What are the guidelines for screening and managing hemochromatosis?

Screening and Management of Hemochromatosis

Routine population-wide screening for hereditary hemochromatosis is not recommended, but targeted screening should be performed in high-risk individuals using transferrin saturation and serum ferritin as initial tests, followed by HFE genetic testing when indicated. 1

Screening Recommendations

Who to Screen

• First-degree relatives of patients with hereditary hemochromatosis should undergo screening with both phenotypic testing (transferrin saturation and ferritin) and HFE genotyping 1, 2
• Case-finding is recommended for individuals with:
  • Suggestive symptoms (weakness, lethargy, arthralgias, impotence) 1, 3
  • Clinical findings (hepatomegaly, skin pigmentation changes, arthritis, cardiomyopathy) 1
  • Associated conditions (type 2 diabetes, cardiac arrhythmias, liver disease, arthritis, hypogonadism) 1
• Highest yield for optional screening would be one-time phenotypic screening of asymptomatic non-Hispanic white men 1

Initial Diagnostic Testing

• Both transferrin saturation (TS) and serum ferritin should be obtained simultaneously rather than relying on a single test 1, 2
• Diagnostic thresholds:
  • Transferrin saturation ≥45% (primary screening test) 1, 2
  • Serum ferritin >300 μg/L in men or >200 μg/L in women 1

Diagnostic Algorithm

Step 1: Initial Iron Studies

• Measure serum transferrin saturation and ferritin 1, 2
• If both normal: no further evaluation needed 1
• If either is abnormal (TS ≥45% or elevated ferritin): proceed to genetic testing 1, 2

Step 2: HFE Genetic Testing

• Test for C282Y and H63D mutations 1, 2
• Interpret results:
  • C282Y/C282Y homozygotes: Most likely to develop iron overload 1, 3
  • C282Y/H63D compound heterozygotes: May develop mild iron overload 1
  • C282Y heterozygotes: Generally not at risk for progressive iron overload 1

Step 3: Assessment of Disease Severity

• Serum ferritin >1000 μg/L with elevated liver enzymes and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 1, 2
• Liver biopsy indicated when:
  • Ferritin >1000 μg/L 1
  • Abnormal liver enzymes 1, 2
  • Need to assess hepatic iron concentration and histopathology 1

Management Approach

• Therapeutic phlebotomy is the mainstay of treatment for confirmed hemochromatosis with iron overload 1, 4
• Monitoring during treatment:
  • Serial measurements of serum ferritin levels and transferrin saturation 3
  • Target ferritin level in the low-normal range 4
• Family screening should be recommended for all first-degree relatives of an identified proband 1
  • For children of a proband, testing the other parent is recommended 1

Important Considerations and Pitfalls

• Serum ferritin can be falsely elevated due to inflammation, liver disease, or other conditions unrelated to iron overload 2
• Penetrance is variable - most C282Y homozygotes develop increased iron stores, but end-organ damage occurs less frequently than previously thought 5, 6
• Mortality risk is modestly increased in patients with phenotypic hemochromatosis but only marginally increased in first-degree relatives 7
• Genetic counseling should be provided before genetic testing, discussing benefits, risks, costs, and social implications 1

Monitoring for Complications

• Regular screening for hepatocellular carcinoma in patients with cirrhosis 3
• Monitoring for other complications including diabetes, cardiomyopathy, arthropathy, and hypogonadism 1, 3