What is the pathophysiology of liver cirrhosis?

Pathophysiology of Liver Cirrhosis

Liver cirrhosis is characterized by the gradual replacement of normal hepatic parenchyma with regenerative nodules and fibrous bands in response to chronic liver injury, leading to portal hypertension and end-stage liver disease. 1, 2

Definition and Etiology

• Cirrhosis represents the final stage of various chronic liver diseases, resulting from persistent necroinflammatory and fibrogenetic processes that transform normal liver architecture into structurally abnormal nodules surrounded by dense fibrotic septa 3
• The most common causes worldwide include viral hepatitis (B and C), alcohol-related liver disease, and metabolic associated steatotic liver disease (formerly non-alcoholic fatty liver disease) 1, 2, 4
• Other etiologies include autoimmune diseases, cholestatic diseases, and iron or copper overload disorders 2

Pathological Process

Fibrosis Development

• Chronic liver injury initiates a wound healing response that becomes dysregulated, leading to abnormal continuation of connective tissue production and deposition 1
• The process begins with deposition of a fine neomatrix within the space of Disse that progressively matures and enlarges over time 1
• Fibrosis typically starts in the centrilobular region (zone 3) and extends toward the portal tract (zone 1) as the disease progresses 1

Architectural Distortion

• Progressive fibrosis leads to bridging between central veins (central-central), central veins to portal tracts, and eventually portal-portal connections 1
• This results in gross architectural distortion with formation of regenerative nodules surrounded by fibrous septa 1, 2
• The normal lobular architecture of the liver is destroyed, leading to impaired hepatic function 3

Vascular Changes

• Cirrhosis causes distortion of the intrahepatic vasculature, leading to direct shunting of portal and arterial blood flow into the hepatic venous outflow 1
• This vascular distortion results in impaired exchange of hepatotrophic factors between hepatic sinusoids and hepatocytes 1
• Fibrosis causes loss of endothelial fenestrations, further affecting delivery of regenerating factors to hepatocytes 1

Hemodynamic Consequences

Portal Hypertension Development

• Increased intrahepatic resistance to portal flow is the primary factor in the development of portal hypertension 1
• This increased resistance has two components:
  1. Structural component (70%): Due to fibrous tissue, vascular distortion from regenerative nodules, and microthrombi 1
  2. Functional component (30%): Due to increased intrahepatic vascular tone from endothelial dysfunction and reduced nitric oxide bioavailability 1

Splanchnic and Systemic Circulation Changes

• Portal hypertension leads to formation of portosystemic collaterals (varices) 1
• Splanchnic vasodilation occurs, increasing flow into the gut and portal venous system 1
• This vasodilation triggers activation of neurohumoral and vasoconstrictive systems, leading to sodium and water retention, increased blood volume, and increased cardiac output 1
• The resulting hyperdynamic circulatory state further increases portal venous inflow and portal pressure 1

Systemic Manifestations and Complications

Effective Arterial Underfilling

• Splanchnic and systemic vasodilation causes effective arterial underfilling 1
• This leads to compensatory activation of vasoconstrictor systems (renin-angiotensin-aldosterone and sympathetic nervous systems) 1
• Renal vasoconstriction results, first conserving sodium, then water, and finally reducing kidney blood flow to a level that impairs glomerular filtration rate 1

Systemic Inflammation

• Advanced cirrhosis is characterized by a state of chronic inflammation with increased circulating levels of pro-inflammatory cytokines and chemokines 1
• This is likely caused by systemic spread of bacteria and bacterial products (PAMPs) due to abnormal bacterial translocation from the gut 1
• Danger associated molecular patterns (DAMPs) released by the diseased liver also contribute to inflammation 1
• Both PAMPs and DAMPs activate immune cells to produce pro-inflammatory molecules and reactive oxygen/nitrogen species 1

Disease Progression

Compensated vs. Decompensated Stages

• Cirrhosis evolves from an asymptomatic phase (compensated cirrhosis) to a symptomatic phase (decompensated cirrhosis) 2, 5
• Decompensation is characterized by development of complications including ascites, variceal hemorrhage, hepatic encephalopathy, and jaundice 1, 5
• The compensated stage is the longest stage and is asymptomatic, while the decompensated stage is much shorter and can rapidly progress to multi-organ failure 1

Hepatocyte Dysfunction and Regeneration

• Cirrhosis impairs the liver's regenerative capacity, which normally depends on the liver's ability to limit cell death and recover adequate synthetic function 1
• Factors like hepatic ischemia-reperfusion injury, parenchymal congestion, and reduced phagocytic ability negatively impact regenerative capacity 1
• The combination of reduced functional hepatocyte mass and impaired regeneration leads to progressive liver failure 1, 3

Clinical Implications

• The pathophysiological changes in cirrhosis lead to decreased levels of hepatocyte regeneration and growth, translating to high mortality rates (5-6.5%) 1
• 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 1
• The risk of complications is higher in patients with Child-Pugh B and C cirrhosis and those with significant portal hypertension 1
• Systemic inflammation and circulatory dysfunction contribute to multi-organ failure in advanced disease 1

Understanding these pathophysiological mechanisms is essential for developing targeted therapies that can halt progression to decompensated cirrhosis or potentially reverse cirrhosis 2, 6.