How should a patient with a high‑sensitivity C‑reactive protein of about 7 mg/L and a ferritin level of approximately 1000 ng/mL be managed?

Management of Elevated hs-CRP (7 mg/L) and Ferritin (1000 ng/mL)

Immediately measure fasting transferrin saturation (TS) to distinguish true iron overload from inflammatory hyperferritinemia, then treat the underlying inflammatory condition—not the ferritin number itself—because with hs-CRP at 7 mg/L and ferritin at 1000 ng/mL, you are almost certainly dealing with systemic inflammation rather than primary iron overload. 1, 2

---

Step 1: Obtain Transferrin Saturation Immediately

• Order a fasting transferrin saturation test the same day, because ferritin alone cannot distinguish iron overload from inflammation. 1, 2
• If TS ≥ 45%, suspect primary iron overload and proceed directly to HFE genetic testing for C282Y and H63D mutations. 1, 2
• If TS < 45% (which is highly likely given the elevated CRP), iron overload is excluded with >90% certainty, and the ferritin elevation reflects inflammation, liver disease, metabolic syndrome, or tissue injury. 1, 2

---

Step 2: Identify the Inflammatory Source

Common Causes When TS < 45%

• Chronic alcohol consumption increases intestinal iron absorption and causes hepatocellular injury, leading to elevated ferritin. 1
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome causes ferritin elevation reflecting hepatocellular injury and insulin resistance rather than true iron overload. 1
• Chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease) elevate ferritin as an acute-phase reactant. 1
• Infections cause ferritin to rise acutely as part of the inflammatory response; investigate for active infection as a cause of the elevated ferritin. 1
• Cell necrosis from muscle injury, hepatocellular necrosis, or tissue breakdown releases ferritin from lysed cells, independent of iron stores. 1

Immediate Laboratory Panel

• Complete metabolic panel including ALT, AST to assess for liver disease. 1, 2
• Fasting glucose and lipid panel to assess for metabolic syndrome. 1
• Complete blood count with differential to assess for anemia, polycythemia, or hematologic malignancy. 1
• Creatine kinase (CK) to evaluate for muscle necrosis. 1
• Hepatitis B surface antigen and hepatitis C antibody because approximately 50% of patients with chronic hepatitis B or C exhibit abnormal serum iron parameters. 1

Imaging

• Abdominal ultrasound to detect fatty infiltration, hepatomegaly, cirrhotic morphology, or biliary abnormalities, because nearly 40% of adults with abnormal liver tests have fatty liver on ultrasound. 1

---

Step 3: Risk Stratification by Ferritin Level

Ferritin 1000 ng/mL: Critical Threshold

• Ferritin >1000 µg/L is a critical threshold indicating 20-45% prevalence of cirrhosis in C282Y homozygotes. 1, 2
• Strongly consider liver biopsy if ferritin >1000 µg/L is accompanied by elevated liver enzymes or platelet count <200,000/µL to assess for cirrhosis. 1, 2
• The combination of ferritin >1000 µg/L, elevated aminotransferases, and platelet count <200,000/µL predicts cirrhosis in ~80% of C282Y homozygotes. 1
• Ferritin >1000 µg/L with elevated bilirubin warrants prompt referral to gastroenterology/hepatology. 2

When Liver Biopsy Is NOT Needed

• You do NOT need liver biopsy if ferritin <1000 µg/L, which has a 94% negative predictive value for advanced fibrosis. 1
• If TS <45% and ferritin is 1000 µg/L with normal liver enzymes and platelet count >200,000/µL, liver biopsy is unnecessary because the ferritin elevation reflects inflammation rather than iron overload. 1, 2

---

Step 4: Management Based on Transferrin Saturation

If TS ≥ 45% (Primary Iron Overload)

• Order HFE genetic testing for C282Y and H63D mutations immediately. 1, 2
• If C282Y homozygote or C282Y/H63D compound heterozygote, initiate therapeutic phlebotomy with a target ferritin of 50-100 µg/L. 2
• Phlebotomy protocol: Remove 500 mL blood weekly or biweekly; monitor hemoglobin/hematocrit before each phlebotomy and allow hemoglobin to fall no more than 20% from baseline; check ferritin every 10-12 phlebotomies. 2
• Screen all first-degree relatives with TS, ferritin, and HFE genetic testing. 2
• Avoid iron supplements, vitamin C supplementation, and raw shellfish. 2

If TS < 45% (Secondary Hyperferritinemia)

• Treat the underlying condition, not the elevated ferritin. 2
• If NAFLD/metabolic syndrome: Focus on weight loss, metabolic control, and lifestyle modification; phlebotomy is NOT indicated. 1, 2
• If chronic alcohol use: Counsel on alcohol cessation; ferritin will normalize with abstinence. 1
• If infection: Treat the infection; ferritin will decrease as inflammation resolves. 1
• If inflammatory bowel disease: Optimize disease-specific anti-inflammatory therapy. 2

---

Step 5: Special Considerations for hs-CRP 7 mg/L

CRP Interpretation

• hs-CRP at 7 mg/L is elevated (normal <5 mg/L) and indicates active systemic inflammation. 1, 3
• The combination of elevated CRP and ferritin is strongly suggestive of secondary hyperferritinemia from inflammation or metabolic causes. 1
• CRP rises 4-6 hours after an inflammatory trigger and peaks at 36-50 hours, so this level suggests ongoing inflammation. 3

Exclude High-Risk Conditions

• If ferritin continues rising or exceeds 4,000-5,000 ng/mL with persistent fever, consider Adult-Onset Still's Disease and measure glycosylated ferritin fraction (<20% is 93% specific for AOSD). 1, 2
• Screen for macrophage activation syndrome if clinical suspicion exists (persistent fever, splenomegaly, cytopenias, elevated triglycerides, abnormal liver function). 1
• Ferritin >10,000 ng/mL rarely represents simple iron overload and requires urgent specialist referral to evaluate for life-threatening conditions (e.g., hemophagocytic lymphohistiocytosis). 1, 2

---

Step 6: When to Refer to Specialist

Immediate Referral Indications

• Ferritin >1000 µg/L with elevated bilirubin. 2
• Ferritin >10,000 µg/L regardless of other findings. 1, 2
• Confirmed TS ≥45% on repeat testing. 2
• Clinical evidence of cirrhosis (platelet count <200,000/µL, elevated bilirubin, hepatomegaly). 2
• Confirmed C282Y homozygosity, which requires therapeutic phlebotomy. 2

---

Critical Pitfalls to Avoid

• Never use ferritin alone to diagnose iron overload; TS must be assessed concurrently. 1, 2
• Do not order HFE genetic testing when TS <45%, as this leads to misdiagnosis and unnecessary phlebotomy. 1, 2
• Do not overlook liver biopsy in patients with ferritin >1000 µg/L and abnormal liver tests, because 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. 1
• Recognize that ferritin is an acute-phase reactant that rises with inflammation, infection, liver disease, malignancy, and tissue necrosis independent of iron stores. 1, 2

---

Bottom Line

The pattern of hs-CRP 7 mg/L with ferritin 1000 ng/mL strongly suggests inflammatory hyperferritinemia rather than iron overload. 1, 2 Measure transferrin saturation immediately to confirm TS <45%, then focus diagnostic efforts on identifying and treating the underlying inflammatory, metabolic, or liver disease—not on lowering the ferritin number itself. 1, 2 Phlebotomy or iron chelation is only indicated if TS ≥45% and genetic testing confirms hereditary hemochromatosis. 1, 2, 4