What are the mechanisms underlying liver dysfunction in dengue infection?

Mechanisms of Liver Dysfunction in Dengue

Liver dysfunction in dengue results from a combination of direct viral hepatocyte invasion, immune-mediated cytopathic damage, hypoxic injury from plasma leakage and shock, and inflammatory cytokine release—with the immune response appearing to play a dominant role particularly in severe disease.

Direct Viral Mechanisms

• Dengue virus directly infects hepatocytes and Kupffer cells, causing cytopathic damage to liver tissue 1.
• The virus targets hepatocytes through specific cellular receptors, leading to hepatocellular injury that manifests as elevated transaminases 2.
• Liver histology in dengue shows patterns consistent with direct viral cytotoxicity, though the exact cellular entry mechanisms differ from other viral hepatitides 3.

Immune-Mediated Injury

• Immune-cytopathic damage represents a major mechanism, particularly in severe dengue where IL-10 and IL-17 levels are significantly elevated and correlate with the degree of liver injury 2.
• Inflammatory signaling pathways including cytokine-cytokine receptor interactions, complement cascades, and coagulation pathways become activated, with IL-6, IL-10, ICAM-1, VCAM-1, MMP9, and NLRP3 serving as biomarkers of progression to severe disease 4.
• The peak of liver enzyme elevation occurs around day 6-7 of illness, approximately 24 hours after peak viremia, suggesting immune-mediated rather than purely direct viral mechanisms 2.
• C-reactive protein levels correlate positively and significantly with AST and ALT elevations across all dengue severity categories, supporting the inflammatory basis of hepatic injury 5.

Hypoxic and Hemodynamic Mechanisms

• Decreased hepatic perfusion from plasma leakage and shock causes ischemic hepatitis, particularly in dengue hemorrhagic fever with significant fluid shifts 3, 1.
• Haemoconcentration and vascular leakage reduce tissue oxygenation, contributing to hepatocellular necrosis 4.
• Severe liver dysfunction (AST/ALT >1000 IU/L) can occur even in the absence of fluid leakage or hematocrit rise ≥20%, indicating that hypoxia alone does not fully explain hepatic injury 2.

Temporal Pattern and Clinical Correlation

• Liver enzyme elevations follow a predictable temporal sequence: peak viremia occurs first, followed 24 hours later by peak AST levels and lowest albumin, then 24 hours after that comes maximum fluid leakage 2.
• AST typically exceeds ALT in dengue (unlike typical viral hepatitis), with AST, ALT, and gamma-glutamyl transferase remaining elevated throughout the illness 2.
• Severe dengue patients demonstrate significantly higher AST and GGT levels on days 5-6 of illness compared to non-severe dengue 2.
• Mixed hepatocellular-cholestatic injury pattern is most common (29.4% of cases), with 63% of dengue patients showing some degree of liver injury that correlates with disease severity 5.

Pathophysiological Integration

• The mechanism is multifactorial: direct viral invasion initiates hepatocyte damage, triggering an inflammatory cascade that amplifies injury through cytokine release and immune cell infiltration 3, 1.
• Leukocyte transendothelial migration and upregulation of adhesion molecules (ICAM-1, VCAM-1) facilitate inflammatory cell recruitment to the liver 4.
• The complement and coagulation cascades become activated, potentially contributing to microvascular thrombosis and further hepatic ischemia 4.

Clinical Implications

• Liver function tests performed before day 5-6 may underestimate the extent of hepatic involvement, as peak injury occurs later in the disease course 2.
• Hepatic dysfunction is more common in dengue hemorrhagic fever, with severe hepatic dysfunction (ALT/AST >10× normal) associated with spontaneous bleeding tendencies 1.
• Acute liver failure in dengue, while rare, carries significant mortality risk and may benefit from supportive measures targeting tissue oxygenation 3.