What are the typical blood work findings in hereditary hemochromatosis (HH), specifically in terms of serum iron, transferrin saturation, and ferritin levels?

Diagnostic Blood Work Findings in Hereditary Hemochromatosis

Hereditary hemochromatosis typically shows elevated transferrin saturation >55% and serum ferritin levels >200 μg/L on blood work, with these two parameters being the key laboratory indicators for diagnosis and further investigation. 1

Primary Laboratory Findings

• Transferrin Saturation:

  • Elevated >55% is a key diagnostic indicator 1
  • Often the earliest and most sensitive biochemical abnormality
  • Represents the percentage of iron bound to transferrin protein in blood
  • Values >45% warrant further investigation

• Serum Ferritin:

  • Elevated >200 μg/L in women and >300 μg/L in men 1, 2
  • Correlates with liver iron content and risk of cirrhosis development
  • Levels <1000 μg/L are typically not associated with cirrhosis 1
  • Levels >1000 μg/L indicate high risk (20-45%) of cirrhosis 2

Diagnostic Algorithm

1. Initial Screening:

   • Order both transferrin saturation and serum ferritin tests
   • If transferrin saturation >55% and ferritin is elevated, proceed to genetic testing

2. Genetic Testing:

   • Test for HFE gene mutations (C282Y and H63D)
   • C282Y homozygosity present in ~90% of hereditary hemochromatosis cases 1
   • Compound heterozygotes (C282Y/H63D) can also develop iron overload, but with lower penetrance 3, 4

3. Confirmatory Testing:

   • Consider liver biopsy in cases with ferritin >1000 μg/L to assess for cirrhosis
   • Historically considered the gold standard but less commonly used with genetic testing availability 1

Interpretation Challenges

• Variable Penetrance:

  • Not all genetic carriers develop iron overload
  • In one study, 80% of male C282Y homozygotes showed biochemical expression 4
  • Some studies have identified C282Y homozygotes with no biochemical evidence of iron overload 5

• Sex Differences:

  • Men typically have higher ferritin levels than women of the same age
  • Premenopausal women often have lower ferritin due to menstrual blood loss
  • Ferritin in women tends to increase sharply during menopause 3

• Early Disease:

  • In precirrhotic or early hemochromatosis, serum ferritin may still be within normal range 6
  • Transferrin saturation often becomes abnormal before ferritin rises

Common Pitfalls

• False Elevations of Ferritin:

  • Ferritin is an acute phase reactant and can be elevated in inflammatory conditions
  • Liver disease, alcohol use, and metabolic syndrome can cause hyperferritinemia without true iron overload 2
  • Always interpret ferritin in conjunction with transferrin saturation

• Diagnostic Thresholds:

  • Different cutoff values have been proposed in various studies
  • Baer et al. suggested diagnostic cutoffs of 500 μg/L for ferritin and 62% for transferrin saturation 1
  • Lower cutoffs increase sensitivity but decrease specificity

• Limited Sensitivity in Early Disease:

  • Some patients with hereditary hemochromatosis may have normal ferritin levels in early stages 6
  • Regular monitoring of at-risk individuals (family members) is important

When interpreting blood work for hereditary hemochromatosis, the combination of elevated transferrin saturation (>55%) and elevated serum ferritin (>200 μg/L) provides the strongest biochemical evidence for the diagnosis, warranting genetic testing for confirmation.