Diagnostic Approach for Hemochromatosis

Initial Laboratory Testing

The American Association for the Study of Liver Diseases recommends beginning with simultaneous measurement of transferrin saturation and serum ferritin as the essential first-line tests for suspected hemochromatosis 1, 2
Diagnostic thresholds that trigger further evaluation include transferrin saturation ≥45% and serum ferritin >300 μg/L in men or >200 μg/L in women 1, 2
The European Association for the Study of the Liver suggests obtaining complete blood count with reticulocytes to exclude anemia and red cell disorders 1

The American College of Medical Genetics recommends proceeding immediately to HFE gene mutation analysis for C282Y and H63D mutations if either transferrin saturation ≥45% or ferritin exceeds the thresholds 1, 2
For patients of Northern European descent, the National Institute of Diabetes and Digestive and Kidney Diseases suggests testing for C282Y first, as this mutation accounts for 85-90% of clinically affected patients 3, 2
C282Y homozygosity confirms HFE-related hemochromatosis 2

The American Association for the Study of Liver Diseases recommends evaluating for cirrhosis and end-organ damage after genetic confirmation using liver assessment, cardiac evaluation, and musculoskeletal assessment 1, 2
If ferritin >1,000 μg/L with elevated ALT/AST and platelet count <200, this predicts cirrhosis in ~80% of C282Y homozygotes—strongly consider liver biopsy 1, 2
The European Society of Cardiology suggests that patients with severe iron overload should undergo ECG and echocardiography to screen for arrhythmias and cardiac dysfunction 1

The American College of Medical Genetics recommends that all first-degree relatives of confirmed hemochromatosis patients should undergo both HFE genetic testing and simultaneous phenotypic screening (transferrin saturation and ferritin) 2, 4
Siblings have the highest yield: 33% show C282Y homozygosity compared to 23% of all first-degree relatives 4

The American Association for the Study of Liver Diseases suggests that MRI should be used to quantify hepatic iron concentration when the cause of hyperferritinemia is unclear despite biochemical testing 1, 3

The United States Preventive Services Task Force recommends that routine population-wide screening is NOT recommended due to low penetrance and uncertain benefit in asymptomatic genotype-positive individuals 3, 4
Targeted case-finding IS appropriate for individuals with suggestive symptoms, abnormal liver function tests of unclear etiology, and one-time screening of asymptomatic non-Hispanic white men 3, 4