Ammonia: more than a neurotoxin?

Ammonia is an inorganic nitrogen compound that is metabolized and produced in all tissues via a number of important biochemical reactions. However, a major source of ammonia generation occurs in the gut following protein digestion and amino acid deamination. The subsequent ammonia-rich portal blood is effectively removed by the urea cycle in a healthy liver, maintaining circulating concentrations of ammonia within 35–65 lM. When liver function is compromized, hyperammonaemia arises delivering toxic concentrations of ammonia to the brain, causing deleterious effects. Ammonia is composed of a gaseous (NH3) and ionic (NH4 ) component, where the ratio of NH3/ NH4 + is a function of pH defined by the Henderson– Hasselbach equation. Under normal physiological conditions (pH 7.4) more than 98% of ammonia is present as NH4 . The ionic properties of NH4 + are unique in comparison to other weak bases, as NH4 + has a comparable ionic radius and diffusion coefficient as potassium (K). Therefore, in addition to ammonia diffusing into cells as a gas (NH3), NH4 + can cross plasma membranes via K transporters/channels. Elevated levels of ammonia lead to new equilibriums across plasma membranes, which in turn elicit alterations in pH. In addition to high ammonia having an effect on cellular metabolism, an increase in NH4 + will specifically have an immediate impact on the membrane potential. These direct effects of increased ammonia will consequently trigger a cascade of pathophysiological events (1). Although ammonia can disperse and enter all organs throughout the body, it is the brain that bears the brunt, as episodes of hyperammonaemia prompt neurological decline. Acquired hyperammonaemia, as observed during liver disease/ failure, consequently leads to hepatic encephalopathy which includes an array of neuropsychiatric abnormalities from cognitive deficits to ataxia, stupor and coma. Inherited hyperammonaemia, as observed in children born with genetic defects in the urea cycle, causes neurological posturing, lethargia and seizures. In both cases, ammonia-lowering strategies remain a primary therapeutic target (2). The study by Jia et al., published in Liver International (3) provides evidence that the toxic effects of ammonia are not restricted to the brain, and that elevated concentrations of blood ammonia cause hepatic dysfunction. Jia and colleagues demonstrated that increasing blood ammonia levels to concentrations between 120–180 lM for 4 weeks (attained through administration of ammonia by gavage twice a day to na€ıve rats) leads to alterations in liver biochemistry (including alanine/aspartate transaminases and total bilirubin) and detection of apoptotic cells in liver (quantified by number of TUNEL-positive cells). Histological analysis revealed no cell degeneration or regeneration, no cell necrosis and no inflammatory infiltration, however, oedematous hepatocytes were noted. The concept that hyperammonaemia, commonly arising under conditions when the liver’s capacity to remove ammonia is reduced causes hepatic damage and hepatocyte apoptosis is paradoxical. For centuries, the liver has been defined as a vital organ for regulating and detoxifying ammonia. Whether ammonia can inadvertently affect the liver, it’s primary source of detoxification, and hence perpetuate a vicious cycle is captivating and further studies are warranted to clarify this dispute. The conclusions by Jia et al., stipulating hyperammonaemia impairs the liver leading to hepatic damage and hepatocyte apoptosis is intriguing, as to date there is little compelling evidence supporting this observation. In studies involving ammonia and different in vivo and in vitro model systems of the liver, hepatocyte cell death was rarely reported (4). Furthermore, children with inborn errors of the urea cycle infrequently present with hepatocyte apoptosis. Conversely, mild hepatic fibrosis, glycogen accumulation and hepatocyte swelling have been found in these young patients, which are assumed to be related to age as the progression to these liver abnormalities is slow (5). Moreover, these pathological findings are believed to be related to the type of urea cycle disorder (specific gene defect) and the accumulation of respective urea cycle intermediates. Further evidence describing ammonia does not impact on liver function, comes from our group, where we recently demonstrated that by preventing the development of hyperammonaemia in bile-duct ligated-induced cirrhotic rats with AST-120 (carbon microspheres), the degree of liver damage was not alleviated (6). In addition, Jover and colleagues elegantly demonstrated that inducing hyperammonaemia by feeding na€ıve rats with a high ammonia diet did not result in alterations in liver biochemistry (7). Also,