What is the most common cause of elevated Liver Function Tests (LFTs)?

Most Common Cause of Elevated Liver Function Tests

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver function tests in developed countries, accounting for approximately 26% of incidental LFT abnormalities in primary care settings. 1, 2

Epidemiology and Prevalence

• NAFLD represents the leading cause of chronic liver disease worldwide, with prevalence of 20-30% in the general population, increasing to 70% with obesity and 90% with diabetes mellitus 1
• In a large prospective primary care cohort study, NAFLD was identified as the commonest cause (26.4%) of incidental LFT abnormalities, followed closely by alcohol excess (25.3%) 2
• NAFLD is recognized as the most common cause of elevated liver enzymes in patients in developed countries 3, 4, 5

Clinical Pattern Recognition

Hepatocellular Pattern (Most Common in NAFLD)

• NAFLD typically presents with mild aminotransferase elevations (<5 times upper reference limit), with ALT and AST being the predominant elevated enzymes 1
• The AST:ALT ratio in NAFLD is typically <1**, which distinguishes it from alcohol-induced liver disease where the ratio is generally **>2 1, 6
• Common causes of mild aminotransferase increases include NAFLD and alcohol-induced liver disease, with uncommon causes being drug-induced liver injury, hepatitis B, hepatitis C, and hereditary hemochromatosis 1

Important Diagnostic Considerations

• The magnitude of LFT abnormality does not correlate with disease severity or prognosis - patients with significant liver fibrosis may have liver enzymes in the normal reference range 1
• NAFLD, alcohol-related liver disease, and hepatitis C are frequently associated with only mild or moderate LFT abnormalities despite potentially having advanced disease 1
• In one study, 7.6% of NAFLD patients with abnormal LFTs had advanced fibrosis, while 57.2% had low risk for advanced fibrosis 2

Differential Diagnosis Framework

When NAFLD is Most Likely:

• Presence of metabolic risk factors: obesity, type 2 diabetes, insulin resistance, metabolic syndrome 1
• AST:ALT ratio <1 1, 6
• Mild to moderate aminotransferase elevations 1

When Alcohol-Induced Liver Disease is More Likely:

• AST:ALT ratio >2 (highly suggestive), with ratios >3 being even more specific 1, 6
• Elevated GGT (detects 75% of habitual drinkers) 6
• Alcohol consumption >20 g/day in females or >30 g/day in males 1

Other Common Causes to Exclude:

• Viral hepatitis (hepatitis B and C) - requires serological testing in high-risk groups even with normal LFTs 1
• Drug-induced liver injury 1
• Hereditary hemochromatosis (check transferrin saturation) 1

Critical Clinical Pitfalls

• Do not assume normal LFTs exclude significant liver disease - many patients with advanced fibrosis have normal liver enzymes and synthetic function 1
• The current upper limit of normal for ALT may be too high (likely includes patients with occult NAFLD), potentially missing early disease 1
• Duration and extent of LFT abnormality are not reliable guides to clinical significance - context and specific analytes matter more 1
• Approximately 20% of patients with alcohol use disorder and abnormal LFTs have a co-existing etiology requiring further investigation 1

Risk Stratification Approach

• For confirmed or suspected NAFLD, calculate non-invasive fibrosis scores (FIB-4 or NAFLD Fibrosis Score) to assess risk of advanced fibrosis 1
• Consider liver ultrasound to detect steatosis, though this does not assess fibrosis stage 1
• In NAFLD patients, progression of fibrosis is associated with weight gain >5 kg, insulin resistance, and pronounced hepatic fatty infiltration 3
• Patients with NASH (not simple steatosis) have reduced survival, dying more often from cardiovascular and liver-related causes 3