What are the mechanisms of immunosuppression caused by liver cirrhosis?

Mechanisms of Immunosuppression in Liver Cirrhosis

Liver cirrhosis causes a complex state of immune dysfunction through multiple interconnected mechanisms, with prostaglandin E2 (PGE2)-mediated immunosuppression, bacterial translocation-driven systemic inflammation, and impaired innate immune cell function being the primary drivers of increased infection susceptibility and mortality.

Core Pathophysiological Mechanisms

Prostaglandin E2-Mediated Immunosuppression

• Elevated PGE2 levels (>7-fold higher than healthy individuals) directly suppress macrophage function through prostanoid type E receptor-2 (EP2) signaling, impairing both proinflammatory cytokine secretion and bacterial killing capacity 1
• This mechanism is particularly pronounced in acutely decompensated cirrhosis and end-stage liver disease, but not in stable compensated cirrhosis (Child-Pugh A) 1
• Decreased serum albumin (<30 mg/dL) in decompensated patients reduces PGE2 binding capacity, increasing its bioavailability and amplifying immunosuppressive effects 1

Bacterial Translocation and Systemic Inflammation

• Increased intestinal permeability, reduced gut motility, and altered gut microbiota composition lead to pathological bacterial translocation of pathogen-associated molecular patterns (PAMPs) from the gut into systemic circulation 2, 3
• The cirrhotic gut microbiota contains more pathogenic microbes than non-cirrhotic individuals, disrupting homeostasis and favoring translocation 3
• Danger-associated molecular patterns (DAMPs) released from the diseased liver due to inflammation, apoptosis, and necrosis further activate innate immune receptors 2
• These PAMPs and DAMPs bind to pattern recognition receptors on immune cells, triggering chronic production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ) and reactive oxygen/nitrogen species 2, 4

Innate Immune Cell Dysfunction

• Monocytes, macrophages, and neutrophils exhibit profound functional impairments that are pivotal to cirrhosis-associated immune dysfunction (CAID) 5
• These cells demonstrate reduced phagocytic capacity, impaired bacterial killing, and decreased chemotaxis 5, 3
• The dysfunction is dynamic and progressive, negatively correlated with liver function deterioration and prognosis 5, 6

The CAID Spectrum: Dual Phenotype

Systemic Inflammation Component

• Two inflammation phenotypes exist: low-grade and high-grade systemic inflammation, both related to liver function severity 6
• High-grade inflammation correlates with hepatic insufficiency severity, bacterial translocation, and organ failure, increasing infection risk and worsening prognosis 6
• Chronic inflammation contributes to hemodynamic derangement (splanchnic vasodilation, hyperdynamic circulation) and kidney injury 2, 5
• Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ) drive liver cell necrosis and progressive fibrosis development 4

Immunodeficiency Component

• Immune paralysis develops, characterized by increased anti-inflammatory cytokines (particularly IL-10) and suppression of pro-inflammatory responses 3, 4
• This creates a paradoxical state where systemic inflammation coexists with profound immunodeficiency 5, 3
• The immunodeficiency component is responsible for the 30% mortality rate in cirrhotic patients and contributes to both acute and chronic decompensation 3

Inflammasome Activation

• Inflammasomes play a central role in the pro-inflammatory response and contribute to profibrotic processes in liver cirrhosis 4
• Inflammasome activation leads to production of chemokines such as CCL2/MCP-1, perpetuating inflammatory cascades 4

Clinical Consequences and Progression

Infection Susceptibility

• The combination of impaired bacterial killing, reduced phagocytosis, and bacterial translocation creates extreme vulnerability to bloodstream infections 3, 1
• These infections frequently progress to systemic inflammatory response syndrome (SIRS), sepsis, multiorgan failure, and death 3
• Patients with decompensated cirrhosis have dramatically increased infection rates compared to compensated patients 5, 6

Dynamic Nature of Immune Dysfunction

• CAID severity is dynamic, progressive, and intimately linked to underlying liver disease severity 5
• The degree of immunosuppression worsens with hepatic decompensation and is associated with Child-Pugh score and MELD score progression 7, 6
• Immune dysfunction can progress to acute-on-chronic liver failure (ACLF), which carries 28-day mortality ≥20% 8, 7

Critical Pathophysiological Distinctions

Albumin's Protective Role

• Albumin functions as a PGE2 scavenger, reducing its bioavailability and modulating immune dysfunction 1
• In vivo administration of human albumin solution to patients with acute decompensation significantly improves macrophage pro-inflammatory cytokine production 1
• This mechanism explains why albumin infusions may reduce infection risk beyond simple volume expansion 1

Portal Hypertension Connection

• Portal hypertension drives splanchnic vasodilation through enhanced endothelial production of vasodilating substances (nitric oxide, carbon monoxide, prostacyclin, endocannabinoids), which is mediated by the chronic inflammatory state 2
• This hemodynamic dysfunction contributes to effective hypovolemia, activating compensatory mechanisms (RAAS, sympathetic nervous system, vasopressin) that further compromise immune function 2, 9

Common Pitfalls and Clinical Implications

• Do not assume all cirrhotic patients have equivalent immune dysfunction—the severity is directly correlated with degree of decompensation and albumin levels 5, 6, 1
• Recognize that compensated cirrhosis (Child-Pugh A) does not exhibit the same PGE2-mediated immunosuppression as decompensated disease 1
• Bacterial translocation is not simply a consequence but an active driver of progressive immune dysfunction and decompensation 2, 3
• The immune dysfunction is potentially modifiable through albumin administration, COX inhibition, and antibiotic prophylaxis targeting bacterial translocation 6, 1
• Immune dysfunction can persist or worsen up to 12 months after precipitating events due to prolonged immune reconstitution phases, particularly with potent immunosuppressive exposures 2