Hepatic encephalopathy: current challenges and future prospects

Abstract

Hepatic encephalopathy (HE) is a common complication of liver dysfunction, including acute liver failure and liver cirrhosis. HE presents as a spectrum of neuropsychiatric symptoms ranging from subtle fluctuating cognitive impairment to coma. It is a significant contributor of morbidity in patients with liver disease. HE is observed in acute liver failure, liver bypass procedures, for example, shunt surgry and transjugular intrahepatic portosystemic shunt, and cirrhosis. These are classified as Type A, B and C HE, respectively. HE can also be classified according to whether its presence is overt or covert. The pathogenesis is linked with ammonia and glutamine production, and treatment is based on mechanisms to reduce the formation and/or removal of these compounds. There is no specific diagnostic test for HE, and diagnosis is based on clinical suspicion, excluding other causes and use of clinical tests that may support its diagnosis. Many tests are used in trials and experimentally, but have not yet gained universal acceptance. This review focuses on the definitions, pathogenesis and treatment of HE. Consideration will be given to existing treatment, including avoidance of precipitating factors and novel therapies such as prebiotics, probiotics, antibiotics, laxatives, branched-chain amino acids, shunt embolization and the importance of considering liver transplant in appropriate cases.

Keywords: covert hepatic encephalopathy; hepatic encephalopathy; lactulose; pathogenesis; probiotics; rifaximin; treatment.

Figure 1

Contributing factors toward pathophysiology of HE. Notes: Ammonia is produced from nitrogenous products by bacterial metabolism of urea and proteins in the gut and from deamination of glutamine in the small intestine. Normally, ammonia is cleared by liver and kidneys and metabolized in skeletal muscle. However, as a result of liver dysfunction and portosystemic shunting, ammonia cannot be cleared adequately. **Increased ammonia levels in the plasma increases metabolism to glutamine (via glutamine synthetase) in astrocytes, which subsequently causes intracellular swelling and edema. Abbreviation: HE, hepatic encephalopathy.

Figure 2

Mechanism of action of nonabsorbable disaccharides. Notes: Lactulose and lacitiol are not absorbed in the small intestine and enter the colon unchanged, where they are metabolized to hydrogen and VFA. Bacteria use these as preferred substrate, thereby reducing the production of ammonia and promoting its incorporation into stool for excretion. Abbreviation: VFA, volatile fatty acids.