What are the possible causes of an elevated serum ferritin and how should it be assessed?

Causes of Elevated Ferritin

Elevated ferritin is most commonly caused by inflammation, liver disease, metabolic syndrome, chronic alcohol use, or malignancy—not iron overload—and the single most critical test to order immediately is a fasting transferrin saturation to distinguish true iron overload (TS ≥45%) from secondary causes (TS <45%). 1, 2

Understanding Ferritin as a Biomarker

Ferritin functions simultaneously as an iron storage marker, an acute-phase reactant, and a marker of cellular injury. 1, 2 It rises during inflammation, infection, hepatocellular damage, tissue necrosis, and malignancy completely independent of actual iron stores. 1, 2 This dual nature makes interpretation impossible without concurrent transferrin saturation measurement. 1, 2

Over 90% of elevated ferritin cases in outpatients are NOT due to iron overload. 2, 3 The most common culprits are chronic alcohol consumption, inflammation, cell necrosis, tumors, and non-alcoholic fatty liver disease/metabolic syndrome. 1, 2

Primary Causes of Elevated Ferritin

Iron Overload Disorders (Require TS ≥45%)

• Hereditary hemochromatosis (HFE-related): C282Y homozygosity or C282Y/H63D compound heterozygosity, occurring in approximately 3–5 per 1,000 individuals, with C282Y homozygosity prevalence of 0.44% in non-Hispanic whites. 1, 2
• Non-HFE hemochromatosis: Mutations in TFR2, SLC40A1, HAMP, or HJV genes. 2

Liver Disease (Most Common Category)

• Chronic alcohol consumption: Increases iron absorption and causes hepatocellular injury, elevating ferritin through both mechanisms. 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome: Ferritin elevation reflects hepatocellular injury and insulin resistance rather than true iron overload; found in nearly 40% of adults with abnormal liver tests. 1, 2
• Viral hepatitis (B and C): Approximately 50% of patients have abnormal serum iron studies; ferritin elevation reflects hepatic inflammation and injury. 1, 2
• Acute hepatitis and cirrhosis: Associated with marked ferritin elevation from hepatocellular necrosis. 2

Inflammatory and Rheumatologic Conditions

• Adult-onset Still's disease (AOSD): Extreme hyperferritinemia (4,000–30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20% (93% specific when combined with 5-fold ferritin elevation). 1, 2
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS): Ferritin typically >5,000–10,000 ng/mL with fever, cytopenias, and multiorgan dysfunction; requires urgent specialist referral. 1, 4, 5
• Chronic rheumatologic diseases: Rheumatoid arthritis, inflammatory bowel disease, and other chronic inflammatory conditions elevate ferritin as an acute-phase reactant. 1, 2
• Systemic inflammatory response syndrome: Broad category of acute inflammatory states. 2

Malignancy

• Solid tumors and lymphomas: Malignancy was the most frequent condition in one large series (153/627 patients), with average ferritin 2,647 μg/L. 6
• Hepatocellular carcinoma: Can cause marked ferritin elevation. 2
• Hematologic malignancies: Most prevalent diagnosis in hospitalized patients with ferritin >2,000 ng/mL (20/77 patients in one series). 5

Infection

• Severe infections: Second most common cause in hospitalized patients with ferritin >2,000 ng/mL (14/77 patients); ferritin rises acutely as part of the inflammatory response. 1, 5
• Active infection: Causes ferritin to rise bidirectionally—infection causes elevated ferritin, not vice versa. 1

Cellular Damage and Tissue Necrosis

• Muscle injury, hepatocellular necrosis, or tissue breakdown: Ferritin is released from necrotic or lysed cells independent of iron stores. 2

Chronic Kidney Disease

• Functional iron deficiency in CKD: Ferritin 500–1,200 ng/mL with transferrin saturation <25% may still warrant IV iron therapy, especially if receiving erythropoietin; this represents iron sequestration despite elevated ferritin. 1
• Liver cell damage in dialysis patients: Documented with ferritin levels exceeding 7,500 ng/mL and transferrin saturation >88%. 1

Diagnostic Algorithm: The Critical First Step

Step 1: Measure Transferrin Saturation Immediately

Never interpret ferritin alone. 1, 2 The transferrin saturation is the single most important test to determine if iron overload is present. 1

• If TS ≥45%: Suspect primary iron overload and proceed immediately to HFE genetic testing for C282Y and H63D mutations. 1, 2
• **If TS <45%:** Iron overload is excluded with >90% certainty; evaluate secondary causes. 1, 2

Step 2: Initial Laboratory Panel (When TS <45%)

• Inflammatory markers: CRP and ESR to detect occult inflammation. 1
• Liver enzymes: Complete metabolic panel including ALT, AST, bilirubin, alkaline phosphatase to assess hepatocellular injury. 1
• Complete blood count with differential: To assess for anemia, polycythemia, cytopenias, or hematologic malignancy. 1
• Creatine kinase (CK): To evaluate for muscle necrosis. 1

Step 3: Assess Clinical Context

• Detailed alcohol history: Chronic consumption is a leading cause. 2
• Metabolic risk factors: Obesity, glucose intolerance, dyslipidemia suggesting NAFLD. 1
• Medication review: Recent IV iron administration can interfere with assays for 4 weeks. 1
• Symptoms of inflammation: Fever, weight loss, night sweats, joint pain. 1, 2

Step 4: Imaging When Indicated

• Abdominal ultrasound: Standard initial workup to evaluate for fatty liver, chronic liver disease, hepatomegaly, or cirrhotic features; nearly 40% of adults with abnormal liver tests have fatty liver on ultrasound. 1
• Liver MRI with T2/T2 relaxometry:* If TS ≥45%, to quantify hepatic iron concentration (correlation coefficient 0.74–0.98 with biochemical hepatic iron concentration, 84–91% sensitivity, 80–100% specificity). 1

Risk Stratification by Ferritin Level

Ferritin Level	Clinical Significance	Action Required
<1,000 μg/L	Low risk of organ damage; 94% negative predictive value for advanced liver fibrosis in hemochromatosis. [1,2]	If TS ≥45% and C282Y homozygote with normal liver enzymes and age <40, can proceed to therapeutic phlebotomy without liver biopsy. [1]
1,000–10,000 μg/L	Higher risk of advanced fibrosis/cirrhosis if iron overload present; 20–45% prevalence of cirrhosis in C282Y homozygotes. [1]	If TS ≥45% with elevated liver enzymes or platelet count <200,000/μL, consider liver biopsy. [1] The combination of ferritin >1,000 μg/L, elevated aminotransferases, and platelet count <200,000/μL predicts cirrhosis in 80% of C282Y homozygotes. [1]
>10,000 μg/L	Rarely represents simple iron overload; suggests life-threatening conditions. [1]	Urgent specialist referral to evaluate for AOSD (measure glycosylated ferritin fraction), HLH/MAS (check for fever, splenomegaly, cytopenias, elevated triglycerides), or severe malignancy. [1]

Special Clinical Contexts

Non-Alcoholic Fatty Liver Disease

When TS <45% with elevated ferritin and ALT, the ferritin rise reflects hepatocellular injury and insulin resistance rather than iron overload. 1 **Treat the underlying metabolic condition with weight loss and metabolic control, not the elevated ferritin itself.** 1 NAFLD patients with elevated ferritin do not automatically require iron overload evaluation unless TS is also elevated (>45%). 1

Inflammatory Bowel Disease

• Ferritin <30 μg/L: Absolute iron deficiency. 1
• Ferritin 30–100 μg/L with TS <16%: Combined iron deficiency and anemia of chronic disease. 1
• Ferritin >100 μg/L with TS <16%: Predominant anemia of chronic disease. 1

Chronic Kidney Disease

• Absolute iron deficiency: Ferritin <100 ng/mL and TS <20%. 1
• Functional iron deficiency: Ferritin 100–700 ng/mL with TS <20% may respond to IV iron therapy despite elevated ferritin, especially if on erythropoiesis-stimulating agents; the DRIVE study showed significant hemoglobin improvement (16 g/L vs 11 g/L, P=0.028) with IV iron in patients with ferritin 500–1,200 μg/L and TS <25%. 1
• Withhold iron therapy: When ferritin exceeds 1,000 ng/mL or TS exceeds 50%. 1

Chronic Hepatitis C

Ferritin elevation mainly reflects hepatocellular injury, systemic inflammation, and insulin resistance rather than true iron overload. 1 Approximately 50% of patients have abnormal serum iron studies. 1 Sicca symptoms affect 20–30% of patients, yet fewer than 5% meet criteria for primary Sjögren's syndrome. 1

Anemia of Chronic Inflammation

The pattern of low TS (<20%) with elevated ferritin (>300 ng/mL) indicates anemia of chronic inflammation, where hepcidin elevation in response to inflammatory cytokines blocks intestinal iron absorption and traps iron in reticuloendothelial macrophages. 1 Do not administer oral or IV iron unless specific exceptions apply (e.g., heart failure with iron deficiency, CKD with functional iron deficiency), as supplementation will not improve anemia and may worsen outcomes. 1

Indications for Specialist Referral

Refer to gastroenterology, hematology, or specialist in iron overload when: 1, 3

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

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload. 1, 2 Ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores. 1, 2
• Do not assume iron overload when TS <45%. 1 In the general population, iron overload is NOT the most common cause of elevated ferritin. 2, 3
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests. 1 This combination warrants histologic assessment for cirrhosis. 1
• Do not order HFE genetic testing when TS <45%. 1 This leads to misdiagnosis and unnecessary phlebotomy. 1
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed. 1 Penetrance is higher in family members than the general population. 1
• Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload. 1 It suggests AOSD, HLH/MAS, or severe malignancy requiring urgent evaluation. 1, 5
• Do not check iron parameters within 4 weeks of IV iron administration. 1 Circulating iron can interfere with assays and lead to spurious results. 1