What causes elevated Aspartate Aminotransferase (AST) levels in patients with dengue fever?

AST Elevation in Dengue Fever

Primary Mechanism of Hepatocellular Injury

AST elevation in dengue fever results from direct viral infection of hepatocytes combined with immune-mediated cytopathic damage, with the virus binding to hepatocytes through angiotensin-converting enzyme 2 (ACE2) receptors that are highly expressed in liver tissue. 1, 2

The dengue virus causes hepatocellular injury through multiple overlapping mechanisms:

• Direct viral cytotoxicity: Dengue virus directly infects hepatocytes and bile duct epithelial cells via ACE2 receptors, leading to cellular damage and enzyme release 1
• Immune-mediated injury: The inflammatory response generates cytokine-mediated damage, with significantly elevated IL-10 and IL-17 levels correlating with severe dengue and hepatic injury 3
• Hypoxic injury: Decreased hepatic perfusion during plasma leakage and shock states contributes to centrilobular hepatocyte damage 3

Characteristic Pattern of Enzyme Elevation

AST rises disproportionately higher than ALT in dengue fever, with AST levels typically 2-3 times greater than ALT—a pattern opposite to most other viral hepatitides. 4, 5

The temporal pattern shows:

• Peak elevation occurs on days 6-7 of illness, approximately 24 hours after peak viremia and 24 hours before maximum plasma leakage 3
• AST levels in dengue fever average 84.5±42.4 IU/L, while in dengue hemorrhagic fever they reach 507±106.8 IU/L 4
• ALT levels are consistently lower: 59.9±31.3 IU/L in dengue fever versus 234±30.6 IU/L in dengue hemorrhagic fever 4
• Transaminases typically normalize within 2 weeks of symptom onset 5

Zonal Pattern of Liver Damage

Dengue-induced hepatocellular damage initiates predominantly in the centrilobular zone and progresses toward the periportal area as disease severity increases. 2

This is demonstrated by:

• Centrilobular enzymes (GLDH, αGST) show marked elevation correlating with AST levels 2
• Periportal enzymes (ARG-1, HPPD) become elevated as disease progresses to severe dengue 2
• The pattern suggests initial hypoxic injury in zone 3 (centrilobular) followed by direct viral and immune-mediated damage extending to zone 1 (periportal) 2, 3

Correlation with Disease Severity

Higher AST levels serve as an early indicator of dengue severity, with levels >400 IU/L significantly associated with dengue hemorrhagic fever and severe dengue. 4, 6

However, important caveats exist:

• While median AST values increase with severity, there is substantial overlap between dengue fever and dengue hemorrhagic fever groups 6
• AST poorly discriminates between non-severe and severe dengue (area under ROC curve = 0.62) 6
• AST ≥1000 IU/L occurs in only a small subset of patients but indicates severe dengue by WHO 2009 criteria 6
• Severe hepatic injury can occur without plasma leakage or hemoconcentration, suggesting immune mechanisms independent of vascular permeability 3

Clinical Significance and Outcomes

Despite marked transaminase elevations (93.3% of patients have elevated AST), acute liver failure is rare in dengue fever, and most patients recover without specific hepatic intervention. 5, 6

Critical points for management:

• Hepatic failure accounts for approximately 60% of dengue-related deaths when it occurs (3 of 5 fatal cases in one series) 5
• Transaminase elevation >10-fold above normal occurs in 11.1% for AST and 7.4% for ALT 5
• Significantly higher AST, ALT, and GGT elevations occur in patients with bleeding episodes 5
• Liver biopsy when performed shows features of lobular hepatitis similar to conventional viral hepatitis 5

Why AST Exceeds ALT

The AST:ALT ratio >1 in dengue fever likely reflects the combination of hepatocellular injury plus AST release from other damaged tissues including endothelial cells, platelets, and cardiac muscle during the systemic inflammatory response. 4, 5

This differs from typical viral hepatitis where ALT predominates because:

• AST is present in mitochondria and cytoplasm of hepatocytes, while ALT is primarily cytoplasmic 7
• Dengue causes more severe mitochondrial damage, releasing mitochondrial AST 2
• Systemic endothelial activation and platelet destruction contribute additional AST from non-hepatic sources 3
• The centrilobular predominance of initial injury affects hepatocytes with higher mitochondrial content 2