What labs are recommended for the diagnosis and management of hemochromatosis?

Diagnostic and Management Labs for Hemochromatosis

The initial approach to diagnosing hemochromatosis should include transferrin saturation (TS) and serum ferritin as the primary screening tests, followed by genetic testing for HFE mutations in those with elevated iron studies. 1

Initial Diagnostic Workup

• Transferrin saturation (TS) is the test of choice for initial screening, calculated as the ratio of serum iron to total iron-binding capacity 1
• Serum ferritin should be measured simultaneously with TS to increase diagnostic accuracy 1
• A TS cutoff value of 45% is recommended for its high sensitivity in detecting C282Y homozygotes, though it has lower specificity than higher cutoff values 1
• Confirmation of an elevated TS with a second determination is advisable, though fasting samples are no longer absolutely necessary 1

Diagnostic Algorithm

Step 1: Iron Studies

• Measure transferrin saturation and serum ferritin 1
• TS less than 45% and normal serum ferritin requires no further evaluation 1
• Elevated TS and serum ferritin warrant further testing 1

Step 2: Genetic Testing

• Test for HFE mutations (C282Y and H63D) in patients with elevated iron studies 1
• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms hereditary hemochromatosis in the presence of iron overload 1

Step 3: Liver Assessment

• Liver biopsy may be indicated to:
  • Document presence of cirrhosis 1
  • Rule out significant iron overload when iron markers are equivocal 1
  • Investigate other possible causes of liver disease 1
• Patients less than 40 years of age with no clinical evidence of liver disease and serum ferritin less than 1,000 μg/L may proceed to treatment without liver biopsy 1

Monitoring During Treatment

• Hemoglobin or hematocrit should be checked before each phlebotomy session 2
• Serum ferritin should be monitored every 10-12 phlebotomies during initial treatment phase 2
• Once ferritin reaches 200 μg/L, check ferritin every 1-2 treatment sessions 3
• During maintenance phase, monitor serum ferritin and transferrin saturation every 6 months 2, 3

Treatment Targets

• Initial iron depletion phase: Continue phlebotomy until serum ferritin reaches 50 μg/L 4, 2
• Maintenance phase: Keep serum ferritin between 50-100 μg/L 2, 3
• If hemoglobin falls below 12 g/dL, reduce frequency of phlebotomy 2
• If hemoglobin falls below 11 g/dL, pause treatment 2

Special Considerations

• Non-HFE forms of inherited iron overload are rare (<5% of cases) and genetic testing is largely unavailable except in research laboratories 1
• In patients with elevated serum ferritin but normal transferrin saturation, consider other causes of hyperferritinemia besides hemochromatosis 5
• Serum ferritin >1,000 ng/mL is an accurate predictor of hepatic fibrosis/cirrhosis 1
• Patients with cirrhosis should be included in a screening program for hepatocellular carcinoma 6, 7

Pitfalls to Avoid

• Relying solely on serum ferritin can lead to false positives due to inflammation 1
• Not confirming elevated TS with a second determination may lead to unnecessary further testing 1
• Failing to consider non-HFE causes in patients with iron overload but negative for common HFE mutations 1
• Overlooking the need for lifelong monitoring during maintenance phase 2, 3
• Continuing vitamin C supplements during treatment, which can accelerate iron mobilization to potentially dangerous levels 2