What is the appropriate workup for a patient suspected of having hemochromatosis (iron overload disorder)?

Hemochromatosis Workup

Begin with fasting transferrin saturation (TS) and serum ferritin measured simultaneously as the essential initial laboratory tests for suspected hemochromatosis. 1, 2

Initial Laboratory Testing

• Measure both fasting transferrin saturation and serum ferritin together – never rely on a single test, as combined interpretation provides optimal diagnostic accuracy 1, 2
• Calculate transferrin saturation as: (serum iron ÷ total iron-binding capacity) × 100 2, 3
• Diagnostic thresholds that trigger genetic testing:
  • Transferrin saturation ≥45% (primary screening marker) 1, 2
  • Serum ferritin >300 μg/L in males or >200 μg/L in females 1, 2

Exclude Secondary Causes of Hyperferritinemia

Before proceeding with genetic testing, evaluate for common causes of elevated ferritin that can mimic hemochromatosis 1:

• Chronic alcohol consumption – obtain detailed alcohol history 1, 4
• Inflammation – check C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) 1
• Cell necrosis – measure AST, ALT, and creatine kinase (CK) 1
• Malignancy – consider CT scan if clinically indicated 1
• Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome – assess blood pressure, BMI, cholesterol, triglycerides, and serum glucose 1

Critical pitfall: Ferritin is an acute-phase reactant and can be markedly elevated without iron overload in chronic liver disease, viral hepatitis, lymphomas, and inflammatory conditions 2, 5, 3

Genetic Testing

If TS ≥45% or ferritin is elevated after excluding secondary causes, proceed with HFE gene mutation analysis for C282Y and H63D mutations 1, 2

• C282Y homozygosity accounts for 85-90% of clinically affected patients 2, 6, 7
• Diagnosis of HFE hemochromatosis requires both:
  • Positive genetic testing (C282Y homozygosity) AND
  • Evidence of increased iron stores 1
• C282Y homozygosity alone without elevated iron parameters does not establish the diagnosis 1

Interpretation of Genetic Results

• C282Y/C282Y homozygotes with elevated iron studies: Diagnosis of HFE hemochromatosis confirmed 1, 2
• C282Y/H63D compound heterozygotes or H63D/H63D homozygotes: First investigate other causes of hyperferritinemia, as these genotypes have lower penetrance and rarely cause significant iron overload alone 1, 2
• Negative HFE testing with confirmed iron overload: Consider testing for rare hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) only after confirming iron excess by MRI or liver biopsy 1

Assessment of Disease Severity and Complications

Liver Disease Assessment

All patients with confirmed hemochromatosis should be non-invasively assessed for liver fibrosis at diagnosis 1

• Liver biopsy is indicated if: 1

  • Serum ferritin >1,000 μg/L
  • Elevated AST or ALT
  • Hepatomegaly on examination
  • Age >40 years in C282Y homozygotes
  • Platelet count <200

• High-risk predictors for cirrhosis (80% probability): Ferritin >1,000 μg/L + elevated ALT/AST + platelet count <200 2, 3

• Low-risk for cirrhosis: Ferritin <1,000 μg/L with normal transaminases and no hepatomegaly 1, 2

Non-Invasive Fibrosis Assessment

• Transient elastography: Liver stiffness <6.4 kPa rules out advanced fibrosis 1
• FIB-4 score: Can be used but has limited validation specifically in hemochromatosis 1
• MRI: Useful for non-invasive quantification of hepatic iron concentration when diagnosis is unclear 1, 2

Extrahepatic Manifestations

Clinically evaluate all patients for: 1

• Skeletal: Joint pain, arthritis, osteoporosis, fractures 1
• Endocrine: Diabetes mellitus, erectile dysfunction, loss of libido, amenorrhea 1
• Cardiac (in severe iron overload):
  • Obtain ECG and echocardiography 1
  • Cardiac MRI for iron quantification if signs/symptoms of heart disease present 1
  • Mandatory cardiac MRI in juvenile hemochromatosis 1

Hepatocellular Carcinoma Screening

• Patients with cirrhosis (METAVIR F4 or Ishak stage 6): HCC screening with ultrasound every 6 months, regardless of iron depletion status 1
• Patients with advanced fibrosis (METAVIR F3): Consider HCC screening every 6 months 1
• Use MRI or CT if ultrasound is technically suboptimal 1

Family Screening

Genetic testing of siblings is mandatory; testing of other first-degree relatives should be strongly considered 1

• Perform both HFE genetic testing and phenotypic screening (TS and ferritin) simultaneously in first-degree relatives 2
• Family screening is cost-effective and identifies at-risk individuals before organ damage occurs 1

Special Considerations for Young Patients

Young individuals (<30 years) with biochemical evidence and clinical manifestations (liver disease, amenorrhea, hypogonadism, cardiomyopathy) should be tested for rare hemochromatosis gene variants (HJV, HAMP, TFR2, SLC40A1) 1, 6

• Juvenile hemochromatosis (HJV mutations) presents with severe cardiac and endocrine manifestations before age 30 6
• These patients require urgent cardiac assessment and aggressive iron removal 1