What is the diagnostic approach for hereditary hemochromatosis?

How to Diagnose Hemochromatosis

Begin with simultaneous measurement of transferrin saturation and serum ferritin as the initial diagnostic tests, followed by HFE genetic testing if either transferrin saturation is ≥45% or ferritin exceeds 300 μg/L in men or 200 μg/L in women. 1

Initial Laboratory Testing

Order both tests together—never rely on a single test. The combination provides optimal diagnostic accuracy for detecting hereditary hemochromatosis. 1, 2

• Transferrin saturation (TS): Calculate as serum iron divided by total iron-binding capacity × 100, with a diagnostic threshold of ≥45% offering the highest sensitivity for detecting C282Y homozygotes 1, 2
• Serum ferritin: Use sex-specific thresholds of >300 μg/L in men or >200 μg/L in women to identify patients requiring further evaluation 1, 2

Critical caveat: Ferritin can be falsely elevated by inflammation, chronic liver disease, malignancy, non-alcoholic fatty liver disease, metabolic syndrome, and alcohol consumption—exclude these before attributing elevated levels to hemochromatosis. 2, 3

When to Suspect Hemochromatosis Clinically

Target testing in patients with:

• Classic symptoms: Fatigue, right upper quadrant pain, arthralgias (especially 2nd and 3rd metacarpophalangeal joints), impotence, decreased libido, symptoms of heart failure or diabetes 1
• Physical findings: Hepatomegaly (particularly with cirrhosis), skin pigmentation, testicular atrophy, congestive heart failure, arthritis, or chondrocalcinosis 1
• Abnormal liver enzymes of unclear etiology 1, 2
• First-degree relatives of confirmed hemochromatosis patients 1, 3

Important note: Most patients today are diagnosed asymptomatically through routine screening or incidental laboratory findings, not through classic end-organ manifestations. 1

Genetic Testing Algorithm

If either TS ≥45% or ferritin is elevated, proceed immediately to HFE mutation analysis for C282Y and H63D mutations. 1, 2

Interpretation of Genetic Results:

• C282Y homozygosity (C282Y/C282Y): Confirms HFE-related hemochromatosis—this accounts for 85-90% of clinically affected patients 2, 4, 5
• Compound heterozygosity (C282Y/H63D): Requires individualized assessment based on iron studies, as this genotype has lower penetrance and rarely causes significant iron overload alone 2
• H63D homozygosity: Investigate for other causes of iron overload if present 2

Before ordering genetic testing, counsel patients about: treatment efficacy (phlebotomy), testing costs, implications for insurance and employment, psychological impact of disease labeling, and need for family screening. 1, 2

Assessment for Advanced Disease and Cirrhosis

Liver biopsy is indicated when: 1, 2

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

Predictive rule: Ferritin >1,000 μg/L combined with elevated ALT/AST and platelet count <200 predicts cirrhosis in approximately 80% of C282Y homozygotes. 2 Conversely, ferritin <1,000 μg/L accurately excludes cirrhosis. 2

Family Screening Protocol

All first-degree relatives of confirmed cases require both HFE genetic testing and phenotypic screening (transferrin saturation and ferritin) performed simultaneously. 2, 3 The yield is particularly high in siblings, with 33% showing C282Y homozygosity. 3

Common Pitfalls to Avoid

• Never screen with ferritin alone—transferrin saturation is the most sensitive early marker and must be measured concurrently 1, 2
• Do not assume normal ferritin excludes hemochromatosis in young patients—only 70% of C282Y homozygotes have elevated ferritin in population studies 1
• Recognize that normal TS with elevated ferritin may indicate non-HFE hemochromatosis or compound heterozygotes—consider alternative diagnoses 2
• Avoid population-wide screening—it is not recommended due to low penetrance and uncertain benefit in asymptomatic genotype-positive individuals 1, 3