What is the diagnosis and management for a patient with hyperferritinemia and high percent transferrin saturation?

Diagnosis: Likely Hereditary Hemochromatosis Requiring Genetic Testing

Your patient has hyperferritinemia (317 μg/L) with elevated transferrin saturation (36%), which warrants HFE genotype testing to evaluate for hereditary hemochromatosis, though the transferrin saturation is below the typical diagnostic threshold of 45%. 1

Immediate Diagnostic Steps

Order HFE genotype testing now to check for C282Y and H63D mutations, as this pattern of elevated ferritin with moderately elevated transferrin saturation (36%) suggests possible iron overload, though it's not definitive. 2, 1

Key Laboratory Tests to Obtain:

• Fasting transferrin saturation (repeat in fasting state if not already done) - the 36% value may increase when properly fasted 1
• Complete metabolic panel with ALT, AST to assess for liver disease 1
• CRP and ESR to rule out inflammatory causes of hyperferritinemia 1
• HFE genetic testing for C282Y and H63D mutations 2, 1

Clinical Context Matters

Your patient's transferrin saturation of 36% is below the 45% threshold typically used to diagnose iron overload, which creates diagnostic uncertainty. 2 However, several conditions can present with this pattern:

Consider These Alternative Diagnoses:

Alcoholic liver disease can cause severely elevated ferritin and transferrin saturation mimicking hemochromatosis, even with underlying cirrhosis - ask specifically about alcohol intake. 3

Metabolic syndrome/NAFLD commonly causes hyperferritinemia with normal or mildly elevated transferrin saturation - assess for obesity, diabetes, hypertension. 2, 4

Inflammatory conditions (rheumatologic diseases, chronic infections) elevate ferritin as an acute-phase reactant while transferrin saturation may be normal or low - check inflammatory markers. 1, 4

Autoimmune hepatitis can rarely present with elevated transferrin saturation simulating iron overload - consider if liver enzymes are elevated. 5

Risk Stratification Based on Ferritin Level

Your patient's ferritin of 317 μg/L is reassuring - this level is well below the 1,000 μg/L threshold associated with significant liver fibrosis or cirrhosis in hemochromatosis. 2

• Ferritin <1,000 μg/L with normal liver enzymes has a 94% negative predictive value for advanced liver fibrosis 1
• Cirrhosis risk is only 20-45% when ferritin exceeds 1,000 μg/L in C282Y homozygotes 1
• No liver biopsy is needed at this ferritin level unless liver enzymes are significantly elevated 2

Management Algorithm Based on Genetic Testing Results

If C282Y Homozygous:

Proceed directly to therapeutic phlebotomy without liver biopsy since ferritin <1,000 μg/L, targeting ferritin 50-100 μg/L. 2, 1

• Remove 500 mL blood weekly or biweekly 1
• Check hemoglobin/hematocrit before each phlebotomy 1
• Monitor ferritin every 10-12 phlebotomies 1
• Once target achieved, maintain with phlebotomy every 2-4 months 1

If C282Y/H63D Compound Heterozygous:

This genotype alone is insufficient to cause significant iron overload without additional risk factors (alcohol, metabolic syndrome). 1 Investigate secondary causes and treat underlying conditions rather than pursuing phlebotomy. 1

If Negative for HFE Mutations:

Focus on secondary causes - the low TIBC (231 mg/dL) suggests possible inflammation or chronic disease. 6, 4

• Evaluate for alcohol use, metabolic syndrome, chronic liver disease 4
• Consider hepatic MRI to quantify liver iron if diagnosis remains unclear 2, 1
• Treat underlying condition rather than the ferritin elevation 1

Critical Pitfalls to Avoid

Do not start phlebotomy based on ferritin alone without confirming elevated transferrin saturation ≥45% and/or positive genetic testing. 1 Your patient's 36% transferrin saturation is borderline and may reflect secondary causes rather than true iron overload.

Do not overlook alcohol consumption - even moderate drinking can disrupt iron metabolism and cause this exact laboratory pattern with elevated ferritin and transferrin saturation. 3, 4

Repeat transferrin saturation in the fasting state - non-fasting samples can underestimate true values. 2, 1

Screen first-degree relatives if genetic testing confirms C282Y homozygosity, as penetrance is higher in family members. 1