Respective Roles of Ammonia, Amino Acids, and Medium‐Sized Molecules in the Pathogenesis of Experimentally Induced Acute Hepatic Encephalopathy

Abstract

Ammonia, amino acids (AA), and middle molecules (MM) have been implicated in the pathogenesis of experimentally induced acute hepatic coma in the pig. Hemodialysis (HD) using either a low- (Cuprophan = CU) or a high-permeability (polyacrylonitrile = AN 69) membrane has demonstrated the role of MM. Selective hemodialysis (SHD) of AA or NH3 and MM was performed by adding either NH3 (group I) or AA (group II) to the dialysate during AN 69 HD; for MM, SHD only was performed by adding NH3 and AA to the dialysate (group III). In group I the brain levels of tyrosine were similar to those in undialyzed animals with decreased striatal dopamine and decreased norepinephrine in the midbrain only. Brain tryptophan was higher than normal, but brain levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid (5-HT, 5-HIAA) were within normal limits. In group II, despite an efficient NH3 clearance, brain NH3 levels were as high as in group I and did not correlate with plasma levels. Brain tyrosine (despite tyrosine overload of the dialysate) was lower than in group I; striatal dopamine decreased (but to a lesser extent than in group I), and norepinephrine was normal. Brain tryptophan was higher than normal, with an increase in brain 5-HT and 5-HIAA. In group III, results were similar to group I, except for a limited increase of 5-HT in the pons. Brain octopamine levels increased only in undialyzed and CU-HD animals, demonstrating a specific relation with MM. These experiments demonstrate the interrelationship between NH3 and neutral AA with regard to passage through the blood-brain barrier and to intracerebral metabolism.

Hepatocyte-like cells differentiated from human induced pluripotent stem cells: Relevance to cellular therapies

“…As mentioned above, the liver is a major site of detoxification, and ammonia is arguably the most important endogenous toxin which requires clearance by the liver (Denis et al, 1983). Ammonia accumulation causes cerebral edema, the most feared complication of acute liver failure (Haussinger et al, 1992).…”

Evidence for the role of ammonia in the intracerebral transfer and metabolism of tryptophan

“…The aim of the present investigations was to establish the effect of NH3 on TRY transport after direct infusion into the internal carotid artery at much lower blood concentrations, similar to those observed after liver ischemia (6). The metabolism of TRY and serotonin corresponds t o the first intracerebral metabolic pathway to be explored with this method and particularly in the hypothalamic area.…”

Effects of Acute Hyperammonemia on Cerebral Amino Acid Metabolism and pHi In Vivo, Measured by 1H and 31P Nuclear Magnetic Resonance

“…Animal models of chronic hyperammonemia, which involve chemical destruction of the liver with CC4 (Haussinger and Gerok, 1984) or shunting of blood from the portal to the systemic circulation (Lee and Fisher,196 l), have increased blood concentrations of several potentially toxic agents, in addition to ammonia, which may affect neural function (Denis et al, 1983). In the present study, we have used an acute infusion of ammonium acetate to achieve a rapid increase in the blood ammonia concentration which then remained reasonably constant during the time metabolic parameters were being measured.…”