How do you manage a patient with a heterozygous HFE (Human Hemochromatosis Protein) gene mutation and elevated ferritin levels?

Management of Heterozygous HFE Gene Mutation with Elevated Ferritin

Heterozygous HFE mutations (single C282Y or H63D) do not cause clinically significant iron overload and should not be treated with phlebotomy—instead, investigate alternative causes of elevated ferritin such as metabolic syndrome, inflammation, alcohol use, or liver disease. 1

Initial Diagnostic Approach

The critical first step is determining whether true iron overload exists versus other causes of hyperferritinemia:

• Measure transferrin saturation (TS) alongside ferritin to distinguish genuine iron overload from inflammatory or metabolic causes of elevated ferritin 1
• Biochemical iron overload requires both TS >45% in females or >50% in males and ferritin >200 μg/L in females or >300 μg/L in males 1
• H63D heterozygotes can be reassured they are not at risk for progressive iron overload and require no specific hemochromatosis-directed therapy 1

Risk Stratification by Genotype

The genotype fundamentally determines your management approach:

• C282Y heterozygotes: Extremely rare to develop clinically significant iron overload without additional genetic or acquired factors 1
• H63D heterozygotes: No risk for progressive iron overload; elevated ferritin reflects other pathology 1
• H63D homozygotes: Can occasionally develop mild iron overload, but this is uncommon and warrants investigation for contributing causes 1

A case report documents a C282Y heterozygote with significant iron overload, but this patient had a strong family history (father died from iron overload complications), suggesting additional unidentified genetic factors 2

Alternative Causes to Investigate

When ferritin is elevated in heterozygous HFE carriers, systematically evaluate:

• Metabolic syndrome components: Obesity, insulin resistance, fatty liver disease (most common cause of elevated ferritin in this population)
• Alcohol consumption: Obtain detailed alcohol history; even moderate intake can elevate ferritin
• Chronic inflammation: Check CRP, evaluate for inflammatory conditions
• Liver disease: Obtain liver function tests (ALT, AST); consider viral hepatitis screening, autoimmune markers
• Secondary iron overload: Transfusion history, ineffective erythropoiesis, chronic hemolysis
• Malignancy: Age-appropriate cancer screening if ferritin markedly elevated without clear cause

When to Consider Phlebotomy

Phlebotomy should only be considered in the rare heterozygote with documented iron overload:

• Confirmed iron overload must be present: elevated TS and elevated ferritin meeting thresholds above 1
• Target ferritin of 50-100 μg/L if phlebotomy is pursued 3, 1
• Consider liver biopsy if ferritin >1,000 μg/L, elevated liver enzymes, or hepatomegaly to assess for fibrosis or cirrhosis 1
• Ferritin <1,000 μg/L accurately predicts absence of cirrhosis 1

Phlebotomy Protocol (If Indicated)

If true iron overload is confirmed and phlebotomy warranted:

• Induction phase: Remove 500 mL weekly or biweekly as tolerated until ferritin reaches 50-100 μg/L 3
• Check hemoglobin before each session; discontinue if hemoglobin <11 g/dL 4
• Monitor ferritin monthly during induction (or every 4th phlebotomy) 4
• Maintenance phase: Continue phlebotomy every 2-4 months to maintain ferritin 50-100 μg/L 3
• Monitor ferritin every 6 months during maintenance 4

Dietary and Lifestyle Modifications

Even without phlebotomy, provide these recommendations:

• Avoid iron supplements and iron-fortified foods 4
• Avoid vitamin C supplements entirely, especially if any iron overload present, as vitamin C accelerates iron mobilization 4, 1
• Limit red meat consumption 4
• Restrict alcohol intake, particularly if liver abnormalities or any iron overload present 4
• Avoid raw or undercooked shellfish in endemic regions due to Vibrio vulnificus risk in iron-loaded states 4

Family Screening

• Recommend genetic testing for first-degree relatives after appropriate counseling 1
• This is particularly important if the patient has documented iron overload despite heterozygous status, suggesting possible compound heterozygosity or other genetic factors

Common Pitfalls to Avoid

• Do not reflexively start phlebotomy based on genotype alone—heterozygotes rarely need treatment 1
• Do not ignore alternative diagnoses—metabolic syndrome and fatty liver are far more common causes of elevated ferritin in this population
• Do not over-phlebotomize—monitor hemoglobin closely and avoid inducing iron deficiency anemia 4
• Do not assume single heterozygous mutations explain iron overload—investigate thoroughly for other causes 1, 2