythemia vera. 1

Assessment of Iron Status in C282Y/H63D Genotype

Management of the HFE genotype must be guided entirely by phenotypic iron parameters, not the genotype itself. 1

Measure Iron Studies

• Fasting transferrin saturation and serum ferritin simultaneously 1, 2
• Biochemical iron overload thresholds for men: transferrin saturation >50% AND ferritin >300 μg/L 1, 2

Interpretation Based on Results

If transferrin saturation ≤50% and ferritin ≤300 μg/L:

• No iron overload is present 1
• Annual monitoring of iron parameters is sufficient 1, 3
• Counsel the patient that C282Y/H63D compound heterozygosity carries a low risk (5.3% over 10 years) of developing iron overload-related disease 4

If transferrin saturation >50% and ferritin >300 μg/L (confirmed iron overload):

• Investigate other causes of iron overload before attributing it to the HFE genotype 1
• Evaluate for heavy alcohol consumption (present in 26% of C282Y/H63D patients with iron overload) 5
• Assess for obesity/metabolic syndrome (present in 66.7% of C282Y/H63D patients with iron overload) 5
• Screen for hepatic steatosis, diabetes, and chronic liver disease 1
• Consider MRI to quantify hepatic iron concentration if the diagnosis remains unclear 1, 2

Phlebotomy Decision Algorithm

Phlebotomy may be considered only if all of the following are met:

1. Confirmed biochemical iron overload (transferrin saturation >50% AND ferritin >300 μg/L) 1
2. Elevated hepatic iron concentration documented by MRI or liver biopsy 1
3. Individualized clinical assessment shows no other reversible cause 1

If phlebotomy is initiated:

• Remove 500 mL of blood weekly or biweekly 2
• Monitor hematocrit before each phlebotomy (do not allow >20% decrease from baseline) 2
• Check ferritin every 10–12 phlebotomies 2
• Target ferritin 50–100 μg/L 2, 3
• Note: C282Y/H63D patients require significantly less iron removal (median 2.1 g) compared to C282Y homozygotes (3.4 g), reflecting lower tissue iron stores 5

Management of Comorbid Factors

Address modifiable risk factors, which are more important than phlebotomy in C282Y/H63D patients: 1, 5

• Alcohol reduction: Limit to <2 drinks/day for men 1
• Weight loss: Target BMI <25 kg/m² through dietary modification and increased physical activity 1, 2
• Metabolic syndrome management: Optimize glucose control, lipid profile, and blood pressure 1
• Avoid vitamin C supplements: These accelerate iron mobilization and increase toxicity risk 1, 2, 6

Assessment for Advanced Liver Disease

Perform non-invasive fibrosis assessment if ferritin >1,000 μg/L or liver enzymes are elevated: 1, 2

• Transient elastography (liver stiffness <6.4 kPa excludes advanced fibrosis) 2
• FIB-4 score 2
• Liver biopsy is indicated if: ferritin >1,000 μg/L, elevated ALT/AST, hepatomegaly, or platelet count <200 × 10⁹/L 1, 3

Family Screening

First-degree relatives should be offered HFE genetic testing and iron studies (transferrin saturation and ferritin) after appropriate counseling. 1, 6, 3

Critical Pitfalls to Avoid

• Do not attribute the polycythemia to hemochromatosis—iron overload causes anemia in advanced disease, not erythrocytosis 1
• Do not initiate phlebotomy based on genotype alone—C282Y/H63D compound heterozygosity is insufficient to cause hemochromatosis 1, 4
• Do not overlook secondary causes of elevated ferritin—inflammation, liver disease, malignancy, and metabolic syndrome are common confounders 1, 3
• Do not assume elevated ferritin equals iron overload—verify with transferrin saturation, which is the most sensitive early marker 1, 3
• Recognize that excess morbidity in C282Y/H63D heterozygotes was not significant after correction for multiple testing in large UK cohort studies 1