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

Abstract

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-

Altered Cerebral Blood Flow and Glucose Metabolism in Patients with Liver Disease and Minimal Encephalopathy

“…Some subjects had CBP or CMR g lc only measured while some had both measurements made. CBP data from the accompanying paper are included in this analy sis (Lockwood et al, 1991). One patient had an end to-side portacaval shunt constructed to treat Budd Chiari syndrome, one had viral hepatitis, and the others had cirrhosis, with one being diagnosed only because of a laparotomy to remove a ruptured spleen.…”

Minimal Hepatic Encephalopathy Impairs Quality of Life

“…MHE being a preclinical stage of HE has similar pathogenesis. [20][21][22] Ammonia is metabolized only by astrocytes in brain and increased ammonia levels causes rise in intracellular glutamine levels leading onto low-grade cerebral edema and HE. 23 Ammonia also modulates glutamate neurotransmission and induces neurosteroid production in neurons, leading to a positive modulatory effect on the gamma-aminobutyric acid-A receptor.…”

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“…Of the possible neurotoxins implicated in hepatic encephalopathy (HE), ammonia was the first to be incriminated (Eck, 1877)and finds itself still the leading candidate as a key factor in its pathogenesis (Butterworth et al, 1987, Butterworth, 1994Lockwood et al, 1991). Recent studies using Positron Emission Tomography (PET) and 13 NH3 confirm that, in chronic liver failure, brain utilizes ammonia at increased rates and that the blood-brain barrier becomes more permeable to ammonia (Lockwood et al, 1991).…”

“…Recent studies using Positron Emission Tomography (PET) and 13 NH3 confirm that, in chronic liver failure, brain utilizes ammonia at increased rates and that the blood-brain barrier becomes more permeable to ammonia (Lockwood et al, 1991).…”