What is the initial step in testing for haemochromatosis?

Testing for Haemochromatosis

The first step in testing for haemochromatosis is the assessment of serum iron parameters, which should include transferrin saturation and serum ferritin. 1

Initial Diagnostic Approach

The European Association for the Study of the Liver (EASL) guidelines provide a clear diagnostic pathway for haemochromatosis with 100% consensus on the initial testing approach:

• Transferrin saturation (TSAT) is the most sensitive first-line test:

  • Values >45% in females and >50% in males warrant further investigation
  • Persistently elevated TSAT is particularly concerning

• Serum ferritin should be measured simultaneously:

  • Elevated levels (>200 μg/L in women, >300 μg/L in men) suggest iron overload
  • Levels >1000 μg/L are associated with a high risk (20-45%) of cirrhosis 2

Subsequent Testing

If initial iron studies are abnormal, the diagnostic algorithm proceeds as follows:

1. Genetic testing:

   • HFE genotyping for p.C282Y should be performed in individuals with biochemical evidence of iron overload 1
   • This is particularly important for those of European origin
   • Adult first-degree relatives of patients with p.C282Y homozygous haemochromatosis should also be tested 1

2. Additional iron parameters:

   • Serum iron concentration and total iron binding capacity can provide supplementary information for differential diagnosis 1
   • Measuring hepcidin is not recommended (100% consensus) 1

3. Imaging studies:

   • MRI should be used to quantify hepatic iron concentrations in cases of:
     • Unclear cause of hyperferritinemia
     • Biochemical iron overload
     • Positive liver iron staining 1

Important Clinical Considerations

• Early diagnosis is crucial as phlebotomy therapy can prevent or reverse organ damage 3

• Elevated ferritin can occur in various conditions besides haemochromatosis:

  • Acute and chronic liver disease
  • Systemic inflammatory states
  • Secondary iron overload syndromes 3

• Diagnosis can be challenging due to uncharacteristic clinical features such as:

  • Fatigue, weakness, lethargy
  • Joint pain and arthritis
  • Diabetes mellitus
  • Sexual dysfunction 2, 4

Common Pitfalls to Avoid

1. Relying solely on ferritin levels: Ferritin is an acute phase reactant and can be elevated in inflammatory conditions without true iron overload 2

2. Missing non-HFE forms: While HFE-related haemochromatosis (particularly C282Y homozygosity) is most common, non-HFE forms exist and may require specialized testing 5

3. Overlooking confounding factors: Alcohol consumption can exacerbate iron overload and complicate diagnosis 4

4. Premature liver biopsy: While historically important, non-invasive testing with iron studies and genetic testing should precede invasive procedures 6

5. Neglecting family screening: Adult first-degree relatives of patients with confirmed haemochromatosis should be tested, as early intervention significantly improves outcomes 7

By following this structured approach to testing for haemochromatosis, clinicians can identify affected individuals early in the disease course, enabling timely intervention that can normalize life expectancy and prevent serious complications.