Masachika Fujiwara

Glutamic acid and glutamine levels in serum and cerebrospinal fluid in hepatic encephalopathy

Significant elevation of glutamic acid and glutamine concentrations in CSF was observed in hepatic encephalopathic patients with fulminant hepatitis and liver cirrhosis. However, the ratios of CSF glutamic acid to CSF glutamine levels and of CSF to serum glutamic acid and glutamine levels were significantly higher only in cirrhotic patients with hepatic encephalopathy. CSF glutamine levels were positively correlated with blood ammonia and CSF tyrosine levels in cirrhotic patients. The results indicate that CSF glutamic acid and glutamine levels are important tools in diagnosing hepatic encephalopathy in severe liver disease.

Ammonia detoxification by accelerated oxidation of branched chain amino acids in brains of acute hepatic failure rats.

BCAA aminotransferase and BCKA dehydrogenase activities are increased in the mitochondrial fractions from the brains of hepatic failure rats treated with two-thirds removal of CCl4-injured liver. Cerebral leucine decarboxylation was accelerated, and it well correlated with arterial blood ammonia levels. Elevation of brain ammonia content following an intraperitoneal injection of ammonium acetate to hepatic failure rats could be prevented by intravenous infusion of BCAA. Significantly increased brain glutamic acid, glutamine, and alanine contents were noted. These results suggested that accelerated brain BCAA catabolism in acute hepatic failure rats reduce the neurotoxicity of ammonia by promoting the synthesis of glutamic acid and glutamine from BCAA.

Amino acid neurotransmitters and their receptors in the brain synaptosomes of acute hepatic failure rats

Ammonia contents in the brain stem and prosencephalon markedly increased in a rat model of acute hepatic failure induced by partial hepatectomy following CCl4 intoxication. In hepatic failure rats, synaptosomal glutamic acid (excitatory amino acid neurotransmitter) contents decreased significantly in the prosencephalon, and GABA (inhibitory amino acid neurotransmitter) contents decreased significantly in the brain stem. The molar ratio of glutamic acid to glutamine significantly diminished in the brain stem. Glutamic acid decarboxylase activity in the synaptosomes and the binding of [3H]glutamic acid and [3H]GABA to synaptosomal membrane preparations were unchanged in acute hepatic failure rats. These results indicate than an insufficiency of both excitatory and inhibitory neurotransmitter amino acids is induced by high ammonia contents in the synaptosomes of the brain stem during acute hepatic failure.

Plasma amino acid imbalance in alcoholic liver cirrhosis.

Plasma amino acid concentrations and plasma glucagon and serum insulin levels were studied in male patients with compensated alcoholic and nonalcoholic liver cirrhosis. Age, nutritional status, and liver function tests were similar in both groups; none of the patients presented hepatic encephalopathy. Plasma valine and leucine concentrations were lower, and tyrosine, higher in alcoholic than nonalcoholic liver cirrhosis. As a result, the molar ratios of branched-chain amino acids (BCAA) to aromatic amino acids (AAA) were reduced markedly in this group. Although correlation coefficients comparing BCAA/AAA ratios and KICG in alcoholic and nonalcoholic liver cirrhosis were similar, a steeper regression line was observed in alcoholics. Plasma glucagon and proline levels were significantly higher in alcoholic than nonalcoholic liver cirrhosis, the former correlated with AAA concentrations only in alcoholic liver cirrhosis, but not with BCAA levels. These results indicated that alcoholic liver cirrhosis presented a more deranged plasma amino acid pattern than nonalcoholic, and the amino acid imbalances, except for depressed BCAA and elevated proline, were derived, in part, from the hyperglucagonemia.

EFFECT OF AZATHIOPRINE AND CARBON TETRACHLORIDE ON INDUCTION OF HYPERPLASTIC LIVER NODULE AND HEPATOCELLULAR CARCINOMA BY DIETHYLNITROSAMINE AND N‐2‐FLUORENYLACETAMIDE IN RATS

The enhancing or inhibitory action of the hepatotoxic agents, carbon tetrachloride (CCl4) and azathioprine (AZP), on the evolution of hyperplastic liver nodule (HN) and hepatocellular carcinoma (HCC) in diethylnitrosamine (DEN)- and N-2-fluorenylacetamide (FAA)-treated rats (control group) was tested. The area of gamma-glutamyl transpeptidase(gamma-GTP)-positive HN and/or foci in the eighth week was remarkably small in rats fed on a diet containing FAA and AZP (the AZP group), but was quite large in rats fed a diet containing FAA in addition to repeated CCl4 injections (the CCl4 group). HCC was first detected in the 21st week and the incidence of HCC within the 36 weeks of the experiment was very high in the CCl4 group. However, no tumor, including HCC, was detected in the AZP group during this observation period. No essential differences in the biochemical characteristics of HCC between the control group and the CCl4 group were observed with respect to several enzyme activities. The increased activity of liver aniline hydroxylase observed 12 hr after the administration of FAA, AZP, or DEN decreased when AZP was administered simultaneously with FAA to rats treated with DEN in advance. The mechanisms of the enhancing of inhibitory effect observed are discussed with special reference to the drug-drug interactions.

Alterations in neutral amino acid transport across the blood-brain barrier in hepatic failure

SummaryThe accelerated transport of the blood neutral amino acids into the brain in encephalopathic patients with fulminant hepatitis and advanced liver cirrhosis was demonstrated not only by determining the cerebrospinal fluid (CSF) aminogram but also by calculating the predicted velocity of the amino acid transport through the blood-brain barrier. Significant elevation in CSF aromatic amino acid (AAA) and methionine levels was observed in the encephalopathic patients. Arousal from hepatic encephalopathy by drip infusion of a branched chain amino acid (BCAA)-enriched solution was obtained coincidentally with the elevated BCAA levels and diminished concentrations of AAA and methionine in CSF. These clinical observations were confirmed experimentally in rats treated with carbon tetrachloride (CCl4) andd-galactosamine by obtaining the elevation of neutral amino acid contents in the brain and the slight increase in the brain uptake index (BUI) of a radiolabeled amino acid.

Hyperammonemia-induced cytotoxic brain edema under osmotic opening of blood-brain barrier in dogs

SummaryInfusion of an ammonium acetate solution into dogs during mannitol-induced reversible opening of the blood-brain barrier (BBB) resulted in a marked rise in intracranial pressure with exclusion of Evans blue dye. This indicated cytotoxic brain edema. These findings suggest a role for hyperammonemia in cerebral edema during acute liver failure.

Characteristic features of plasma amino acid, plasma pancreatic glucagon, serum insulin concentrations in cirrhotic patients with histories of chronic alcohol consumption

SummaryPlasma amino acid, plasma pancreatic glucagon and serum insulin levels were simultaneously measured in cirrhotic patients with (drinkers) and without a history of alcohol drinking (non-drinkers), as compared to those in alcoholics without liver disease. Clinical characteristics in drinkers and non-drinkers, such as the extent of liver dysfunction, which may affect plasma amino acid levels, were strictly matched. Plasma pan creatic glucagon levels in the drinker group were much higher than those in the non-drinker group. In the former group, the elevated plasma pancreatic glucagon levels were correlated (p<0.05) to total amino acid levels (the sum of 20 kinds of L-amino acid concentrations) and, elevated AAA concentrations leading to a diminished BCAA/AAA ratio. Drinkers with histories of hepatic encephalopathy presented grossly elevated glucagon levels and severely abnormal aminograms similar to those observed in hepatic insufficiency.

Prevention of ammonia-induced brain edema in dogs infused with a branched-chain amino acid solution

Infusion of an ammonium acetate solution into dogs during mannitol-induced reversible opening of the blood-brain barrier resulted in a marked rise in intracranial pressure (ICP). The preventive effect of a branched-chain amino acid (BCAA) solution on ammonia-induced brain edema was tested by measuring ICP and brain water content. The BCAA solution apparently prevented ammonia-induced brain edema, indicating that BCAA accelerated ammonia detoxification in the brain.

Effects of high hepatic acetaldehyde level following simultaneous administration of ethanol and cyanamide on liver function in rats

SummaryExtremely high concentrations of hepatic acetaldehyde were induced in rats by the intragastric administration of ethanol and cyanamide, an aldehyde dehydrogenase inhibitor; and these high levels were maintained for 4 weeks. Liver function tests, including mitochondrial ornithine carbamoyltransferase (OCT) and GOT activities, were within normal limits, and no increase in either hepatic triglyceride or collagen contents was observed. These results suggest that hepatotoxic effects of ethanol are not derived from the high acetaldehyde levels in the liver.