**2.1 The ammonia theory**

Ammonia is produced predominantly from dietary nitrogenous components, bacterial metabolism of these nitrogenous products in the colon and in small intestine from glutamine by glutaminase enzyme.(11) Eventually this ammonia from gastrointestinal tract enters portal circulation for its final destination of urea cycle in the liver to be converted as urea which will subsequently be excreted by kidneys.(12) Under normal conditions, ammonia is eliminated through urea formation in the liver but in patients with acute liver failure, brain and muscle cells are also involved in the metabolism. Elevated levels of ammonia may cause severe toxicity so it must be removed from the body.(13) Because of liver disease and portosystemic collaterals in cirrhosis, ammonia concentration in blood rises hence crosses the blood brain barrier.(14) In Brain, astrocytes are the only cells capable of metabolizing ammonia and express the enzyme glutamine synthase for the conversion of ammonia into glutamine. So, ammonia detoxification in astrocytes leads to accumulation of glutamine which being an osmolyte, causes movement of water inside the astrocyte and causes cerebral edema i-e 'Trojan horse' hypothesis(14-16). Some of the studies had shown the ammonia induced expression of aquaporin water channel on astrocytes. (17)

This has been seen in autopsies of patients with cirrhosis in which brain tissue had shown swollen astrocytes with enlarged nuclei along with displacement of chromatin to the perimeter of the cell, this condition is known as Alzheimer type II astrocytosis.(18) Acute insult of ammonia leads to calcium dependent glutamate release from astrocytes, which causes increased neuronal activity (as seen in Type A HE). A prolonged exposure to ammonia leads to glutamine induced osmotic stress, which causes compensatory release of myoinositol and taurine from the astrocytes, which may lead to down regulation of glutamate receptors and neuroinhibitory state of HE (as seen in Type C HE). Elevated intracellular ammonia levels also results in altered neurotransmission by agonizing GABA tone.(19)

precipitated or spontaneous is clinically relevant since the management of each category is very different. Nowadays MHE has been recognized as the major factor in impairing the health related quality of life (HRQOL) in patients with cirrhosis.(6, 7) And MHE has prognostic significance because it predicts the occurrence of overt HE and is not useful

The pathophysiology of hepatic encephalopathy is intricate and exact mechanisms leading to HE are not clearly understood. Hepatic encephalopathy pathogenesis has many components which include ammonia, inflammatory cytokines, benzodiazepine like compounds and manganese like substances which impair neuronal function.(9) The role of ammonia has dominated explanations for the pathogenesis of HE but it cannot single handedly explain all the neurological changes seen in HE. Evidence regarding other concurrent factors has emerged over the years and it is thought that these factors either work alone or in synergy to cause astrocytes to swell and fluid to accumulate in brain which causes the symptoms of HE(10). Some factors and conditions also appear to precipitate HE

Ammonia is produced predominantly from dietary nitrogenous components, bacterial metabolism of these nitrogenous products in the colon and in small intestine from glutamine by glutaminase enzyme.(11) Eventually this ammonia from gastrointestinal tract enters portal circulation for its final destination of urea cycle in the liver to be converted as urea which will subsequently be excreted by kidneys.(12) Under normal conditions, ammonia is eliminated through urea formation in the liver but in patients with acute liver failure, brain and muscle cells are also involved in the metabolism. Elevated levels of ammonia may cause severe toxicity so it must be removed from the body.(13) Because of liver disease and portosystemic collaterals in cirrhosis, ammonia concentration in blood rises hence crosses the blood brain barrier.(14) In Brain, astrocytes are the only cells capable of metabolizing ammonia and express the enzyme glutamine synthase for the conversion of ammonia into glutamine. So, ammonia detoxification in astrocytes leads to accumulation of glutamine which being an osmolyte, causes movement of water inside the astrocyte and causes cerebral edema i-e 'Trojan horse' hypothesis(14-16). Some of the studies had shown the ammonia induced expression of aquaporin water channel on

This has been seen in autopsies of patients with cirrhosis in which brain tissue had shown swollen astrocytes with enlarged nuclei along with displacement of chromatin to the perimeter of the cell, this condition is known as Alzheimer type II astrocytosis.(18) Acute insult of ammonia leads to calcium dependent glutamate release from astrocytes, which causes increased neuronal activity (as seen in Type A HE). A prolonged exposure to ammonia leads to glutamine induced osmotic stress, which causes compensatory release of myoinositol and taurine from the astrocytes, which may lead to down regulation of glutamate receptors and neuroinhibitory state of HE (as seen in Type C HE). Elevated intracellular ammonia levels also results in altered neurotransmission by agonizing GABA

predictor for mortality in cirrhosis.(8)

**2. Pathophysiology** 

**2.1 The ammonia theory** 

(Box A).

astrocytes. (17)

tone.(19)

Hyper ammonia lead to abnormal cerebral blood flow and glucose metabolism and this had been seen in studies of single photon emission tomographic (SPECT) in which redistribution of blood flow form cerebral cortex to subcortical regions had been demonstrated. This abnormality lead to different HE features.(17, 20)
