What causes elevated ferritin levels in patients, particularly those with a history of chronic diseases such as rheumatoid arthritis (RA) or chronic kidney disease (CKD)?

Elevated Ferritin: Causes and Clinical Significance

Direct Answer

Ferritin elevation is most commonly caused by inflammation, chronic liver disease (especially alcohol-related and NAFLD), malignancy, and infection—not iron overload—accounting for over 90% of cases in outpatient settings. 1

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Primary Diagnostic Framework

The key to understanding elevated ferritin is recognizing that ferritin functions as an acute-phase reactant, rising during inflammation independent of actual iron stores. 1 This means the majority of elevated ferritin cases do not represent true iron overload.

Most Common Causes (>90% of Cases)

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury, releasing ferritin from damaged liver cells 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome causes ferritin elevation through hepatocellular injury and insulin resistance rather than iron overload 1, 2
• Inflammation from any source triggers ferritin release as an acute-phase reactant 1, 2
• Cell necrosis (muscle injury, hepatocellular necrosis, tissue breakdown) releases stored ferritin from damaged cells 1
• Malignancy is the most frequent cause in hospitalized patients with markedly elevated ferritin (>1000 μg/L), including solid tumors, lymphomas, and hepatocellular carcinoma 1, 3

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Context-Specific Causes

In Patients with Chronic Diseases

For rheumatoid arthritis patients:

• Chronic inflammatory conditions cause persistent ferritin elevation through cytokine-mediated acute-phase response 1
• Adult-onset Still's disease presents with extreme hyperferritinemia (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20% 1

For chronic kidney disease patients:

• Inflammatory iron block occurs where hepcidin elevation traps iron in storage sites, causing elevated ferritin with low transferrin saturation (<20%) 1
• Functional iron deficiency can paradoxically occur despite elevated ferritin (100-700 ng/mL) when erythropoiesis is pharmacologically stimulated 1
• Transfusional iron overload in dialysis patients can cause ferritin levels exceeding 7,500 ng/mL 2

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Secondary Causes by Category

Liver Disease

• Alcoholic liver disease 1, 2
• Viral hepatitis B and C 1, 2
• Acute hepatitis with hepatocellular necrosis 1
• Cirrhosis 1

Inflammatory/Rheumatologic Conditions

• Systemic inflammatory response syndrome 1
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 1, 3
• Chronic rheumatologic diseases 1

Hematologic Causes

• Thalassemia syndromes 4
• Myelodysplastic syndrome 4
• Myelofibrosis 4
• Sickle cell disease 4

Infections

• Any active infection triggers ferritin elevation as part of acute-phase response 1
• The association is bidirectional: infection causes elevated ferritin, not vice versa 1, 2

Medications

• Iron supplements and IV iron preparations directly increase iron stores 5
• Blood transfusions (particularly repeated) lead to transfusional iron overload 5
• Statins may cause liver enzyme elevations with secondary ferritin increase 5
• Methotrexate can cause liver inflammation and fibrosis 5

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True Iron Overload (Minority of Cases)

Hereditary Hemochromatosis

• HFE-related hemochromatosis (C282Y homozygosity or C282Y/H63D compound heterozygosity) is the classic genetic cause 1, 2, 4
• Non-HFE hemochromatosis involves mutations in TFR2, SLC40A1, HAMP, or HJV genes 1, 2
• Ferroportin disease (HFE4) causes reticuloendothelial iron overload through impaired macrophage iron recycling 6

Critical Diagnostic Point

Iron overload is NOT the most common cause of elevated ferritin in the general population. 1 The American Association for the Study of Liver Diseases emphasizes that transferrin saturation ≥45% is required to suspect primary iron overload—without this, secondary causes predominate. 1

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Diagnostic Algorithm

Step 1: Measure Transferrin Saturation Simultaneously

• If TS ≥45%: Suspect primary iron overload → proceed with HFE genetic testing for C282Y and H63D mutations 1, 2
• If TS <45%: Iron overload unlikely → investigate secondary causes (inflammation, liver disease, malignancy, infection) 1

Step 2: Assess Inflammatory Markers

• Check CRP and ESR to detect occult inflammation 1
• Elevated inflammatory markers with elevated ferritin strongly suggest secondary hyperferritinemia 1

Step 3: Evaluate Liver Function

• Check AST, ALT, and albumin to assess hepatocellular injury 1
• Elevated transaminases with normal TS suggest NAFLD or alcoholic liver disease 1

Step 4: Risk Stratification by Ferritin Level

• <1,000 μg/L: Low risk of organ damage; negative predictive value 94% for advanced fibrosis 1
• 1,000-10,000 μg/L: Higher risk if iron overload present; consider liver biopsy if TS ≥45% with elevated liver enzymes 1
• >10,000 μg/L: Rarely represents simple iron overload; urgent evaluation for life-threatening conditions (HLH/MAS, severe infection, malignancy) 1, 7

Step 5: Consider Specific High-Risk Conditions

• If ferritin >4,000-5,000 ng/mL with persistent fever: Measure glycosylated ferritin fraction (<20% is 93% specific for adult-onset Still's disease) 1
• If ferritin >5,000 ng/mL with cytopenias and multiorgan dysfunction: Consider hemophagocytic lymphohistiocytosis 1

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Critical Pitfalls to Avoid

• Never use ferritin alone to diagnose iron overload without checking transferrin saturation—ferritin is an acute-phase reactant elevated in inflammation, liver disease, and malignancy independent of iron stores 1, 5
• Do not assume iron overload when TS <45%—over 90% of elevated ferritin cases are NOT due to iron overload 1
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests, as this combination predicts cirrhosis in 80% of C282Y homozygotes 1
• Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload—the positive predictive value for HLH is low, but more common explanations include chronic transfusion (35%), liver disease (27%), and hematologic malignancy (16%) 7
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1

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Management Principles

Treat the underlying condition, not the elevated ferritin itself. 1 Management depends entirely on the cause:

• For NAFLD/metabolic syndrome: Weight loss and metabolic syndrome management 1
• For inflammatory conditions: Disease-specific anti-inflammatory therapy 1
• For confirmed hereditary hemochromatosis (C282Y homozygote with TS ≥45%): Initiate therapeutic phlebotomy 1
• For functional iron deficiency in CKD: Consider IV iron trial despite elevated ferritin if TS <20% 1
• For malignancy: Oncologic treatment 1