What is the likely diagnosis and recommended management for a patient with a transferrin saturation of 94% and a serum iron level of 325 µg/dL?

Severe Iron Overload Requiring Immediate Evaluation

You have severe iron overload with a transferrin saturation of 94% and serum iron of 325 µg/dL, which strongly indicates hereditary hemochromatosis or another primary iron overload disorder requiring immediate HFE genetic testing and urgent assessment for organ damage. 1, 2

Immediate Diagnostic Steps

Order HFE genetic testing for C282Y and H63D mutations immediately, as a transferrin saturation ≥45% is the key discriminator for true iron overload and warrants genetic evaluation. 1, 3 Your saturation of 94% far exceeds this threshold and indicates profound iron overload. 2

Critical Laboratory Panel

• Complete metabolic panel including ALT, AST, and bilirubin to assess for hepatocellular injury and liver dysfunction 1
• Complete blood count with platelet count – a platelet count <200,000/µL combined with your ferritin level predicts cirrhosis in 80% of C282Y homozygotes 1, 3
• Fasting glucose to screen for diabetes, a common complication of iron overload 1
• Prothrombin time/INR to assess synthetic liver function 1

Risk Stratification and Organ Damage Assessment

Your transferrin saturation of 94% places you at extremely high risk for organ damage. 2 A transferrin saturation >55% is associated with significantly increased all-cause mortality (hazard ratio 1.60), with deaths commonly attributed to cirrhosis and diabetes. 2

Liver Assessment

**If your ferritin is >1000 µg/L with elevated liver enzymes or platelet count <200,000/µL, you require liver biopsy to assess for cirrhosis.** 1, 3 The combination of ferritin >1000 µg/L, elevated aminotransferases, and platelet count <200,000/µL predicts cirrhosis in approximately 80% of C282Y homozygotes. 1, 3

• Consider liver MRI with T2/T2 relaxometry* to quantify hepatic iron concentration non-invasively, which shows 84-91% sensitivity and 80-100% specificity for iron overload 1
• Abdominal ultrasound should be performed to evaluate for hepatomegaly, cirrhotic morphology, or fatty liver 1

Cardiac Evaluation

You need cardiac assessment with ECG and echocardiography to screen for arrhythmias and cardiac dysfunction, as iron deposition in the myocardium can cause life-threatening cardiomyopathy. 1

Expected Genetic Results and Management

C282Y homozygosity or C282Y/H63D compound heterozygosity will confirm HFE-related hereditary hemochromatosis, which accounts for >80% of clinically overt hemochromatosis cases. 3, 2

Therapeutic Phlebotomy Protocol

Initiate therapeutic phlebotomy immediately once hereditary hemochromatosis is confirmed, even before biopsy results if you are <40 years old with normal liver enzymes. 1

• Remove 500 mL of blood weekly or biweekly as tolerated 1
• Check hemoglobin/hematocrit before each phlebotomy and allow hemoglobin to fall no more than 20% from baseline 1
• Target ferritin of 50-100 µg/L for the induction phase endpoint 1
• Check ferritin every 10-12 phlebotomies during the induction phase 1
• Once target ferritin is achieved, transition to maintenance phlebotomy every 2-4 months to keep ferritin in the 50-100 µg/L range 1

Critical Dietary and Lifestyle Modifications

• Avoid all iron supplements and iron-fortified foods 1
• Avoid vitamin C supplementation, as it accelerates iron mobilization and increases oxidative stress 1
• Avoid raw shellfish due to the risk of Vibrio vulnificus infection in iron-overloaded patients 1
• Limit alcohol consumption, as chronic alcohol use can worsen iron absorption and hepatocellular injury 3

Important Differential Consideration

Severe alcoholic hepatitis can mimic iron overload with markedly elevated transferrin saturation and ferritin, even though transferrin saturation >45% has high sensitivity for iron overload, it has low specificity and can identify people with acute liver disease. 4 However, your transferrin saturation of 94% is extraordinarily high and more consistent with true iron overload than secondary causes. 4

• A detailed alcohol history is essential to evaluate whether alcohol-related liver disease is contributing to your iron parameters 3
• Alcoholic hepatitis disrupts iron metabolism by suppressing hepcidin transcription through oxidative stress, which can release large amounts of iron into circulation 3

Family Screening

All first-degree relatives should undergo screening with transferrin saturation, ferritin, and HFE genetic testing once your diagnosis is confirmed, as penetrance is higher in family members than in the general population. 1

Expected Outcomes with Treatment

Therapeutic phlebotomy prevents hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadism, arthropathy, and cardiomyopathy when initiated before severe iron overload develops. 1 However, it does not reverse established cirrhosis, though it prevents progression. 1

Urgent Specialist Referral Indications

You require immediate referral to gastroenterology/hepatology or hematology given your extremely elevated transferrin saturation. 1 Specific referral triggers include:

• Transferrin saturation ≥45% on repeat testing (yours is 94%) 1
• Evidence of organ damage (cardiac evaluation, liver assessment) 1
• Ferritin >1000 µg/L with elevated bilirubin 1
• Clinical evidence of cirrhosis 1

Critical Pitfall to Avoid

Never interpret serum iron alone without calculating transferrin saturation, as serum iron concentration varies significantly with meals, diurnal variation, and inflammation. 5, 3 Your transferrin saturation of 94% is the critical diagnostic finding, not just the serum iron of 325 µg/dL. 3