What is the appropriate work‑up and management for an adult with elevated serum ferritin?

Elevated Ferritin: Diagnostic Work-Up and Management

Initial Diagnostic Approach

The single most important test is fasting transferrin saturation (TS), which must be measured simultaneously with ferritin to distinguish true iron overload from secondary causes. 1

First-Line Laboratory Panel

Order the following tests immediately:

• Fasting transferrin saturation (TS) – the critical discriminator between primary iron overload (TS ≥45%) and secondary hyperferritinemia (TS <45%) 1, 2
• Complete metabolic panel including ALT, AST, alkaline phosphatase, and bilirubin to assess hepatocellular injury 1
• Inflammatory markers (CRP and ESR) to detect occult inflammation 1, 2
• Complete blood count with differential to evaluate for anemia, polycythemia, or hematologic malignancy 2

Algorithmic Management Based on Transferrin Saturation

If TS ≥45%: Primary Iron Overload Pathway

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

• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms hereditary hemochromatosis and warrants therapeutic intervention 1, 2, 3
• Consider liver biopsy if ferritin >1000 μg/L AND any of the following: elevated liver enzymes, platelet count <200,000/μL, age >40 years, or hepatomegaly 1, 2
• The combination of ferritin >1000 μg/L, elevated aminotransferases, and platelets <200,000/μL predicts cirrhosis in 80% of C282Y homozygotes 1, 2
• Initiate therapeutic phlebotomy (500 mL weekly or biweekly) with target ferritin 50-100 μg/L if hereditary hemochromatosis is confirmed 1
• Screen all first-degree relatives with TS, ferritin, and HFE genetic testing 1

If TS <45%: Secondary Hyperferritinemia Pathway

Iron overload is excluded with >90% certainty; evaluate secondary causes instead. 1, 2, 4

The most common causes (accounting for >90% of cases) include: 1, 2

• Chronic liver disease – alcoholic liver disease, NAFLD/metabolic syndrome, viral hepatitis (check hepatitis B surface antigen, hepatitis C antibody) 1, 2
• Inflammatory conditions – rheumatologic diseases, inflammatory bowel disease, infections 1, 2
• Malignancy – solid tumors, lymphomas, hepatocellular carcinoma 1, 2
• Cell necrosis – check creatine kinase for muscle injury 2
• Chronic kidney disease – particularly in patients on erythropoiesis-stimulating agents 1

Additional Diagnostic Testing for Secondary Causes

• Abdominal ultrasound to evaluate for fatty liver, hepatomegaly, cirrhotic morphology, or biliary abnormalities 2
• Alcohol consumption history – detailed quantification is essential 2
• Fasting glucose and lipid panel to assess metabolic syndrome 1
• Autoimmune hepatitis workup if ALT markedly elevated: ANA, ASMA, immunoglobulin levels 1

Risk Stratification by Ferritin Level

Ferritin <1000 μg/L

• Low risk of organ damage – 94% negative predictive value for advanced liver fibrosis 1, 2, 4
• If C282Y homozygote with TS ≥45%, age <40, normal liver enzymes, and no hepatomegaly: proceed directly to therapeutic phlebotomy without liver biopsy 1

Ferritin 1000-10,000 μg/L

• Higher risk of advanced fibrosis/cirrhosis if iron overload present 1, 2
• Liver biopsy strongly recommended if ferritin >1000 μg/L with elevated liver enzymes OR platelet count <200,000/μL 1, 2
• If TS <45%, most commonly due to chronic liver disease, malignancy, or infection 3, 5, 6

Ferritin >10,000 μg/L

Rarely represents simple iron overload; requires urgent specialist referral. 1, 2, 7, 8

Consider life-threatening conditions:

• Hemophagocytic lymphohistiocytosis (HLH) – ferritin >13,405 μg/L has 76% sensitivity and 79% specificity for HLH 8
• Adult-onset Still's disease (AOSD) – ferritin often 4,000-30,000 ng/mL (occasionally up to 250,000 ng/mL); measure glycosylated ferritin fraction (<20% is 93% specific for AOSD when combined with 5-fold ferritin elevation) 9, 1
• Acute hepatitis – check viral hepatitis panel, acetaminophen level, autoimmune markers 8
• Severe infection/sepsis – ferritin rises as acute-phase reactant 5, 8
• Macrophage activation syndrome – look for persistent fever, splenomegaly, cytopenias, elevated triglycerides 1

The four causes associated with extreme hyperferritinemia (>25,000 μg/L) are: HLH, infections, acute hepatitis, and cytokine release syndromes 8

Management Strategy

For Confirmed Iron Overload (TS ≥45%)

• Therapeutic phlebotomy is the treatment of choice 1
• Remove 500 mL blood weekly or biweekly until ferritin reaches 50-100 μg/L 1
• Check hemoglobin/hematocrit before each phlebotomy; allow no more than 20% drop from baseline 1
• Check ferritin every 10-12 phlebotomies 1
• Once target achieved, maintain with phlebotomy every 2-4 months 1
• Avoid iron supplements, vitamin C supplementation, and raw shellfish 1

For Secondary Hyperferritinemia (TS <45%)

Treat the underlying condition, not the elevated ferritin itself. 1, 4

• NAFLD/metabolic syndrome – weight loss, metabolic control, lifestyle modification 1, 4
• Inflammatory conditions – disease-specific anti-inflammatory therapy 1
• Chronic liver disease – address underlying etiology (alcohol cessation, antiviral therapy for hepatitis) 1, 2
• Malignancy – oncologic treatment 1
• Monitor ferritin every 3 months as a marker of treatment response; declining ferritin indicates improvement 4

Special Clinical Contexts

Chronic Kidney Disease

• Elevated ferritin (500-1200 μg/L) with low TS (<25%) may represent functional iron deficiency that responds to IV iron therapy, especially in patients on erythropoiesis-stimulating agents 1
• Withhold iron therapy when ferritin exceeds 1000 ng/mL or TS exceeds 50% 1

Inflammatory Bowel Disease

• Ferritin <30 μg/L indicates absolute iron deficiency 2
• Ferritin >100 μg/L with low TS suggests anemia of chronic disease 2

NAFLD with Elevated Ferritin

• Ferritin elevation reflects hepatocellular injury and insulin resistance, not iron overload 1, 4
• Do NOT perform phlebotomy unless TS ≥45% 4
• Ferritin levels correlate with insulin resistance and age, independent of iron stores 4

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload – this leads to misdiagnosis and inappropriate phlebotomy 1, 2, 4
• Do not order HFE genetic testing when TS <45% – over 90% of elevated ferritin cases with TS <45% are due to secondary causes 1, 2, 4
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests 1, 2
• Do not assume iron overload when TS <45% – iron overload is NOT the most common cause of elevated ferritin in the general population 1, 2
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1, 2
• Recognize that ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 2, 3, 5

Indications for Specialist Referral

Refer to gastroenterology/hepatology or hematology when:

• Ferritin >1000 μg/L with elevated bilirubin 1, 2
• Ferritin >10,000 μg/L regardless of other findings 1, 2, 7, 8
• Confirmed TS ≥45% on repeat testing 1, 2
• Clinical evidence of cirrhosis (platelet count <200,000/μL, elevated bilirubin, hepatomegaly) 1, 2
• Confirmed C282Y homozygosity requiring therapeutic phlebotomy 1, 2
• Suspicion of HLH, AOSD, or other life-threatening inflammatory syndromes 9, 1, 8