What is the significance of elevated ferritin levels?

Significance of Elevated Ferritin Levels

Elevated ferritin is primarily a marker of inflammation, liver disease, or malignancy rather than iron overload in 90% of cases, but when accompanied by transferrin saturation ≥45%, it indicates true iron overload requiring immediate evaluation for hereditary hemochromatosis and potential organ damage. 1, 2

Primary Diagnostic Significance

Ferritin serves as a dual marker with distinct clinical implications:

• Ferritin is an acute-phase reactant that rises with inflammation, infection, liver disease, and malignancy, making it a highly sensitive but poorly specific marker for iron status 1, 3
• The combination of elevated ferritin AND transferrin saturation ≥45% distinguishes true iron overload from secondary causes and mandates HFE genotype testing for hereditary hemochromatosis 1, 4
• Ferritin alone without transferrin saturation cannot diagnose iron overload—this is a critical pitfall to avoid 1

Common Causes by Frequency

The most frequent etiologies of hyperferritinemia in clinical practice include:

• Malignancy (most common cause in tertiary care settings, accounting for 24% of cases with ferritin >1000 μg/L) 5
• Infection (most common in general hospital populations, particularly non-HIV infections) 6
• Chronic liver disease from alcohol, viral hepatitis, or NAFLD 7, 1
• Iron overload syndromes including hereditary hemochromatosis (second most common at 22% of cases) 5
• Metabolic syndrome, obesity, and diabetes 2
• Chronic kidney disease (ferritin 500-1200 μg/L with low transferrin saturation <25% may still require IV iron for anemia) 1
• Rheumatologic diseases including rheumatoid arthritis and other chronic inflammatory conditions 7, 1

Critical Thresholds and Their Significance

Ferritin >1000 μg/L

• Indicates 20-45% prevalence of cirrhosis in C282Y homozygotes with hereditary hemochromatosis 1
• Requires specialist referral to gastroenterology, hematology, or iron overload specialist regardless of transferrin saturation 1, 2
• Mandates liver disease evaluation with liver function tests and consideration of non-invasive fibrosis assessment 1
• Consider liver biopsy if accompanied by elevated liver enzymes or platelet count <200,000/μL to assess for cirrhosis 1
• Below 1000 μg/L with normal transaminases, the risk of advanced liver fibrosis is very low (negative predictive value 94%) 1

Ferritin >10,000 μg/L

• Suggests life-threatening conditions requiring urgent specialist referral 1
• Consider adult-onset Still's disease, hemophagocytic lymphohistiocytosis (HLH), or macrophage activation syndrome (average ferritin 14,242 μg/L in these conditions) 1, 5
• 75% of patients with ferritin >20,000 μg/L have HLH, though the differential remains broad 8

Ferritin 500-1500 μg/L

• In chronic kidney disease with transferrin saturation <25%, IV iron may still be beneficial despite elevated ferritin 1
• In chronic inflammation with ferritin ≥50 μg/L, iron deficiency may still be present and requires additional markers like C-reactive protein or total iron binding capacity 7

Diagnostic Algorithm

Step 1: Measure Both Ferritin and Transferrin Saturation

• Always measure fasting transferrin saturation alongside ferritin—never interpret ferritin in isolation 1, 4

Step 2: Interpret Based on Transferrin Saturation

• If TS ≥45% with elevated ferritin: Suspect iron overload and proceed to HFE genotype testing for C282Y and H63D mutations 1, 4
• If TS <45% with elevated ferritin: Evaluate for secondary causes (inflammation, liver disease, malignancy) 1

Step 3: Assess for Secondary Causes When TS <45%

• Check inflammatory markers (CRP, ESR) to identify chronic inflammatory conditions 1
• Assess liver enzymes (ALT, AST) for liver disease 1
• Evaluate for alcohol consumption, metabolic syndrome, obesity, diabetes 2
• Screen for malignancy and infection based on clinical context 5, 6

Step 4: Risk Stratification for Iron Overload

• If C282Y homozygote with ferritin <1000 μg/L, normal transaminases, age <40: Therapeutic phlebotomy can proceed without liver biopsy 1
• If ferritin >1000 μg/L with elevated liver enzymes or platelets <200,000/μL: Strongly consider liver biopsy 1
• MRI with T2/T2 relaxometry* provides non-invasive quantification of hepatic iron concentration (correlation 0.74-0.98 with biochemical measurement, 84-91% sensitivity, 80-100% specificity) 1

Management Based on Underlying Cause

For Hereditary Hemochromatosis

• Initiate therapeutic phlebotomy with target ferritin <50 μg/L for confirmed hemochromatosis 1, 4
• Screen first-degree relatives with genotyping as penetrance is higher in family members 1

For Secondary Causes

• Treat the underlying condition rather than the elevated ferritin itself 1
• Weight loss through dietary modification and increased physical activity for metabolic syndrome and fatty liver disease 4
• Reduce alcohol intake in patients with excessive consumption 4
• Avoid iron supplementation in patients with elevated ferritin unless true iron deficiency is confirmed 4

For Transfusional Iron Overload

• Consider chelation therapy when serum ferritin consistently >1000 μg/L after transfusion of ≥100 mL/kg packed red blood cells 9
• In β-thalassemia major, ferritin >2500 μg/L indicates increased risk of heart failure (risk increases even at >1000 μg/L) 1

Special Populations

Chronic Kidney Disease

• IV iron may be beneficial despite ferritin 500-1200 μg/L if transferrin saturation <25% 1
• Safety concerns exist with IV iron when ferritin >800 ng/mL 4

Sickle Cell Disease

• Ferritin levels do not correlate precisely with liver iron concentration in this population 7
• Ferritin <1500 ng/mL generally correlates with well-controlled liver iron (90% have liver iron <7 mg/g dry weight) 7
• Ferritin >2500-3000 ng/mL usually associated with high liver iron (>10-15 mg/g dry weight), though exceptions exist 7
• Cardiac iron loading in SCD develops only with prolonged elevated liver iron concentration 7

Post-Bariatric Surgery

• Chronic inflammatory conditions and liver disease may result in increased ferritin independent of iron status 7
• Ferritin ≥50 μg/L with chronic inflammation may still indicate iron deficiency—consider C-reactive protein or total iron binding capacity 7

Common Pitfalls to Avoid

• Never use ferritin alone to diagnose iron overload—always measure transferrin saturation 1
• Do not overlook the need for liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests 1
• Do not delay treatment while awaiting cardiac MRI in patients with severe hemochromatosis and signs of heart disease 1
• Recognize that 41-70% of patients with hyperferritinemia have multiple underlying causes, and the more causes present, the higher the ferritin level 6
• Do not assume extremely high ferritin always indicates HLH—various diseases can cause marked hyperferritinemia independently 6, 8