What are the causes of elevated Liver Function Tests (LFTs)?

Causes of Elevated Liver Function Tests (LFTs)

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of elevated LFTs in developed countries, affecting 20-30% of the general population, followed by alcohol-related liver disease and chronic viral hepatitis. 1

Major Causes of Elevated LFTs

Hepatocellular Pattern (Predominant ALT/AST Elevation)

• Non-alcoholic fatty liver disease (NAFLD): Most common cause in developed countries, affecting up to 70% in obesity and 90% in diabetes 1
• Alcohol-related liver disease: Typically shows AST:ALT ratio >2 (often >3), with AST usually 2-6 times the upper limit of normal 1
• Viral hepatitis:
  • Acute: Hepatitis A, B, C, D, E
  • Other viral causes: EBV, CMV, HSV 1
• Drug-induced liver injury (DILI): From prescription medications, OTC drugs, herbal supplements 1
• Muscle injury/rhabdomyolysis: Can be confirmed by elevated creatine kinase (CK) 1
• Autoimmune hepatitis
• Hemochromatosis
• Wilson's disease 2

Cholestatic Pattern (Predominant ALP Elevation)

• Biliary obstruction: Gallstones, strictures, tumors
• Primary biliary cholangitis
• Primary sclerosing cholangitis
• Drug-induced cholestasis
• Infiltrative disorders: Sarcoidosis, amyloidosis
• Malignancies: Primary or metastatic liver cancer 1

Mixed Pattern

• Drug-induced liver injury
• Alcoholic hepatitis
• Alpha-1-antitrypsin deficiency 1, 2

Non-Hepatic Causes of Elevated LFTs

• Elevated ALP:

  • Bone disorders (Paget's disease, osteomalacia)
  • Pregnancy
  • Growing children
  • Certain malignancies 1

• Elevated AST/ALT:

  • Muscle disorders
  • Thyroid disorders
  • Celiac disease
  • Adrenal insufficiency 1

Pattern Recognition in LFT Interpretation

1. Hepatocellular pattern: ALT/AST elevated more than ALP

   • Mild: <5× upper limit of normal
   • Moderate: 5-10× upper limit of normal
   • Severe: >10× upper limit of normal 1

2. Cholestatic pattern: ALP elevated more than ALT/AST

   • NAFLD patients with cholestatic pattern have higher rates of advanced fibrosis (31.3%) compared to mixed (4.5%) or hepatocellular patterns (18.2%) 3
   • Cholestatic pattern is associated with higher prevalence of diabetes, hypertension, and metabolic comorbidities 3

3. Mixed pattern: Both ALT/AST and ALP elevated proportionally 1

Special Considerations

Drug-Induced Liver Injury

• Many medications can cause elevated LFTs through various mechanisms
• Example: Thiazolidinediones like pioglitazone can cause rare but serious liver injury
• Monitoring recommendations for medications like pioglitazone:
  • Baseline ALT before starting therapy
  • Periodic monitoring during treatment
  • Discontinue if ALT >3× upper limit of normal or jaundice develops 4

Genetic Factors

• Variation in LFT proteins has significant heritable basis (20-77%)
• Common environmental factors also affect most LFTs (24-54%)
• Age, sex, BMI, and alcohol use contribute significantly to inter-individual variation 5

Diagnostic Approach

1. First-line testing for elevated liver enzymes:

   • Hepatitis serology (HBsAg, HCV antibody)
   • Complete blood count with platelets
   • Liver function panel
   • Prothrombin time
   • Creatine kinase (to rule out muscle origin) 1

2. Second-line testing based on initial results:

   • Autoimmune markers
   • Iron studies
   • Ceruloplasmin
   • Alpha-1 antitrypsin levels
   • Additional viral serology (HEV, EBV, CMV) 1

3. Imaging:

   • Abdominal ultrasound is first-line to assess for fatty liver, biliary obstruction, and masses
   • CT or MRI for further characterization if needed 1

Common Pitfalls in LFT Interpretation

1. Poor predictive value of isolated LFTs: Only 3.9% of patients with abnormal values are diagnosed with significant liver disease within 5 years 1

2. Isolated ALP elevation: Warrants thorough investigation as 57% of cases are associated with underlying malignancy 1

3. Muscle injury misdiagnosis: Elevated AST/ALT can be from muscle injury rather than liver disease; check CK levels 1

4. Medication effects: Always review all medications, including OTC and supplements 1, 4

5. Normal LFTs don't exclude liver disease: Early stages of many liver diseases may present with normal LFTs 2