Cerebral metabolism in hepatic insufficiency

Fazekas, Joseph F.; Ticktin, Howard E.; Ehrmantraut, Wilfred R.; Alman, Ralph W.

doi:10.1016/0002-9343(56)90098-5

Cited by 149 publications

(34 citation statements)

References 9 publications

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“…The observation, in hepatic coma, of a decrease in cerebral oxygen consumption [12,22] and an increase in some intermediates of glucose metabolism [11,35] supports this hypothesis. However the influence of variations in ammonium metabolism on the regulation of carbohydrate metabolism is still debated [10,34].…”

mentioning

confidence: 77%

Diabetogenic effect and inhibition of insulin secretion induced in normal rats by ammonium infusions

Schlienger¹,

Imler²,

Stahl³

1975

Diabetologia

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Summary. In order to explain the abnormalities of glucose metabolism previously observed in patients with blood ammonia elevation, the effect of a transitory hyperammonemia on I. V. glucose tolerance was investigated in rats. An I. V. glucose tolerance test was performed in 3 groups of 15 rats 60 min after the beginning of a 95 rain infusion of either a 2 ml isotonic NaC1 solution (control group) or ammonium acetate solutions at low (0.50 gmol/kg/min. NI-I4+ ) or high doses (1.70 ~tmol/kg/min NH4+ ). The "high" NH4+ infusion produced an increase of blood ammonia to levels near 1000 ~tg/100 ml, a significant decrease in the K coefficient for glucose disappearance (2.53 x 10-24-0.20 compared to 4.92 x 10 -a 4-0.13 in control group) and a suppression of the radioimmunological plasma insulin (I. R. I.) response to glucose.With the "low" NH 4 -/-infusion the hyperammonemia was less pronounced (200-300 gg/100 ml), but the decrease in K(3.02 x 10 -2 4-0.15) and in the first phase of I.R.I. release remained significant. The decrease in glucose disappearance rate could be accounted for by the proportional decrease in insulin secretion. Thus glucose intolerance induced by ammonium acetate infusions may be due to a direct effect of NI"I 4 "1-on the pancreas. These abnormalities in glucose metabolism depend on the quantity of infused ammonium.Key words: Rat, ammonium infusion, blood ammonia, glucose metabolism, plasma immunoreactive insulin.In 1955 Bessman et al [4] suggested that the neurotoxicity of hyperammonemia in porto-systemic encephalopathy results from a disturbance in cerebral glucose utilization. The observation, in hepatic coma, of a decrease in cerebral oxygen consumption [12,22] and an increase in some intermediates of glucose metabolism [11,35] supports this hypothesis. However the influence of variations in ammonium metabolism on the regulation of carbohydrate metabolism is still debated [10,34]. Recently, we noted that I. V. glucose tolerance was worse in cirrhotic patients with hepatic coma than in those without porto-systemic encephalopathy [30]. One factor which could explain this observation, was the increase in arterial blood ammonia which was consistently observed during hepatic coma. Thus we noted in both normal and cirrhotic subjects, infused with ammonium chloride or acetate, that a transitory elevation in arterial blood ammonia invariably brought about a very significant diminution in I. V. glucose tolerance [31] and an inhibition of the insulin secretion induced by the glucose load [32]. However, in these studies, we were unable to show any correlation between these anomalies and the blood ammonia levels. The aim of * Presented at the 9th Meeting of the European Association for the Study of the Liver. Hemsedal, Norway, september [6][7] 1974 the present study was to compare in normal rats the action of a moderate or gross hyperammonemia on glucose tolerance and insulin secretion. Material and MethodsThree groups of 15 male Wistar rats, weighing 250-300 g and fasted for 20 hours, were used. Afte...

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confidence: 77%

Diabetogenic effect and inhibition of insulin secretion induced in normal rats by ammonium infusions

Schlienger¹,

Imler²,

Stahl³

1975

Diabetologia

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“…Previously, it was reported that unconjugated and conjugated bile acids inhibit brain respiration in vitro (33,34). Because brain oxygen uptake is reduced in patients with hepatic coma, bile acids are believed to be involved in the pathogenesis of hepatic coma (35). Therefore, binding of CDCA with proteins in the brain might protect against CDCA's deleterious effects.…”

Section: Figmentioning

confidence: 99%

Presence of protein-bound unconjugated bile acids in the cytoplasmic fraction of rat brain

Mano

Goto

Uchida

et al. 2004

Journal of Lipid Research

113

100

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Using liquid chromatography/electrospray ionization mass spectrometry, we have found three unconjugated bile acids [cholic acid (CA), chenodeoxycholic acid (CDCA), and deoxycholic acid (DCA)] in the rat brain cytoplasmic fraction. CDCA was detected only upon extraction with high concentrations of guanidine, indicating that it is bound noncovalently to protein in the brain. The most abundant of the three, it was present at a concentration of 1.6 nmol/g wet weight ( ‫ف‬ 15 mg of protein) of brain, corresponding to almost 30 times its serum concentration. CA and DCA were present at 1/30th the concentration of CDCA. Bile acids conjugated with amino acids, sulfuric acid, and glucuronic acid were not detected. These data clearly demonstrate that unconjugated CDCA and, to a lesser extent, CA and DCA, exists in the rat brain. Bile acids are synthesized in the liver from cholesterol by the action of hepatic enzymes and excreted into the small intestine via the bile duct. In the intestinal lumen, they assist lipolysis and the absorption of fats by forming mixed micelles and then return to the liver upon absorption in the ileum and proximal colon. Because of their efficient hepatic uptake, bile acids have low concentrations in the peripheral blood. Recent observations also indicate that the nuclear bile acid receptor, the farnesoid X receptor, regulates the bile acid pool by repressing the transcription of genes encoding hepatocyte transporters (1) as well as cholesterol 7 ␣ -hydroxylase (2, 3), which is the ratelimiting enzyme for bile acid biosynthesis.

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“…Each of the above mechanisms might result in interference with cerebral energy metabolism, and such a cerebral disturbance is now theorized as the ultimate basis of ammonia intoxication (8). Although many indirect observations supporting this thesis have been compiled (9)(10)(11)(12), no comprehensive study of intracerebral energy metabolism in ammonia intoxication has been reported.…”

Section: Introductionmentioning

confidence: 94%

Studies on the Intracerebral Toxicity of Ammonia*

Schenker¹,

McCandless²,

Brophy³

et al. 1967

J. Clin. Invest.

198

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Summary. Interference with cerebral energy metabolism due to excess ammonia has been postulated as a cause of hepatic encephalopathy. Furthermore, consideration of the neurologic basis of such features of hepatic encephalopathy as asterixis, decerebrate rigidity, hyperpnea, and coma suggests a malfunction of structures in the base of the brain and their cortical connections.The three major sources of intracerebral energy, adenosine triphosphate (ATP), phosphocreatine, and glucose, as well as glycogen, were assayed in brain cortex and base of rats given ammonium acetate with resultant drowsiness at 5 minutes and subsequent coma lasting at least 30 minutes.Cortical

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Cerebral metabolism in hepatic insufficiency

Cited by 149 publications

References 9 publications

Diabetogenic effect and inhibition of insulin secretion induced in normal rats by ammonium infusions

Diabetogenic effect and inhibition of insulin secretion induced in normal rats by ammonium infusions

Presence of protein-bound unconjugated bile acids in the cytoplasmic fraction of rat brain

Studies on the Intracerebral Toxicity of Ammonia*

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