What are the typical lab findings for hemochromatosis?

Typical Laboratory Findings in Hemochromatosis

The primary laboratory findings in hemochromatosis are elevated transferrin saturation (≥45%) and increased serum ferritin levels, with transferrin saturation being the earliest and most sensitive marker for detecting hereditary hemochromatosis. 1

Initial Laboratory Evaluation

• Transferrin saturation (TS) and serum ferritin should always be measured together as the initial laboratory tests for diagnosing hemochromatosis, rather than relying on a single test 1
• 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
• 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
• In the HEIRS study of 99,711 participants, mean transferrin saturation values were significantly greater in whites than in blacks 2

Serum Ferritin Patterns

• Serum ferritin levels are typically elevated in hemochromatosis, with values >300 μg/L in 88% of male C282Y homozygotes and >200 μg/L in 57% of female C282Y homozygotes who were previously undiagnosed 3
• 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
• In most circumstances, 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

Prognostic Value of Laboratory Findings

• 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 (ALT or AST) 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) 1

Genetic Testing Correlation with Laboratory Values

• Among C282Y homozygotes, 98% have transferrin saturation ≥45% 4
• In a population-based study, 15 of 16 subjects homozygous for C282Y had transferrin saturation ≥45%; in one subject it was 43% 5
• Not all C282Y homozygotes develop iron overload; in one study, 25% of homozygotes maintained normal serum ferritin levels over a four-year period 5
• The C282Y mutation does not explain high mean serum ferritin levels and transferrin saturation values in non-white populations 3

Diagnostic Algorithm

1. Measure both transferrin saturation and serum ferritin as initial tests 1
2. If either TS ≥45% or ferritin is above the upper limit of normal, proceed to HFE mutation analysis 1
3. Interpret results based on genotype:
   • C282Y homozygotes: Confirms hereditary hemochromatosis 1, 6
   • Compound heterozygotes (C282Y/H63D): May have mild iron overload, especially with additional risk factors 1, 6
   • Single heterozygotes: Generally do not have significant iron overload unless other factors are present 7

Common Pitfalls and Caveats

• 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, 8
• Serum ferritin can be elevated in the absence of increased iron stores in patients with necroinflammatory liver disease, lymphomas, and other inflammatory conditions 1
• The C282Y mutation does not explain high transferrin saturation and serum ferritin levels in non-white persons, suggesting different genetic or environmental factors in these populations 3