What are the possible causes of an elevated ferritin level and how should it be evaluated?

Elevated Ferritin: Causes and Diagnostic Approach

Elevated ferritin is most commonly caused by inflammation, chronic liver disease (especially fatty liver and alcohol-related), metabolic syndrome, cell necrosis, malignancy, or infection—not iron overload—and the single most important test to order immediately is a fasting transferrin saturation to distinguish true iron overload (TS ≥45%) from these secondary causes (TS <45%). 1

Primary Diagnostic Framework

Measure transferrin saturation (TS) alongside ferritin immediately. This is the critical first step that determines your entire diagnostic pathway. 1, 2

When TS ≥45%: Suspect Primary Iron Overload

• Order HFE genetic testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis. 1, 3
• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms HFE-related hemochromatosis. 1, 3
• Consider liver MRI to quantify hepatic iron concentration if TS ≥45%. 1
• Liver biopsy is indicated when ferritin >1,000 μg/L with elevated liver enzymes (ALT/AST) or platelet count <200,000/μL, as this combination predicts cirrhosis in ~80% of C282Y homozygotes. 1, 2

When TS <45%: Evaluate Secondary Causes (>90% of Cases)

Iron overload is excluded with >90% certainty when TS <45%. 1, 4 The ferritin elevation reflects one of the following:

Liver Disease (Most Common)

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury. 1
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome causes ferritin elevation reflecting hepatocellular injury and insulin resistance, not true iron overload. 1, 4
• Viral hepatitis (B and C) causes hyperferritinemia in ~50% of patients. 1, 2
• Acute hepatitis releases ferritin from damaged hepatocytes. 1
• Order abdominal ultrasound to detect fatty liver (present in ~40% of patients with abnormal liver tests), hepatomegaly, or cirrhotic features. 1

Inflammatory Conditions

• Chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease) elevate ferritin as an acute-phase reactant. 1
• Systemic inflammatory response syndrome drives ferritin elevation. 1
• Adult-onset Still's disease (AOSD) causes extreme hyperferritinemia (4,000–30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20%. 1
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome should be considered when ferritin >5,000–10,000 ng/mL with cytopenias, fever, and multiorgan dysfunction. 1, 5
• Check CRP and ESR to detect occult inflammation. 1, 2

Malignancy

• Solid tumors, lymphomas, and hepatocellular carcinoma can cause marked ferritin elevation. 1, 5
• Malignancy was the most frequent cause of ferritin >1,000 μg/L in one large series (153/627 patients). 5

Cell Necrosis

• Muscle injury, hepatocellular necrosis, or tissue breakdown releases ferritin from lysed cells independent of iron stores. 1
• Check creatine kinase (CK) to evaluate for muscle necrosis. 1

Infections

• Active infection causes ferritin to rise acutely as part of the inflammatory response. 1

Metabolic Syndrome

• Ferritin correlates with insulin resistance and age in fatty liver patients, independent of iron stores. 4

Risk Stratification by Ferritin Level

Ferritin Level	Clinical Significance	Action Required
<1,000 μg/L	94% negative predictive value for advanced fibrosis; low risk of organ damage [1,2,4]	If TS <45%: evaluate secondary causes. If TS ≥45% with normal liver enzymes and age <40: proceed to phlebotomy without biopsy. [1,2]
1,000–10,000 μg/L	In C282Y homozygotes: 20–45% prevalence of cirrhosis [1,2]	Consider liver biopsy if elevated liver enzymes or platelet count <200,000/μL. [1,2]
>10,000 μg/L	Rarely represents simple iron overload; suggests life-threatening conditions [1,5]	Urgent specialist referral to evaluate for AOSD, hemophagocytic lymphohistiocytosis, severe infection, or malignancy. [1,2]

Complete Initial Laboratory Panel

Order these tests simultaneously:

• Fasting transferrin saturation (morning sample preferred) 1, 2
• Complete metabolic panel including ALT, AST, bilirubin, alkaline phosphatase 1, 2
• Complete blood count with differential and platelet count 1, 2
• Inflammatory markers: CRP and ESR 1, 2
• Creatine kinase (CK) to assess for muscle necrosis 1
• Hepatitis B surface antigen and hepatitis C antibody 2

Special Clinical Contexts

Chronic Kidney Disease with Anemia

• Functional iron deficiency can occur despite elevated ferritin (100–700 ng/mL) when TS <20% in patients on erythropoiesis-stimulating agents. 1, 2
• IV iron may be beneficial in CKD patients with ferritin 500–1,200 ng/mL but TS <25%. 1, 2
• Withhold iron therapy when ferritin exceeds 1,000 ng/mL or TS exceeds 50%. 2

Inflammatory Bowel Disease

• Ferritin <30 μg/L indicates absolute iron deficiency. 1
• Ferritin >100 μg/L with TS <16% suggests anemia of chronic disease. 1, 2

Adult-Onset Still's Disease

• Glycosylated ferritin fraction <20% is 93% specific for AOSD when combined with 5-fold ferritin elevation. 1
• Ferritin correlates with disease activity and often normalizes with remission. 1

Critical Pitfalls to Avoid

• Never use ferritin alone to diagnose iron overload—TS must be measured simultaneously. 1, 2, 4
• Do not order HFE genetic testing when TS <45%—this leads to misdiagnosis and inappropriate phlebotomy. 1, 4
• Do not assume iron overload when TS <45%—over 90% of elevated ferritin cases are due to secondary causes. 1, 4
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests. 1, 2
• Do not perform therapeutic phlebotomy without confirmed iron overload (TS ≥45% and evidence of end-organ damage). 2, 4
• Recognize that ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores. 1, 3, 6, 7

Management Strategy

When TS ≥45% (Confirmed Iron Overload)

• Initiate therapeutic phlebotomy with target ferritin 50–100 μg/L. 1, 2
• Remove 500 mL blood weekly or biweekly; check hemoglobin/hematocrit before each session. 2
• Check ferritin every 10–12 phlebotomies. 2
• Screen all first-degree relatives with TS, ferritin, and HFE genetic testing. 1, 2

When TS <45% (Secondary Hyperferritinemia)

• Treat the underlying condition, not the elevated ferritin itself. 1, 2, 4
• For NAFLD/metabolic syndrome: weight loss, metabolic control, and lifestyle modification. 1, 4
• For inflammatory conditions: disease-specific anti-inflammatory therapy. 1, 2
• For malignancy: oncologic treatment. 1
• Monitor ferritin every 3 months as a marker of treatment response—declining ferritin indicates improvement in underlying inflammation and metabolic dysfunction. 4

Indications for Specialist Referral

Refer to gastroenterology/hepatology when:

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