Role of Ammonia in the Pathogenesis of Hepatic Encephalopathy

There is consensus that excess of gut-derived ammonia which is not cleared from the blood plays an important role in the pathogenesis of HE. However, as discussed elsewhere in this book, a growing body of evidence suggests signi fi cant contribution of other factors, such as proin fl ammatory cytokines and hyponatremia. Moreover, there is a long list of gut-derived toxins that accumulate in the body when the detoxifying capacity of the liver is compromised, many of which may enter the brain [ 1 ] . It thus appears worthwhile to distinguish the speci fi c roles of ammonia in inducing HE. This will be done in fi ve discrete sections. The fi rst issue addressed in this chapter is the degree of correlation between blood ammonia levels and severity of HE as graded by the West Haven scale (assignment to grades I–IV). The impact of changes in the rate of ammonia generation in the peripheral tissues is brie fl y accounted for. Next, the contribution of ammonia to the speci fi c pathophysiological manifestations of advanced stages of HE is analyzed. The key parameters under evaluation are brain edema, which is the major cause of death in patients with HE accompanying acute liver failure (ALF), and increased cerebral blood fl ow (CBF), which is a causative factor in brain edema. Further, the role of ammonia in the development of cognitive and motor impairment is assessed. Wherever the net effect of ammonia could not be directly evaluated in a clinical setting, its distinct role is demonstrated in experimental animals with “simple” hyperammonemia not complicated by liver