What is the recommended approach for diagnosing and managing hereditary hemochromatosis (HH), particularly in individuals with a family history and suspected HFE (human ferritin heavy chain) mutations?

Genetic Testing for Hemochromatosis

Direct Answer

Genetic testing for HFE mutations (C282Y and H63D) should be performed after confirming elevated iron studies—specifically transferrin saturation ≥45% and/or elevated serum ferritin (>300 μg/L in men, >200 μg/L in women)—or when there is a positive family history of hereditary hemochromatosis. 1, 2

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Diagnostic Algorithm

Step 1: Initial Biochemical Screening

Start with simultaneous measurement of transferrin saturation and serum ferritin—not one or the other. 2, 3

• Transferrin saturation ≥45% is the most sensitive early marker for hemochromatosis and should be calculated from serum iron divided by total iron-binding capacity 2
• Serum ferritin thresholds: >300 μg/L in men or >200 μg/L in women suggest increased risk and warrant further investigation 1, 3
• These two tests together provide higher diagnostic accuracy than either alone 2

Critical pitfall: Serum ferritin can be falsely elevated by inflammation, liver disease, malignancy, metabolic syndrome, or alcohol use—these must be excluded before proceeding with genetic testing. 2, 3

Step 2: When to Order HFE Genetic Testing

Order HFE mutation analysis (C282Y and H63D) if: 1, 2, 3

• Transferrin saturation ≥45% and/or ferritin above normal limits
• First-degree relative has confirmed hemochromatosis (test regardless of iron studies)
• Clinical suspicion with symptoms (fatigue, arthralgias, hepatomegaly, diabetes, cardiomyopathy, hypogonadism) even if iron studies are borderline 1

Step 3: Interpretation of Genetic Results

C282Y homozygotes (C282Y/C282Y): 1, 2

• Confirms HFE-related hemochromatosis diagnosis
• Present in ~90% of clinically affected patients
• Highest risk for iron overload and end-organ damage

Compound heterozygotes (C282Y/H63D): 4, 2

• Lower penetrance than C282Y homozygotes
• Manage based on phenotype (iron studies), not genotype alone
• If iron overload present, investigate other contributing causes (alcohol, fatty liver disease, other genetic variants)
• May require phlebotomy only if confirmed biochemical iron overload exists

H63D homozygotes or heterozygotes: 4

• H63D heterozygotes can be reassured—no risk for progressive iron overload
• H63D homozygotes rarely develop mild iron overload; if present, search for other causes

Negative HFE testing with iron overload: 5

• Consider non-HFE hemochromatosis (mutations in hemojuvelin, transferrin receptor 2, HAMP, ferroportin genes)
• Whole exome sequencing may be considered for diagnostic characterization

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Pre-Test Counseling Requirements

Before ordering genetic testing, discuss with the patient: 1, 3

• Available treatment (phlebotomy) and its efficacy
• Costs of testing and ongoing monitoring
• Implications for insurability and employment
• Psychological impact of disease labeling
• Family screening implications—first-degree relatives will need testing
• Possibility of uncertain or variant genotypes

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Assessment for Advanced Disease

After confirming genetic diagnosis, assess for cirrhosis and end-organ damage: 2, 6

Liver biopsy is indicated if: 2

• Serum ferritin >1,000 μg/L
• Elevated liver enzymes (ALT/AST)
• Hepatomegaly on exam
• Age >40 years in C282Y homozygotes
• Platelet count <200 (suggests portal hypertension)

Ferritin <1,000 μg/L accurately predicts absence of cirrhosis—liver biopsy can be avoided in this scenario. 4

Additional assessments: 6

• Liver function tests (ALT, AST)
• Fasting glucose or HbA1c (screen for diabetes)
• Echocardiogram if cardiac symptoms present
• Screening for hepatocellular carcinoma (ultrasound every 6 months) if cirrhosis confirmed

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Family Screening Protocol

All first-degree relatives of a confirmed proband must be screened. 3, 6

Testing approach for relatives: 3

• Both phenotypic testing (transferrin saturation and ferritin) AND HFE genotyping
• Test the other parent if children of proband need assessment
• Provide genetic counseling before testing

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Population Screening: Not Recommended

Routine population-wide screening is NOT recommended by the American College of Physicians and USPSTF. 1, 3

Rationale: 1

• Low penetrance—only ~10% of C282Y homozygotes develop clinically significant disease
• 50% of C282Y homozygotes have normal transferrin saturation
• 99% are free of clinical symptoms
• Uncertain benefit of early treatment in asymptomatic genotype-positive individuals

Targeted case-finding IS appropriate for: 1, 3

• Individuals with suggestive symptoms (arthralgias, fatigue, impotence, skin pigmentation changes)
• Abnormal liver function tests of unclear etiology
• Family history of hemochromatosis
• One-time screening of asymptomatic non-Hispanic white men (highest yield group)

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Common Pitfalls to Avoid

Do not order genetic testing before measuring iron studies unless there is a strong family history—phenotypic screening comes first. 2, 3

Do not assume elevated ferritin alone means hemochromatosis—this pattern is unusual for HFE-related disease, which typically shows elevated transferrin saturation first. 2

Do not treat H63D heterozygotes or compound heterozygotes based on genotype alone—treatment decisions require confirmed biochemical iron overload. 4, 2

Do not forget to counsel about vitamin C supplementation—patients with confirmed hemochromatosis should avoid vitamin C supplements as they accelerate iron mobilization and increase toxicity risk. 4, 2

Do not overlook family screening—this is a critical component of management and has higher yield than population screening. 3, 6