What are the causes of portal hypertension?

Causes of Portal Hypertension

Portal hypertension is most commonly caused by cirrhosis from any chronic liver disease, but the causes are best understood through an anatomical classification system that divides them into prehepatic, intrahepatic, and posthepatic categories based on the site of increased resistance to blood flow. 1

Anatomical Classification Framework

The American Association for the Study of Liver Diseases recommends organizing causes by anatomical location, which has both diagnostic and prognostic implications 1:

Prehepatic Causes

• Portal vein thrombosis - the most common prehepatic cause 1
• Splenic vein thrombosis 1
• Mesenteric vein obstruction 1

These conditions result in normal hepatic venous pressure gradient (HVPG) measurements because the wedged pressure does not reflect portal pressure 1

Intrahepatic Causes

Cirrhotic causes (accounting for the majority of cases in Western countries) 1, 2:

• Chronic viral hepatitis B/C 1, 3
• Alcoholic liver disease 1
• Non-alcoholic steatohepatitis (NASH) 1, 3
• Autoimmune hepatitis 1
• Primary biliary cirrhosis - notably can develop portal hypertension even before established cirrhosis 1, 2
• Hereditary hemochromatosis 1
• Wilson's disease 1

Non-cirrhotic intrahepatic causes 1:

• Idiopathic non-cirrhotic portal hypertension (INCPH) - caused by thrombophilia (40% prevalence), immunological disorders, specific medications, or HIV infection 1
• Schistosomiasis - a major cause in endemic areas 1
• Congenital hepatic fibrosis 1
• Sarcoidosis 1
• Nodular regenerative hyperplasia 1

Posthepatic Causes

• Budd-Chiari syndrome - thrombosis of hepatic veins or inferior vena cava 1
• Sinusoidal obstruction syndrome (veno-occlusive disease) 1
• Right heart failure 1

Pathophysiological Mechanisms

Portal hypertension develops through two primary mechanisms 1, 3:

1. Increased intrahepatic vascular resistance (70% structural, 30% functional):

   • Structural component: architectural distortion from fibrous tissue, regenerative nodules, vascular distortion, and microthrombi 1
   • Functional component: active intrahepatic vasoconstriction from endothelial dysfunction and reduced nitric oxide bioavailability 1, 3

2. Increased portal venous inflow: paradoxically occurs despite collateral formation due to splanchnic arteriolar vasodilation 1, 4

Critical Diagnostic Pitfalls

When evaluating portal hypertension without obvious cirrhosis, systematically exclude all causes starting with Doppler ultrasound to assess portal and hepatic vein patency 1:

• Liver biopsy remains essential to exclude cirrhosis in suspected non-cirrhotic portal hypertension and identify specific pathology like nodular regenerative hyperplasia or obliterative portal venopathy 1
• Thrombophilia workup is necessary if INCPH is suspected, as 40% have underlying prothrombotic conditions 1
• Low liver stiffness (<12 kPa) despite signs of portal hypertension suggests INCPH rather than cirrhosis, as patients are often radiologically misclassified 3

Special Population Considerations

Patients with hepatitis C and bridging fibrosis can develop varices even without established cirrhosis, with 16% prevalence 1. This highlights that portal hypertension is not exclusively a cirrhotic phenomenon.

Non-cirrhotic portal hypertension typically presents with 1:

• Splenomegaly and hypersplenism
• Variceal bleeding
• Normal or near-normal liver function at diagnosis
• Better prognosis than cirrhotic portal hypertension