Ammonia: Key factor in the pathogenesis of hepatic encephalopathy

Butterworth, Roger F.; Giguère, Jean-François; Michaud, Jean; Lavoie, Joël; Layrargues, Gilles Pomier

doi:10.1007/bf02833598

Cited by 369 publications

(195 citation statements)

References 22 publications

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“…42 The most prominent neuropathologic feature of HE is the alteration of astrocyte morphology and function. 2,43,44 Therefore, it may be speculated that the present findings may be partly related to the changes in astrocyte characteristics. Further studies are necessary to assess this possibility.…”

Section: Discussionmentioning

confidence: 82%

Increased density of brain histamine H1 receptors in rats with portacaval anastomosis and in cirrhotic patients with chronic hepatic encephalopathy

Lozeva¹

2001

Hepatology

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The binding properties and the regional densities of histamine H 1 receptors were studied in brain of rats with portacaval anastomosis (PCA) and in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy (HE). Receptor binding studies and quantitative receptor autoradiography were performed, employing [ 3 H]mepyramine. Histamine H 1 receptors in rat brain displayed a higher density and a lower affinity compared with control human frontal cortex. Specific [ 3 H]mepyramine binding was heterogeneously distributed throughout the brain in both species. In human brain, binding was highest in the parietal and temporal cortices and lowest in caudate-putamen. In rat brain, binding was highest in the suprachiasmatic nucleus, dentate gyrus of the hippocampus, ventromedial hypothalamus, and nucleus accumbens. Hepatic encephalopathy (HE) is a potential long-term complication of chronic liver disease. Despite extensive research and a succession of different hypotheses, the exact mechanisms underlying the development of the clinical symptoms of HE are not well understood. 1,2 Consequently, progress in the treatment of HE in cirrhotic patients has been limited. Among the least exploited consequences of HE are the marked changes in the brain histaminergic system, which have been previously documented both in patients with HE 3 and in rats with portacaval anastomosis (PCA), a well-established animal model of the disease. [4][5][6][7][8] There is substantial evidence that histamine acts as a neurotransmitter in mammalian brain. 9 Histaminergic neurons are located exclusively in the tuberomammillary nucleus of the posterior hypothalamus and send their varicose fibers to almost every region of the brain. 10 This widespread distribution of histaminergic neurons suggests that the brain histaminergic system is involved in the regulation of a wide range of neurobiologic functions. Histaminergic signaling is mediated by 3 types of receptors, histamine H 1 , H 2 , and H 3 receptors, distinguished by their pharmacologic properties, specific anatomic location, and by the intracellular responses they mediate. 11,12 Interest has focused on the histamine H 1 receptors, because histamine, through the activation of the postsynaptic histamine H 1 receptors, is involved in the regulation of the neuroendocrine system, 13,14 locomotor activity, 15-17 circadian rhythmicity, 18,19 and the sleep-wake cycle, 20 as well as in various behaviors, including feeding and drinking (for a review, see Schwartz, 9 Yamatodani et al., 21 and Sakata 22 ).We have previously shown that altered histaminergic neurotransmission is an important part of the neurophysiologic background responsible for the behavioral changes after PCA surgery in the rat, leading us to propose that it may contribute to the pathogenesis of HE in human subjects. [6][7][8] Relating the functions controlled by histamine to the clinical presentation of HE, it appears a priori that histamine could participate in the pathogenesis of the sleep disturbances, decreased spontaneous vo...

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Section: Discussionmentioning

confidence: 82%

Increased density of brain histamine H1 receptors in rats with portacaval anastomosis and in cirrhotic patients with chronic hepatic encephalopathy

Lozeva¹

2001

Hepatology

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“…There are also similarities between the neuropathologic lesions observed in the brains of monkeys and humans intoxicated with manganese (Yamada et al, 1996) and the brains of cirrhotic patients who died with hepatic encephalopathy (Butterworth et al, 1987); Alzheimer type II changes have been observed in both circumstances and were predominant present in basal ganglia.…”

Section: Relationship Between Brain Manganese Accumulation and Neurolmentioning

confidence: 79%

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Layrargues

Rose

Spahr

et al. 1998

Metabolic Brain Disease

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Amongst the potential neurotoxins implicated in the pathogenesis of hepatic encephalopathy, manganese emerges as a new candidate. In patients with chronic liver diseases, manganese accumulates in blood and brain leading to pallidal signal hyperintensity on T1-weighted Magnetic Resonance (MR) Imaging. Direct measurements in globus pallidus obtained at autopsy from cirrhotic patients who died in hepatic coma reveal 2 to 7-fold increases of manganese concentration. The intensity of pallidal MR images correlates with blood manganese and with the presence of extrapyramidal symptoms occurring in a majority of cirrhotic patients. Liver transplantation results in normalization of pallidal MR signals and disappearance of extrapyramidal symptoms whereas transjugular intrahepatic portosystemic shunting induces an increase in pallidal hyperintensity with a concomitant deterioration of neurological dysfunction. These findings suggest that the toxic effects of manganese contribute to extrapyramidal symptoms in patients with chronic liver disease. The mechanisms of manganese neurotoxicity are still speculative, but there is evidence to suggest that manganese deposition in the pallidum may lead to dopaminergic dysfunction. Future studies should be aimed at evaluating the effects of manganese chelation and/or of treatment of the dopaminergic deficit on neurological symptomatology in these patients.

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“…8 These observations are in agreement with the fact that cerebral edema is a consequence of hyperammonemia. 2,9,10 Indeed, the cause of astrocyte edema is unknown but it could reflect the osmotic effect of accumulated intracellular glutamine which is the primary metabolic product of ammonia metabolism in the brain. 1 Glutamine synthetase, which is responsible for this, is located in astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Hyperammonemia after high-dose chemotherapy and stem cell transplantation

Frère

Canivet

Gennigens

et al. 2000

Bone Marrow Transplant

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Summary:We report a patient with multiple myeloma who suffered from hyperammonemia after a second stem cell autograft. This syndrome is not well known but is associated with a high mortality rate. Considering the possibility of this diagnosis in patients developing confusion and neurological degradation with respiratory alkalosis after intensive chemotherapy, could allow earlier treatment and perhaps improved survival. Possible mechanisms and potential therapies are discussed. With rapid recognition and treatment of the syndrome, the patient fully recovered. One and a half years later, she is still alive and well, on interferon for persisting myeloma. Bone Marrow Transplantation (2000) 26, 343-345. Keywords: peripheral blood stem cell transplantation; multiple myeloma; hyperammonemia A 62-year-old Caucasian woman was a heavy smoker suffering from emphysema and ischemic cardiopathy. In February 1996, a diagnosis of IgA lambda multiple myeloma was made (IgA 29 g/l, Bence-Jones negative, multiple bone lesions on clavicles and skull). She was classified as stage IIIA according to the Durie and Salmon classification. She received seven courses of VMCP (vincristine, cyclophosphamide, melphalan and prednisolone) without a good response. Consequently, she was treated with four cycles of VAD (vincristine, doxorubicine, dexamethasone) followed by mobilization chemotherapy with cyclophosphamide plus etoposide to collect peripheral blood stem cells (PBSC) for two autotransplants. Before transplantation, she was in partial response (Ͼ50%). A first stem cell autograft was carried out in March 1997 after melphalan 200 mg/m 2 without any significant complication. She entered complete remission. Despite this, a relapse was observed 9 months later.A second transplant was thus undertaken in February 1998. Conditioning consisted of TBI (6 × 2 Gy) and mel- phalan (140 mg/m 2 ). On day 5, the patient developed fever and dyspnea with bronchospasm. Broad-spectrum antibiotics including teicoplanine, imipenem, gentamicin and amphotericin B were unsuccessful. Several blood cultures yielded Candida famata and a chest CT-scan showed disseminated micronodules. 5-Fluorocytosine was started in addition to amphotericin B and the central catheter was removed. Two days later, blood cultures became negative, fever disappeared and the CRP returned to normal. Simultaneously, the patient developed mental confusion with respiratory alkalosis, which prompted her admission to an intensive care unit where tracheal intubation was necessary.A cerebral CT-scan did not explain the confusion but an electroencephalogram showed a pattern compatible with metabolic encephalopathy. Arterial plasma ammonia concentrations were measured and revealed very high levels, ie Ͼ120 mol/l (N Ͻ 40 mg/l). There was neither alteration of liver function nor other metabolic disturbances. A lumbar puncture showed an increase of glutamine and ammonia (102 mol/l). Orotic acid was undetectable in the urine. A liver biopsy was performed and confirmed our suspicion of idiopathic hypera...

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Ammonia: Key factor in the pathogenesis of hepatic encephalopathy

Cited by 369 publications

References 22 publications

Increased density of brain histamine H1 receptors in rats with portacaval anastomosis and in cirrhotic patients with chronic hepatic encephalopathy

Increased density of brain histamine H1 receptors in rats with portacaval anastomosis and in cirrhotic patients with chronic hepatic encephalopathy

Untitled

Hyperammonemia after high-dose chemotherapy and stem cell transplantation

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