Abstract
Marked alteration of neutral amino acid levels in the circulating blood was observed in patients with severe liver diseases. Km value and predicted velocity (Vpre) of a specific carriermediated transport system of neutral amino acids across the blood-brain barrier (BBB)(Pardridge; Neurochem., 28, 103, 1977) would be changed in these cases. Greater extent of aminogram abnormality in cerebro-spiral fluid (CSF) as compared to that in the serum indicates that the accerelated transport through BBB may be involved in pathogenesis of hepatic encephalopathy. We tried to perform a quantitative analysis of BBB amino acid transports from a ratio ([CSF]/Vpre) of the measured concentrations in CSF ([CSF]) to calculated Vpre values. An availability of the theoretical application for infering a close participation of abnormal BBB transport of amino acids to hepatic encephalopathy is also evaluated.
Five cases with fulminant hepatitis, 8 with liver cirrhosis without encephalopathy and 7 with encephalopathy were adapted as clinical materials for this study. Samplings of their CSF and sera for amino acid analysis were carried out simultaneously.
Aromatic amino acids (AAA) and methionine increased to a greater extent in CSF of encephalopathic patients, while branched chain amino acids (BCAA) in CSF remained unchanged even with their marked decreases of the serum levels. Ratios of CSF levels to serum concentrations of amino acids ([CSF]/[Serum]) elevated significantly in neutral amino acids such as AAA, methionine and BCAA in comatous cases. Furthermore, a direct correlation between [CSF]. tyrosine and [Serum] tyrosinewere not confirmed in encephalopathic patients in contrast to subjects with tyrosine no neurological abnormality. Total concentrations of three BCAAs and ratios of [CSF] phenylalanine/ [Serum] phenylalanine were, however, well correlated inversely each other, suggesting that serum BCAA can regulate AAA entry into the brain in a fasion of competition at level of BBB. Vpre values of BCAA and AAA were significantly smaller and much larger, respectively, in patients with severe liver diseases; this may directly reflect the deranged serum aminogram. [CSF]/Vpre of all the amino acids including even BCAA increased greatly only in encephalopathic patients, indicating that their transports in coma were accelerated abnormally over their theoretical velocities. Improvement of both [CSF] and Vpre for each amino acid was obtained rapidly following intravenous administration of a BCAA-rich solution. Stable [CSF]/Vpre during this infusion indicated an availability of theoretical application for analyzing BBB function in liver diseases.
Abnormal transport of neutral amino acids through BBB may play an important role on the pathogenesis of hepatic encephalopathy in severe liver diseases. Arousal observed reliablly and rapidly following infusion of a BCAA-rich solution may indicate, at least partly, to be due to marked decreases of [CSFAAA].
