What is the next step in management for a patient with elevated ferritin levels and a negative C-Reactive Protein (CRP) result, considering the potential for iron overload and the need for aspirin therapy for cardiovascular risk?

Management of Elevated Ferritin with Negative CRP

The next step is to measure fasting transferrin saturation (TS) to distinguish between true iron overload and secondary causes of hyperferritinemia, as this single test determines whether genetic testing and phlebotomy are needed versus treating an underlying non-iron condition. 1

Immediate Diagnostic Testing Required

• Order fasting transferrin saturation immediately - this is the most critical test to determine if iron overload is actually present, as ferritin alone cannot distinguish between true iron overload and secondary causes 1
• Measure complete metabolic panel including AST and ALT to assess for hepatocellular injury 1
• Check complete blood count with differential to evaluate for anemia, polycythemia, or hematologic malignancy 1
• Measure creatine kinase (CK) to evaluate for muscle necrosis as a cause of ferritin elevation 1

The negative CRP is helpful as it reduces likelihood of acute inflammation, but over 90% of elevated ferritin cases are NOT due to iron overload even without inflammation - they result from chronic alcohol consumption, metabolic syndrome/NAFLD, liver disease, malignancy, or cell necrosis 1

Algorithmic Approach Based on Transferrin Saturation Results

If TS ≥45%: Suspect Primary Iron Overload

• Order HFE genetic testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis 1
• If C282Y homozygote is confirmed, this establishes HFE hemochromatosis diagnosis 1
• Initiate therapeutic phlebotomy and screen first-degree relatives 1
• Consider liver biopsy if ferritin >1000 μg/L with elevated liver enzymes, as this combination predicts cirrhosis in 80% of C282Y homozygotes when platelet count is also <200,000/μL 1

If TS <45%: Iron Overload is Unlikely - Investigate Secondary Causes

Do not assume iron overload when TS <45% - in the general population, iron overload is NOT the most common cause of elevated ferritin 1

Systematically evaluate for these conditions:

• Chronic alcohol consumption - obtain detailed alcohol history, as alcohol increases iron absorption and causes hepatocellular injury 1
• Metabolic syndrome/NAFLD - assess for obesity, diabetes, hypertension, dyslipidemia; ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload 1
• Liver disease - check hepatitis B and C serologies, review liver enzymes for acute or chronic hepatitis 1
• Malignancy - the most frequent cause of markedly elevated ferritin in one large series (153/627 patients); assess for B symptoms, lymphadenopathy, consider age-appropriate cancer screening 1, 2
• Cell necrosis - elevated CK suggests muscle injury; elevated transaminases suggest hepatocellular necrosis 1

Aspirin Therapy Considerations

Aspirin can be safely initiated for cardiovascular risk reduction regardless of ferritin level when clinically indicated, as elevated ferritin alone does not contraindicate aspirin therapy 3

However, apply standard aspirin precautions:

• Avoid if history of stomach ulcers or bleeding problems 3
• Use caution if age ≥60 years (higher risk of stomach bleeding) 3
• Avoid if taking blood thinners or other NSAIDs 3
• Avoid if consuming ≥3 alcoholic drinks daily 3

The concern about iron overload and aspirin is misplaced here - aspirin decisions should be based on cardiovascular risk and bleeding risk, not ferritin levels 3

Critical Pitfalls to Avoid

• Never use ferritin alone to diagnose iron overload - ferritin is an acute phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1
• Do not initiate therapeutic phlebotomy without confirming TS ≥45% - venesection is not appropriate for secondary hyperferritinemia and will not address the underlying condition 4
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests - this combination warrants histologic assessment for cirrhosis 1
• Recognize that ferritin <1000 μg/L has high negative predictive value for cirrhosis (94% in hemochromatosis patients), so aggressive intervention is less urgent at lower levels 1

When to Refer

Refer to gastroenterologist, hematologist, or physician with iron overload expertise if:

• Serum ferritin >1000 μg/L 4
• Cause of elevated ferritin remains unclear after initial evaluation 4
• TS ≥45% with confirmed C282Y homozygosity requiring phlebotomy management 1
• Ferritin continues rising or exceeds 4000-5000 μg/L (consider rare conditions like adult-onset Still's disease) 1