In a 29-year-old Black male who is 6 ft 5 in and weighs 318 lb (severe obesity), with negative anti‑Jo‑1 (anti‑Jo‑1) and negative ENA panel (extractable nuclear antigen panel), mildly elevated creatine kinase (CK), normal ferritin, normal erythrocyte sedimentation rate (ESR), normal C‑reactive protein (CRP), and elevated homocysteine, what is the most likely diagnosis?

Diagnostic Assessment: Likely Metabolic/Nutritional Myopathy with Cardiovascular Risk

Based on the clinical presentation—mildly elevated CK (371 U/L, just above normal), normal inflammatory markers (ESR 2, CRP 3.3), negative autoimmune panel, and elevated homocysteine (21.6 μmol/L) in a young obese male—this most likely represents a metabolic or nutritional myopathy rather than an autoimmune inflammatory myositis.

Primary Diagnostic Considerations

Most Likely: Metabolic Myopathy with B-Vitamin Deficiency

The constellation of findings points away from inflammatory myositis:

• Minimal CK elevation (371 vs normal <366): This is barely elevated and inconsistent with active myositis, which typically shows CK >10× upper limit of normal 1
• Normal inflammatory markers: ESR of 2 and CRP of 3.3 are essentially normal, whereas inflammatory myositis typically shows highly elevated inflammatory markers 2
• Negative autoimmune panel: Anti-Jo-1 and ENA panel negativity makes autoimmune myositis unlikely 2

The Elevated Homocysteine is Key

At 21.6 μmol/L, this patient has moderate hyperhomocysteinemia (normal <15 μmol/L). This suggests:

• B-vitamin deficiency (folate, B6, B12, or riboflavin) causing impaired homocysteine metabolism 3, 4
• Dietary insufficiency likely in the context of severe obesity (BMI ~37) with possible poor nutritional quality
• Increased cardiovascular risk: Each 5 μmol/L increase in homocysteine increases stroke odds by 59% 4

Differential Diagnosis to Exclude

Rule Out First:

1. Statin-induced myopathy: Obtain medication history. If on statins, this could explain mild CK elevation 5. However, statin myopathy typically presents with myalgias and CK >3× ULN

2. Hypothyroidism: Check TSH—can cause mild CK elevation and muscle symptoms

3. Vitamin D deficiency: Common in obesity, causes myalgias with normal/minimal CK elevation

4. Renal dysfunction: Check creatinine and eGFR—hyperhomocysteinemia occurs with decreased renal clearance 3, 4

5. MTHFR polymorphism: Consider genetic testing for MTHFR C677T variant if homocysteine remains elevated despite supplementation 4

Recommended Diagnostic Workup

Immediate labs needed:

• Complete metabolic panel (creatinine, eGFR, liver function)
• TSH and free T4
• Vitamin B12, folate, vitamin B6 levels
• 25-OH vitamin D
• Fasting glucose and HbA1c (obesity + cardiovascular risk)
• Lipid panel

If muscle symptoms are prominent:

• Repeat CK after 48 hours off any strenuous activity
• Aldolase level
• Consider EMG only if CK significantly elevated or true weakness present 2

Management Approach

Immediate Actions:

1. B-vitamin supplementation: Start folic acid 0.5-5 mg daily plus vitamin B12 0.5 mg daily to lower homocysteine 3. This combination can reduce homocysteine by ~12 μmol/L 3

2. Cardiovascular risk modification:

   • At age 29 with homocysteine 21.6 μmol/L and severe obesity, this patient has significantly elevated cardiovascular risk 4
   • Address hypertension if present
   • Initiate weight loss program targeting 10% body weight reduction

3. Discontinue statins temporarily if currently prescribed, to assess if CK normalizes 5

Follow-up Strategy:

• Recheck homocysteine in 6-8 weeks after B-vitamin supplementation
• Recheck CK after addressing reversible causes
• If CK rises significantly (>1000 U/L) or true proximal weakness develops, reconsider inflammatory myopathy with muscle biopsy 1

Critical Pitfalls to Avoid

Do not pursue aggressive immunosuppression based on this presentation—the normal inflammatory markers and minimal CK elevation do not support autoimmune myositis 2, 1.

Do not dismiss the homocysteine elevation—this represents a modifiable cardiovascular risk factor that requires treatment regardless of whether it's causing muscle symptoms 6, 4.

Do not assume seronegative myositis without objective weakness, significantly elevated CK (>10× ULN), or confirmatory EMG/MRI findings 7. True seronegative immune-mediated necrotizing myopathy presents with CK levels in the thousands to tens of thousands 1, 7.

Expected Outcome

With B-vitamin supplementation and weight management, expect homocysteine to normalize within 2-3 months 3. If symptoms persist despite normalized labs, reassess for alternative diagnoses including occult inflammatory myopathy, but current presentation makes this unlikely.