What is the workup for elevated Creatine Phosphokinase (CPK) and liver enzymes in an 18-year-old patient with normal renal function, history of Polycystic Ovary Syndrome (PCOS) and bipolar disorder, on lamotrigine, metformin, and low-dose terzepatide?

Workup for Elevated CPK and Liver Enzymes in an 18-Year-Old with PCOS and Bipolar Disorder

The workup for elevated CPK and liver enzymes in this patient should focus first on medication-related causes, particularly lamotrigine and metformin, while also evaluating for rhabdomyolysis and other causes of liver injury. 1

Initial Assessment and Immediate Considerations

Medication Review

• Lamotrigine: Can cause elevated liver enzymes and rarely drug-induced liver injury
• Metformin: Rarely associated with hepatotoxicity but can contribute to lactic acidosis
• Tirzepatide: New medication with limited long-term safety data in adolescents

Laboratory Evaluation

1. Comprehensive liver panel:

   • ALT, AST patterns (hepatocellular vs cholestatic)
   • Total/direct bilirubin
   • Alkaline phosphatase
   • GGT
   • Albumin, total protein
   • Prothrombin time/INR

2. CPK fractionation and additional tests:

   • CPK isoenzymes to determine source (muscle, cardiac, brain)
   • Myoglobin (serum and urine)
   • Aldolase (another marker of muscle injury)
   • Lactate dehydrogenase (LDH)

3. Renal function assessment:

   • BUN, creatinine (already noted as normal)
   • Urinalysis (looking for myoglobinuria)
   • Electrolytes (particularly potassium)

Differential Diagnosis Evaluation

Medication-Induced Causes

• Obtain timing relationship: When did elevations occur relative to medication initiation?
• Check for drug interactions: Particularly between lamotrigine and other medications
• Assess medication adherence: Sudden changes in dosing can affect levels

Rhabdomyolysis Evaluation

• If CPK >5× ULN (~1000 IU/L): Consider this a sign of rhabdomyolysis 1
• Recent physical activity: Excessive exercise can cause transient CPK elevation
• Trauma history: Even minor trauma can cause muscle breakdown
• Seizure history: Unwitnessed seizures can cause CPK elevation

Liver-Specific Workup

• Viral hepatitis panel: Hepatitis A, B, C serologies
• Autoimmune markers: ANA, ASMA, anti-LKM antibodies
• Iron studies: Ferritin, iron, TIBC (for hemochromatosis)
• Ceruloplasmin: For Wilson's disease (especially important in young patients)
• Alpha-1 antitrypsin: For alpha-1 antitrypsin deficiency

PCOS-Related Considerations

• Metabolic panel: Glucose, insulin levels, HbA1c
• Lipid profile: Dyslipidemia common in PCOS
• Liver ultrasound: To assess for fatty liver (common in PCOS)

Management Algorithm

1. If CPK >5× ULN or liver enzymes >3× baseline or >300 U/L:

   • Consider temporary interruption of lamotrigine and metformin 1
   • Ensure adequate hydration
   • Monitor renal function closely
   • Repeat labs in 2-5 days

2. If symptoms present (fatigue, nausea, right upper quadrant pain):

   • More urgent evaluation needed
   • Consider hospitalization if CPK >10,000 IU/L or liver enzymes >8× ULN
   • Evaluate for acute liver failure signs (encephalopathy, coagulopathy)

3. If asymptomatic with mild elevations:

   • May continue medications with close monitoring
   • Repeat labs in 1-2 weeks
   • Consider dose reduction of medications

Special Considerations

Bipolar Medication Management

• Abrupt discontinuation of lamotrigine can precipitate mood instability
• If lamotrigine must be discontinued, consider psychiatric consultation for alternative mood stabilizer

PCOS Management

• Metformin is beneficial for both PCOS and possibly mood symptoms 2
• Consider alternative PCOS treatments if metformin must be discontinued

Tirzepatide Considerations

• Limited data on hepatic effects in adolescents
• Low-dose usage may have minimal impact, but should be evaluated

Common Pitfalls to Avoid

1. Assuming single etiology: Multiple factors often contribute to enzyme elevations
2. Overlooking non-medication causes: Exercise, viral infections, and dietary supplements can all cause elevations
3. Premature medication discontinuation: Balance risk of untreated bipolar disorder against hepatic concerns
4. Inadequate follow-up: Enzyme elevations require serial monitoring until resolution

Follow-up Recommendations

• Repeat laboratory testing within 1-2 weeks if mild elevations
• More frequent monitoring (every 2-3 days) if moderate to severe elevations
• Consider hepatology consultation if:
  • Liver enzymes >5× baseline or >500 U/L
  • CPK >10,000 IU/L
  • Persistent elevations despite medication adjustments
  • Evidence of synthetic dysfunction (elevated INR, low albumin)

Remember that transient elevations in CPK and liver enzymes can occur in adolescents and often resolve spontaneously 1, but systematic evaluation is essential to rule out serious underlying conditions.