Due to the presence of scarring within the liver, cirrhosis leads to obstruction of the passage of blood through the liver causing portal hypertension. This means it is difficult for blood from the intestines to go through the liver to get back to the heart. Portal-systemic anastamoses (“shunts“) develop, and portal blood (from the intestinal veins) will bypass the liver and return to the heart via another route without undergoing first-pass detoxification by the liver. The toxic substances which accumulate in the setting of liver failure and affect the brain have been thought to include ammonia (NH₃) and mercaptans. Ammonia is normally converted to urea by the liver and, as with mercaptans, is produced by the bacterial breakdown of protein in the intestines. Ammonia can cross the blood-brain barrier, where it causes the support cells of the brain (astrocytes) to swell. The swelling of the brain tissue increases intracranial pressure, and can lead to coma or death via herniation of the brainstem. Disorders and conditions such as alcoholic liver disease, hepatitis C, hepatitis B, hemochromatosis, Wilson disease, age above 50 years and male gender may lead to hepatic encephalopathy.

Following important aspects about pathophysiology of hepatic encephalopathy:^[1][2][3][4]

• Due to the presence of scarring within the liver, cirrhosis leads to obstruction of the passage of blood through the liver causing portal hypertension.
• Portal hypertension makes it difficult for blood from the intestines to go through the liver to the heart.
• As a result portal-systemic anastamoses (“shunts“) develop, and portal blood (from the intestinal veins) will bypass the liver and return to the heart via another route without undergoing first-pass detoxification by the liver.
• Furthermore, in cirrhosis and other forms of liver disease, the liver will not be fully functional, so even blood that does travel through the liver may not be as detoxified as it otherwise would be.
• The toxic substances accumulate, of which ammonia (NH₃) and mercaptans are the most common toxic substrates responsible for encephalopathy.
• Ammonia is normally converted to urea by the liver and, as with mercaptans, is produced by the bacterial breakdown of protein in the intestine.
• Ammonia and mercaptans can cross the blood-brain barrier, which causes astrocytes (support cells) to swell and subsequent inflammation.
• The swelling of the brain tissue increases intracranial pressure, and can lead to coma or death via herniation of the brainstem.

There is no established relation between hepatic encephalopathy and genetic inheritance.

Any disorders with liver failure may lead to hepatic encephalopathy.

• Disorders and conditions which may lead to hepatic encephalopathy include:^{[5][6][7][8][9][10]}
  • Alcoholic liver disease
  • Hepatitis C
  • Hepatitis B
  • Hemochromatosis
  • Wilson’s disease
  • Age above 50 years
  • Male gender
  • Eating too much protein
  • Bleeding from the intestines, stomach, or esophagus
  • Shunt placement or complications (Transjugular intrahepatic portosystemic shunt)

Microscopic studies of specimens from patients with hepatic encephalopathy suggests:^[3]

• Astrocytic changes
• Cellular swelling