What is the pathophysiology of portal hypertension?

Pathophysiology of Portal Hypertension

Portal hypertension is primarily caused by increased intrahepatic resistance to portal blood flow, followed by increased portal venous inflow, resulting in a pathological increase in portal pressure with hepatic venous pressure gradient (HVPG) >5 mmHg, with clinically significant portal hypertension (CSPH) occurring at HVPG ≥10 mmHg. 1

Fundamental Mechanisms

• Portal hypertension develops through a combination of increased intrahepatic resistance and increased portal blood flow, following the hydraulic equivalent of Ohm's law where "Pressure = Resistance × Flow" 2, 1

• The increased intrahepatic resistance has two primary components:

  • Structural/mechanical component (70%): Due to fibrous tissue, vascular distortion from regenerative nodules, and microthrombi 2
  • Functional component (30%): Due to active intrahepatic vasoconstriction resulting from endothelial dysfunction with reduced nitric oxide (NO) bioavailability 2

• Portal pressure increases initially due to these resistance factors, but is maintained and worsened by the subsequent development of increased portal venous inflow 2

Portal Venous Inflow Mechanisms

• Splanchnic arteriolar vasodilation occurs concomitantly with or even preceding the formation of portosystemic collaterals 2

• Increased splanchnic nitric oxide (NO) production is the main factor leading to vasodilation and increased splanchnic blood flow 2

• Additional factors contributing to increased splanchnic blood flow include:

  • Hyperglucagonemia 2
  • Neoangiogenesis (formation of new blood vessels) 2
  • Systemic vasodilation leading to hyperdynamic circulatory state 2

Portosystemic Collateral Formation

• Portosystemic collaterals develop as a consequence of increased portal pressure, with gastroesophageal varices being the most clinically significant 2

• Collateral formation was previously thought to be simple dilation of preexisting vascular channels, but research now implicates active neoangiogenesis in this process 2

• Despite the development of collaterals, portal hypertension persists because:

  • The collaterals have higher resistance than normal liver vasculature 2
  • Increased splanchnic blood flow continues to feed the portal system 2

Hyperdynamic Circulatory State

• Systemic vasodilation leads to activation of neurohumoral and vasoconstrictive systems 2

• This activation results in:

  • Sodium and water retention 2
  • Increased blood volume 2
  • Increased cardiac output 2

• This hyperdynamic circulatory state further increases portal venous inflow and portal pressure, creating a vicious cycle 2

• Activated vasoconstrictive systems (norepinephrine, angiotensin-2, anti-diuretic hormone) further contribute to intrahepatic vasoconstriction 2

Clinical Significance of Portal Pressure Measurements

• Normal HVPG: 1-5 mmHg 1

• Portal hypertension: HVPG >5 mmHg 1

• Clinically significant portal hypertension (CSPH): HVPG ≥10 mmHg 2, 1

• Patients with CSPH (HVPG ≥10 mmHg) are at risk for developing clinical complications including:

  • Gastroesophageal varices (present in approximately 50% of cirrhotic patients) 2
  • Variceal hemorrhage 2
  • Ascites 3
  • Hepatic encephalopathy 4

• HVPG ≥16 mmHg is strongly associated with increased mortality 2, 1

Therapeutic Implications

• Understanding the dual mechanisms of portal hypertension guides therapeutic approaches:

  • Structural component: Targeted by treating the underlying cause of cirrhosis and using antifibrotic agents 2
  • Functional component: Targeted by vasodilators that improve endothelial dysfunction (e.g., statins) 2
  • Splanchnic vasodilation: Targeted by splanchnic vasoconstrictors like non-selective beta-blockers 2

• HVPG reduction of ≥10% after therapy is associated with decreased risk of first variceal hemorrhage 2, 1

• In patients with decompensated cirrhosis, liver transplantation should be considered as definitive treatment 3