What are the differential diagnoses for a patient with elevated ferritin (iron storage protein) and high vitamin B12 levels?

Differential Diagnoses for Elevated Ferritin and Elevated Vitamin B12

The combination of high ferritin and high B12 most commonly points to liver disease (particularly alcoholic liver disease or NAFLD), malignancy (especially hepatocellular carcinoma or hematologic malignancies), or active inflammatory/infectious processes—not iron overload. 1, 2

Critical First Step: Measure Transferrin Saturation

• Check fasting transferrin saturation (TS) immediately to determine if iron overload is present, as this single test determines the entire diagnostic pathway 1, 3
• If TS <45%, iron overload is excluded with >90% probability, and the ferritin elevation is secondary to inflammation, liver disease, metabolic syndrome, or malignancy 1, 3
• If TS ≥45%, proceed with HFE genetic testing for hereditary hemochromatosis (C282Y and H63D mutations) 1, 3

Primary Differential Diagnoses

Liver Disease (Most Common)

• Alcoholic liver disease causes both elevated ferritin and elevated B12 through hepatocellular injury and impaired B12 clearance 1, 4
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome accounts for >90% of outpatient hyperferritinemia cases and can elevate B12 through hepatocyte damage 1, 3
• Acute hepatitis (viral hepatitis B or C) releases both ferritin and B12 from damaged hepatocytes 1
• Cirrhosis of any etiology impairs B12 metabolism and releases ferritin from necrotic liver cells 1

Malignancy (Second Most Common)

• Hepatocellular carcinoma is a critical diagnosis to exclude, as it elevates both ferritin (tumor marker) and B12 (impaired hepatic clearance) 1, 2
• Hematologic malignancies (lymphomas, leukemias, myelodysplastic syndromes) produce ferritin as an acute-phase reactant and B12 through increased cell turnover 1, 2
• Solid tumors (breast, lung, renal cell carcinoma) can elevate ferritin as a paraneoplastic phenomenon 1, 2

Inflammatory/Infectious Conditions

• Active infection causes ferritin to rise acutely as part of the inflammatory response, while B12 may be elevated through hepatic inflammation 1, 3
• Systemic inflammatory response syndrome elevates both markers as acute-phase reactants 1
• Adult-onset Still's disease causes extreme hyperferritinemia (4,000-30,000 ng/mL) with glycosylated ferritin <20% 1
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome presents with markedly elevated ferritin (often >10,000 μg/L) and elevated B12 2, 5

Chronic Kidney Disease

• End-stage renal disease impairs B12 excretion and causes functional iron deficiency with elevated ferritin despite low transferrin saturation 1

Cell Necrosis

• Rhabdomyolysis or massive muscle injury releases ferritin from damaged cells 1
• Hepatocellular necrosis from any cause (ischemia, toxins, drugs) releases both ferritin and B12 1, 4

Essential Diagnostic Workup

Initial Laboratory Tests

• Transferrin saturation (fasting) to distinguish iron overload from secondary causes 1, 3
• Complete metabolic panel including AST, ALT, alkaline phosphatase, bilirubin, albumin to assess hepatocellular injury 1, 3
• Complete blood count with differential to evaluate for cytopenias, leukocytosis, or abnormal cell populations 6, 3
• Inflammatory markers (CRP, ESR) to detect occult inflammation 1, 3
• Creatine kinase to evaluate for muscle necrosis 1
• Reticulocyte count to assess bone marrow response 6

Second-Line Testing Based on Initial Results

• HFE genetic testing (C282Y and H63D mutations) if TS ≥45% 1, 3
• Liver imaging (ultrasound or CT) to evaluate for hepatic masses, cirrhosis, or fatty infiltration 1
• Hepatitis B and C serologies if liver enzymes are elevated 1
• Serum protein electrophoresis if hematologic malignancy is suspected 1
• Glycosylated ferritin fraction if Adult-onset Still's disease is suspected (fraction <20% is 93% specific) 1
• Bone marrow biopsy if cytopenias or abnormal blood counts suggest hematologic malignancy 1

Advanced Testing for Persistent Elevation

• Liver MRI with iron quantification (T2* or R2 relaxometry) if ferritin >1,000 μg/L and TS ≥45% to assess hepatic iron concentration 1, 7
• Liver biopsy only if ferritin >1,000 μg/L with elevated liver enzymes and platelet count <200,000/μL to assess for cirrhosis 1

Risk Stratification by Ferritin Level

• Ferritin <1,000 μg/L: Low risk of organ damage even if iron overload is present; focus on identifying secondary causes 1, 3
• Ferritin 1,000-10,000 μg/L: Higher risk of advanced fibrosis/cirrhosis if iron overload is confirmed; requires liver imaging or biopsy if TS ≥45% and liver enzymes are elevated 1
• Ferritin >10,000 μg/L: Rarely represents simple iron overload; strongly suggests HLH/MAS, severe hepatocellular necrosis, or malignancy requiring urgent specialist referral 1, 5

Critical Diagnostic Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without confirming TS ≥45%, as ferritin is an acute-phase reactant elevated in countless inflammatory conditions independent of iron stores 1, 3
• **Do not assume iron overload when TS <45%**, as >90% of elevated ferritin cases are not due to iron overload 1, 3
• Do not overlook malignancy, particularly hepatocellular carcinoma, as the combination of elevated ferritin and B12 with liver enzyme abnormalities warrants imaging 1, 2
• Do not fail to check glycosylated ferritin if ferritin is extremely elevated (>5,000 μg/L) with fever and arthritis, as this may represent Adult-onset Still's disease 1
• Recognize that B12 elevation is NOT a sign of B12 deficiency; it reflects impaired hepatic clearance, increased cell turnover, or release from damaged cells 6

Management Algorithm

If TS <45% (Most Likely Scenario)

• Treat the underlying condition, not the ferritin or B12 numbers 1, 3
• Address metabolic syndrome components: weight loss, glycemic control, lipid management, blood pressure control 3
• Discontinue alcohol if alcoholic liver disease is suspected 1, 4
• Initiate disease-specific therapy for inflammatory conditions or malignancy 1

If TS ≥45%

• Order HFE genetic testing for C282Y and H63D mutations 1, 3
• If C282Y homozygote with elevated iron stores, diagnose HFE hemochromatosis and initiate therapeutic phlebotomy 1
• If ferritin >1,000 μg/L with elevated liver enzymes, consider liver biopsy to assess for cirrhosis 1
• Screen first-degree relatives if hereditary hemochromatosis is confirmed 1

Follow-Up Strategy

• Monitor ferritin every 6-12 months if it remains elevated but <1,000 μg/L with normal TS 3
• Refer to hepatology if ferritin exceeds 1,000 μg/L or continues to rise despite management of underlying conditions 3
• Refer to hematology if cytopenias, abnormal blood counts, or suspected hematologic malignancy 6