Causes and pathogenesis of hepatic encephalopathy

The most common cause of hepatic encephalopathy (HE) is cirrhosis of the liver (98% of all HE episodes occur in patients with cirrhosis). Although less common, other liver diseases such as hepatitis, fatty liver and acute liver failure also contribute to the incidence of HE.1

The precise pathophysiological mechanisms responsible for the development of HE have not yet been fully understood. However, while a variety of factors can precipitate or exacerbate HE, raised serum ammonia (hyperammonemia) remains the primary candidate in its aetiology. A synergistic effect between other pathogenetic factors may also exist.2-4

Ammonia is of central importance in the pathogenesis of HE. Under normal physiological conditions ammonia is cleared primarily by urea synthesis in the liver. However, if the liver is functionally impaired or a portosystemic shunt is present, this function is compromised and the extrahepatic ammonia metabolism by the brain and musculature becomes more important.2-4

Raised ammonia levels contribute to the pathogenesis of HE via multiple mechanisms. Ammonia contributes to alteration in neurotransmission, oxidative stress, and cerebral edema and astrocyte swelling in acute liver failure.5,6

Although the mechanism responsible for the neurotoxicity of ammonia has not yet been fully clarified, experimental evidence is available which implicate:5,6

  • Changes in pH
  • Alterations in cerebral energy metabolism
  • Disturbances in membrane potential, neurotransmission
  • Direct modulation of neuronal activity

Functional impairment of the astroglia leading to neuronal cell dysfunction is perhaps the most important neurotoxic mechanism of ammonia. The synergistic effects of excess ammonia and inflammation lead to a spectrum of neurocognitive symptoms – including confusion, disorientation and poor coordination – this severely impacts patient mortality and quality of life.5,6


1. Blachier M et al. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58(3):593-608.
2. Jalan R et al. The molecular pathogenesis of hepatic encephalopathy. Int J Biochem Cell Biol. 2003;35(8):1175-81.
3. Häussinger D, Schliess F. Pathogenetic mechanisms of hepatic encephalopathy. Gut. 2008;57(8):1156-65.
4. Zhan T, Stremmel W. The diagnosis and treatment of minimal hepatic encephalopathy. Dtsch Arztebl Int. 2012;109(10):180-7.
5. Prakash R, Mullen KD. Mechanisms, diagnosis and management of hepatic encephalopathy. Nat Rev Gastroenterol Hepatol. 2010;7(9):515-25.
6. Sturgeon JP, Shawcross DL. Recent insights into the pathogenesis of hepatic encephalopathy and treatments. Expert Rev Gastroenterol Hepatol. 2013 Nov 18. [Epub ahead of print].