Diagnostic Approach to Hereditary Hemochromatosis

Initial Screening Tests

Simultaneous measurement of transferrin saturation and serum ferritin constitutes the essential first‑line diagnostic strategy for hereditary hemochromatosis. 1
A transferrin saturation ≥ 45 % is the most sensitive early marker and the primary threshold that triggers further evaluation for iron overload. 1
Transferrin saturation is calculated as (serum iron ÷ total iron‑binding capacity) × 100. 1
Serum ferritin must be measured at the same time as transferrin saturation to achieve optimal diagnostic accuracy. 1
Diagnostic ferritin thresholds are > 300 µg/L in men and > 200 µg/L in women. 1
Ferritin > 1,000 µg/L predicts cirrhosis risk, especially when accompanied by elevated liver enzymes and a platelet count < 200 × 10³/µL. 1
Ferritin is an acute‑phase reactant that rises with inflammation, liver disease, malignancy, or tissue necrosis independent of iron stores. 1

When transferrin saturation ≥ 45 % and ferritin is elevated, immediate HFE genetic testing for C282Y and H63D mutations is recommended. 1

ALT, AST, and platelet count should be obtained to evaluate cirrhosis risk. 1
The combination of ferritin > 1,000 µg/L + elevated aminotransferases + platelet count < 200 × 10³/µL predicts cirrhosis in approximately 80 % of C282Y homozygotes. 1
A platelet count < 200 × 10³/µL suggests advanced liver disease. 1
When ferritin is elevated but transferrin saturation < 45 %, C‑reactive protein (CRP) and erythrocyte sedimentation rate (ESR) should be measured to identify inflammatory causes of secondary hyperferritinemia. 5

Liver biopsy is indicated if ferritin > 1,000 µg/L and liver enzymes (ALT/AST) are elevated. 1
Liver biopsy is also indicated if ferritin > 1,000 µg/L and platelet count < 200 × 10³/µL. 1
In C282Y homozygotes aged > 40 years with ferritin > 1,000 µg/L, biopsy is recommended. 1
Presence of hepatomegaly on physical examination warrants biopsy. 1

Ferritin < 1,000 µg/L provides a 94 % negative predictive value for advanced fibrosis, obviating the need for biopsy. 1
Confirmed C282Y homozygotes who are < 40 years old with normal liver enzymes do not require biopsy. 5

Magnetic resonance imaging (MRI) can be used to quantify hepatic iron concentration when the cause of hyperferritinemia remains unclear after biochemical testing. 3

Ferritin must never be used alone to diagnose iron overload; transferrin saturation must be assessed concurrently. 1
A transferrin saturation < 45 % should not be interpreted as iron overload—over 90 % of elevated‑ferritin cases with low saturation are due to secondary causes. 1
Genetic testing should not be ordered when transferrin saturation < 45 %, to avoid misdiagnosis and unnecessary treatment. 5
Failure to perform liver biopsy in patients with ferritin > 1,000 µg/L and abnormal liver tests may miss advanced disease. 1
Normal transferrin saturation occurs in up to 33 % of C282Y homozygotes because of biological variability; repeat testing may be necessary. 5

All first‑degree relatives of a confirmed hemochromatosis patient should undergo both HFE genetic testing and simultaneous phenotypic screening (transferrin saturation and ferritin). 1
Siblings have a 33 % probability of being C282Y homozygous. 4