What is the pathophysiology of liver cirrhosis?

Pathophysiology of Liver Cirrhosis

Liver cirrhosis is characterized by the progressive replacement of healthy liver tissue with fibrotic tissue and regenerative nodules, leading to architectural distortion that increases intrahepatic resistance to blood flow, resulting in portal hypertension and subsequent complications. 1

Initial Pathological Process

• Chronic liver injury initiates a dysregulated wound healing response that leads to abnormal continuation of connective tissue production and deposition 1
• The fibrosis process begins with deposition of fine neomatrix within the space of Disse that progressively matures and enlarges over time 1
• Fibrosis typically starts in the centrilobular region and extends toward the portal tract as the disease progresses 1
• This process leads to the formation of regenerative nodules surrounded by fibrous bands, which is the defining histological feature of cirrhosis 2

Portal Hypertension Development

• Portal pressure increases initially due to increased resistance to blood flow through the liver, which has two main components: 3

  • Structural component (70%): Architectural distortion from fibrous tissue, vascular distortion from regenerative nodules, and microthrombi 3
  • Functional component (30%): Increased intrahepatic vascular tone due to endothelial dysfunction and reduced nitric oxide bioavailability 3

• Despite the formation of porto-systemic collaterals, portal hypertension persists due to: 3

  • Increased portal venous inflow resulting from splanchnic arteriolar vasodilation
  • Insufficient portal decompression through collaterals as they have higher resistance than normal liver

Systemic Hemodynamic Changes

• Splanchnic vasodilation leads to increased flow into the gut and portal venous system 3

• This vasodilation triggers activation of neurohumoral and vasoconstrictive systems, causing: 3

  • Sodium and water retention
  • Increased blood volume
  • Increased cardiac output
  • Development of a hyperdynamic circulatory state that further increases portal venous inflow and portal pressure

• Advanced cirrhosis is characterized by chronic inflammation with increased circulating levels of pro-inflammatory cytokines and chemokines 1

• Systemic inflammation and circulatory dysfunction contribute to multi-organ failure in advanced disease 1

Disease Progression and Stages

• Cirrhosis progresses through distinct stages: 3

  • Compensated cirrhosis (asymptomatic, longest stage)
    • Mild portal hypertension
    • Clinically significant portal hypertension with gastroesophageal varices
  • Decompensated cirrhosis (symptomatic)
    • Characterized by complications: ascites, variceal hemorrhage, hepatic encephalopathy
  • Late decompensation
    • Refractory ascites, hyponatremia, hepatorenal syndrome
    • Recurrent hepatic encephalopathy
    • Jaundice

• Gastroesophageal varices are present in approximately 50% of patients with cirrhosis, with prevalence correlating with disease severity (40% in Child A vs. 85% in Child C patients) 3

Clinical Implications

• Portal hypertension drives the development of gastroesophageal varices, which are present in 30-40% of patients with compensated cirrhosis and up to 85% of those with decompensated cirrhosis 4
• If untreated, recurrent variceal hemorrhage occurs in 60% of patients, usually within 1-2 years of index hemorrhage 3
• The risk of complications is higher in patients with Child-Pugh B and C cirrhosis and those with significant portal hypertension 4
• Mortality from variceal hemorrhage differs depending on whether it presents as an isolated complication (20% 5-year mortality) or in association with other complications (over 80% 5-year mortality) 3

Common Pitfalls in Understanding Cirrhosis Pathophysiology

• Failing to recognize that increased intrahepatic resistance has both structural and functional components, with the latter being potentially modifiable 3
• Not appreciating that portal hypertension persists despite collateral formation due to increased portal venous inflow and high collateral resistance 3
• Overlooking the role of systemic inflammation in disease progression and multi-organ failure 1
• Underestimating the importance of splanchnic vasodilation in maintaining and worsening portal hypertension 3