Respective roles of ammonia, amino acids, and medium-sized molecules in the pathogenesis of experimentally induced acute hepatic encephalopathy.

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.