New aspects on etiology, biochemistry, and therapy of portal systemic encephalopathy: a critical survey

There is scientific agreement that portal systemic encephalopathy (PSE) is caused morphologically by portal systemic shunts and biochemically by constituents of the portal venous blood. Ammonium has a key role in the pathogenesis of PSE. Direct correlations with the degree of PSE have been established exclusively with glutamine, i.e. the terminal product of the peripheral detoxification of ammonium. In PSE, ammonium is probably responsible for damage to astrocytic and neuronal cells. Ammonium's toxic effect is due to the intracerebral glutamine synthesis. After several metabolic steps, which will be discussed in detail, brain cell damage is caused directly or indirectly (exitotoxically) by energy deficiency. Hyperammonemia and PSE are each well defined though different forms of disturbance. Therefore, ammonium is not the sole decisive factor in the pathogenesis of PSE. We performed a detailed and critical analysis of all studies on amino acid therapy of PSE, especially those that were randomized and controlled. This analysis revealed a close and direct correlation between qualitative and quantitative dosages of amino acids on one hand, and parallel improvements of amino acid imbalance (essentially associated with PSE) and degree of PSE on the other. A close and direct dose/efficacy correlation must be assumed. Disturbed plasmatic amino acid homeostasis and cerebral monoaminergic neurotransmission are probably important pathogenic factors of PSE. A fundamental cofactor in the efficacy of each adequate amino acid therapy might be a substantial decrease of endogenous ammonium production. Physiologic benzodiazepines may also have an important function in the pathogenesis of PSE: not so, however, the glutamate-ergic and GABA-ergic neurotransmission, which are disturbed principally in PSE. In close correlation to pathogenesis, established and proposed therapies of PSE are critically discussed.