What is the best approach to manage a patient with anemia and elevated ferritin levels, potentially indicating iron overload or hemochromatosis?

Anemia with High Ferritin: Diagnostic and Management Approach

The most critical first step is to measure transferrin saturation (TS) alongside ferritin, as TS ≥45% indicates true iron overload requiring genetic testing, while TS <20% with elevated ferritin indicates anemia of chronic disease or functional iron deficiency—two completely different pathophysiologic states requiring opposite management strategies. 1, 2

Initial Diagnostic Algorithm

Step 1: Measure Transferrin Saturation Immediately

• Order fasting transferrin saturation (morning sample preferred) to distinguish true iron overload from secondary causes of hyperferritinemia 2, 3
• Over 90% of elevated ferritin cases are NOT due to iron overload—ferritin is an acute phase reactant that rises with inflammation, liver disease, malignancy, and tissue necrosis independent of actual iron stores 2, 4
• Never use ferritin alone to diagnose iron overload, as this is the most common diagnostic pitfall 2, 5

Step 2: Interpret Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

• Order HFE genetic testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis 1, 2
• C282Y homozygotes or C282Y/H63D compound heterozygotes confirm HFE hemochromatosis 1, 2
• Consider non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) if iron overload is confirmed but C282Y homozygosity is excluded 1, 2
• Initiate therapeutic phlebotomy if hereditary hemochromatosis is confirmed, and screen first-degree relatives 2, 5

If TS <20%: Anemia of Chronic Disease or Functional Iron Deficiency

• This pattern (low TS with elevated ferritin) indicates iron sequestration in storage sites, where hepcidin elevation from inflammatory cytokines blocks iron release from reticuloendothelial macrophages 2
• Check inflammatory markers (CRP, ESR) to confirm inflammatory state 2, 4
• Evaluate for underlying causes: chronic infection, inflammatory bowel disease, rheumatologic conditions, malignancy, chronic kidney disease 1, 2, 4

Step 3: Complete Laboratory Evaluation

• Complete blood count with differential to assess anemia severity, MCV, and rule out hematologic malignancy 2
• Comprehensive metabolic panel including AST, ALT, alkaline phosphatase, bilirubin, albumin to evaluate hepatocellular injury 2, 4
• Creatinine and eGFR to assess renal function, as chronic kidney disease is a common cause of functional iron deficiency 1, 2
• Fasting glucose and lipid panel to screen for metabolic syndrome/NAFLD, which accounts for over 90% of hyperferritinemia cases when combined with other metabolic conditions 2, 4

Risk Stratification by Ferritin Level

Ferritin <1000 μg/L

• Low risk of organ damage with 94% negative predictive value for advanced liver fibrosis in hemochromatosis 2, 6
• If C282Y homozygote with TS ≥45%, can proceed to therapeutic phlebotomy without liver biopsy 2

Ferritin 1000-10,000 μg/L

• Higher risk of advanced fibrosis/cirrhosis if iron overload is present 2
• The combination of ferritin >1000 μg/L, elevated aminotransferases, and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 2
• Liver biopsy should be considered if ferritin >1000 μg/L with elevated liver enzymes or platelet count <200,000/μL 2

Ferritin >10,000 μg/L

• Rarely represents simple iron overload—requires urgent specialist referral to evaluate for life-threatening conditions 2
• Consider Adult-Onset Still's Disease (measure glycosylated ferritin fraction <20%, which is 93% specific for AOSD) 2
• Screen for hemophagocytic lymphohistiocytosis/macrophage activation syndrome (persistent fever, splenomegaly, cytopenias, elevated triglycerides) 2

Management Based on Diagnosis

For True Iron Overload (TS ≥45%)

• Therapeutic phlebotomy is first-line treatment for HFE hemochromatosis 1, 2
• Target ferritin 50-100 μg/L to prevent iron-related organ damage 6
• For ferroportin disease with loss-of-function mutations, patients have low tolerance to phlebotomy—extend phlebotomy intervals if anemia develops despite elevated ferritin 1
• Iron chelation therapy (deferasirox) should only be considered when serum ferritin is consistently >1000 mcg/L and patient cannot tolerate phlebotomy 7

For Anemia of Chronic Disease (TS <20%, Ferritin >100 μg/L)

• Do NOT administer oral or IV iron in pure inflammatory iron block, as iron supplementation will not improve anemia and may worsen outcomes by feeding bacterial infections and promoting oxidative stress 2
• Treat the underlying inflammatory condition, not the elevated ferritin 2, 4
• Disease-specific anti-inflammatory therapy for rheumatologic conditions, oncologic treatment for malignancy, metabolic syndrome management (weight loss, glycemic control) for NAFLD 2

For Functional Iron Deficiency in Chronic Kidney Disease (Exception)

• In CKD patients on erythropoiesis-stimulating agents, ferritin 100-700 ng/mL with TS <20% may represent functional iron deficiency that responds to IV iron therapy 1, 2
• Trial of IV iron (50-125 mg weekly for 8-10 doses) can distinguish functional iron deficiency from pure inflammatory block—no response indicates inflammatory block 2
• Monitor serum ferritin and preferably do not exceed 500 mg/L to avoid toxicity of iron overload, especially in children and adolescents 1

For Iron-Refractory Iron Deficiency Anemia (IRIDA)

• Repeated administration of intravenous iron (iron sucrose or iron gluconate) increases hemoglobin and ferritin, though complete normalization is seldom achieved 1
• Do not attempt to correct hemoglobin to reference range, as this may place the patient at risk for iron overload 1
• Monitor serum ferritin levels and do not exceed 500 mg/L to avoid toxicity, especially in children and adolescents 1

Critical Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without checking transferrin saturation—this is the single most common error 2, 3
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests, as this combination warrants histologic assessment for cirrhosis 2
• Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin 2
• Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload and requires evaluation for life-threatening conditions like Adult-Onset Still's Disease or hemophagocytic lymphohistiocytosis 2
• In hemochromatosis patients on maintenance phlebotomy, monitor hemoglobin and serum ferritin to prevent iatrogenic iron deficiency from excessive therapeutic phlebotomy 5
• Interrupt deferasirox in pediatric patients with acute illnesses causing volume depletion (vomiting, diarrhea, decreased oral intake), as continued administration when body iron burden is approaching normal range can result in life-threatening adverse events 7