Pathogenesis of Hepatic Encephalopathy-with Special Reference to the Roles of Ammonia

Walker, Charles O.; Schenker, Steven

doi:10.1093/ajcn/23.5.619

Cited by 104 publications

(23 citation statements)

References 37 publications

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“…Four weeks after portacaval shunt, moderate hyperammonemia has little effect on CBF or oxygen metabolism; however, 8 weeks after portacaval shunt, the same degree of hyper ammonemia leads to marked reduction in both of these variables (Gjedde et aI., 1978). These obser vations are consistent with clinical observations (Walker and Schenker, 1970) suggesting the devel opment of "toxin hypersensitivity" in patients with liver disease. This is an extremely important con cept that has been overlooked by most investi gators.…”

supporting

confidence: 90%

Metabolic Encephalopathies: Opportunities and Challenges

Lockwood

1987

J Cereb Blood Flow Metab

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supporting

confidence: 90%

Metabolic Encephalopathies: Opportunities and Challenges

Lockwood

1987

J Cereb Blood Flow Metab

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“…Patients with chronic liver disease appear to be come more sensitive to the effects of neurotoxins, such as ammonia, as liver disease progresses. This phenomenon has been termed "toxin hypersensitiv ity" by Walker and Schenker (1970), and evaluated experimentally in rats with hyperammonemia due to chronic portacaval shunts. The increase in the brain:blood ammonia ratio reported by Ehrlich et al (1980), regional accumulations of ammonia in the brain reported by Butterworth et al (1988), the in creased effect of ammonia on cerebral blood flow and oxygen metabolism reported by Gjedde et aI.…”

Section: Discussionmentioning

confidence: 99%

Cerebral Ammonia Metabolism in Patients with Severe Liver Disease and Minimal Hepatic Encephalopathy

Lockwood

Yap

Wong³

1991

J Cereb Blood Flow Metab

300

184

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Summary: Cerebral ammonia metabolism was studied in five control subjects and five patients with severe liver disease exhibiting minimal hepatic encephalopathy. The arterial ammonia concentration in the control subjects was 30 ± 7 /l-mollL (mean ± SD) and 55 ± 13 /l-mollL in the patients (p < 0.01). In the normal subjects. the whole brain values for cerebral blood flow. cerebral metabolic rate for ammonia. and the permeability-surface area product for ammonia were 0.58 ± 0.12 ml g-I min-I, 0.35 ± 0. 15 /l-mol 100 g--I min-I, and 0.13 ± 0.03 ml g-I min -I. respectively. In the patients, the respective val ues were 0.46 ± 0. 16 ml g -I min -I (not different from control), 0.91 ± 0.36 /l-mol 100 g-I min -I (p < 0.025), Abbreviations used: aPS, apparent permeability-surface area product; PET, positron emission tomography; rCMRA, regional cerebral metabolic rate of ammonia. 337and 0.22 ± 0.07 ml g -I min -I (p < 0.05). The increased permeability-surface area product of the blood-brain bar rier permits ammonia to diffuse across the blood-brain barrier into the brain more freely than normal. This may cause ammonia-induced encephalopathy even though ar terial ammonia levels are normal or near normal and ex plain the emergence of toxin hypersensiti vity as liver dis ease progresses. Greater emphasis on early detection of encephalopathy and aggressive treatment of minimal hy perammonemia may retard the development of ammonia induced complications of severe liver disease. Key Words: Hepatic encephalopathy-Ammonia-Blood brain barrier-Positron emission tomography. lock, 1958). This has raised doubt about the impor tance of ammonia in coma production.We have used positron emission tomography (PET) to investigate cerebral ammonia metabolism in patients with severe liver disease and in a group of normal controls. We report a significant increase in the cerebral metabolic rate for ammonia in the patients with liver disease that is associated with an increase in the cerebral extraction of ammonia and an increase in the apparent permeability-surface area (aPS) product. The resulting increase in the ease with which ammonia moves into the brain from the blood may account for the development of toxin hypersensitivity and explain the presence of cere bral dysfunction in patients with near-normal arte rial ammonia concentrations. A preliminary report of this work has been presented in abstract form (Lockwood and Yap, 1989). METHODS Patient selectionPatients and controls were enrolled in this study using informed consent guidelines and protocols approved by the University of Texas Health Science Center at Hous-

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“…The contribution of ammonia to the pathogenesis of hepatic encephalopathy has been widely investigated (Walker and Schenker 1970;Schenker et al 1974). Amino acids imbalance (Fischer et al 1975) and short-chain fatty acid (Chen et al 1970;Zieve et al 1974) have recently been proposed as etiological factors in hepatic encephalopathy.…”

Section: Discussionmentioning

confidence: 99%

Diurnal fluctuation of blood ammonia levels in adult-type citrullinemia.

Yajima

Hirasawa

Saheki

1982

Tohoku J. Exp. Med.

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A 48-year-old man, who was diagnosed as adult-type citrullinemia by quantitative estimation of men cycle enzymes in the liver, showed a regular nocturnal rice of blood ammonia level. In order to elucidate the mechanism of diurnal fluctuation of blood ammonia level, the patient was put into fasting state for four days. The blood ammonia level rose at the night of the first fasting day even though no food was taken, then it decreased gradually and reached the lowest level in the morning of the third fasting day. Intravenous administration of amino acids mixture under the same starved condition gave rise to a significant elevation of blood ammonia level. Based on these results, it was concluded that hyperammonemia of adult-type citrullinemia could result from the accumulation of free ammonia which was produced from thn catabolism of amino acids absorbed frcm the small intestine and surpassed the urea synthesis of defective urea cycle to flood into the blood. Furthermore, the rise of blood ammonia level at the night of the first fasting day suggested that the circadian rhythm of amino acid-carbohydrate metabolim might superimpcse on the process mentioned above, adult-type citrullinemia; hyperammonemia; diurnal fluctuation A 48-year-old man with adult-type citrullinemia has been described in our previous report (Yajima et al. 1981). He showed repetitive episodes of encephalopathy and was diagnosed by quantitative estimation of amino acids and urea cycle enzymes in the liver. In this case, a regular diurnal fluctuation of the blood ammonia level was seen and the drip infusion of glutamate-arginine mixture and oral administration of citrate lowered the blood ammonia level. But the liver function tests of the patient became worse one month after the laparotomy for the evaluation of urea cycle enzymes and he clinically deteriorated to the state of general liver failure with jaundice and ascites. He died two months after the laparotomy. At the stage of general liver failure, citrate ingestion was ineffective and regular diurnal fluctuation of blood ammonia was no longer seen.

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Pathogenesis of Hepatic Encephalopathy-with Special Reference to the Roles of Ammonia

Cited by 104 publications

References 37 publications

Metabolic Encephalopathies: Opportunities and Challenges

Metabolic Encephalopathies: Opportunities and Challenges

Cerebral Ammonia Metabolism in Patients with Severe Liver Disease and Minimal Hepatic Encephalopathy

Diurnal fluctuation of blood ammonia levels in adult-type citrullinemia.

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