What is the appropriate evaluation and management approach for a patient with elevated serum ferritin?

Approach to High Ferritinemia

Initial Laboratory Assessment

Immediately order a fasting transferrin saturation (TS) alongside ferritin—this single test determines whether you are dealing with true iron overload (TS ≥45%) or secondary hyperferritinemia (TS <45%), which accounts for over 90% of cases. 1

Core Initial Tests

• Transferrin saturation (TS) – the most critical discriminator between iron overload and inflammatory causes 1
• Complete metabolic panel including ALT, AST to assess hepatocellular injury 1
• Inflammatory markers (CRP, ESR) to detect occult inflammation 1
• Complete blood count with differential to evaluate for anemia, polycythemia, or hematologic malignancy 1
• Creatine kinase (CK) to evaluate for muscle necrosis 1

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Algorithmic Approach Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

When TS ≥45% with elevated ferritin, immediately proceed to HFE genetic testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis. 1, 2

Genetic Confirmation

• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms HFE-related hereditary hemochromatosis 1
• C282Y homozygosity occurs in approximately 0.44% of non-Hispanic white individuals 1

Risk Stratification by Ferritin Level in Confirmed Hemochromatosis

Ferritin Level	Risk & Action	Citation
<1,000 µg/L	Low risk of organ damage (94% NPV for advanced fibrosis); if age <40, normal liver enzymes, no hepatomegaly: start therapeutic phlebotomy without biopsy	[1,2]
1,000–10,000 µg/L	20–45% prevalence of cirrhosis in C282Y homozygotes; consider liver biopsy if elevated ALT or platelet count <200,000/µL	[1,2]
>10,000 µg/L	Rarely simple iron overload; urgent specialist referral for life-threatening conditions (hemophagocytic lymphohistiocytosis, macrophage activation syndrome)	[1,2]

When to Perform Liver Biopsy

Consider liver biopsy when ferritin >1,000 µg/L AND (elevated liver enzymes OR platelet count <200,000/µL OR age >40 years OR hepatomegaly), as this combination predicts cirrhosis in ~80% of C282Y homozygotes. 1, 2

Alternatively, liver MRI with T2/T2* relaxometry can quantify hepatic iron concentration non-invasively (correlation coefficient 0.74–0.98 with biochemical hepatic iron concentration, 84–91% sensitivity, 80–100% specificity). 1

Therapeutic Phlebotomy Protocol for Confirmed Hemochromatosis

• Remove 500 mL blood weekly or biweekly as tolerated 2
• Check hemoglobin/hematocrit before each phlebotomy; allow hemoglobin to fall no more than 20% from baseline 2
• Check ferritin every 10–12 phlebotomies 2
• Induction goal: ferritin 50–100 µg/L 2
• Maintenance: phlebotomy every 2–4 months once target ferritin achieved 2
• Avoid iron supplements, vitamin C supplementation (accelerates iron mobilization), and raw shellfish (Vibrio vulnificus risk) 2

Family Screening

Screen all first-degree relatives with TS, ferritin, and HFE genetic testing regardless of symptoms, as penetrance is higher in family members than the general population. 1, 2

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If TS <45%: Evaluate Secondary Causes

When TS <45%, iron overload is excluded with >90% certainty, and the elevated ferritin reflects inflammation, liver disease, metabolic syndrome, malignancy, or tissue necrosis—NOT iron overload. 1, 3

Most Common Secondary Causes (>90% of Cases)

• Chronic alcohol consumption – increases iron absorption and causes hepatocellular injury 1
• Inflammation – ferritin is an acute-phase reactant that rises with infection, rheumatologic disease, inflammatory bowel disease 1, 3
• Cell necrosis – muscle injury, hepatocellular necrosis, tissue breakdown releases ferritin from lysed cells 1
• Tumors – solid tumors, lymphomas, hepatocellular carcinoma 1
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome – ferritin reflects hepatocellular injury and insulin resistance, not iron overload 1

Targeted Evaluation for Secondary Causes

• Alcohol history – detailed quantification of consumption; consider phosphatidyl ethanol testing 1
• Metabolic syndrome assessment – fasting glucose, lipid panel, BMI, blood pressure 1
• Liver disease evaluation – viral hepatitis B and C serology (50% of chronic hepatitis patients have abnormal iron studies), autoimmune hepatitis panel (ANA, ASMA, immunoglobulins) if ALT markedly elevated 1
• Abdominal ultrasound – detects fatty liver in ~40% of patients with abnormal liver tests and elevated ferritin; also identifies hepatomegaly, cirrhotic morphology, biliary abnormalities 1
• Malignancy screening – age-appropriate cancer screening; 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

Special Clinical Contexts

Inflammatory Bowel Disease (IBD):

• Ferritin <30 µg/L = absolute iron deficiency 1
• Ferritin 30–100 µg/L with TS <16% = combined iron deficiency and anemia of chronic disease 1
• Ferritin >100 µg/L with TS <16% = predominant anemia of chronic disease 1

Chronic Kidney Disease (CKD):

• Ferritin 100–700 ng/mL with TS <20% may represent functional iron deficiency that responds to IV iron therapy despite elevated ferritin 1, 2, 3
• A trial of weekly IV iron (50–125 mg for 8–10 doses) can distinguish functional iron deficiency from pure inflammatory block 1, 3
• Withhold iron therapy when ferritin exceeds 1,000 ng/mL or TS exceeds 50% 2

Anemia of Chronic Disease (TS <20% with ferritin >300 ng/mL):

• Do NOT administer oral or IV iron unless specific exceptions apply (CKD with functional iron deficiency, congestive heart failure with iron deficiency) 3
• Iron is sequestered in storage sites by hepcidin elevation in response to inflammatory cytokines (IL-6, TNF-α) 3
• Treat the underlying inflammatory condition, NOT the elevated ferritin 2, 3

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Management Strategy by Etiology

For Confirmed Hereditary Hemochromatosis (TS ≥45%, C282Y homozygote)

Initiate therapeutic phlebotomy immediately with target ferritin 50–100 µg/L; phlebotomy before cirrhosis/diabetes develops significantly reduces morbidity and mortality. 2

For Secondary Hyperferritinemia (TS <45%)

Treat the underlying condition—weight loss and metabolic control for NAFLD, disease-specific anti-inflammatory therapy for rheumatologic conditions, antiviral therapy for hepatitis C, oncologic treatment for malignancy. 1, 2

Phlebotomy is ONLY indicated for confirmed iron overload with TS ≥45% and evidence of end-organ damage—NOT for secondary hyperferritinemia. 2

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Indications for Specialist Referral

Refer to gastroenterology/hepatology or hematology when: 1, 2

• Ferritin >1,000 µg/L with elevated bilirubin
• Ferritin >10,000 µg/L regardless of other findings
• Confirmed TS ≥45% on repeat testing
• Clinical evidence of cirrhosis (platelet count <200,000/µL, elevated bilirubin, hepatomegaly)
• Confirmed C282Y homozygosity requiring therapeutic phlebotomy
• Cause of elevated ferritin remains unclear after initial workup

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Critical Pitfalls to Avoid

• Never use ferritin alone to diagnose iron overload—TS must be assessed concurrently, as ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 3
• Do not order HFE genetic testing when TS <45%—this leads to misdiagnosis and unnecessary phlebotomy 1, 2
• Do not overlook liver biopsy in patients with ferritin >1,000 µg/L and abnormal liver tests—histology is needed to confirm 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 under these circumstances 1
• Recognize that extremely high ferritin (>10,000 µg/L) rarely represents simple iron overload—urgent evaluation for life-threatening conditions is required 1, 2