Differential Diagnosis and Work-Up for Elevated CRP and Ferritin
When both CRP and ferritin are elevated, you are dealing with an inflammatory process, not iron overload, and your immediate priority is to identify the underlying inflammatory, infectious, or malignant condition driving these acute-phase reactants.
Understanding the Clinical Pattern
Both CRP and ferritin rise as acute-phase reactants during inflammation, infection, tissue injury, and malignancy—independent of actual iron stores 1. This combination signals active systemic inflammation rather than primary iron overload 1. Ferritin has high sensitivity but poor specificity for iron overload because it increases in inflammatory conditions, liver disease, malignancy, and tissue necrosis 1. CRP becomes elevated early in bacterial infections, active rheumatoid disease, Crohn's disease, acute myocardial infarction, and after major trauma 2.
The single most important initial test is transferrin saturation (TS): if TS <45%, iron overload is excluded with >90% certainty, and the elevated ferritin reflects inflammation or other secondary causes 1. If TS ≥45%, you must consider primary iron overload disorders and proceed to HFE genetic testing 1.
Differential Diagnosis by Clinical Context
Inflammatory & Rheumatologic Conditions
Adult-onset Still's disease (AOSD): Suspect when ferritin exceeds 4,000–5,000 ng/mL with persistent fever 1, 3. Measure glycosylated ferritin fraction; <20% is 93% specific for AOSD 1. Ferritin correlates with disease activity and often normalizes with remission 1.
Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome: Consider when ferritin >5,000 ng/mL with cytopenias, fever, and multiorgan dysfunction 1. This is a life-threatening condition requiring urgent specialist referral 3.
Chronic rheumatologic diseases: Rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus elevate ferritin as an acute-phase reactant 1. In SLE, CRP and ferritin responses are highly variable and do not always reflect disease activity 4.
ANCA-associated vasculitis: Elevated ferritin (not CRP) correlates with severe kidney injury, higher BVAS scores, and worse renal prognosis 5. High ferritin reflects a higher proportion of glomeruli with cellular crescents 5.
Infectious Causes
Active bacterial infection: CRP rises early in bacterial infections 2. Investigate for occult infection as a cause of elevated ferritin 1. The association is bidirectional: infection causes ferritin to rise, not vice versa 1.
Viral hepatitis (B and C): Approximately 50% of patients with chronic hepatitis B or C have abnormal serum iron studies 1. Ferritin elevation reflects hepatocellular injury and inflammation rather than true iron overload 1.
Liver Disease
Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome: Ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload 1. Abdominal ultrasound identifies fatty liver in ~40% of adults with abnormal liver tests 1.
Alcoholic liver disease: Chronic alcohol consumption increases iron absorption and causes hepatocellular injury 1. Elevated ferritin with elevated ALT and normal TS strongly suggests NAFLD or alcoholic liver disease 1.
Acute hepatitis: Causes marked ferritin elevation due to hepatocellular necrosis 1.
Malignancy
Solid tumors and lymphomas: Ferritin serves as a tumor marker 1. Assess for B symptoms, lymphadenopathy, and consider CT imaging if suspected 1.
Hepatocellular carcinoma: A potential cause of elevated ferritin 1.
Other Causes
Cell necrosis: Muscle injury, hepatocellular necrosis, or tissue breakdown releases ferritin from lysed cells 1.
Chronic kidney disease: Ferritin is an acute-phase reactant that can be elevated even when functional iron deficiency exists 6. 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 1, 3.
Metabolic syndrome: A common cause of hyperferritinemia 1.
Diagnostic Work-Up Algorithm
Step 1: Measure Transferrin Saturation (TS) Immediately
- Order fasting TS alongside ferritin to distinguish true iron overload from secondary causes 1.
- If TS ≥45%: Suspect primary iron overload and proceed immediately to HFE genetic testing for C282Y and H63D mutations 1.
- If TS <45%: Iron overload is unlikely; evaluate secondary causes 1.
Step 2: Assess Inflammatory Markers and Liver Function
- Complete metabolic panel: Check ALT, AST, bilirubin, alkaline phosphatase, and albumin to assess hepatocellular injury 1.
- Inflammatory markers: Measure ESR and repeat CRP to confirm ongoing inflammation 1.
- Complete blood count (CBC) with differential: Evaluate for anemia, polycythemia, cytopenias, or hematologic malignancy 1.
Step 3: Evaluate for Specific High-Risk Conditions
- If ferritin >4,000–5,000 ng/mL with persistent fever: Measure glycosylated ferritin fraction (<20% is 93% specific for AOSD) 1, 3.
- If ferritin >5,000 ng/mL with cytopenias, fever, and multiorgan dysfunction: Screen for HLH/macrophage activation syndrome (elevated triglycerides, abnormal liver function, splenomegaly) 1.
- If ferritin >10,000 ng/mL: Rarely represents simple iron overload; requires urgent specialist referral 1, 3.
Step 4: Rule Out Common Secondary Causes
- Chronic alcohol consumption: Obtain detailed alcohol history 1.
- Viral hepatitis: Check hepatitis B surface antigen and hepatitis C antibody 1.
- NAFLD/metabolic syndrome: Assess for obesity, glucose intolerance, dyslipidemia; consider abdominal ultrasound 1.
- Malignancy: Assess for B symptoms, lymphadenopathy, unexplained weight loss; consider CT imaging if suspected 1.
- Infection: Investigate for active infection (blood cultures, urinalysis, chest X-ray as clinically indicated) 1.
Step 5: Risk Stratification by Ferritin Level
| Ferritin Level | Clinical Implication | Action |
|---|---|---|
| <1,000 µg/L | Low risk of organ damage; 94% negative predictive value for advanced fibrosis [1] | If TS <45%, no further iron-overload evaluation needed [1] |
| 1,000–10,000 µg/L | Increased risk of advanced fibrosis/cirrhosis if iron overload present [1] | If TS ≥45% with elevated liver enzymes or platelet count <200,000/µL, consider liver biopsy [1] |
| >10,000 µg/L | Rarely due to simple iron overload; mandates urgent specialist referral [1,3] | Evaluate for AOSD, HLH, or other life-threatening conditions [1,3] |
Step 6: Consider Liver Biopsy or Advanced Imaging
- Liver biopsy indicated if: Ferritin >1,000 µg/L and elevated liver enzymes or platelet count <200,000/µL 1, 3.
- MRI with T2/T2 relaxometry:* Non-invasive method to quantify hepatic iron concentration if TS ≥45% 1, 3.
Management Strategy
Treat the underlying condition, not the elevated ferritin itself 3. The ferritin will normalize once the inflammatory process resolves 1.
- For inflammatory conditions: Disease-specific anti-inflammatory therapy 1.
- For NAFLD/metabolic syndrome: Weight loss and metabolic control 1, 3.
- For viral hepatitis: Direct-acting antivirals; viral eradication frequently reduces ferritin levels 1.
- For malignancy: Oncologic treatment 1.
- For infection: Appropriate antimicrobial therapy 1.
Do not initiate phlebotomy or iron chelation unless TS ≥45% and iron overload is confirmed 1, 3.
Critical Pitfalls to Avoid
- Never use ferritin alone to diagnose iron overload without confirming TS ≥45% 1, 3.
- Do not assume iron overload when TS <45%; in the general population, iron overload is not the most common cause of elevated ferritin 1.
- Do not overlook liver biopsy in patients with ferritin >1,000 µg/L and abnormal liver tests 1, 3.
- Do not delay specialist referral when ferritin >10,000 µg/L or when clinical suspicion for AOSD, HLH, or malignancy is high 1, 3.
- Recognize that extremely high ferritin (>10,000 µg/L) rarely represents simple iron overload and requires urgent evaluation for life-threatening conditions 1, 3.