Ammonia in liver

B8. Bessman, S. P., and Bessman, A. N., The cerebral and peripheral uptake of ammonia in liver disease with an hypothesis for the mechanism of hepatic coma. J. Clin. Invest. 32, 622 (1955). 

Gay, W.M.B., C.W.Crane, and W.D.Stone. 1969. The metabolism of ammonia in liver disease a comparison of urinary data following oral and intravenous loading of [15N] ammonium lactate. Clin. Sci. 37(3) 815-823. 

Shimamoto, C., Hirata, L, Katsu, K. Breath and blood ammonia in liver cirrhosis. Hepato-Gastroenterol. 2000 47 443 -445... 

StaM, J. Studies of the blood ammonia in liver disease. Its diagnostic, prognostic and therapeutic significance. Ann. Intern. Med. 1963 58 1-24... 

Bacterial urease. A major source of ammonia in liver (approximately 25%) is produced by the action of certain bacteria in the intestine that possess the enzyme urease. Urea present in the blood circulating through the lower digestive tract diffuses across cell membranes and into the intestinal lumen. Once urea is hydrolyzed by bacterial urease to form ammonia, the latter substance diffuses back into the blood, which transports it to the liver. 

Regulation of carbamoyl-phosphate synthase (ammonia) in liver in relation to urea cycle activity, A. J. Meijer,... 

Ammonia has deleterious effects on brain function by direct and indirect mechanisms. Concentrations of ammonia in the 1-2 mmol/1 range, equivalent to those reported in the brain in liver failure, impair postsynaptic inhibition in cerebral cortex and brainstem by a direct effect on Cl extrusion from the postsynaptic neuron. Millimolar concentrations of ammonia also inhibit excitatory neurotransmission. Synaptic transmission from Schaffer collaterals to CA1 hippocampal neurons is reversibly depressed by 1 mmol/1 ammonia, and the firing of CA1 neurons by iontophoretic application of glutamate is inhibited by 2 mmol/1 ammonia [10],... 

Organic cyanide compounds, or nitriles, have been implicated in numerous human fatalities and signs of poisoning — especially acetonitrile, acrylonitrile, acetone cyanohydrin, malonitrile, and succinonitrile. Nitriles hydrolyze to carboxylic acid and ammonia in either basic or acidic solutions. Mice (Mus sp.) given lethal doses of various nitriles had elevated cyanide concentrations in liver and brain the major acute toxicity of nitriles is CN release by liver processes (Willhite and Smith 1981). In general, alkylnitriles release CN much less readily than aryl alkylnitriles, and this may account for their comparatively low toxicity (Davis 1981). 

The experiments described above indicated amino acids were oxidatively deaminated in liver and their a-amino groups converted to urea. A start on investigations of the mechanism of urea biosynthesis was made by Schultzen and Nenki (1869) who concluded that amino acids gave rise to cyanate which might combine with ammonia from proteins to produce urea. Von Knieren (1873) demonstrated that when he drank an ammonium chloride solution, or gave it to a dog, there was an increase in the formation of urea, without any rise in urinary ammonia. His results were consistent with the cyanate theory but did not eliminate the possibility that urea arose from ammonium carbonate which could be dehydrated to urea ... 

The ammonia produced from asparagine and glutamine is released into the hepatic portal vein, for removal by the liver and conversion to urea. The concentration of ammonia in the blood in the hepatic portal vein is about ten times higher than in the hepatic vein, indicating the quantitative importance of the liver in removing this ammonia. 

Figure 8.25 Excess ammonia in the muscle is used to form alanine. Ammonia is released from several reactions and is incorporated into alanine via glutamate dehydrogenase and transamination. OG - oxoglutarate. Alanine is released into the blood from volece it is removed by the liver.

The concentration of ammonia in the liver is not saturating for carbamoyl phosphate synthetase, so that the greater the flux of ammonia into or within the liver, the higher the concentration of ammonia and the higher the activity of the synthetase. The effect of ammonia concentration is, therefore, a mass-action effect. 

Within a cell, a nncleotidase catalyses the hydrolysis of either a ribonncleotide or deoxyribonucleotide (Fignre 10.8). The qnantitatively important pathway for degradation of AMP in liver and mnscle involves deamination to IMP, catalysed by AMP deaminase, producing ammonia, and snbseqnent hydrolysis of IMP to inosine. This may be an important sonrce of inosine for synthesis of phosphati-dylinositol, a key phospholipid in membranes. 

The toxicity of ammonia was dramatically demonstrated by experiments carried out as early as 1931 injection of the enzyme urease, which catalyses the conversion of urea to ammonia, into rabbits rapidly caused their death. The normal concentration of ammonia in blood is about 0.02 mmol/L toxicity becomes apparent at a concentration of abont 0.2 mmol/L or above (see Table 10.1). Ammonia toxicity in very young children is usually associated with vomiting and eventually coma. It is almost invariably due to the deficiency of an enzyme of the urea cycle (see below). In adults, ammonia accnmulation, and hence toxicity, usually results from damage to the liver caused by poisons, alcohol or viral infection. 

Transient, mild increases in liver enzyme levels, up to three times the upper limit of normal, do not necessitate discontinuation of valproate. Although y-glutamyltransferase levels are often checked by clinicians, these levels are often increased, without clinical significance, in patients receiving valproate and carbamazepine (Dean and Penry 1992). Likewise, plasma ammonia levels are often increased transiently during valproate treatment, but this finding does not necessitate interruption of treatment (Jaeken et al. 1980). Increases in transaminase levels are often dose dependent. If no... 

Glutamate Releases Its Amino Group as Ammonia in the Liver... 

FIGURE 18-8 Ammonia transport in the form of glutamine. Excess ammonia in tissues is added to glutamate to form glutamine, a process catalyzed by glutamine synthetase. After transport in the bloodstream, the glutamine enters the liver and NH) is liberated in mitochondria by the enzyme glutaminase. 

The urea cycle begins inside liver mitochondria, but three of the subsequent steps take place in the cytosol the cycle thus spans two cellular compartments (Fig. 18-10). The first amino group to enter the urea cycle is derived from ammonia in the mitochondrial matrix—NHj arising by the pathways described above. 

The liver also receives some ammonia via the portal vein from the intestine, from the bacterial oxidation of amino acids. Whatever its source, the Nib generated in liver mitochondria is immediately used, together with C02 (as HCO3) produced by mitochondrial respiration, to form carbamoyl phosphate in the matrix (Fig. 18-1 la see also Fig. 18-10). This ATP-dependent reaction is catalyzed by carbamoyl phosphate synthetase I, a regulatory enzyme (see below). The mitochondrial form of the enzyme is distinct from the cytosolic (II) form, which has a separate function in pyrimidine biosynthesis (Chapter 22). 

Ammonia is produced by all tissues during the metabolism of a variety of compounds, and it is disposed of primarily by formation of urea in he liver. However, the level of ammonia in the blood must be kept very fcw, because even slightly elevated concentrations (hyperammonemia) ae toxic to the central nervous system (CNS). There must, therefore, be a metabolic mechanism by which nitrogen is moved from peripheral tissues to the liver for ultimate disposal as urea, while at the same hre low levels of circulating ammonia must be maintained. 

The first human experiments which suggested a toxic effect of ammonia in disease were done by Van Caulaert. The revival and extension of this work by the group led by Davidson (G2) in the Boston City Hospital has stimulated widespread interest in ammonia as a factor in the production of mental symptoms in liver disease. The ability of various factors, such as urea feedings, high-protein diet, cation resins in the ammonia cycle, and amino acids, to induce symptoms of coma in patients with liver disease (G2, M3, M4, P7, S8) made it quite clear that ammonia was associated with the symptom complex called hepatic coma. The severe toxicity of ammonia in animals and the ability of intravenous or oral ammonium salts to provoke episodes of impending liver coma tended to substantiate the clinical impressions. Rapid confirmation of these observations was furnished by the experiments of other groups (Bll, C2, E2, FI). 

The significance of ammonia in clinical disease was broadened markedly when it was discovered that ammonia poisoning might be the mechanism of the cerebral symptoms associated with chronic heart failure. It has been known for a long time that the mental symptoms associated with heart failure could not be correlated with the oxygen supply to the brain, which remains, in most cases, adequate. The work of A. N. Bessman (B4) demonstrated that the ammonia content of the blood was elevated in heart failure, probably due to the chronic passive congestion of the liver which prevented the liver from removing the normally formed ammonia from the portal system. When the blood ammonia fell, the mental symptoms of heart failure were relieved. This has been confirmed by Calkins and Delph (Cl), who studied twenty-six cases of heart failure and found the blood ammonia to be elevated only in the two patients who had mental symptoms. 

K2. Kirk, E., Amino acid and ammonia metabolism in liver disease. Acta Med. Scand. Suppl. 78 (1936). 

The major enzyme involved in the formation of ammonia in the liver, brain, muscle, and kidney is glutamate dehydrogenase, which catalyzes the reaction in which ammonia is condensed with 2-oxoglutarate to form glutamate (Sec. 15.1). Small amounts of ammonia are produced from important amine metabolites such as epinephrine, norepinephrine, and histamine via amine oxidase reactions. It is also produced in the degradation of purines and pyrimidines (Sec. 15.6) and in the small intestine from the hydrolysis of glutamine. The concentration of ammonia is regulated within narrow limits the upper limit of normal in the blood in humans is 70/tmol L-1. It is toxic to most cells at quite low concentrations hence there are specific chemical mechanisms for its removal. The reasons for ammonia toxicity are still not understood. The activity of the urea cycle in the liver maintains the concentration of ammonia in peripheral blood at 20/ molL. ... 

Since the disaccharide lactulose cannot be hydrolyzed by digestive enzymes, it also acts as an osmotic laxative. Fermentation of lactulose by colon bacteria leads to acidification of bowel contents and a reduced number of bacteria. Lactulose is used in liver failure to forestall hepatic coma by preventing bacterial production of ammonia and its subsequent absorption (absorbable NH3 —< nonabsorbable NH4 ). Another disaccharide, lac-titol, produces a similar effect. 

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