Pathophysiology of Liver Cirrhosis
Core Pathological Mechanism
Liver cirrhosis develops through progressive replacement of healthy liver tissue with fibrotic tissue and regenerative nodules, creating architectural distortion that increases intrahepatic resistance to blood flow, ultimately leading to portal hypertension and multi-organ complications. 1
The fundamental process begins when chronic liver injury triggers a dysregulated wound healing response, causing abnormal continuation of connective tissue production and deposition. 2 This is not a simple scarring process—it represents a complex remodeling of the entire hepatic architecture.
Fibrosis Development and Progression
The fibrotic process follows a predictable anatomical pattern:
Initial deposition occurs as a fine neomatrix within the space of Disse (the space between hepatocytes and sinusoidal endothelial cells) that progressively matures and enlarges over time. 1, 2
Spatial progression typically starts in the centrilobular region and extends toward the portal tract as disease advances. 1, 2
End result is the formation of regenerative nodules surrounded by fibrous bands, fundamentally disrupting normal liver architecture and blood flow patterns. 3, 4
Portal Hypertension: The Central Hemodynamic Consequence
Portal hypertension develops through a two-component mechanism that perpetuates itself:
Structural Component (70% of resistance)
- Architectural distortion from fibrous tissue deposition 1
- Vascular distortion from regenerative nodules 1
- Formation of microthrombi within the hepatic vasculature 1
Functional Component (30% of resistance)
- Increased intrahepatic vascular tone due to endothelial dysfunction 1
- Reduced nitric oxide bioavailability within the liver 1
A critical pathophysiological paradox occurs: Despite the formation of portosystemic collaterals that should theoretically decompress the portal system, portal hypertension persists and often worsens due to increased portal venous inflow resulting from splanchnic arteriolar vasodilation. 1 This creates a vicious cycle where the body's compensatory mechanisms actually perpetuate the problem.
Systemic Hemodynamic Derangements
The hemodynamic consequences extend far beyond the liver itself:
Splanchnic vasodilation increases blood flow into the gut and portal venous system, paradoxically worsening portal hypertension despite collateral formation. 1, 2
Neurohumoral activation occurs as the body attempts to compensate for perceived underfilling, triggering vasoconstrictive systems that cause sodium and water retention, increased blood volume, and increased cardiac output. 1
Systemic inflammation characterizes advanced cirrhosis, with elevated circulating pro-inflammatory cytokines and chemokines, likely caused by systemic spread of bacteria and bacterial products from the gut. 1, 2
Disease Stages and Clinical Progression
Cirrhosis progresses through distinct clinical phases with dramatically different prognoses:
Compensated Cirrhosis
- Represents the longest stage and remains asymptomatic 1, 2
- Patients progress to decompensation at 5-7% per year 5
- Gastroesophageal varices are present in 30-40% of compensated patients 2, 5
Decompensated Cirrhosis
- Characterized by development of ascites, variceal hemorrhage, hepatic encephalopathy, and jaundice 1, 2
- Much shorter duration and can rapidly progress to multi-organ failure 2
- Varices are present in up to 85% of decompensated patients 2, 5
Late Decompensation
- Manifests as refractory ascites, hyponatremia, hepatorenal syndrome, recurrent hepatic encephalopathy, and jaundice 1
- Represents multi-organ failure driven by progressive portal hypertension, systemic inflammation, and liver failure 3
Critical Clinical Implications
Portal hypertension is the primary driver of complications, not liver synthetic dysfunction alone. This explains why some patients with preserved synthetic function still develop life-threatening complications:
Variceal hemorrhage risk correlates with portal pressure and disease severity—if untreated, recurrent hemorrhage occurs in 60% of patients within 1-2 years. 1
Mortality patterns differ dramatically: isolated variceal hemorrhage carries 20% 5-year mortality, but when combined with other complications, mortality exceeds 80% at 5 years. 1
Child-Pugh B and C patients face substantially higher complication risks due to both portal hypertension and impaired hepatic reserve. 1, 2
Common Pitfall to Avoid
Do not confuse cirrhosis with "pseudocirrhosis"—conditions like hereditary hemorrhagic telangiectasia can produce nodular regenerative hyperplasia, fibrosis around abnormal vessels, and portal hypertension that mimics cirrhosis on imaging, but these patients maintain normal liver synthetic function and do not have true cirrhosis. 6 This distinction is critical because prognosis and management differ substantially.