What is the recommended workup for hemochromatosis (iron overload disorder)?

Diagnostic Workup for Hemochromatosis

The recommended workup for hemochromatosis follows a three-step algorithm: initial serologic testing with transferrin saturation and serum ferritin, followed by genetic testing, and in select cases, liver biopsy to assess for fibrosis or cirrhosis. 1

Step 1: Initial Serologic Testing

• Fasting transferrin saturation (TS) - primary screening test

  • Threshold: >45% in females, >50% in males 1
  • Should be measured after overnight fast (though recent evidence suggests non-fasting samples may be acceptable) 1
  • Confirm elevated values with a second determination 1

• Serum ferritin - should be measured simultaneously

  • Threshold: >200 μg/L in females, >300 μg/L in males 1
  • Values >1,000 μg/L strongly associated with hepatic fibrosis/cirrhosis 1

• Complete blood count with reticulocytes - to exclude anemia and red cell disorders 1

Step 2: Genetic Testing

If transferrin saturation and ferritin are elevated:

• HFE gene mutation analysis for:

  • C282Y homozygosity (most common cause)
  • C282Y/H63D compound heterozygosity
  • H63D homozygosity 1

• In patients of non-European origin with clinical suspicion and elevated iron studies:

  • Consider direct sequencing of multiple genes (HFE, HJV, TFR2, CP, SLC40A1) 1

Step 3: Assessment for End-Organ Damage

Liver Assessment:

• Non-invasive fibrosis assessment:

  • Transient elastography (FibroScan) - values <6.4 kPa rule out advanced fibrosis 1
  • Serum markers: FIB-4, APRI (though thresholds may differ from other liver diseases) 1

• Liver biopsy indicated in:

  • C282Y homozygotes with serum ferritin >1,000 μg/L 1
  • Elevated liver enzymes (ALT/AST) 1
  • Hepatomegaly 1
  • Age >40 years 1
  • Cases with equivocal iron markers 1
  • Non-HFE genotypes with suspected iron overload 1

Cardiac Assessment:

• ECG and echocardiography for patients with severe iron overload 1
• Cardiac MRI for iron quantification in:
  • Patients with signs/symptoms of heart disease 1
  • Juvenile hemochromatosis 1

Other Assessments:

• Joint evaluation - particularly ankles, hips, hands/wrists 1
• Endocrine evaluation - glucose tolerance test if diabetes suspected 1

Special Considerations

Family Screening

• First-degree relatives of patients with HFE-related hemochromatosis should undergo:
  • Serum ferritin and transferrin saturation testing
  • HFE mutation analysis 1

Common Pitfalls to Avoid

1. Misinterpreting hyperferritinemia - Always rule out common causes before genetic testing:

   • Chronic alcohol consumption
   • Inflammation (check CRP)
   • Cell necrosis (check AST, ALT, CK)
   • Malignancy
   • Non-alcoholic fatty liver disease/metabolic syndrome 1, 2

2. Relying solely on genetic testing - Diagnosis requires both genetic predisposition AND evidence of increased iron stores 1

3. Missing non-HFE hemochromatosis - Rare forms due to mutations in other genes (HAMP, HJV, TFR2, SLC40A1) should be considered in patients with iron overload but negative HFE testing 3

4. Overlooking the need for liver biopsy - Essential in patients with ferritin >1,000 μg/L to assess for cirrhosis, which significantly impacts prognosis and management 1

Early diagnosis and treatment with phlebotomy can prevent serious complications including cirrhosis, hepatocellular carcinoma, diabetes, arthropathy, and cardiac disease, significantly improving morbidity, mortality, and quality of life 1, 4.