Laboratory Findings in Hemochromatosis

Initial Laboratory Evaluation

The American Association for the Study of Liver Diseases recommends that transferrin saturation and serum ferritin should always be measured together as the initial laboratory tests for diagnosing hemochromatosis, rather than relying on a single test 1, 2
Transferrin saturation is calculated from the ratio of serum iron to total iron-binding capacity, with a diagnostic threshold of ≥45% offering high sensitivity for detecting C282Y homozygotes 1, 2
A cutoff TS value of 45% has high sensitivity but lower specificity for detecting C282Y homozygotes, meaning it will also identify persons with minor secondary iron overload and some heterozygotes 1

Serum ferritin levels are typically elevated in hemochromatosis, and serum ferritin has less biological variability than TS but has a significant false positive rate due to elevations related to inflammation, necroinflammatory liver disease, lymphomas, and other chronic inflammatory conditions 1
Serum ferritin provides additional confirmation of the significance of an elevated TS in C282Y homozygotes 1
Serum ferritin levels have additional value as a predictor of advanced fibrosis and cirrhosis in confirmed hemochromatosis 1

A serum ferritin level <1000 μg/L is an accurate predictor for the absence of cirrhosis in hemochromatosis patients 1
A serum ferritin level >1000 μg/L with elevated aminotransferase levels and a platelet count <200 predicted the presence of cirrhosis in 80% of C282Y homozygotes 1
All-cause mortality significantly increases for persons with transferrin saturation above 55% compared to those with lower values (hazard ratio, 1.60) 3, 4

The American Association for the Study of Liver Diseases recommends measuring both transferrin saturation and serum ferritin as initial tests, and if either TS ≥45% or ferritin is above the upper limit of normal, proceed to HFE mutation analysis 1, 2
C282Y homozygotes: Confirms hereditary hemochromatosis 1, 5
Compound heterozygotes (C282Y/H63D): May have mild iron overload, especially with additional risk factors 2, 5

Iron overload may be present in a patient with elevated ferritin and normal TS, particularly in non-HFE-related iron overload or in C282Y/H63D compound heterozygotes 1
A normal TS with elevated ferritin should prompt investigation for other causes of hyperferritinemia, including inflammation, liver disease, and metabolic conditions 1, 6
Serum ferritin can be elevated in the absence of increased iron stores in patients with necroinflammatory liver disease, lymphomas, and other inflammatory conditions 1