What is the diagnostic approach for hemochromatosis?

Diagnostic Approach for Hemochromatosis

Begin with simultaneous measurement of transferrin saturation (TS) and serum ferritin as the initial laboratory tests, followed by HFE genetic testing if either value is elevated. 1, 2

Initial Laboratory Testing

Order both tests together, not sequentially:

• Transferrin saturation ≥45% is the primary screening threshold, offering high sensitivity for detecting C282Y homozygotes 1, 2
• Serum ferritin >300 μg/L in men or >200 μg/L in women suggests increased risk and warrants further investigation 1, 2
• Fasting samples are no longer absolutely necessary, though confirming an elevated TS with a second determination is advisable 1

Critical pitfall: Serum ferritin can be falsely elevated by inflammation, chronic liver disease (alcoholic liver disease, hepatitis B/C, NAFLD), malignancy, or metabolic syndrome—these must be excluded before attributing elevation to iron overload 1, 2, 3

Genetic Testing Algorithm

If either TS ≥45% OR ferritin is elevated, proceed immediately to HFE mutation analysis:

• Test for C282Y and H63D mutations in the HFE gene 1, 2
• C282Y homozygosity (C282Y/C282Y) confirms HFE-related hemochromatosis and is present in ~90% of hereditary hemochromatosis cases 1, 2
• Compound heterozygosity (C282Y/H63D) or H63D homozygosity with confirmed iron overload requires investigation for other causes 2

Before genetic testing, discuss with patients: treatment efficacy, costs, social implications including insurance and psychological impact, and limitations of current genetic knowledge 1

Risk Stratification for Liver Disease

In confirmed C282Y homozygotes, assess for cirrhosis risk:

• Serum ferritin >1,000 μg/L with elevated ALT/AST and platelet count <200 predicts cirrhosis in ~80% of cases 2
• Liver biopsy should be considered in C282Y homozygotes with ferritin >1,000 μg/L, elevated liver enzymes, hepatomegaly, or age >40 years to assess for cirrhosis 2
• MRI can quantify hepatic iron concentrations when the cause of hyperferritinemia is unclear 2

Who Should Be Tested

Target these high-risk populations, NOT general population screening:

• First-degree relatives of patients with hemochromatosis (both phenotypic testing and HFE genotyping) 1, 2, 3
• Patients with unexplained liver disease, elevated liver function tests, or hepatomegaly 1
• Individuals with suggestive symptoms: chronic fatigue, arthralgias, diabetes, impotence/loss of libido, amenorrhea, congestive heart failure, or arrhythmias 1
• Patients with abnormal iron studies found incidentally 1

Population-wide screening is NOT recommended due to low clinical penetrance of C282Y homozygosity in unselected populations 1, 3

Interpretation Nuances

Normal TS (<45%) with elevated ferritin is an unusual pattern for classic HFE hemochromatosis, which typically presents with elevated TS as the earliest marker—consider non-HFE forms or secondary causes 2

TS cutoff of 45% versus 55%: While 45% offers higher sensitivity, using 55% (as suggested by the American College of Physicians) provides better specificity and positive predictive value, reducing false positives from minor secondary iron overload 1

In patients <35 years old: Normal ferritin combined with TS <45% has a 97% negative predictive value for excluding iron overload 1

Non-HFE Hemochromatosis

If HFE testing is negative but iron overload persists, consider rare non-HFE forms involving mutations in HJV, HAMP, TFR2, or SLC40A1 genes—these account for <5% of cases and genetic testing is largely unavailable outside research laboratories 1, 4