Ammonia-Induced Encephalopathy

Lockwood, Alan H.

doi:10.1007/978-1-4684-1209-3_9

Cited by 10 publications

(6 citation statements)

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“…During the terminal phases of the diseases that produce cirrhosis, repeated episodes of encephalopathy contribute to the morbidity and mortality of the condition. Convincing clinical and experimental evidence links hyperammonemia with the development of encephalopathy and coma (1)(2)(3)(4)(5)(6)(7)(8). Ammonia-rich hepatic portal blood is shunted into the systemic circulation as a complication ofportal hypertension, or as the result of surgical procedures.…”

Section: Discussionmentioning

confidence: 99%

“…Hyperammonemia is strongly implicated in the pathogenesis of hepatic or portal-systemic encephalopathy (1)(2)(3)(4)(5)(6)(7)(8). In humans, this disorder is characterized by an altered level ofconsciousness, impaired cognitive functions, occasional movement disorders, abnormal muscle tone, hyperactive deep tendon reflexes, and an extensor plantar sign, due to corticospinal tract dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Cerebral glucose metabolism after portacaval shunting in the rat. Patterns of metabolism and implications for the pathogenesis of hepatic encephalopathy.

et al. 1986

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The regional cerebral metabolic rate for glucose was measured in normal and portacaval shunted rats and the effects of unilateral carotid infusions of "threshold" amounts of ammonia were assessed. 8 wk after shunting the glucose metabolic rate was increased in all 20 brain regions sampled. Effects on subcortical and phylogenetically older regions of the brain were most pronounced with a 74% increase observed in the reticular formation at the collicular level. Increases in the cerebral cortex ranged from 12 to 18%. Unilateral infusions of ammonia did not affect behavior but altered the electroencephalogram and selectively increased the glucose metabolic rate in the thalamus, hypothalamus, and substantia nigra in half ofthe animals, a pattern similar to that seen after a portacaval shunt, suggesting hyperammonemia as the cause of postshunt increases in glucose metabolism. Visual inspection of autoradiograms, computed correlation coefficients relating interregional metabolism, and principal component analysis suggest that normal cerebral metabolic and functional interrelationships are altered by shunting. Ammonia stimulation of the hypothalamic satiety centers may suppress appetite and lead to cachexia. Reductions in the ammonia detoxification capacity of skeletal muscle may increase the probability of developing future episodes of hyperammonemia, perpetuating the process. Direct effects of ammonia on specific brain centers such as the dorsomedial hypothalamus and reticular activating system may combine with global disruptions of cerebral metabolic-functional relationships to produce the protean manifestations of portal-systemic encephalopathy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cerebral glucose metabolism after portacaval shunting in the rat. Patterns of metabolism and implications for the pathogenesis of hepatic encephalopathy.

et al. 1986

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“…Ammonia is clearly neurotoxic (Torda, 1953;Raabe, 1987) and increased plasma ammonia concentrations are widely regarded as a major contributor to alterations in consciousness and neurological status in hepatic encephalopathy (HE) (Beaubernard et al, 1977;Lockwood, 1985;Zieve, 1987). Alterations in the permeability of the blood-brain barrier (BBB) have been suggested to contribute to the pathogenesis of HE (Laursen and Westergaard, 1977;Livingston et al, 1977;Horowitz et al, 1983;Zaki et al, 1983;Sears et al, 1985;Basset et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Changes in the permeability of the blood-brain barrier in acute hyperammonemia

Ziylan

Üzüm

Bernard

et al. 1993

Molecular and Chemical Neuropathology

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This study was designed to determine the contribution of elevated plasma ammonia levels to blood-brain barrier (BBB) abnormalities in the presence of intact liver. The permeability changes of the BBB were investigated grossly with Evans blue (EB) and quantitatively by measuring the blood-to-brain transfer content for alpha-aminoisobutyric acid (AIB) in normal rats and rats subjected to sublethal doses of ammonium acetate (NH4OAc) (750 and 600 mg/kg ip; at 30-min intervals). Some rats were pretreated with dexamethasone (DXN). Injection of NH4OAc increased both plasma and brain ammonia concentrations about 16-and 5-fold, respectively, above the control level. In rats receiving NH4OAc injection, the blood-to-brain transfer constant (Ki) for AIB was increased 3- to 11-fold. The elevated Ki values were limited to certain gray matter areas and less pronounced permeability changes were detected in white matter. Extravasation sites of EB were more restricted and were especially observed in thalamus and cerebellum, whereas cortex and white matter were unaffected. Dexamethasone pretreatment for 3 d reduced both leakage of EB and the Ki for AIB in NH4OAc injected animals, whereas acute treatment appeared ineffective. Dexamethasone did not prevent the development of coma but slightly decreased the ammonia concentration in plasma and brain. The results obtained indicate that hyperammonemia may disrupt BBB integrity not only to AIB and EB but also enhance the transport of other solutes.

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“…Although the effects of hyperammonemia will be stressed, because of the wealth of literature on the subject and new experimental studies that provide insight into the function of brain and the limbic system in the disorder, other mechanisms may be operative as well. For a comprehensive reviews of hepatic encephalopathy, see Lockwood, (Lockwood 1985(Lockwood , 1987.…”

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confidence: 99%

Metabolic Encephalopathy

Lockwood

1990

Tohoku J. Exp. Med.

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Disorders of metabolism are the most common cause of coma of unknown etiology. Hyperammonemia is important as an etiologic factor in the development of hepatic encephalopathy, operating via direct and indirect mechansims that affect the function of the limbic system. The entry of ammonia into the brain is controlled by blood-brain pH gradients, and cerebral blood flow, coupled with regional variations in the capillary surface area-permeability product. In the brain, ammonium ions may inhibit the generation of action potentials, by substituting for potassium and sodium in current generation, and interfere with the chloride pump, producing a reversible depolarizing shift of the inhibitory post synaptic equilibrium potential toward the equilibrium potential. Ammonia entering the brain is quickly trapped by the ATP-consuming glutamine synthetase reaction leading to energy depletion in the reticular activating system. Ammonia may also interfere with ATP production due to a suspected inhibition of the malate aspartate shuttle, the mechanism for moving reducing equivalents into mitochondria for oxidative phosphorylation. Ammonia also depletes glutamate, causing a potential dysruption of glutamatergic neurotransmission. We recently evaluated the effects of chronic portacaval shunts (PCS) and ammonia on regional brain glucose metabolism using the 14C-deoxyglucose technique and found important direct and indirect effects on the limbic system. After a PCS, glucose metabolism was significantly increased in all 20 brain regions that were sampled, with the smallest increase in the cortex and the greatest increase in the reticular activating system. The pattern of glucose metabolism appeared to be different in the two groups, an impression that was confirmed by multivariate statistical analytical techniques. Assuing that differences in metabolic rate are linked to differences in function, we hypothesized that the hyperammonemia associated with a PCS causes a functional reorganization of the brain that may be responsible for the development of HE. When intracarotid infusions of ammonia were given, glucose metabolism in the ventromedial nucleus of the hypothalamus was activated. Since stimulation of this nucleus inhibits feeding behaviors, we postulated that ammonia's action on satiety centers is directly responsible for appetite loss and the development of cachexia, important elements of chronic liver disease. Since skeletal muscle is an

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Ammonia-Induced Encephalopathy

Cited by 10 publications

References 92 publications

Cerebral glucose metabolism after portacaval shunting in the rat. Patterns of metabolism and implications for the pathogenesis of hepatic encephalopathy.

Cerebral glucose metabolism after portacaval shunting in the rat. Patterns of metabolism and implications for the pathogenesis of hepatic encephalopathy.

Changes in the permeability of the blood-brain barrier in acute hyperammonemia

Metabolic Encephalopathy

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