What is the recommended evaluation and management for an elevated serum iron level?

Evaluation and Management of Elevated Serum Iron

When serum iron is elevated, immediately calculate transferrin saturation (TS) by dividing serum iron by total iron-binding capacity—never interpret serum iron alone—because TS ≥45% is the critical threshold that distinguishes true iron overload requiring genetic testing from secondary causes. 1

Initial Diagnostic Approach

Measure transferrin saturation and serum ferritin simultaneously as the first-line screening tests for iron overload. 1 Serum iron concentration alone is highly variable due to diurnal fluctuations, postprandial changes, and inflammation, making it unreliable as a standalone marker. 1

Key Laboratory Tests to Order Immediately

• Transferrin saturation (TS): Calculated as (serum iron ÷ TIBC) × 100 1
• Serum ferritin: Must be measured concurrently with TS 1, 2
• Complete metabolic panel: Including ALT, AST to assess hepatocellular injury 1, 2
• Complete blood count: To evaluate for anemia, polycythemia, or hematologic disorders 2, 3
• Inflammatory markers: CRP and ESR to detect occult inflammation 1, 2

Algorithmic Decision Tree Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

This pattern indicates true iron overload and mandates immediate HFE genetic testing for C282Y and H63D mutations. 1 The 45% threshold provides 84% sensitivity in men and 73% sensitivity in women for detecting C282Y homozygosity. 1

Proceed with:

• HFE genetic testing for C282Y and H63D mutations 1, 2
• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms hereditary hemochromatosis 1, 4

If TS <45%: Iron Overload Excluded with >90% Certainty

When TS is below 45%, primary iron overload is unlikely and secondary causes of hyperferritinemia predominate—over 90% of elevated ferritin cases in this scenario are due to inflammation, chronic alcohol consumption, cell necrosis, tumors, or metabolic syndrome/NAFLD, not iron overload. 1, 2, 3, 5

Evaluate for secondary causes:

• Chronic liver disease: Alcoholic liver disease, NAFLD, viral hepatitis B or C 1, 2, 3, 4
• Inflammatory conditions: Rheumatologic diseases, inflammatory bowel disease, infections 1, 2, 3
• Malignancy: Solid tumors, lymphomas, hepatocellular carcinoma 1, 2, 3
• Cell necrosis: Muscle injury, hepatocellular necrosis 2, 3
• Metabolic syndrome/NAFLD: Ferritin reflects hepatocellular injury and insulin resistance, not iron stores 1, 2, 3

Risk Stratification by Ferritin Level

Ferritin <1,000 μg/L

• Low risk of organ damage with 94% negative predictive value for advanced liver fibrosis 1, 2
• In C282Y homozygotes with TS ≥45%: Can proceed directly to therapeutic phlebotomy without liver biopsy if age <40 years, normal liver enzymes, and no hepatomegaly 1, 2

Ferritin 1,000–10,000 μg/L

• Higher risk of advanced fibrosis/cirrhosis if iron overload is present 1, 2
• In C282Y homozygotes: The combination of ferritin >1,000 μg/L, elevated aminotransferases, and platelet count <200,000/μL predicts cirrhosis in 80% of cases 1, 2
• Consider liver biopsy if ferritin >1,000 μg/L with elevated liver enzymes or platelet count <200,000/μL 1, 2

Ferritin >10,000 μg/L

• Rarely represents simple iron overload—mandates urgent specialist referral to evaluate for life-threatening conditions such as adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 1, 2, 3
• Measure glycosylated ferritin fraction: <20% is 93% specific for adult-onset Still's disease when combined with 5-fold ferritin elevation 2, 3

Management of Confirmed Hereditary Hemochromatosis

Therapeutic Phlebotomy Protocol

Initiate phlebotomy in C282Y homozygotes with TS ≥45% and elevated ferritin to prevent organ damage. 1, 2

Induction phase:

• Remove 500 mL of blood weekly or biweekly as tolerated 1, 2
• Check hemoglobin/hematocrit before each phlebotomy; allow hemoglobin to fall no more than 20% from baseline 1, 2
• Check ferritin every 10–12 phlebotomies 1, 2
• Target ferritin: 50–100 μg/L 1, 2

Maintenance phase:

• Once target ferritin achieved, continue maintenance phlebotomy every 2–4 months to keep ferritin 50–100 μg/L 1, 2
• Monitor ferritin every 3 months once stable 2

Family Screening

Screen all first-degree relatives with both HFE genotype testing and phenotype (ferritin and TS) regardless of symptoms. 1, 2 Penetrance is higher in family members than in the general population. 2

Dietary and Lifestyle Modifications

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

When to Consider Liver Biopsy

Liver biopsy is indicated when ferritin >1,000 μg/L AND any of the following:

• Elevated liver enzymes (ALT, AST) 1, 2
• Platelet count <200,000/μL 1, 2
• Age >40 years 2
• Hepatomegaly 2

Alternative non-invasive assessment:

• MRI with T2/T2 relaxometry* to quantify hepatic iron concentration (correlation coefficient 0.74–0.98 with biochemical hepatic iron concentration, 84–91% sensitivity, 80–100% specificity) 2
• Liver elastography or non-invasive fibrosis scores (FIB-4, NAFLD Fibrosis Score) 2, 3

Specialist Referral Indications

Refer to gastroenterology/hepatology or hematology when:

• Ferritin >1,000 μg/L with elevated bilirubin 2
• Ferritin >10,000 μg/L regardless of other findings 2
• Confirmed TS ≥45% on repeat testing 2
• Clinical evidence of cirrhosis (platelet count <200,000/μL, elevated bilirubin, hepatomegaly) 2
• Confirmed C282Y homozygosity requiring therapeutic phlebotomy 2

Critical Pitfalls to Avoid

• Never interpret serum iron alone without calculating transferrin saturation—serum iron is too variable to be diagnostic 1, 2
• Never use ferritin alone to diagnose iron overload—ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 2, 3
• Do not order HFE genetic testing when TS <45%—this leads to misdiagnosis and unnecessary phlebotomy 2, 3
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests—histologic assessment for cirrhosis is essential 1, 2
• Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin 2, 3, 5
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1, 2

Expected Outcomes with Treatment

Therapeutic phlebotomy initiated before severe iron overload prevents hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadism, arthropathy, and cardiomyopathy. 1, 2 Survival is normal in patients treated before development of cirrhosis or diabetes, confirming the critical importance of early diagnosis and treatment. 1 However, phlebotomy does not reverse established cirrhosis, though it prevents progression. 2