How should I evaluate and manage a patient with elevated iron studies (high serum iron, ferritin, and transferrin saturation)?

Evaluation and Management of Elevated Iron Studies

When you encounter elevated serum iron, ferritin, and transferrin saturation together, immediately measure a fasting transferrin saturation (TS) to confirm the elevation, then proceed directly to HFE genetic testing for C282Y and H63D mutations if TS ≥45%, as this pattern strongly suggests hereditary hemochromatosis or another primary iron overload disorder requiring urgent intervention to prevent cirrhosis, hepatocellular carcinoma, and cardiac disease. 1, 2

Initial Diagnostic Algorithm

Step 1: Confirm the Elevation with Proper Testing

• Obtain a second fasting transferrin saturation measurement to confirm the elevation, as biological variability can occur and recent dietary iron intake can falsely elevate serum iron levels 2, 3
• Measure serum ferritin simultaneously with transferrin saturation—this combination is essential for proper iron status assessment and prevents diagnostic errors 1, 2
• Ensure the patient has avoided all iron-containing supplements and high-iron foods for at least 24 hours before blood draw, and perform testing in the morning 3

Step 2: Determine if True Iron Overload is Present

The transferrin saturation is the single most important discriminator between true iron overload and secondary causes of hyperferritinemia. 1, 3

• If TS ≥45% with elevated ferritin: This pattern indicates primary iron overload—proceed immediately to HFE genetic testing for C282Y and H63D mutations 1, 3, 2
• If TS <45% despite elevated ferritin: Iron overload is unlikely; over 90% of these cases are caused by inflammation, chronic alcohol consumption, liver disease (NAFLD, viral hepatitis), cell necrosis, or malignancy—not hemochromatosis 1, 3

Step 3: Rule Out Secondary Causes Before Genetic Testing

Before proceeding to genetic testing, systematically exclude common causes that account for over 90% of elevated iron studies 1, 3:

• Check complete metabolic panel including ALT, AST, bilirubin, and albumin to assess for hepatocellular injury 1, 2
• Evaluate for liver disease: Chronic alcohol consumption, NAFLD/metabolic syndrome, viral hepatitis B and C, acute hepatitis 1, 3
• Assess for inflammation: Check CRP and ESR—ferritin is an acute-phase reactant that rises with inflammation independent of iron stores 1, 3, 4
• Consider malignancy: Solid tumors, lymphomas, hepatocellular carcinoma 1, 3
• Evaluate for cell necrosis: Check creatine kinase for muscle injury 3

Genetic Testing and Diagnosis

When to Order HFE Testing

• Order HFE genetic testing for C282Y and H63D mutations when TS ≥45% after excluding secondary causes 1, 3, 2
• For males: TS >50% with ferritin >300 μg/L warrants genetic testing 2
• For females: TS >45% with ferritin >200 μg/L warrants genetic testing 2

Interpreting Genetic Results

• C282Y homozygosity confirms hereditary hemochromatosis diagnosis—this genotype is present in >80% of patients with clinically overt hemochromatosis 1, 3, 2
• C282Y/H63D compound heterozygosity can cause iron overload, but management should be guided by phenotype (ferritin level, organ involvement) not genotype alone 1, 2
• H63D compound heterozygosity alone appears insufficient to cause significant iron overload without additional acquired risk factors 1

Risk Stratification by Ferritin Level

Once iron overload is confirmed, ferritin level determines urgency and approach 1, 2:

• Ferritin <1,000 μg/L: Low risk of cirrhosis (negative predictive value 94%)—proceed directly to therapeutic phlebotomy without liver biopsy if age <40 years, normal liver enzymes, and no hepatomegaly 1, 3, 2
• Ferritin 1,000-10,000 μg/L: Higher risk of advanced fibrosis/cirrhosis (20-45% prevalence in C282Y homozygotes)—strongly consider liver biopsy if accompanied by elevated liver enzymes or platelet count <200,000/μL 1, 3, 2
• Ferritin >10,000 μg/L: Rarely represents simple iron overload—requires urgent specialist referral to evaluate for life-threatening conditions such as adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 1, 3

Assessment for Organ Damage

Before initiating treatment, assess for organ involvement 1, 2:

• Liver assessment: ALT, AST, bilirubin, albumin, platelet count; consider liver elastography or MRI with iron quantification if ferritin >1,000 μg/L 1, 3
• Cardiac evaluation: ECG and echocardiography to screen for arrhythmias and cardiac dysfunction if severe iron overload suspected; cardiac MRI for myocardial iron quantification if signs of heart disease present 1
• Endocrine assessment: Fasting glucose and lipid panel for metabolic syndrome; evaluate for hypogonadism if clinically indicated 1
• Joint assessment: 86.5% of hemochromatosis patients report joint pain, particularly affecting 2nd and 3rd metacarpophalangeal joints, ankles, hips, and wrists 1

Therapeutic Phlebotomy Protocol

Induction Phase

For confirmed hereditary hemochromatosis with elevated iron stores, initiate therapeutic phlebotomy immediately with a target ferritin of 50-100 μg/L. 1, 2

• Remove 450-500 mL blood weekly (or 7 mL/kg in smaller patients) during induction phase 1, 2
• Check hemoglobin/hematocrit before each phlebotomy—allow hemoglobin to fall no more than 20% from baseline 1
• Check ferritin every 10-12 phlebotomies (or monthly) during induction 1, 2
• Monitor liver enzymes every 3 months during induction phase 2

Maintenance Phase

• Once target ferritin of 50-100 μg/L is achieved, continue maintenance phlebotomy every 2-4 months to keep ferritin in this range 1, 2
• Monitor ferritin every 6 months and transferrin saturation annually during maintenance 2

Expected Outcomes

• Therapeutic phlebotomy prevents hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadism, arthropathy, and cardiomyopathy when initiated before severe iron overload develops 1
• Phlebotomy before development of cirrhosis and/or diabetes significantly reduces morbidity and mortality 1
• Does not reverse established cirrhosis, but prevents progression 1

Critical Management Considerations

Absolute Contraindications

• Avoid iron supplements entirely during and after treatment 1, 2
• Avoid vitamin C supplementation during phlebotomy therapy—it accelerates iron mobilization and increases oxidative stress 1
• Avoid raw shellfish due to risk of Vibrio vulnificus infection in iron-overloaded patients 1

Alcohol Restrictions

• Avoid alcohol completely during iron depletion phase 2
• Limit to very small amounts if iron overload, organ disease, or liver abnormalities present 2

Dietary Modifications

• Avoid iron-fortified foods and limit red meat consumption 2

Family Screening

Screen all first-degree relatives of patients with confirmed C282Y homozygous hemochromatosis with both HFE genotype testing and phenotype (ferritin and TS) after informed consent 1, 2

• Penetrance is higher in family members than the general population 1
• Early detection and treatment in relatives prevents organ damage 1

Special Clinical Contexts

Chronic Kidney Disease with Anemia

• For dialysis patients with ferritin 500-1,200 ng/mL but TS <25%, intravenous iron may still be beneficial despite elevated ferritin, especially if receiving erythropoietin therapy—this represents functional iron deficiency 5, 1, 3
• The DRIVE study demonstrated significant hemoglobin improvement (16 g/L vs 11 g/L, P=0.028) with IV iron in this population 5, 3
• Withhold iron therapy when ferritin exceeds 1,000 ng/mL or TS exceeds 50% in CKD patients 1

Inflammatory Conditions

• In inflammatory states, ferritin rises acutely while TS often drops, creating a pattern of elevated ferritin with low TS—this represents inflammatory iron block, not true iron overload 1, 3, 4
• Treat the underlying condition, not the elevated ferritin in patients with secondary hyperferritinemia 1, 3

Common Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload—ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 3, 4
• Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin 1, 3
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests—this combination predicts cirrhosis in 80% of C282Y homozygotes 1, 3
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1, 2
• Do not delay treatment while awaiting cardiac MRI in patients with severe hemochromatosis and signs of heart disease 1

When to Refer to Specialist

• Ferritin >1,000 μg/L regardless of TS—refer to gastroenterology/hepatology for further evaluation 1
• TS ≥45% after initial workup—refer to hematology or hepatology 1, 2
• Evidence of organ damage (cardiac dysfunction, cirrhosis, endocrine abnormalities) 1
• Ferritin >10,000 μg/L—requires urgent specialist referral 1, 3