What could cause a mildly elevated creatine kinase (CK) level of 379 U/L in a patient who is not taking a statin?

Causes of CK Elevation to 379 U/L Without Statin Use

A CK level of 379 U/L represents a mild elevation (approximately 2-3 times the upper limit of normal) and in a patient not taking statins, the most common causes include recent exercise or physical activity, hypothyroidism, other medications (particularly antipsychotics, fibrates, or daptomycin), muscle trauma, and less commonly inflammatory myopathies or metabolic muscle diseases.

Most Common Etiologies to Consider

Exercise and Physical Activity

• Recent strenuous exercise or unaccustomed physical activity is the most frequent benign cause of mild CK elevation 1
• Eccentric exercise can produce CK elevations exceeding 10,000 U/L in healthy individuals without causing renal impairment or requiring treatment 1
• A CK of 379 U/L is consistent with mild exertional muscle damage and typically resolves spontaneously within days to weeks 1

Hypothyroidism

• Thyroid dysfunction is a critical consideration, as hypothyroidism commonly causes CK elevation and can present with minimal systemic symptoms 2
• Hypothyroid myopathy can produce CK elevations ranging from mild to extremely high (>29,000 IU/L), though most are modest 2
• The American College of Cardiology recommends obtaining TSH in any patient with muscle symptoms or unexplained CK elevation 3, 4
• Thyroid hormone replacement results in resolution of symptoms and normalization of CK 2

Medication-Induced Myopathy (Non-Statin)

Fibrates (fenofibrate, gemfibrozil):

• Fibrates increase risk for myopathy and can cause diffuse myalgias, muscle tenderness, weakness, and marked CPK elevations 5
• Risk is particularly elevated in elderly patients and those with diabetes, renal insufficiency, or hypothyroidism 5
• Patients should be advised to report unexplained muscle pain, tenderness, or weakness, and CPK should be assessed if these symptoms occur 5

Antipsychotic Medications:

• Antipsychotics can cause CK elevation through multiple mechanisms, including drug-induced rhabdomyolysis 6
• Routine CK monitoring in asymptomatic patients on antipsychotics is not recommended, but careful symptom monitoring is essential 6

Daptomycin:

• Daptomycin causes myopathy manifested as muscle pain or weakness with elevated CPK 7
• Post-marketing reports include rhabdomyolysis, particularly when combined with HMG-CoA reductase inhibitors 7

Essential Diagnostic Workup

Immediate Laboratory Assessment

• Obtain TSH to rule out hypothyroidism as a contributing factor 3, 4, 2
• Measure baseline CK for comparison if symptoms develop or worsen 3
• Check serum creatinine and urinalysis to assess for rhabdomyolysis if CK is markedly elevated 3
• Consider ALT, AST, and LDH, which can also be elevated in muscle injury 3

Clinical History Focus

• Detailed inquiry about recent exercise, physical activity, or trauma 3, 1
• Complete medication review, including over-the-counter supplements and recent medication changes 3, 6
• Assessment for muscle symptoms: pain, weakness, tenderness, or dark urine 3
• Screen for systemic symptoms suggesting hypothyroidism, inflammatory conditions, or infection 3, 2

Management Algorithm Based on CK Level and Symptoms

For CK 379 U/L (Approximately 2-3× ULN) Without Symptoms:

• No immediate intervention required if patient is asymptomatic 3
• Rule out exercise as cause and advise moderation in physical activity 3
• Obtain TSH and review medications 3, 4
• Repeat CK in 2-4 weeks to assess trend 8

For CK 379 U/L With Muscle Symptoms:

• Discontinue any potentially causative medications (fibrates, antipsychotics, daptomycin) 5, 7, 6
• Obtain TSH, creatinine, and urinalysis 3, 4
• Monitor CK weekly until symptoms resolve and CK normalizes 3, 8
• Consider referral to rheumatology or neurology if symptoms persist beyond 2 months 3

Critical Thresholds and Red Flags

When to Hospitalize or Escalate Care:

• CK >10 times ULN with muscle symptoms requires immediate discontinuation of causative agents and close monitoring 3
• Presence of dark urine, myoglobinuria, or rising creatinine suggests rhabdomyolysis requiring urgent intervention 3, 5
• Severe weakness limiting mobility, respiratory symptoms, or dysphagia warrant hospitalization 3

Alternative Diagnoses to Consider if CK Remains Elevated:

• If CK elevation persists beyond 2 months without clear cause, consider inflammatory myopathies, metabolic muscle diseases, or paraneoplastic syndromes 3
• Autoantibody testing for myositis (anti-TIF1γ, anti-NXP2) may be indicated 3
• EMG, MRI imaging, or muscle biopsy should be considered when diagnosis is uncertain 3

Common Pitfalls to Avoid

• Do not dismiss mild CK elevation without checking TSH, as hypothyroidism can present with minimal systemic symptoms 3, 2
• Avoid routine CK monitoring in asymptomatic patients, as it provides little clinical value 3
• Do not overlook recent exercise as a benign cause—CK can remain elevated for 7-10 days after strenuous activity 1
• Remember that normal or minimally elevated CK does not exclude myopathy in symptomatic patients 8, 4
• Consider drug interactions and cumulative effects when multiple medications affecting the mevalonate pathway are used together 9