What additional markers should be checked in an adult patient with elevated ferritin (iron storage protein) and no known pre-existing medical conditions?

Workup of Elevated Ferritin

When evaluating elevated ferritin, immediately measure fasting transferrin saturation (TS) alongside ferritin—this single test determines whether you're dealing with true iron overload (TS ≥45%) or secondary causes (TS <45%), which account for over 90% of cases. 1

Initial Laboratory Panel

Order these tests simultaneously with ferritin and transferrin saturation:

• Complete blood count (CBC) with differential to assess for anemia, polycythemia, or hematologic malignancy 2, 1
• Comprehensive metabolic panel (CMP) including AST, ALT, alkaline phosphatase, and albumin to evaluate hepatocellular injury 1, 3
• Inflammatory markers: CRP and ESR to detect occult inflammation, as ferritin is an acute-phase reactant that rises independent of iron stores 1, 3
• Creatine kinase (CK) to assess for muscle necrosis or rhabdomyolysis, which releases ferritin from damaged cells 3

Algorithmic Approach Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

• Order HFE genetic testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis 1, 3
• C282Y homozygotes with elevated TS confirm HFE hemochromatosis and can proceed directly to therapeutic phlebotomy 1
• Consider liver MRI (T2* or R2 relaxometry) to quantify hepatic iron concentration non-invasively 4
• Liver biopsy is indicated if ferritin >1000 μg/L with elevated liver enzymes, age >40 years, or platelet count <200,000/μL (80% risk of cirrhosis in C282Y homozygotes) 1

If TS <45%: Evaluate Secondary Causes

This pattern indicates the elevated ferritin is NOT due to iron overload. Focus on these common etiologies:

• Metabolic syndrome/NAFLD: Check fasting insulin, HOMA-IR index, HbA1c, and consider FibroScan or FIB-4 score for liver fibrosis 1, 3, 5
• Alcohol consumption: Obtain detailed alcohol history (grams per day), as chronic alcohol use is among the most common causes 1, 6
• Malignancy screening: Review CBC for cytopenias, order serum protein electrophoresis (SPEP), and consider age-appropriate cancer screening 7, 8
• Infection: Evaluate for active infection with appropriate cultures and imaging, as infection causes acute ferritin elevation 1, 8
• Chronic kidney disease: Check creatinine and GFR, as CKD patients may have functional iron deficiency despite elevated ferritin 1

Additional Testing for Specific Clinical Contexts

If Ferritin >10,000 μg/L (Medical Emergency)

• Urgent specialist referral required, as this rarely represents simple iron overload 1
• Consider Adult-onset Still's Disease (AOSD): Order glycosylated ferritin fraction—levels ≤20% are 93% specific for AOSD when combined with 5-fold ferritin elevation 1
• Evaluate for hemophagocytic lymphohistiocytosis (HLH): Check triglycerides, fibrinogen, soluble IL-2 receptor, and bone marrow biopsy 7, 8

If Ferritin 1,000-10,000 μg/L

• Hepatocellular injury is the most common cause in this range 8
• Risk stratification: Ferritin >1000 μg/L with elevated ALT and platelets <200,000/μL predicts cirrhosis in 80% of C282Y homozygotes 1
• Consider liver biopsy if abnormal liver tests present 1

If Functional Iron Deficiency Suspected (CKD, IBD)

• Soluble transferrin receptor (sTfR): Elevated in true iron deficiency but normal in inflammatory block 1, 3
• Reticulocyte hemoglobin content (CHr or RET-He): Directly assesses iron availability for erythropoiesis 1
• Trial of IV iron: In CKD patients with ferritin 100-700 μg/L and TS <20%, weekly IV iron (50-125 mg for 8-10 doses) can differentiate functional deficiency from inflammatory block 1

Critical Pitfalls to Avoid

• Never interpret ferritin in isolation—always measure transferrin saturation simultaneously, as ferritin alone cannot distinguish iron overload from inflammation 1, 5, 6
• Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin 1
• C282Y heterozygosity alone does not cause clinically significant iron overload—a second cofactor (alcohol, NAFLD, hepatitis C) is required 3
• Avoid checking iron parameters within 4 weeks of IV iron administration, as circulating iron interferes with assays 1
• Ferritin <1000 μg/L has low risk of organ damage even with true iron overload, so aggressive workup may not be warranted if TS is normal 1, 3

Hematologic Causes Requiring Specific Evaluation

• Polycythemia vera: Look for aquagenic pruritus (itching after water contact), elevated hemoglobin/hematocrit, and order JAK2 mutation testing 2
• Lymphoma: Assess for B symptoms (fever, night sweats, weight loss), lymphadenopathy, and consider CT imaging if suspected 2
• Tissue transglutaminase (TTG) antibodies: Check if unexplained iron deficiency coexists with elevated ferritin (celiac disease) 2