What are the biochemical characteristics of sepsis cholestasis?

Biochemical Characteristics of Sepsis Cholestasis

Sepsis cholestasis is characterized by elevated alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and bilirubin levels, with minimal or no elevation in aminotransferases in early stages, accompanied by inflammatory markers that correlate with sepsis severity and mortality. 1

Key Laboratory Findings

Primary Cholestatic Markers

• Alkaline Phosphatase (ALP): Significantly elevated, typically >1.5-1.67 times the upper limit of normal (ULN) 1, 2
• Gamma-glutamyl transpeptidase (GGT): Markedly increased, often >3 times ULN 1, 2
• Direct (conjugated) bilirubin: Predominant elevation 1, 3
  • Hyperbilirubinemia may precede other clinical manifestations of sepsis 3
  • Bilirubin elevation is primarily in the conjugated fraction 4

Hepatocellular Markers

• Aminotransferases (AST/ALT): Minimal or no elevation in early stages of sepsis cholestasis 1
  • May increase in later stages or with more severe sepsis
  • Significantly lower than seen in hepatocellular injury patterns

Inflammatory and Sepsis Markers

• C-reactive protein (CRP): Significantly elevated 1
• Procalcitonin (PCT): Elevated, correlating with sepsis severity 1
• Serum lactate: Elevated (>2 mmol/L in septic shock), associated with poor outcomes 1
• White blood cell count: Often elevated (>12,000/ml) or decreased (<4,000/ml) with >10% immature forms 1

Other Biochemical Alterations

• Albumin: Decreased due to inflammatory response and capillary leak 1
• Coagulation parameters: May be altered, reflecting liver dysfunction
• Bile acids: Increased in plasma, particularly conjugated fractions 4
• Glucose metabolism: Hyperglycemia in early sepsis followed by hypoglycemia in later stages 1
• Lipid metabolism: Increased lipolysis with elevated plasma triglycerides and free fatty acids 1

Diagnostic Considerations

1. Confirm hepatobiliary origin of ALP elevation:

   • Verify with GGT and/or ALP isoenzyme fractionation 2
   • ALP is also found in bone, intestines, kidneys, and white blood cells 2
   • Concomitantly elevated GGT confirms that elevated ALP originates from the liver 2

2. Rule out other causes of cholestasis:

   • Extrahepatic biliary obstruction (e.g., choledocholithiasis, malignancy, strictures) 2
   • Other cholestatic liver diseases (e.g., primary biliary cholangitis, primary sclerosing cholangitis) 2
   • Drug-induced liver injury 2
   • Pre-existing liver disease 1

3. Differentiate from other forms of liver injury in sepsis:

   • Ischemic liver injury (shock liver) typically shows marked aminotransferase elevation 5
   • Progressive sclerosing cholangitis can develop in severe cases 5

Pathophysiological Mechanisms

The biochemical profile of sepsis cholestasis reflects specific pathophysiological mechanisms:

• Proinflammatory cytokines and nitric oxide impair hepatocellular and ductal bile formation 5
• Altered expression of bile acid transporters:
  • Downregulation of bile acid excretion pumps toward bile canaliculi
  • Upregulation of alternative transporters toward systemic circulation 4
• Loss of feedback inhibition of bile acid synthesis 4
• Cytoplasmic retention of nuclear FXR/RXR heterodimer (transcription factors regulating bile acid metabolism) 4

Clinical Significance

• Cholestatic pattern may be an early indicator of sepsis, sometimes preceding other clinical manifestations 3
• Degree of cholestasis correlates with sepsis severity and mortality 1
• Hyperbilirubinemia in sepsis may represent an adaptive response rather than purely pathological cholestasis 4
• Resolution of cholestasis typically follows successful treatment of the underlying infection 6

Monitoring Parameters

• Serial measurements of bilirubin, ALP, and GGT to track progression 1
• Inflammatory markers (CRP, PCT, lactate) to assess sepsis severity 1
• Fractionation of elevated bilirubin to determine direct (conjugated) component 2

The biochemical profile of sepsis cholestasis is distinct from other forms of liver injury and should raise suspicion for underlying infection when observed, particularly when accompanied by elevated inflammatory markers.