What are the initial steps in a hemochromatosis (iron overload disorder) workup?

Initial Workup for Hemochromatosis

The initial steps in a hemochromatosis workup should include serum transferrin saturation and ferritin measurements, followed by HFE gene mutation analysis if either test is abnormal. 1

Step 1: Iron Studies

The first step in evaluating for hemochromatosis is to assess serum iron parameters:

• Transferrin saturation (TS): Primary screening test

  • TS ≥ 45% is considered elevated and requires further evaluation
  • Should be measured in the morning (fasting is not mandatory but may be considered for confirmation) 1

• Serum ferritin: Should be measured simultaneously with TS

  • Elevated levels vary by gender: >200 μg/L in women or >300 μg/L in men 1
  • Ferritin >1000 μg/L with elevated liver enzymes and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 1

• Additional iron parameters that may provide supplementary information:

  • Serum iron concentration
  • Transferrin or total iron binding capacity 1

Step 2: Genetic Testing

If either transferrin saturation is ≥45% or ferritin is elevated:

• HFE gene mutation analysis should be performed to detect:

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

• Pre-test genetic counseling should be provided to discuss:

  • Benefits and risks of genetic testing
  • Available treatments and their efficacy
  • Potential social issues (insurance, psychological impact) 1

Step 3: Liver Assessment

Liver biopsy is no longer routinely required for diagnosis but should be considered in specific circumstances:

• Serum ferritin >1000 μg/L
• Abnormal liver enzymes
• Age >40 years
• Non-HFE iron overload suspected 1

Liver biopsy helps to:

• Determine presence/absence of advanced fibrosis or cirrhosis
• Quantify hepatic iron concentration
• Rule out other liver diseases 1

Family Screening

Once a proband is identified:

• Screen all first-degree relatives

• For adult relatives, perform both:

  • Phenotypic testing (TS and ferritin)
  • HFE mutation analysis 1

• For children of an identified proband:

  • Consider testing the other parent first
  • If the other parent has normal results, the child is an obligate heterozygote and needs no further testing 1

Clinical Evaluation

Assess for symptoms and signs of iron overload:

• Nonspecific symptoms:

  • Fatigue, weakness, lethargy
  • Weight loss 1

• Organ-specific symptoms:

  • Abdominal pain (hepatomegaly)
  • Arthralgias/arthritis
  • Diabetes
  • Loss of libido, impotence
  • Cardiac symptoms (heart failure, arrhythmias) 1

• Physical findings:

  • Hepatomegaly
  • Skin pigmentation
  • Arthritis/joint swelling
  • Signs of liver disease
  • Testicular atrophy 1

Common Pitfalls to Avoid

1. Relying on a single test: Always measure both TS and ferritin, as either one alone may miss cases 1

2. Misinterpreting elevated ferritin: Remember that ferritin is an acute phase reactant and may be elevated in:

   • Inflammatory conditions
   • Alcohol consumption
   • Metabolic syndrome
   • Fatty liver disease 1

3. Overlooking hemochromatosis in women of childbearing age: While less common due to menstrual blood loss, women can still develop significant iron overload 2

4. Failing to screen first-degree relatives: Family screening is essential for early detection and prevention of complications 1

5. Overreliance on liver biopsy: With the advent of genetic testing, liver biopsy is now more selectively used for prognostic purposes rather than diagnosis 1