What is the differential diagnosis for a patient with elevated ferritin and CRP levels, presenting with tachycardia, insomnia, and mental fog?

Differential Diagnosis: Elevated Ferritin (934 ng/mL) and CRP (7.20 mg/dL) with Palpitations, Insomnia, and Mental Fog

Your presentation most likely represents an inflammatory or metabolic condition causing secondary hyperferritinemia, not iron overload, and you must measure transferrin saturation immediately to distinguish between these fundamentally different pathophysiologic processes. 1

Critical First Step: Measure Transferrin Saturation

• Check fasting transferrin saturation (TS) now—this single test determines your entire diagnostic pathway. 1, 2
• If TS <45%, iron overload is excluded and your ferritin elevation is secondary to inflammation, metabolic syndrome, liver disease, or other non-iron causes (>90% probability). 1, 2
• If TS ≥45%, proceed with HFE genetic testing for hereditary hemochromatosis (C282Y and H63D mutations). 1, 3

Most Likely Diagnoses Based on Your Presentation

Primary Considerations (Inflammatory/Metabolic)

• Metabolic syndrome/NAFLD is the leading cause of this ferritin level (934 ng/mL) combined with elevated CRP, accounting for >90% of outpatient hyperferritinemia cases. 1
• Chronic inflammation from any source elevates both CRP and ferritin as acute-phase reactants, independent of actual iron stores. 1, 4
• Thyroid dysfunction (particularly hyperthyroidism) can cause palpitations, insomnia, mental fog, and elevate inflammatory markers—check TSH, free T4. 1

Cardiac Considerations

• Elevated CRP (7.20 mg/dL) is associated with cardiovascular inflammation and may contribute to palpitations through inflammatory effects on cardiac tissue. 4
• Your ferritin level (934 ng/mL) is below the threshold (>2,500 ng/mL) associated with cardiac iron deposition and arrhythmias. 1

Sleep-Related Pathology

• Restless leg syndrome causes insomnia and is associated with low-normal ferritin, but your level (934 ng/mL) makes this diagnosis unlikely as a primary cause. 5
• However, check ferritin trends—if it was previously lower, RLS could be contributing to insomnia despite current elevation. 5

Inflammatory/Rheumatologic Conditions

• Adult-onset Still's disease (AOSD) presents with extreme hyperferritinemia (typically 4,000-30,000 ng/mL) with glycosylated ferritin <20%, making this unlikely at your ferritin level. 1
• Chronic rheumatologic diseases can cause this degree of ferritin elevation with systemic symptoms—consider if you have joint pain, rashes, or other inflammatory features. 1

Infection and Malignancy

• Active infection causes ferritin to rise acutely as part of the inflammatory response—your CRP elevation supports this possibility. 1, 6
• Malignancy (solid tumors, lymphomas, hepatocellular carcinoma) was the most common cause of ferritin >1,000 ng/mL in one large series, though your level is just below this threshold. 7
• Hematologic malignancies (particularly acute myeloblastic leukemia, T/NK cell lymphoma) are strongly associated with hyperferritinemia in hospitalized patients. 6

Liver Disease

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury with ferritin elevation—assess alcohol intake honestly. 1
• Viral hepatitis (B and C) and acute hepatitis cause ferritin elevation through hepatocellular necrosis. 1
• Check liver enzymes (AST, ALT, GGT, bilirubin, albumin) to assess for hepatocellular injury. 1, 3

Risk Stratification by Ferritin Level

• Your ferritin (934 ng/mL) is below 1,000 ng/mL, indicating low risk for cirrhosis or advanced organ damage even if iron overload were present (which is unlikely). 1
• Ferritin >1,000 ng/mL with elevated liver enzymes and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes, but you haven't reached this threshold. 1
• Ferritin >10,000 ng/mL rarely represents simple iron overload and requires urgent evaluation for life-threatening conditions like hemophagocytic lymphohistiocytosis. 1

Essential Diagnostic Workup

Immediate Laboratory Tests

• Transferrin saturation (fasting, morning preferred) 1, 2, 3
• Complete metabolic panel (AST, ALT, GGT, bilirubin, albumin) to assess liver function 1, 3
• TSH and free T4 to evaluate thyroid function causing your symptoms 1
• Complete blood count with differential to assess for anemia, infection, or hematologic malignancy 1
• Fasting glucose, HbA1c, lipid panel to evaluate metabolic syndrome 1, 3

Additional Tests Based on Clinical Context

• Inflammatory markers: ESR to complement CRP assessment 1
• Infectious workup: Blood cultures, viral hepatitis panel (HBV, HCV) if clinically indicated 1
• Glycosylated ferritin fraction if AOSD is suspected (requires ferritin >2,000 ng/mL and systemic symptoms) 1
• Electrocardiogram and echocardiogram to evaluate palpitations structurally 1

Critical Diagnostic Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without confirming TS ≥45%—ferritin is an acute-phase reactant elevated in countless inflammatory conditions. 1, 2
• Do not initiate phlebotomy therapy when TS <45%—this indicates ferritin elevation is not from iron overload. 2
• Do not overlook malignancy—it was the most common cause of ferritin >1,000 ng/mL in a large academic center series. 7
• Recognize that extremely high CRP (>10 mg/dL) combined with high ferritin increases mortality risk—your CRP of 7.20 mg/dL warrants close monitoring. 8
• Do not assume hereditary hemochromatosis—only 70% of C282Y homozygotes have elevated ferritin, and phenotypic expression occurs in <10% of genetic carriers. 9

Management Algorithm Based on Transferrin Saturation

If TS <45% (Most Likely Scenario)

• Treat the underlying inflammatory or metabolic condition, not the ferritin number. 1, 3
• Address metabolic syndrome components: weight loss, glycemic control, lipid management, blood pressure control. 3
• Investigate and treat active infection if present. 1
• Consider non-invasive liver fibrosis assessment (FibroScan/transient elastography) if NAFLD is suspected. 3
• Recheck ferritin in 3-6 months after implementing lifestyle changes. 3

If TS ≥45% (Less Likely)

• Proceed with HFE genetic testing for C282Y and H63D mutations. 1, 3
• If C282Y homozygote or C282Y/H63D compound heterozygote with elevated iron stores, diagnose HFE hemochromatosis. 9, 1
• Therapeutic phlebotomy can begin without liver biopsy if ferritin <1,000 ng/mL, normal liver enzymes, and age <40. 1
• Consider liver MRI to quantify hepatic iron concentration. 1

Symptom-Specific Considerations

Palpitations ("Strong Heartbeat")

• Evaluate for hyperthyroidism, anemia, cardiac arrhythmias, and anxiety disorders. 1
• Your ferritin level is far below the threshold (>2,500 ng/mL) for cardiac iron deposition causing arrhythmias. 1
• Elevated CRP may reflect cardiovascular inflammation contributing to symptoms. 4

Insomnia

• Screen for restless leg syndrome (though your high ferritin makes this less likely as primary cause). 5
• Evaluate for hyperthyroidism, anxiety, depression, and sleep apnea. 1
• Elevated CRP is independently associated with psychological distress and depression. 4

Mental Fog

• Assess thyroid function, vitamin B12, vitamin D, and screen for depression. 1
• Elevated CRP (>7 mg/dL) is associated with increased risk for psychological distress and depression (OR 2.02 for CRP 3.01-10.00 mg/dL). 4
• Consider inflammatory effects on cognitive function. 4

Follow-Up Strategy

• If ferritin remains elevated but <1,000 ng/mL with normal TS, continue monitoring every 6-12 months. 3
• Refer to hepatology if ferritin exceeds 1,000 ng/mL or continues to rise despite management of underlying conditions. 3
• Urgent specialist referral if ferritin exceeds 10,000 ng/mL to evaluate for life-threatening conditions like hemophagocytic lymphohistiocytosis. 1