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

Management of High Ferritin

Initial Diagnostic Step: Measure Transferrin Saturation Immediately

The single most important action is to measure fasting transferrin saturation (TS) alongside ferritin, as this distinguishes true iron overload (requiring genetic testing and possible phlebotomy) from the 90% of cases caused by inflammation, liver disease, metabolic syndrome, or malignancy. 1, 2

Why This Matters

• Ferritin is an acute phase reactant that rises with inflammation, infection, liver disease, and tissue damage—completely independent of actual iron stores 1, 2
• Over 90% of elevated ferritin cases are NOT due to iron overload 1, 3
• Using ferritin alone without TS leads to misdiagnosis and inappropriate treatment 1, 2

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Algorithmic Approach Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

1. Order HFE genetic testing for C282Y and H63D mutations immediately 1, 2, 4

2. If C282Y homozygote confirmed:

   • This is hereditary hemochromatosis 1, 2
   • Initiate therapeutic phlebotomy (500 mL weekly) targeting ferritin 50-100 μg/L 2, 4
   • Screen all first-degree relatives with HFE genotype testing and iron studies 2, 4

3. Risk stratification by ferritin level:

   • Ferritin <1000 μg/L: Proceed directly to phlebotomy if age <40, normal liver enzymes, no hepatomegaly (94% negative predictive value for cirrhosis) 1, 2, 4
   • Ferritin >1000 μg/L: Consider liver biopsy, especially if elevated ALT/AST or platelets <200,000/μL (20-45% prevalence of cirrhosis in C282Y homozygotes at this threshold) 1, 2, 4

If TS <45%: Evaluate Secondary Causes

This pattern indicates the elevated ferritin is NOT from iron overload. 1, 2 Investigate these common causes:

1. Liver Disease (Most Common)

• Check ALT, AST, complete metabolic panel 1, 2
• Order abdominal ultrasound to evaluate for fatty liver, chronic liver disease, hepatomegaly 1
• Common culprits:
  • Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome 1, 2
  • Alcoholic liver disease 1, 2
  • Viral hepatitis B or C 1, 2

2. Inflammation/Infection

• Check CRP, ESR 1, 2
• Evaluate for active infection, chronic inflammatory conditions 1, 2
• If ferritin >4000-5000 μg/L with persistent fever: Consider adult-onset Still's disease—measure glycosylated ferritin fraction (<20% is 93% specific for AOSD) 1, 2

3. Malignancy

• Solid tumors, lymphomas, hepatocellular carcinoma 1, 5, 6
• Check CBC with differential, consider age-appropriate cancer screening 1

4. Cell Necrosis

• Check creatine kinase (CK) for muscle injury 1
• Hepatocellular necrosis releases ferritin independent of iron stores 1

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Critical Ferritin Thresholds for Action

Ferritin >1000 μg/L

• Refer to gastroenterology/hematology regardless of TS 2, 3
• Evaluate for liver disease with liver function tests 2
• Consider non-invasive fibrosis assessment or liver biopsy 2, 4
• This threshold has 100% sensitivity (but only 70% specificity) for cirrhosis in hemochromatosis patients 2

Ferritin >10,000 μg/L

• Urgent specialist referral required 2
• Rarely represents simple iron overload 1
• Consider life-threatening conditions:
  • Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 1, 5, 6
  • Adult-onset Still's disease (average ferritin 14,242 μg/L in these cases) 5
  • Severe infection or malignancy 5, 6, 7

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Special Clinical Contexts

Chronic Kidney Disease with Anemia

• Exception to the rule: Elevated ferritin (500-1200 μg/L) with low TS (<25%) may represent functional iron deficiency that responds to IV iron therapy, especially if on erythropoietin 1, 2, 4
• This is NOT inflammatory iron block—trial of IV iron (50-125 mg weekly for 8-10 doses) can distinguish between the two 1

Inflammatory Iron Block Pattern

• Low TS (<20%) with elevated ferritin (>300 μg/L) indicates anemia of chronic inflammation 1
• Do NOT supplement iron in this pattern—iron is sequestered and supplementation won't improve anemia and may worsen outcomes 1
• Treat the underlying inflammatory condition instead 2, 4

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Common Pitfalls to Avoid

1. Never use ferritin alone to diagnose iron overload—always check TS simultaneously 1, 2, 4

2. Don't assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin 1, 3

3. Don't overlook liver biopsy in patients with ferritin >1000 μg/L AND abnormal liver tests—this combination warrants histologic assessment 1, 2, 4

4. Don't fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 2, 4

5. Don't supplement iron when TS <20% with ferritin >300 μg/L—this represents inflammatory iron block where supplementation is harmful 1

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When to Refer

• Ferritin >1000 μg/L (any TS level) → Gastroenterology/Hematology 2, 3
• Ferritin >10,000 μg/L → Urgent specialist referral 2
• TS ≥45% with elevated ferritin → Consider genetics/hematology for hemochromatosis workup 1, 2
• Ferritin rising despite treatment of underlying cause → Specialist evaluation 2

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Monitoring During Treatment

For Confirmed Hemochromatosis on Phlebotomy:

• Check hemoglobin/hematocrit before each phlebotomy 2, 4
• Check ferritin every 10-12 phlebotomies 2, 4
• Target ferritin 50-100 μg/L for induction phase 2, 4
• Once target reached, maintenance phlebotomy every 2-4 months 2

For Secondary Causes:

• Monitor ferritin monthly initially 1
• Treat the underlying condition (weight loss for NAFLD, disease-specific therapy for inflammatory conditions, oncologic treatment for malignancy) 1, 2
• The elevated ferritin itself is not the treatment target 2, 4