What laboratory tests should be ordered for the diagnosis and management of hemochromatosis?

Laboratory Tests for Diagnosis and Management of Hemochromatosis

For the diagnosis and management of hemochromatosis, a combination of transferrin saturation (TS) and serum ferritin should be obtained as the initial laboratory tests, rather than relying on a single test. 1

Initial Diagnostic Testing

• Transferrin saturation (TS) is the primary screening test for hemochromatosis, calculated from the ratio of serum iron to total iron-binding capacity 1
• Serum ferritin should be measured simultaneously with TS to increase diagnostic accuracy 1
• The diagnostic threshold for TS is ≥45%, which offers high sensitivity for detecting C282Y homozygotes 1
• Normal TS ranges from 20-50% in healthy individuals, while patients with hemochromatosis typically have values of 45-100% (asymptomatic) or 80-100% (symptomatic) 1
• Unsaturated iron binding capacity (UIBC) may be used as an alternative to TS with similar reliability (optimal threshold of 143 μg/dL) 2

Follow-up Testing After Abnormal Iron Studies

• If either TS ≥45% or ferritin is above the upper limit of normal, HFE mutation analysis should be performed 1
• HFE genetic testing looks for C282Y and H63D mutations, the most common genetic variants associated with hemochromatosis 1
• Serum ferritin values in hemochromatosis typically range from:
  • Men: 150-1000 μg/L (asymptomatic) or 500-6000 μg/L (symptomatic) 1
  • Women: 120-1000 μg/L (asymptomatic) or 500-6000 μg/L (symptomatic) 1

Assessing Disease Severity and Complications

• A serum ferritin level >1000 μg/L with elevated liver enzymes (ALT or AST) and platelet count <200 predicts cirrhosis in approximately 80% of C282Y homozygotes 1
• Liver function tests (ALT, AST) should be performed to assess for hepatic involvement 1
• Complete blood count with platelets helps assess for advanced liver disease 1
• Liver biopsy may be indicated in specific circumstances:
  • When iron markers are equivocal
  • To rule out significant iron overload
  • To investigate other possible causes of liver disease
  • To document the presence of cirrhosis 1

Family Screening

• For first-degree relatives of a patient with hemochromatosis:
  • Both genotype (HFE mutation analysis) and phenotype (ferritin and TS) should be performed simultaneously 1
  • For children of an identified proband, HFE testing of the other parent is recommended 1
  • If the other parent has normal results, the child is an obligate heterozygote and needs no further testing 1

Monitoring During Treatment

• During therapeutic phlebotomy:
  • Hemoglobin levels should be monitored before each phlebotomy 3
  • Serum ferritin should be checked periodically to prevent iron deficiency 3
  • Target ferritin levels during maintenance therapy should be in the low-normal range 3

Pitfalls and Caveats

• Serum ferritin has less biological variability than TS but can be falsely elevated due to inflammation, liver disease, or other conditions unrelated to iron overload 1
• A normal TS with elevated ferritin may still indicate iron overload in non-HFE hemochromatosis or C282Y/H63D compound heterozygotes 1
• Most heterozygotes (C282Y or H63D) have normal iron studies and do not require ongoing monitoring 4
• Fasting samples for TS are no longer absolutely necessary, though confirming an elevated TS with a second determination (preferably fasting) is advisable 1
• Excessive phlebotomy can lead to iron deficiency, which should be prevented by monitoring hemoglobin and ferritin levels 3