What is the appropriate management for a patient with elevated ferritin levels?

Management of Elevated Ferritin Levels

The first critical step is to measure fasting transferrin saturation (TS) alongside ferritin, as over 90% of elevated ferritin cases are NOT due to iron overload but rather inflammation, liver disease, malignancy, or metabolic conditions. 1, 2

Initial Diagnostic Workup

Order these tests immediately: 1, 2

• Fasting transferrin saturation (TS) - the single most important discriminator
• Complete metabolic panel (ALT, AST, albumin) to assess hepatocellular injury
• Complete blood count with differential
• Inflammatory markers (CRP, ESR) to detect occult inflammation
• Creatine kinase (CK) if muscle injury suspected

Algorithmic Approach Based on Transferrin Saturation

If TS ≥45% with elevated ferritin:

This pattern suggests primary iron overload. 1, 2

Proceed immediately to HFE genetic testing for C282Y and H63D mutations. 1, 2, 3

• C282Y homozygotes: Confirms HFE hemochromatosis - proceed to risk stratification below 1, 2
• C282Y/H63D compound heterozygotes: May have mild iron overload 1, 3
• Negative HFE testing: Consider non-HFE hemochromatosis (TFR2, SLC40A1, HAMP, HJV gene mutations) 3, 4

If TS <45% with elevated ferritin:

Iron overload is unlikely - focus on secondary causes: 1, 2, 3

Most common causes (>90% of cases): 3, 5

• Chronic alcohol consumption (increases iron absorption and causes hepatocellular injury)
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome
• Inflammation (acute phase response)
• Malignancy (solid tumors, lymphomas, hepatocellular carcinoma)
• Liver disease (viral hepatitis B/C, cirrhosis)
• Infection (ferritin rises acutely as inflammatory response)
• Chronic kidney disease
• Cell necrosis (muscle injury, hepatocellular necrosis)

Risk Stratification by Ferritin Level

Ferritin <1000 μg/L:

Low risk of organ damage (negative predictive value 94% for advanced fibrosis). 1, 2

If C282Y homozygote with TS ≥45%: 1, 2

• Age <40 years, normal liver enzymes, no hepatomegaly: Proceed directly to therapeutic phlebotomy without liver biopsy
• Target ferritin: 50-100 μg/L
• Protocol: Remove 500 mL blood weekly or biweekly
• Check hemoglobin/hematocrit before each session
• Check ferritin every 10-12 phlebotomies

Ferritin 1000-10,000 μg/L:

Critical threshold - 20-45% prevalence of cirrhosis in C282Y homozygotes. 1, 2, 3

Strongly consider liver biopsy if ANY of the following: 1, 2

• Elevated liver enzymes (ALT, AST)
• Platelet count <200,000/μL
• Age >40 years
• Hepatomegaly present

This combination predicts cirrhosis in 80% of C282Y homozygotes. 1, 2

If liver biopsy not indicated, consider non-invasive assessment: 6

• MRI with T2/T2* relaxometry to quantify hepatic iron concentration (84-91% sensitivity, 80-100% specificity)

Ferritin >10,000 μg/L:

Rarely represents simple iron overload - urgent specialist referral required. 1, 3

Consider life-threatening conditions: 1, 7

• Adult-onset Still's disease (check glycosylated ferritin <20% = 93% specific)
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome
• Severe infection/sepsis
• Malignancy (most common cause in one study with average ferritin 2647 μg/L) 7

Management Based on Underlying Cause

Confirmed Hereditary Hemochromatosis (C282Y homozygote):

Therapeutic phlebotomy is the cornerstone of treatment. 1, 2

Induction phase: 1, 2

• Remove 500 mL blood weekly or biweekly
• Continue until ferritin reaches 50-100 μg/L
• Check hemoglobin before each session (don't allow >20% drop from baseline)
• Monitor ferritin every 10-12 phlebotomies

Maintenance phase: 1, 2

• Continue phlebotomy every 2-4 months to maintain ferritin 50-100 μg/L
• Monitor ferritin monthly initially, then every 3 months once stable
• Screen all first-degree relatives with iron studies and HFE genetic testing (Grade 1A recommendation) 1, 2

Secondary Causes (TS <45%):

Treat the underlying condition, NOT the elevated ferritin. 1, 2

• NAFLD/metabolic syndrome: Weight loss, metabolic management 2, 3
• Inflammatory conditions: Disease-specific anti-inflammatory therapy 1, 2
• Malignancy: Oncologic treatment 2
• Infection: Antimicrobial therapy 3, 8
• Alcohol-related: Abstinence and hepatology referral 3

Special Clinical Contexts

Chronic Kidney Disease with Anemia:

Elevated ferritin (500-1200 μg/L) with low TS (<25%) may represent functional iron deficiency that responds to IV iron therapy. 1, 2

• Trial of weekly IV iron (50-125 mg for 8-10 doses) can differentiate functional deficiency from inflammatory block 1
• Withhold iron therapy if ferritin >1000 ng/mL or TS >50% 1
• Safety concerns exist with IV iron when ferritin >800 ng/mL 1

Inflammatory Bowel Disease:

Ferritin <30 μg/L indicates true iron deficiency despite inflammation.** 1 **Ferritin >100 μg/L with low TS suggests anemia of chronic disease. 1

Sickle Cell Disease/Thalassemia:

Ferritin >2500-3000 ng/mL indicates increased risk of heart failure and cardiac iron loading. 1

Critical Pitfalls to Avoid

Never use ferritin alone without transferrin saturation to diagnose iron overload - ferritin is an acute phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores. 1, 2, 3

Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests - this combination has 100% sensitivity for cirrhosis. 1, 2

Do not assume iron overload when TS <45% - in the general population, iron overload is NOT the most common cause of elevated ferritin. 3, 5

Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed - penetrance is higher in family members. 1, 2

Avoid iron supplementation in patients with elevated ferritin and TS ≥45% - this worsens iron overload. 1

Do not delay specialist referral when ferritin >1000 μg/L regardless of TS - refer to gastroenterology, hematology, or iron overload specialist for comprehensive evaluation including non-invasive fibrosis assessment and cardiac evaluation if severe iron overload suspected. 1