What are the diagnostic criteria and treatment options for hemochromatosis?

How to Diagnose Hemochromatosis

Begin with simultaneous measurement of fasting transferrin saturation (TS) and serum ferritin—never rely on a single test—and if either TS ≥45% or ferritin is above the upper limit of normal, proceed immediately to HFE genetic testing for C282Y and H63D mutations. 1, 2

Initial Laboratory Testing

The diagnostic approach requires obtaining both iron parameters together at the first evaluation:

• Transferrin saturation (TS) is calculated as serum iron divided by total iron-binding capacity × 100, with a diagnostic threshold of ≥45% offering high sensitivity for detecting hemochromatosis 1, 2
• Serum ferritin must be measured simultaneously, with abnormal values defined as >300 μg/L in men or >200 μg/L in women 1
• TS is the earliest and most sensitive marker, typically becoming abnormal before ferritin elevation occurs 2

Critical pitfall: Ferritin can be falsely elevated in over 90% of cases due to inflammation, chronic liver disease, malignancy, metabolic syndrome, or alcohol use—conditions that must be excluded before attributing elevation to iron overload 2, 3, 4. In the absence of elevated TS, an isolated ferritin rise is likely nonspecific 1.

Genetic Testing Criteria

Proceed to HFE mutation analysis when:

• TS ≥45% and/or ferritin above upper limit of normal 1, 2
• Suggestive symptoms present (fatigue, arthralgias, hepatomegaly, diabetes, cardiomyopathy, hypogonadism, skin hyperpigmentation) 1, 2
• First-degree relative has confirmed hemochromatosis 1

For C282Y homozygotes specifically: The diagnosis of HFE-related hemochromatosis is confirmed when elevated iron parameters (TS >45% in females or >50% in males, plus ferritin >200 μg/L in females or >300 μg/L in males and post-menopausal women) are present alongside C282Y/C282Y genotype 1, 2.

Genotype-Specific Diagnostic Requirements

The diagnostic pathway diverges based on genetic results:

• C282Y homozygotes: Elevated serum iron parameters alone are sufficient for diagnosis—no liver biopsy or MRI required unless assessing for cirrhosis 1
• Other HFE genotypes (C282Y/H63D compound heterozygotes, H63D homozygotes, or non-HFE mutations): Diagnosis requires documented hepatic iron overload on MRI or liver biopsy, not just elevated serum markers 1

This distinction is crucial because compound heterozygotes rarely develop significant iron overload from genetics alone and require investigation for secondary causes 2, 4.

Assessment of Disease Severity

Once diagnosis is established, stratify risk for advanced liver disease:

• Ferritin <1000 μg/L accurately predicts absence of cirrhosis with 94% negative predictive value 1, 2, 4
• Ferritin >1000 μg/L plus elevated ALT/AST plus platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 1, 2
• Liver biopsy is indicated when ferritin >1000 μg/L, elevated liver enzymes, hepatomegaly, age >40 years, or when assessing non-HFE hemochromatosis 1, 2

Family Screening Protocol

Once a proband is identified:

• Screen all first-degree relatives with simultaneous HFE genetic testing and phenotypic testing (ferritin and TS) at a single visit 1, 2
• For children of a proband, test the other parent first—if normal, the child is an obligate heterozygote and requires no further testing 1

Pre-Test Counseling Requirements

Before ordering genetic testing, discuss with patients:

• Treatment efficacy (phlebotomy prevents organ damage if initiated early) 1, 2
• Costs of testing and lifelong monitoring 1, 2
• Implications for insurability and employment 1, 2
• Psychological impact of genetic disease labeling 1, 2
• Family screening obligations 1, 2
• Possibility of uncertain or variant genotypes 1, 2

Common Diagnostic Pitfalls to Avoid

• Never interpret ferritin in isolation—always correlate with TS, as normal TS with elevated ferritin may still indicate iron overload in non-HFE hemochromatosis or compound heterozygotes 1, 3
• C282Y heterozygosity alone does not cause clinically relevant iron overload—a second cofactor (alcohol, NAFLD, hepatitis C) is required 3
• Not every elevated ferritin requires phlebotomy—iron overload is unlikely if TS <45% 3
• A cutoff of 45% for TS has high sensitivity but lower specificity, potentially identifying secondary iron overload requiring further evaluation 2
• In individuals <35 years, normal ferritin combined with TS <45% has 97% negative predictive value for excluding iron overload 1, 2

Imaging Considerations

• MRI should quantify hepatic iron concentration in patients with unclear hyperferritinemia, biochemical iron overload without C282Y homozygosity, or positive liver iron staining 1
• Cardiac MRI is indicated in patients with signs of heart disease or juvenile forms of hemochromatosis 1
• Hepcidin measurement is not recommended for diagnosis 1