What to do with elevated liver enzymes?

Management of Elevated Liver Enzymes

The management of elevated liver enzymes should follow a systematic approach based on the pattern and severity of elevation, with immediate discontinuation of potentially hepatotoxic medications when ALT/AST ≥5× ULN or when ALT/AST ≥3× ULN with total bilirubin ≥2× ULN. 1

Initial Assessment and Pattern Recognition

• Determine the pattern of liver enzyme elevation: hepatocellular (predominant ALT/AST elevation), cholestatic (predominant ALP/GGT elevation), or mixed pattern to guide further evaluation 2
• Categorize severity of elevation:
  • Mild to moderate (<3× ULN)
  • Severe (>3× ULN)
  • Very severe (>5× ULN or >20× ULN) 2, 1
• For ALT/AST >3× ULN, stop potentially hepatotoxic medications and perform comprehensive evaluation 1
• For severe elevations (ALT/AST >20× ULN), consider immediate hospitalization and specialist consultation 1

Comprehensive Diagnostic Workup

• Review all current medications and supplements for potential hepatotoxicity 1, 2
• Obtain core laboratory panel:
  • Complete blood count with platelets
  • Comprehensive metabolic panel
  • Additional liver function tests: total and direct bilirubin, albumin, INR 2
• Perform abdominal ultrasound to assess liver parenchyma, biliary tract, and for signs of cirrhosis or focal lesions 2
• Consider additional testing based on clinical suspicion:
  • Viral hepatitis serologies (HBV, HCV)
  • Autoimmune markers
  • Iron studies
  • Non-invasive fibrosis assessment (FIB-4, Fibrosure, Fibrometer, Hepascore) 2, 3

Management Based on Etiology

• For medication-induced liver injury:
  • Immediately discontinue suspected hepatotoxic medications when ALT/AST ≥5× ULN or when ALT/AST ≥3× ULN with total bilirubin ≥2× ULN 1
  • For methotrexate-induced elevations, stop medication if ALT/AST >3× ULN and consider restarting at a lower dose after normalization 1
• For immune checkpoint inhibitor-related hepatitis:
  • Initiate corticosteroids (1-2 mg/kg/day methylprednisolone or equivalent) for grade 3-4 elevations 1
  • Consider mycophenolate mofetil (not infliximab) and hepatology consultation for steroid-refractory cases 1
• For non-alcoholic fatty liver disease (NAFLD):
  • Implement lifestyle modifications (weight loss, exercise) and monitor liver enzymes every 3-6 months 2
• For viral hepatitis:
  • Consider antiviral therapy for chronic HBV infection with elevated liver enzymes 2
  • For patients coinfected with HIV and HCV, coordinate care with providers experienced in treating both infections 4

Monitoring and Follow-up

• For mild elevations (<3× ULN) without clear cause:
  • Repeat testing in 2-4 weeks to establish trend 5, 2
  • For grade 1 elevations (ALT/AST 1-3× ULN), monitor liver enzymes every 1-2 weeks 1
• For grade 2-4 elevations (ALT/AST >3× ULN):
  • Increase monitoring frequency to every 3 days until improvement 1
  • If liver enzymes remain elevated after 3 months despite addressing modifiable factors, consider more urgent evaluation 5
• For patients on specific medications:
  • NSAIDs: periodic measurements of liver enzymes approximately twice yearly for chronic daily use 5
  • Methotrexate: monitor liver enzymes approximately every 3-4 months for stable doses 5
  • TNFα inhibitors: measure liver enzymes approximately every 3-6 months 5

Referral Criteria

• Refer patients with ALT >8× ULN or >5× baseline in those with elevated baseline 2
• Refer patients with ALT >3× ULN with total bilirubin >2× ULN (meets Hy's Law criteria) 2
• Refer patients with evidence of synthetic dysfunction (elevated INR, low albumin) 2
• Refer patients with persistent elevation >2× ULN after 3 months despite addressing modifiable factors 2
• Consider liver biopsy if enzymes remain elevated despite discontinuation of potential causative agents 1

Special Considerations

• For patients with tuberculosis treatment and hepatotoxicity:
  • If AST/ALT rises to five times normal or bilirubin rises, stop rifampicin, isoniazid, and pyrazinamide 4
  • If the patient is unwell or sputum smear positive within two weeks of starting treatment, consider streptomycin and ethambutol until liver function normalizes 4
  • Once liver function normalizes, drugs can be reintroduced sequentially (isoniazid, then rifampicin, then pyrazinamide) with careful monitoring 4
• For patients coinfected with HIV and HCV:
  • Advise against excessive alcohol consumption 4
  • Consider vaccination against hepatitis A 4
  • Monitor liver enzymes carefully when initiating antiretroviral therapy 4

Common Pitfalls to Avoid

• Avoid ignoring mild elevations in liver enzymes, as 84% remain abnormal on retesting after 1 month 5
• Avoid premature discontinuation of all medications before identifying the likely causative agent 1
• Avoid simply repeating the same panel of tests without a diagnostic plan 5
• Don't overlook the potential relationship between liver function and other factors that could affect liver enzymes (medications, alcohol use, and other modifiable factors) 5