What is the pathophysiology of portal hypertension?

Pathophysiology of Portal Hypertension

Portal hypertension develops through a dual mechanism of increased intrahepatic resistance and increased portal blood flow, following the hydraulic equivalent of Ohm's law where "Pressure = Resistance × Flow." 1

Initial Mechanisms of Portal Hypertension

• Portal pressure increases initially due to increased resistance to portal blood flow, which is the primary factor in the pathophysiology of portal hypertension 2
• This increased resistance has two components:
  • Structural component (70%): Due to architectural distortion of the liver from fibrous tissue, regenerative nodules, and microthrombi 2
  • Functional component (30%): Due to increased intrahepatic vascular tone from endothelial dysfunction, primarily resulting from reduced nitric oxide (NO) bioavailability 2

Progression and Maintenance of Portal Hypertension

• Portal hypertension leads to the formation of portosystemic collaterals that divert portal blood to the systemic circulation, bypassing the liver 2, 3
• Despite collateral formation, portal hypertension persists due to two key factors:
  1. Increased portal venous inflow: Results from splanchnic arteriolar vasodilation that occurs concomitantly with collateral formation 2
  2. Insufficient portal decompression: Collaterals have higher resistance than the normal liver, making them inadequate for fully normalizing portal pressure 2

Splanchnic and Systemic Hemodynamic Changes

• Splanchnic vasodilation is primarily mediated by increased nitric oxide production in the splanchnic circulation 2
• Additional factors contributing to splanchnic hyperemia include:
  • Hyperglucagonemia 2
  • Neoangiogenesis (formation of new blood vessels) 2
  • Various endogenous vasodilators 3
• These changes lead to a hyperdynamic circulatory state characterized by:
  • Reduced arterial pressure and peripheral resistance 3, 4
  • Increased cardiac output 3, 4
  • Expanded plasma volume due to renal sodium retention 3, 4

Clinical Significance of Portal Pressure Measurements

• Portal hypertension is defined as hepatic venous pressure gradient (HVPG) >5 mmHg 1
• Clinically significant portal hypertension (CSPH) occurs at HVPG ≥10-12 mmHg 2, 1
• Patients with CSPH are at risk for developing complications, particularly gastroesophageal varices 2
• HVPG ≥16 mmHg is strongly associated with increased mortality 1

Consequences of Portal Hypertension

• Formation of gastroesophageal varices, the most relevant portosystemic collaterals 2
• Variceal hemorrhage, the most common lethal complication of cirrhosis 2
• Ascites, splenomegaly, and hypersplenism 5, 6
• Portal hypertensive gastropathy 5
• Hepatic hydrothorax 5

Pathophysiological Basis for Treatment

• Treating the underlying etiology of cirrhosis targets the structural component of increased intrahepatic resistance 2
• Vasodilators (like carvedilol) target the functional component by improving endothelial dysfunction 2
• Non-selective beta-blockers reduce portal pressure by:
  • Causing splanchnic vasoconstriction (β2-adrenergic blocking effect) 2
  • Decreasing cardiac output (β1-adrenergic blocking effect) 2
• Statins may improve endothelial dysfunction and have antifibrotic properties 2

Clinical Progression

• Portal hypertension typically progresses from mild (HVPG >5 but <10 mmHg) to clinically significant (HVPG ≥10 mmHg) 1
• As portal pressure increases, the risk of developing complications like varices, ascites, and hepatic encephalopathy increases 2, 1
• In compensated cirrhosis, HVPG reduction of ≥10% after therapy is associated with decreased risk of first variceal hemorrhage 1

Understanding this complex pathophysiology is crucial for appropriate management strategies that target the various mechanisms involved in portal hypertension.