What are the likely diagnoses and recommended work‑up and treatment for a 33‑year‑old Asian man with hypertension, markedly elevated ferritin (~1000 ng/mL), very high C‑reactive protein (~103 mg/L), elevated lipoprotein‑associated phospholipase A₂ activity, increased asymmetric dimethylarginine, intermittent fever, and ear erythema when lying supine?

Likely Diagnoses and Recommended Work-Up

This 33-year-old Asian man with hypertension, markedly elevated ferritin (1000 ng/mL), very high CRP (103 mg/L), intermittent fever, and ear erythema when supine most likely has an inflammatory or rheumatologic condition—particularly Adult-Onset Still's Disease (AOSD)—rather than primary iron overload, and requires immediate measurement of transferrin saturation, glycosylated ferritin fraction, and comprehensive inflammatory work-up to distinguish between life-threatening systemic inflammatory syndromes and secondary hyperferritinemia.

Critical First Diagnostic Step: Measure Transferrin Saturation

The single most important test is fasting transferrin saturation (TS), which determines whether this represents true iron overload or secondary hyperferritinemia 1.

• If TS ≥45%: Suspect primary iron overload (hereditary hemochromatosis or non-HFE hemochromatosis) and proceed to HFE genetic testing for C282Y and H63D mutations 1, 2
• **If TS <45%**: Iron overload is excluded with >90% probability, and the presentation represents secondary hyperferritinemia from inflammation, infection, malignancy, or metabolic disease 1, 3

Never diagnose iron overload based on ferritin alone—over 90% of elevated ferritin cases are NOT due to iron overload but rather chronic alcohol consumption, inflammation, cell necrosis, tumors, or metabolic syndrome 1.

Most Likely Diagnoses Based on Clinical Pattern

Primary Consideration: Adult-Onset Still's Disease (AOSD)

The combination of intermittent fever, markedly elevated ferritin (~1000 ng/mL), very high CRP (103 mg/L), and ear erythema strongly suggests AOSD 1, 4:

• Ferritin levels in AOSD typically range 4,000-30,000 ng/mL (occasionally up to 250,000 ng/mL), and correlate with disease activity 1
• While this patient's ferritin of 1000 ng/mL is at the lower end for AOSD, the extremely elevated CRP (103 mg/L) with fever and ear erythema is highly characteristic 1
• Glycosylated ferritin fraction <20% is 93% specific for AOSD when combined with 5-fold ferritin elevation 1
• The ear erythema when lying supine may represent the characteristic evanescent salmon-pink rash of AOSD

Secondary Considerations

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS):

• Consider if ferritin continues rising or exceeds 4,000-5,000 ng/mL with persistent fever, splenomegaly, cytopenias, elevated triglycerides, and abnormal liver function 1, 2
• Average ferritin in HLH/MAS is 14,242 μg/L 4

Systemic Infection:

• Active infection causes ferritin to rise acutely as part of the inflammatory response 1
• The intermittent fever pattern requires exclusion of occult bacterial, viral, or fungal infection

Malignancy (particularly lymphoma or solid tumors):

• Most frequent cause of markedly elevated ferritin in one large series (153/627 patients) 4
• Assess for B symptoms (fever, night sweats, weight loss), lymphadenopathy 1

Metabolic Syndrome/NAFLD:

• Ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload 1, 3
• Hypertension is consistent with metabolic syndrome
• However, the extremely elevated CRP (103 mg/L) argues against NAFLD alone as the primary cause 1

Essential Immediate Laboratory Work-Up

Tier 1: Critical Discriminatory Tests (Order Immediately)

1. Fasting transferrin saturation (morning sample preferred) 1, 2
2. Glycosylated ferritin fraction (if available; <20% is 93% specific for AOSD) 1
3. Complete blood count with differential (assess for cytopenias, leukocytosis, anemia) 1, 2
4. Comprehensive metabolic panel including AST, ALT, bilirubin, alkaline phosphatase, albumin 1, 2
5. ESR (additional inflammatory marker) 1
6. Prothrombin time/INR (reflects synthetic liver function) 2

Tier 2: Exclude Specific High-Risk Conditions

1. Blood cultures (if fever present) 1
2. Hepatitis B surface antigen and hepatitis C antibody (50% of viral hepatitis patients have abnormal iron studies) 2
3. ANA, anti-smooth muscle antibody (ASMA), immunoglobulin levels (autoimmune hepatitis can mimic iron overload) 2
4. Fasting glucose, HbA1c, lipid panel (assess metabolic syndrome) 1, 3
5. Creatine kinase (evaluate muscle necrosis) 1
6. Lactate dehydrogenase, triglycerides (if HLH/MAS suspected) 1

Tier 3: Cardiovascular Risk Stratification

The elevated Lp-PLA2 activity (128 ng/mL) and ADMA indicate increased cardiovascular risk:

• Lp-PLA2 >234.5 ng/mL is associated with endothelial dysfunction, impaired coronary flow reserve, and adverse cardiac events 5
• Lp-PLA2 predicts cardiovascular mortality independently of established risk factors, even in patients with high CRP 6
• The combination of elevated CRP and ferritin is strongly suggestive of secondary hyperferritinemia from inflammation, which independently increases cardiovascular risk 7
• Serum ferritin is a significant predictor of hypertension development, possibly mediated by fatty liver disease and insulin resistance 8

Imaging Studies

1. Abdominal ultrasound: Evaluate for fatty liver, hepatomegaly, splenomegaly, cirrhotic morphology 1, 2
2. Chest X-ray: If infection or lymphoma suspected 1
3. CT chest/abdomen/pelvis: If lymphoma or malignancy suspected based on clinical findings 1

Algorithmic Diagnostic Approach

If Transferrin Saturation ≥45%:

1. Order HFE genetic testing for C282Y and H63D mutations 1, 2
2. If C282Y homozygote: Diagnose hereditary hemochromatosis
   • Consider liver biopsy if ferritin >1000 μg/L AND (elevated liver enzymes OR platelet count <200,000/μL OR age >40 years) 9, 1, 2
   • The combination of ferritin >1000 μg/L, elevated aminotransferases, and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 1
3. If NOT C282Y homozygote: Consider non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 1, 3

If Transferrin Saturation <45% (Most Likely Scenario):

1. If ferritin continues rising or exceeds 4,000-5,000 ng/mL with persistent fever:

   • Measure glycosylated ferritin fraction (<20% is 93% specific for AOSD) 1
   • Screen for macrophage activation syndrome: persistent fever, splenomegaly, cytopenias, elevated triglycerides, abnormal liver function 1

2. If glycosylated ferritin <20% OR clinical features strongly suggest AOSD:

   • Refer to rheumatology urgently for AOSD work-up and treatment 1
   • Disease-specific anti-inflammatory therapy (corticosteroids, IL-1 or IL-6 inhibitors) 2

3. If infection suspected:

   • Complete infectious work-up including blood cultures, viral serologies
   • Treat underlying infection; ferritin should normalize with resolution 1

4. If malignancy suspected:

   • CT imaging, hematology/oncology referral 1, 4

5. If metabolic syndrome/NAFLD suspected (less likely given CRP 103 mg/L):

   • Weight loss, metabolic syndrome management
   • Treat underlying liver disease, not the elevated ferritin 2

Critical Management Considerations

Do NOT Initiate Phlebotomy

Phlebotomy is ONLY indicated for confirmed iron overload with TS ≥45% 2. In this patient with likely inflammatory disease:

• Phlebotomy will not improve symptoms and may worsen anemia
• The treatment target is the underlying inflammatory condition, not the ferritin level 2

Urgent Specialist Referral Indications

Refer immediately to rheumatology/hematology if:

• Ferritin >1000 μg/L with persistent fever and very high CRP (this patient) 1, 2
• Ferritin continues rising despite initial work-up 2
• Evidence of HLH/MAS (cytopenias, splenomegaly, multiorgan dysfunction) 1, 2

Refer to gastroenterology/hepatology if:

• Ferritin >1000 μg/L AND elevated bilirubin 2
• TS ≥45% on repeat testing 2
• Abnormal liver imaging requiring further evaluation 2

Common Pitfalls to Avoid

1. Never use ferritin alone without transferrin saturation to diagnose iron overload 1, 2
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
3. Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests 1
4. Recognize that ferritin is an acute-phase reactant elevated in inflammation, infection, and liver disease independent of iron stores 1, 3
5. Do not delay specialist referral when ferritin >1000 μg/L with fever and very high CRP—this may represent life-threatening AOSD or HLH/MAS 1, 2
6. Extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload and requires urgent specialist referral 1, 2

Expected Timeline and Follow-Up

• Transferrin saturation results: 1-2 days
• Glycosylated ferritin fraction: 3-7 days (if available)
• HFE genetic testing: 1-2 weeks
• Specialist appointment: Within 1-2 weeks given ferritin >1000 μg/L with fever and very high CRP 1, 2

The intermittent fever with ear erythema, markedly elevated CRP (103 mg/L), and ferritin ~1000 ng/mL create a clinical picture most consistent with systemic inflammatory disease, particularly AOSD, rather than primary iron overload 1, 4. The cardiovascular risk markers (elevated Lp-PLA2, ADMA) reflect the systemic inflammatory state and require aggressive cardiovascular risk factor management regardless of the underlying diagnosis 6, 7, 8, 5.