What Causes Elevated Liver Enzymes in NAFLD
Elevated liver enzymes in NAFLD result from hepatocyte injury caused by fat accumulation (steatosis) and subsequent lipotoxicity, with ALT and AST released into serum when hepatocytes are damaged by metabolic insults, inflammation, and oxidative stress. 1
Primary Mechanism: Hepatocyte Injury from Fat Accumulation
The fundamental cause is hepatocellular injury that directly releases ALT and AST into the bloodstream 1. This occurs through a progressive pathophysiologic cascade:
- Initial fat accumulation (steatosis) develops from insulin resistance and metabolic syndrome, leading to excessive hepatic triglyceride storage 1
- Lipotoxicity occurs when hepatocytes accumulate toxic lipid species beyond simple triglycerides, causing cellular damage 2, 3
- Mitochondrial dysfunction and oxidative stress from excessive fatty acid oxidation generates reactive oxygen species that injure hepatocytes 2, 4
- Inflammation (NASH) develops in 25-30% of NAFLD cases when lipid-induced hepatocyte injury triggers inflammatory responses 1
Enzyme Pattern Characteristics
The specific enzyme elevation pattern helps distinguish NAFLD from other liver diseases:
- **AST:ALT ratio <1** is characteristic of NAFLD, contrasting with the ratio >2 seen in alcoholic liver disease 1, 5
- Mild aminotransferase elevations are typical, with NAFLD being the most common cause of mild enzyme increases 1
- ALT elevation is directly linked to hepatocyte injury severity, making it a more specific marker for metabolic liver disease 1
The "Two-Hit" Pathophysiology
Understanding the mechanistic progression explains why enzymes become elevated:
First Hit - Fat Accumulation:
- Insulin resistance drives excessive hepatocyte triglyceride accumulation 4
- High-calorie diets rich in saturated fats, refined carbohydrates, and fructose promote fat deposition 1
- Adipose tissue dysfunction increases free fatty acid delivery to the liver 2
Second Hit - Cellular Injury:
- Oxidative stress from mitochondrial fatty acid oxidation damages hepatocytes 4
- NF-κB-dependent inflammatory cytokine expression causes inflammation 4
- Endoplasmic reticulum stress and cell death pathways are activated 1
Metabolic Context and Risk Factors
Enzyme elevation severity correlates with specific metabolic conditions:
- Type 2 diabetes and metabolic syndrome are strongly associated with higher enzyme levels and more severe hepatocyte injury 1
- Obesity increases NAFLD prevalence to 70%, with more pronounced hepatic inflammation 1
- Insulin resistance is the central metabolic driver, present even in lean NAFLD patients 1, 2
Progression to Advanced Disease
Enzyme elevations signal risk for disease progression:
- Progressive fibrosis develops in approximately 40% of patients, associated with ongoing hepatocyte injury 6
- NASH with inflammation causes more severe enzyme elevations and reduced survival compared to simple steatosis 6
- Weight gain >5 kg and worsening insulin resistance correlate with fibrosis progression and persistent enzyme elevation 6
Clinical Implications
NAFLD is the most common cause of unexplained elevated liver enzymes in developed countries, affecting 17-46% of adults 1. The presence of elevated enzymes should trigger:
- Screening for metabolic syndrome components (waist circumference, blood pressure, glucose, lipids) 1
- Assessment for type 2 diabetes using fasting glucose, HbA1c, or oral glucose tolerance testing 1
- Evaluation for disease severity using fibrosis markers, as enzyme levels alone don't predict fibrosis stage 1
Important Caveats
- Normal liver enzymes do NOT exclude NAFLD or even progressive disease - 7% of lean NAFLD patients and many with metabolic syndrome have normal enzymes despite active liver disease 1
- Enzyme levels don't correlate with fibrosis severity - patients can have advanced fibrosis with minimal enzyme elevation 1
- Other causes must be excluded, including viral hepatitis, hemochromatosis, autoimmune hepatitis, and medication-induced injury 1