Sepsis-Associated Cholestasis (SAC) 

Sepsis-associated cholestasis (SAC) is a functional intrahepatic cholestasis occurring during systemic infection, commonly seen in ICU patients with severe sepsis or septic shock. 

  • It may be the earliest sign of sepsis
  • It occurs without biliary obstruction
  • It is usually reversible with infection control
  • It correlates with severity and mortality


1. Definition

Sepsis-associated cholestasis is defined as:

Conjugated hyperbilirubinemia and biochemical cholestasis occurring during sepsis in the absence of mechanical biliary obstruction or primary hepatobiliary disease.

It is also called:

  • Sepsis-induced cholestasis
  • Cholestatic jaundice of sepsis
  • Intrahepatic cholestasis of critical illness


2. Epidemiology

  • Seen in 10–40% of septic ICU patients
  • More common in:
    • Gram-negative bacteremia
    • Intra-abdominal sepsis
    • Prolonged septic shock
  • Higher incidence in:
    • Elderly
    • Malnourished patients
    • Patients with multi-organ failure

It is part of sepsis-associated liver dysfunction (SALD).


3. Pathophysiology 

SAC is primarily a cytokine-mediated transporter dysfunction, not structural obstruction.

A. Inflammatory Cytokines

During sepsis, high levels of:

  • TNF-α
  • IL-1
  • IL-6
  • Endotoxin (LPS)

Cause:

  1. ↓ Expression of hepatocyte bile transporters:
    • BSEP (Bile Salt Export Pump)
    • MRP2 (Multidrug Resistance Protein 2)
    • NTCP (Na⁺ taurocholate cotransporting polypeptide)
  1. Impaired bile canalicular secretion
  2. Reduced bile flow (cholestasis)


B. Microcirculatory Dysfunction

Septic shock →

  • Hepatic sinusoidal hypoperfusion
  • Endothelial dysfunction
  • Mitochondrial injury

But note:

  • SAC can occur without overt ischemic hepatitis


C. Endotoxin Effect

Lipopolysaccharide (LPS):

  • Directly inhibits bile secretion
  • Alters tight junctions
  • Reduces bile acid transport


D. Role of Nitric Oxide

Excess NO in sepsis:

  • Impairs hepatocyte ATP generation
  • Reduces canalicular contractility


E. Summary of Mechanism

Sepsis → Cytokines + endotoxin → Transporter downregulation → Impaired bile excretion → Conjugated hyperbilirubinemia

No mechanical obstruction. No primary hepatocyte necrosis (early).


4. Clinical Features

Often subtle.

Presentation:

  • Jaundice (usually mild–moderate)
  • Dark urine
  • Rarely pruritus (acute ICU setting)

Important:

  • Jaundice may precede hypotension.
  • Sometimes first clue to occult infection.


5. Laboratory Pattern (High-Yield Table)

Parameter

Typical Finding

Total bilirubin

Elevated (2–15 mg/dL)

Direct (conjugated) bilirubin

Predominantly elevated

AST/ALT

Mildly elevated (usually <5× normal)

ALP

Mild–moderate elevation

GGT

Elevated

PT/INR

Usually normal initially

Albumin

Low (in prolonged sepsis)

Predominant conjugated hyperbilirubinemia with mild transaminase rise in septic patient → Think SAC.


6. Imaging Findings

Ultrasound – First-line test

Typical findings:

  • Normal liver echotexture
  • No biliary dilatation
  • Normal CBD diameter
  • No obstructing stone

Imaging is mainly done to exclude obstruction.


7. Differential Diagnosis in ICU

Very important for clinical exams.

Condition

Key Differentiator

Obstructive jaundice

Dilated CBD on ultrasound

Drug-induced cholestasis

Temporal relation to drug

Ischemic hepatitis

Massive AST/ALT (>1000 IU/L)

Acute viral hepatitis

Markedly high transaminases

TPN-associated cholestasis

Prolonged parenteral nutrition

Acalculous cholecystitis

Gallbladder wall thickening


8. Relationship with Sepsis Severity

Hyperbilirubinemia is incorporated in:

SOFA Score

  • Bilirubin levels contribute to hepatic SOFA component.
  • Higher bilirubin = higher mortality.

Bilirubin (mg/dL)

SOFA Score

<1.2

0

1.2–1.9

1

2.0–5.9

2

6.0–11.9

3

>12

4


9. Prognostic Significance

  • Associated with:
    • Multi-organ dysfunction
    • Higher ICU mortality
  • Bilirubin >4 mg/dL correlates with worse outcome
  • Persistent hyperbilirubinemia = poor prognosis

But:

It is usually reversible with infection control.


10. Management (Guideline-Based)

1. Treat Underlying Sepsis (Primary Treatment)

According to international sepsis guidelines:

  • Early broad-spectrum antibiotics
  • Source control (drain abscess, remove infected catheter)
  • Hemodynamic optimization
  • Maintain MAP ≥65 mmHg
  • Lactate clearance strategy

There is no specific therapy for SAC.


2. Hemodynamic Optimization

Avoid:

  • Prolonged hypotension
  • Excessive vasoconstriction
  • Hypoxia

Maintain adequate hepatic perfusion.


3. Avoid Hepatotoxic Drugs

Be cautious with:

  • High-dose paracetamol
  • Certain antibiotics
  • Azoles
  • TPN overload


4. Nutrition

  • Early enteral nutrition preferred
  • Avoid prolonged TPN
  • Adequate protein support


5. Role of Ursodeoxycholic Acid?

  • No strong evidence in acute ICU SAC
  • Not routine recommendation


6. Role of Steroids?

  • Not for cholestasis itself
  • Only if indicated for septic shock (per shock guidelines)


11. Histopathology (Rarely Needed)

If biopsy done (uncommon in ICU):

  • Canalicular cholestasis
  • Minimal inflammation
  • No significant hepatocyte necrosis
  • No bile duct obstruction