How should I evaluate and treat a patient with a transferrin saturation of 93% and no obvious cause such as chronic transfusions, iron supplementation, or liver disease?

Evaluation and Management of Transferrin Saturation of 93%

A transferrin saturation of 93% is markedly elevated and requires immediate genetic testing for hereditary hemochromatosis (HFE gene mutations, particularly C282Y homozygosity) along with serum ferritin measurement, followed by hepatic MRI to quantify tissue iron overload if genetic testing is positive or if ferritin is significantly elevated. 1

Initial Diagnostic Workup

Confirm the Elevated Transferrin Saturation

• Repeat fasting morning measurement of transferrin saturation, as diurnal variation causes levels to rise in the morning and fall at night, and serum iron increases after meals 1
• Ensure the sample was not drawn within 4 weeks of any intravenous iron infusion, as circulating iron interferes with the assay and can produce falsely elevated results 2
• A transferrin saturation >50% in males or >45% in females indicates iron overload and warrants further investigation 1

Obtain Serum Ferritin

• Measure serum ferritin concentration to assess total body iron stores, as 1 μg/L of serum ferritin is equivalent to approximately 10 mg of stored iron 1
• Ferritin >300 μg/L in males or >200 μg/L in females, combined with elevated transferrin saturation, strongly suggests iron overload 1
• Important caveat: Ferritin is an acute-phase reactant and can be elevated by chronic infection, inflammation, hepatitis, cirrhosis, neoplasia, or arthritis independent of iron status 1

Genetic Testing for Hereditary Hemochromatosis

Order HFE genotyping for C282Y and H63D mutations in individuals of European origin with biochemical evidence of iron overload (transferrin saturation >50% in males or >45% in females with elevated ferritin) 1

• C282Y homozygosity accounts for >80% of clinically overt hereditary hemochromatosis cases 1
• C282Y/H63D compound heterozygosity or H63D homozygosity can cause mild iron overload, particularly with additional environmental risk factors 1
• If genetic testing is negative for these common mutations, investigate secondary causes of iron overload 3

Assess for Secondary Causes of Iron Overload

Exclude Common Secondary Causes

If HFE genetic testing is negative or shows only heterozygosity without C282Y homozygosity:

• Chronic liver disease: Alcoholic liver disease, viral hepatitis, or nonalcoholic fatty liver disease can disrupt iron metabolism and cause severely elevated transferrin saturation 1, 4, 5
• Hematologic disorders: Thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, or pyruvate kinase deficiency 3
• Iatrogenic causes: Multiple blood transfusions or excessive iron supplementation 3
• Metabolic syndrome: Obesity, hyperlipidemia, abnormal glucose metabolism, or hypertension are associated with hepatic iron overload despite normal transferrin saturation in some cases 5

Evaluate Liver Function and Inflammation

• Obtain liver enzymes (AST, ALT) and inflammatory markers (CRP, ESR) to assess for chronic liver disease or inflammation 1, 6
• Elevated AST index and cirrhosis are associated with nontransferrin-bound iron (NTBI), which can cause iron-induced cellular damage 6
• Alcohol consumption history is critical, as heavy alcohol intake increases iron absorption and can cause transferrin saturation >70% with severe hepatic iron overload 1, 4

Quantify Tissue Iron Overload

Hepatic MRI with R2* Quantification

Order hepatic MRI with R2 sequences to quantify liver iron concentration* in patients with biochemical iron overload (elevated transferrin saturation and ferritin) or unclear cause of hyperferritinemia 1

• MRI enables non-invasive quantification of hepatic iron and predicts the number of phlebotomies required for treatment 1
• MRI can assess extrahepatic organ involvement (spleen, pancreas, heart, brain) to determine the distribution of iron overload 1
• Cardiac MRI should be performed if there are signs of heart disease or in juvenile forms of hemochromatosis 1

Consider Liver Biopsy in Select Cases

• Liver biopsy is NOT recommended solely for diagnosing hepatic iron overload 1
• Biopsy can be performed to assess liver fibrosis if serum ferritin >1,000 μg/L or if liver enzymes are elevated 1
• In patients with an otherwise clear diagnosis of cirrhosis, liver biopsy is not recommended 1

Assess for Advanced Liver Fibrosis

Non-Invasive Fibrosis Assessment

All patients with hemochromatosis should be non-invasively assessed for liver fibrosis at diagnosis to guide treatment and follow-up 1

• Transient elastography can rule out advanced fibrosis if liver stiffness is <6.4 kPa 1
• FIB-4 score is the best-evaluated serum-based marker for fibrosis in chronic liver diseases, though evidence is limited in hemochromatosis 1
• Patients with ferritin <1,000 μg/L, normal transaminases, and no liver enlargement have very low risk of advanced fibrosis 1

Treatment and Monitoring

Phlebotomy Therapy

Therapeutic phlebotomy is the primary treatment for iron overload once the diagnosis is confirmed 1

• Iron overload should be managed by phlebotomy regardless of genotype (C282Y homozygotes, compound heterozygotes, or secondary causes) 1
• Target transferrin saturation ≥20% after iron depletion to ensure adequate iron availability for erythropoiesis 2
• Management of additional environmental risk factors (alcohol cessation, weight loss, treatment of fatty liver disease) is crucial 1

Lifestyle Modifications

• Alcohol consumption should be avoided or limited to occasional and very small amounts in the presence of iron overload, organ disease, or liver abnormalities 1
• Avoid raw or undercooked seafood, particularly in warm coastal waters, due to risk of life-threatening Vibrio vulnificus infection in patients with iron overload (mortality rate >50% in fulminant sepsis) 1
• Weight loss through dietary modification and increased physical activity should be recommended in patients with fatty liver disease 1

Family Screening

Adult first-degree relatives of patients with C282Y homozygous hemochromatosis should be tested for the C282Y variant in HFE after informed consent for genetic testing 1

Common Pitfalls to Avoid

• Do not assume elevated transferrin saturation always indicates hereditary hemochromatosis: Alcoholic liver disease can cause transferrin saturation >70% and mimic hemochromatosis, especially with underlying cirrhosis 4, 6
• Do not rely on ferritin alone: Ferritin can be elevated by inflammation, infection, malignancy, or liver disease independent of iron status 1
• Do not measure iron parameters within 4 weeks of IV iron infusion: Circulating iron produces falsely elevated transferrin saturation 2
• Do not overlook metabolic syndrome: Obesity, hyperlipidemia, and abnormal glucose metabolism are associated with hepatic iron overload even with normal transferrin saturation 5
• Transferrin saturation >100% ("oversaturation") indicates free iron toxicity: This can occur with rapid IV iron infusion and may cause hypotension, malaise, and cellular damage from reactive oxygen species 7