What is the assessment and plan for hemochromatosis?

Assessment and Management of Hemochromatosis

The assessment and management of hemochromatosis should begin with serum iron studies (transferrin saturation and serum ferritin) followed by genetic testing for HFE mutations in those with elevated iron parameters, with phlebotomy as the mainstay of treatment for confirmed cases with iron overload. 1, 2

Diagnostic Assessment

Initial Laboratory Testing

• The first step in testing for hemochromatosis is the assessment of serum iron parameters, which must include transferrin saturation and serum ferritin 1
• Diagnostic thresholds for abnormal iron studies are transferrin saturation ≥45% and serum ferritin >300 μg/L in men or >200 μg/L in women 2, 3
• Serum iron and total iron binding capacity measurements can provide additional information for differential diagnosis 1
• Measuring hepcidin is not recommended for diagnosis 1

Genetic Testing

• Individuals with elevated transferrin saturation and high serum ferritin should undergo genetic testing for HFE mutations after obtaining informed consent 1
• Genotyping for p.C282Y in HFE should be performed in individuals of European origin with biochemical evidence of iron overload (females with transferrin saturation >45% and serum ferritin >200 μg/L; males with transferrin saturation >50% and ferritin >300 μg/L) 1
• Adult first-degree relatives of patients with p.C282Y homozygous hemochromatosis should be tested for the p.C282Y variant 1, 3
• Testing for non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) should be considered when iron overload is confirmed but C282Y homozygosity is absent 1

Imaging and Biopsy

• MRI should be used to quantify hepatic iron concentrations and assess extrahepatic organ involvement in patients with unclear cause of hyperferritinemia or biochemical iron overload 1
• Liver biopsy is no longer necessary to diagnose hemochromatosis in C282Y homozygotes with increased iron stores 1
• Liver biopsy should be considered in C282Y homozygous patients with serum ferritin above 1000 μg/L, elevated liver enzymes, hepatomegaly, or age over 40 years to assess for cirrhosis 1, 2
• Cardiac MRI can be performed in patients with hemochromatosis and signs of heart disease, and in juvenile forms of hemochromatosis 1

Management Plan

Therapeutic Phlebotomy

• Phlebotomy is the mainstay of treatment for confirmed hemochromatosis with iron overload 3, 4
• The goal of phlebotomy is to achieve and maintain serum ferritin levels in the low-normal range 1
• Patients who are compound heterozygous for p.C282Y/p.H63D or homozygous for p.H63D with confirmed iron overload may be treated with phlebotomy, but this requires individualized clinical assessment 1
• If serum ferritin falls below 1000 μg/L at two consecutive visits, consider dose reduction of phlebotomy frequency, especially if the patient is on an intensive regimen 5
• If serum ferritin falls below 500 μg/L, interrupt phlebotomy therapy and continue monthly monitoring 5

Iron Chelation Therapy

• Iron chelation therapy with deferasirox may be considered in patients who cannot tolerate phlebotomy 5
• Prior to starting deferasirox, evaluate baseline renal function, serum ferritin level, and liver function 5
• Monitor serum ferritin monthly and adjust the dose of deferasirox based on serum ferritin trends 5
• Deferasirox can cause serious adverse effects including renal failure, hepatic failure, and gastrointestinal hemorrhage, requiring close monitoring 5

Monitoring and Follow-up

• Monitor serum ferritin and transferrin saturation regularly during treatment 1
• Perform regular assessments of liver function, renal function, and complete blood counts 5
• Conduct auditory and ophthalmic testing before starting treatment and at regular intervals (every 12 months) 5
• Evaluate for complications including arthropathy, diabetes, cardiac disease, and hypogonadism 6

Special Considerations

Family Screening

• Siblings of patients with HFE-related hemochromatosis must undergo screening due to their 25% chance of being susceptible 1
• Family screening should include both phenotypic testing (transferrin saturation and ferritin) and HFE genotyping 3

Lifestyle Modifications

• Heavy alcohol intake should always be discouraged in patients with hemochromatosis 1
• Patients with hemochromatosis, especially if iron overloaded, should avoid raw seafood due to the risk of severe Vibrio vulnificus infections 1
• The risk of Vibrio vulnificus infection is likely mitigated in patients with normal serum ferritin and normal transferrin saturation 1

Pitfalls to Avoid

• Do not diagnose HFE hemochromatosis based on C282Y homozygosity alone; evidence of increased iron stores is required 1
• Before diagnosing hemochromatosis, exclude common causes of hyperferritinemia including chronic alcohol consumption, inflammation, cell necrosis, tumors, and non-alcoholic fatty liver disease 1, 2
• Serum ferritin can be falsely elevated due to inflammation, making it less specific than transferrin saturation for diagnosis 1, 3
• Avoid continued aggressive iron depletion when ferritin levels approach normal range, as this can lead to adverse effects 5