Which blood tests are used to diagnose hereditary hemochromatosis?

Blood Tests for Diagnosing Hemochromatosis

Begin with simultaneous measurement of transferrin saturation and serum ferritin—these two tests together form the essential first-line diagnostic approach for hereditary hemochromatosis. 1, 2, 3

Initial Screening Tests

Transferrin Saturation (Primary Screening Test)

• Transferrin saturation ≥45% is the most sensitive early marker and the primary threshold that triggers further evaluation for iron overload 1, 2, 3
• Calculate as: (serum iron ÷ total iron binding capacity) × 100 1, 2
• This test has 84% sensitivity in men and 73% sensitivity in women for detecting C282Y homozygosity 4
• Never interpret serum iron alone—always calculate transferrin saturation 4

Serum Ferritin (Concurrent Measurement Required)

• Must be measured simultaneously with transferrin saturation for optimal diagnostic accuracy 1, 2, 3
• Diagnostic thresholds: >300 μg/L in men or >200 μg/L in women 1, 2, 3, 5
• Ferritin >1,000 μg/L predicts cirrhosis risk, especially when combined with elevated liver enzymes and platelet count <200,000/μL 1, 2, 4
• Critical caveat: Ferritin is an acute-phase reactant that rises with inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 2, 4, 6

Diagnostic Algorithm Based on Initial Results

If Transferrin Saturation ≥45% AND Elevated Ferritin:

• Proceed immediately to HFE genetic testing for C282Y and H63D mutations 1, 2, 3, 7, 5
• C282Y homozygosity confirms HFE-related hemochromatosis and accounts for 85-90% of clinically affected patients 2, 3, 8, 7, 5
• C282Y/H63D compound heterozygosity also confirms diagnosis 2, 3, 7

If Transferrin Saturation <45%:

• Iron overload is excluded with >90% certainty 4
• Elevated ferritin in this context reflects secondary causes: chronic alcohol consumption, inflammation, cell necrosis, tumors, or metabolic syndrome/NAFLD—not hemochromatosis 1, 4, 6
• Do not order HFE genetic testing when transferrin saturation is <45% 4, 6

Additional Laboratory Tests for Disease Severity Assessment

Liver Function Tests

• Obtain ALT, AST, and platelet count to assess for cirrhosis risk 1, 2, 3
• The combination of ferritin >1,000 μg/L + elevated aminotransferases + platelet count <200,000/μL predicts cirrhosis in ~80% of C282Y homozygotes 1, 2, 4, 3

Complete Blood Count

• Check CBC with differential to exclude anemia and red cell disorders 3
• Platelet count <200,000/μL suggests advanced liver disease 1, 2, 4

Inflammatory Markers (When Ferritin is Elevated but TS <45%)

• Measure CRP and ESR to identify inflammatory causes of secondary hyperferritinemia 4

When to Consider Liver Biopsy

Liver biopsy is indicated when:

• Ferritin >1,000 μg/L with elevated liver enzymes (ALT/AST) 1, 2, 4, 3
• Ferritin >1,000 μg/L with platelet count <200,000/μL 1, 2, 4
• Age >40 years in C282Y homozygotes with ferritin >1,000 μg/L 1, 2, 3
• Hepatomegaly on examination 1, 3

Liver biopsy is NOT needed when:

• Ferritin <1,000 μg/L (94% negative predictive value for advanced fibrosis) 1, 4
• Normal liver enzymes and age <40 years in confirmed C282Y homozygotes 4

Alternative/Supplementary Tests

MRI for Hepatic Iron Quantification

• Use MRI to quantify hepatic iron concentration when the cause of hyperferritinemia is unclear despite biochemical testing 2, 4, 3
• Particularly useful when transferrin saturation is ≥45% 4

Unsaturated Iron Binding Capacity (UIBC)

• UIBC has equal reliability to transferrin saturation for detecting hemochromatosis 9
• Optimum threshold: 143 μg/dL (25.6 μmol/L) with sensitivity 0.91 and specificity 0.95 9
• Can be used as an inexpensive alternative to transferrin saturation 9

Critical Pitfalls to Avoid

• Never use ferritin alone to diagnose iron overload—transferrin saturation must be assessed concurrently 1, 2, 4, 6
• Do not assume iron overload when transferrin saturation <45%—over 90% of elevated ferritin cases with low transferrin saturation are NOT due to iron overload 1, 4, 6
• Do not order genetic testing when transferrin saturation <45%—this leads to misdiagnosis and unnecessary treatment 4, 6
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests 1, 4
• Recognize that normal transferrin saturation occurs in up to 33% of C282Y homozygotes due to biological variability—repeat testing may be needed 4

Family Screening Protocol

• All first-degree relatives of confirmed hemochromatosis patients should undergo both HFE genetic testing AND simultaneous phenotypic screening (transferrin saturation and ferritin) 1, 3, 8, 5
• Siblings have 33% probability of C282Y homozygosity 3
• Genetic testing should be offered after 18 years of age 5