What is the next step in managing a patient with significantly elevated ferritin and high-sensitivity C-reactive protein (hs-CRP)?

Workup for hs-CRP 7.2 mg/dL and Ferritin 934 ng/mL

Immediately measure fasting transferrin saturation (TSAT) to determine if this represents iron overload or secondary hyperferritinemia—this single test dictates your entire diagnostic pathway. 1

Critical First Step: Transferrin Saturation

• **If TSAT <45%**, iron overload is excluded with >90% probability, and the ferritin elevation is secondary to inflammation, metabolic syndrome, liver disease, or malignancy 1, 2
• If TSAT ≥45%, proceed immediately with HFE genetic testing (C282Y and H63D mutations) to diagnose hereditary hemochromatosis 1, 2
• The combination of elevated ferritin with elevated CRP (7.2 mg/dL, above the 5 mg/dL threshold) strongly suggests secondary hyperferritinemia from inflammation or metabolic causes rather than primary iron overload 2

Most Likely Diagnosis

Metabolic syndrome/NAFLD accounts for over 90% of outpatient hyperferritinemia cases when combined with elevated inflammatory markers. 1, 2 The ferritin level of 934 ng/mL falls well below the 1,000 ng/mL threshold associated with cirrhosis risk, indicating low probability of advanced organ damage even if iron overload were present 1, 3.

Essential Laboratory Workup

Order the following tests immediately:

• Fasting transferrin saturation (morning sample preferred) 1, 2
• Complete metabolic panel including AST, ALT, alkaline phosphatase, bilirubin, albumin 1, 2
• Complete blood count with differential to assess for cytopenias, leukocytosis, or hematologic malignancy 1, 4
• Fasting glucose, HbA1c, and lipid panel to evaluate for metabolic syndrome 1
• TSH and free T4 to exclude thyroid dysfunction 1
• ESR as an additional inflammatory marker 2
• Hepatitis B and C serology if liver enzymes are elevated 2, 3

Secondary Causes to Systematically Exclude

Liver Disease (Most Common)

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury—obtain detailed alcohol history 2, 3, 5
• NAFLD/metabolic syndrome is the leading cause when ferritin and CRP are both elevated 1, 2
• Viral hepatitis (B or C) requires serologic testing 2, 3

Inflammatory Conditions

• Chronic infection causes ferritin to rise as an acute-phase reactant—evaluate for occult infection sources 1, 2
• Malignancy (solid tumors, lymphomas, hepatocellular carcinoma) was the most frequent cause in one series of markedly elevated ferritin 4, 6
• Adult-onset Still's disease should be considered if ferritin rises above 4,000-5,000 ng/mL with persistent fever—measure glycosylated ferritin fraction (<20% is 93% specific for AOSD) 7, 2, 8

Other Conditions

• Cell necrosis from muscle injury or hepatocellular damage—check creatine kinase 2
• Chronic kidney disease can cause functional iron deficiency despite elevated ferritin 1, 2
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome if ferritin >5,000 ng/mL with cytopenias, fever, and multiorgan dysfunction 7, 9

Critical Diagnostic Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without confirming TSAT ≥45%, as ferritin is an acute-phase reactant elevated in countless inflammatory conditions 1, 2, 3
• Do not initiate phlebotomy therapy when TSAT <45%, as this indicates ferritin elevation is not from iron overload 1, 3
• Do not overlook liver biopsy if ferritin exceeds 1,000 ng/mL with abnormal liver enzymes, as this combination warrants histologic assessment for cirrhosis 2, 3
• Recognize that extremely high ferritin (>10,000 ng/mL) rarely represents simple iron overload and requires urgent evaluation for life-threatening conditions like HLH, severe AOSD, or malignancy 2, 4, 8

Management Algorithm Based on TSAT Results

If TSAT <45% (Expected in >90% of Cases)

Treat the underlying condition, not the ferritin number: 1, 2

• For metabolic syndrome/NAFLD: Implement weight loss, glycemic control, lipid management, and blood pressure optimization 1
• For chronic inflammation: Initiate disease-specific anti-inflammatory therapy 2
• For alcohol-related liver disease: Counsel on alcohol cessation 2, 3
• For malignancy: Pursue oncologic treatment 2

If TSAT ≥45%

• Order HFE genetic testing for C282Y and H63D mutations immediately 1, 2, 3
• C282Y homozygotes confirm HFE hemochromatosis—initiate therapeutic phlebotomy and screen first-degree relatives (25% chance of being affected) 2, 3
• Consider liver biopsy if age >40 years, elevated AST, hepatomegaly, or platelet count <200,000/μL, as the combination of ferritin >1,000 ng/mL with these features predicts cirrhosis in 80% of C282Y homozygotes 7, 2, 3

Follow-Up Strategy

• Monitor ferritin every 6-12 months if it remains elevated but <1,000 ng/mL with normal TSAT 1
• Refer to hepatology if ferritin exceeds 1,000 ng/mL, continues to rise despite management of underlying conditions, or if TSAT becomes ≥45% on repeat testing 1, 2
• Recheck inflammatory markers (CRP, ESR) after treating underlying conditions to confirm resolution 2

Special Considerations for Specific Symptoms

If the patient reports palpitations, evaluate for hyperthyroidism, anemia, cardiac arrhythmias, and anxiety disorders 1. If insomnia is present, screen for restless leg syndrome (consider iron supplementation if ferritin ≤75 ng/mL despite the elevated current level), hyperthyroidism, anxiety, depression, and sleep apnea 1.