What is the approach to evaluating hemochromatosis?

Evaluation of Hemochromatosis

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

Initial Diagnostic Testing

Step 1: Serum Iron Studies

• Transferrin saturation (TS) and serum ferritin should be measured simultaneously 1, 2
  • TS ≥45% has high sensitivity for detecting C282Y homozygotes 2
  • Abnormal values: TS >45% in women and >50% in men 1
  • Ferritin >200 μg/L in women and >300 μg/L in men 1
• Additional iron studies that may provide supplemental information:
  • Serum iron concentration
  • Transferrin or total iron binding capacity 1
• Measuring hepcidin is not recommended 1

Step 2: Genetic Testing

• If TS is elevated (≥45%) or ferritin is above upper limit of normal, proceed with genetic testing for HFE mutations 1, 2
• Test for the C282Y and H63D variants in the HFE gene 1
• Most common genotypes causing hemochromatosis:
  • C282Y homozygosity (most common)
  • C282Y/H63D compound heterozygosity (less common)

Diagnostic Algorithm

1. Abnormal iron studies + C282Y homozygosity = Diagnosis of HFE hemochromatosis
2. Abnormal iron studies + C282Y/H63D compound heterozygosity:
   • Investigate for other causes of iron overload 1
   • Treatment decisions require individualized clinical assessment 1
3. Abnormal iron studies + negative HFE testing:
   • Consider MRI to quantify hepatic iron concentration 1
   • Consider liver biopsy for histopathology and iron quantification 1

Indications for Liver Biopsy

Liver biopsy should be considered in the following scenarios:

• Serum ferritin >1,000 μg/L (predictor of advanced fibrosis) 1, 2
• Age >40 years with clinical evidence of liver disease 2
• Elevated liver enzymes 2
• Non-C282Y homozygotes with iron overload to determine iron distribution and exclude other liver diseases 1

MRI Assessment

• MRI should be used to quantify hepatic iron concentrations in patients with:
  • Unclear cause of hyperferritinemia
  • Biochemical iron overload
  • Positive liver iron staining 1
• Cardiac MRI can be performed in patients with signs of heart disease and in juvenile forms of hemochromatosis 1

Family Screening

• Adult first-degree relatives of patients with C282Y homozygous hemochromatosis should be tested for the C282Y variant 1, 2
• For children of an identified proband, testing the other parent is recommended first 1
  • If the other parent has normal HFE testing, the child is an obligate heterozygote and needs no further testing

Common Pitfalls to Avoid

1. Misinterpreting elevated ferritin: Ferritin can be elevated in inflammatory conditions, alcoholic liver disease, viral hepatitis, and non-alcoholic fatty liver disease 2

2. Overlooking non-HFE hemochromatosis: Not all iron overload is due to HFE mutations; rare forms exist 3

3. Inadequate family screening: Many homozygous relatives have biochemical evidence of disease but remain undiagnosed 2

4. Ignoring risk of Vibrio vulnificus infection: Patients with hemochromatosis (especially if iron overloaded) are at risk for severe Vibrio vulnificus infections from contaminated seafood 1

5. Missing comorbid conditions: HFE mutations can be cofactors in other liver diseases 2

By following this systematic approach to evaluating hemochromatosis, early diagnosis can be achieved, allowing for timely intervention with phlebotomy therapy to prevent complications such as cirrhosis, hepatocellular carcinoma, diabetes, arthropathy, and cardiomyopathy.