A controlled study was carried out in two groups of 20 patients with cirrhosis of the liver and deep coma in order to compare the efficacy of intravenous branched-chain amino acid solutions in 20% glucose (group A) vs lactulose plus glucose in isocaloric amount (group B). There were 3 drop-outs from each group. Plasma amino acids and ammonia were assayed at fixed intervals throughout the 10-day observation period. Routine tests were assayed daily. Complete mental recovery was obtained in 70% of patients in group A and in 47% in group B. The difference was not significant, likely due to the lack of placebo group. With the exception of free tryptophan/all competing amino acids ratio, the modifications in plasma amino acid levels showed no correlation with the clinical course under either treatment. Ammonia, like free tryptophan, decreased significantly upon mental recovery, paralleling the clinical course throughout the study. In conclusion, branched-chain amino acids are at least as effective as lactulose in deep hepatic coma. It is suggested that branched-chain amino acids may reverse coma either by competing with brain entry of the aromatic amino acid or by metabolically decreasing free tryptophan and ammonia.
Recurrent episodes of hepatic encephalopathy (HE) frequently occur in patients with cirrhosis of the liver especially after surgical portal systemic anastomosis.l The prevention of these recurrent episodes of HE is based on neomycin, purging of the gastrointestinal tract, lactulose and restriction of protein intake.
The most characteristic feature of the plasma amino acid (AA) profile in chronic liver failure is the rise in the three aromatic AA (AAA), phenylalanine (PHE), tyrosine (TYR) and free tryptophan (F. TRY) and the fall in the three branched-chain AA (BCAA), valine (VAL) leucine (LEU) and isoleucine (ILEU).1,2 These alterations of plasma AA are in turn responsible for brain accumulation of AAA. In fact, blood-brain entry of AAA is increased either because of a decreased competition by BCAA which use the same transport system across the blood-brain-barrier (BBB)3 or because an increased activity of the transport system itself.4,5 Brain accumulation of AAA may profoundly alter the synthesis of neurotransmitters leading to a depletion of putative neurotransmitters, norepinephrine and dopamine, and an accumulation of false neurotransmitters (such as octopamine and phenylethanolamine)6,7,8 or inhibitory neurotransmitters (such as serotonin).9 The false neurotransmitters hypothesis offers an appealing explanation for the neurologic disorders and coma that complicate chronic liver failure.
The efficacy of branched chain amino acids in two consecutive clinical studies in patients with severe hepatic encephalopathy was tested. In the preliminary uncontrolled study 19 patients with grade 3-4 hepatic encephalopathy were given an intravenous solution containing leucine 11 g/l, isoleucine 9 g/l, and valine 8.4 g/l in 20% dextrose. A complete recovery of mental state was obtained in all patients in a mean time of 20.5 hours. In a subsequent controlled study 40 patients with grade 3-4 hepatic encephalopathy were randomly assigned to receive intravenous branched chain amino acid in 20% dextrose (group A) or oral lactulose (group B). Twelve patients (70.6%) in group A and eight (47%) in group B regained consciousness in a mean time of 27.6 and 31.5 hours, respectively. The difference in the recovery rate between the two groups, although evident, was not significant. Intravenous branched chain amino acids are thus at least as effective as lactulose in reversing hepatic coma. These data argue strongly in favour of a therapeutic effect of branched chain amino acids in the treatment of hepatic encephalopathy in patients with chronic liver failure.
A controlled study was carried out in two groups of 20 patients with cirrhosis of the liver and deep coma in order to compare the efficacy of intravenous branched-chain amino acid solutions in 20% glucose (group A) vs lactulose plus glucose in isocaloric amount (group B). There were 3 drop-outs from each group. Plasma amino acids and ammonia were assayed at fixed intervals throughout the 10-day observation period. Routine tests were assayed daily. Complete mental recovery was obtained in 70% of patients in group A and in 47% in group B. The difference was not significant, likely due to the lack of placebo group. With the exception of free tryptophan/all competing amino acids ratio, the modifications in plasma amino acid levels showed no correlation with the clinical course under either treatment. Ammonia, like free tryptophan, decreased significantly upon mental recovery, paralleling the clinical course throughout the study. In conclusion, branched-chain amino acids are at least as effective as lactulose in deep hepatic coma. It is suggested that branched-chain amino acids may reverse coma either by competing with brain entry of the aromatic amino acid or by metabolically decreasing free tryptophan and ammonia.
