Cerebellar inhibition in hepatic encephalopathy

ObjectivePrevious animal work reported that hyperammonemia leads to opposing changes of GABAergic neurotransmission in terms of increase in the cerebellum and decrease in the cerebral cortex. In this study, we investigate GABAergic tone in the cerebellum in patients with hepatic encephalopathy (HE) at different stages of the disease and its relation to critical flicker frequency (CFF) and ataxia.MethodsCerebellar inhibition using transcranial magnetic stimulation was investigated in 15 patients with different stages of HE and 15 healthy controls. All patients were assessed using CFF and the score for assessment and rating of ataxia (SARA).ResultsDecreased cerebellar inhibition (CBI) was observed in manifest HE at interstimulus interval from 5 to 7 ms. However, the degree of CBI at 7 ms correlated significantly with disease severity measured with SARA and with CFF by trend.ConclusionReduced CBI in HE patients indicates affection of the cerebellar efferent pathway. The disease severity dependent increase of CBI magnitude supports the notion of disease stage dependent increase of GABAergic neurotransmission in Purkinje cells.SignificanceThe results support previous animal experiments showing increase of GABA-ergic neurotransmission in the cerebellum and decrease in the motor cortex in HE.     

Value of plasmapheresis in hepatic encephalopathy

Plasmapheresis is used for treating the complications of liver failure. We performed plasmapheresis on 6 children with hepatic encephalopathy resulting from acute hepatic failure and prospectively assessed its effects on neurologic and electrophysiologic (electroencephalography and evoked potentials) function. Clinical improvement was observed in 3 of 6 patients; changes in the serum ammonia value or the results of initial electrophysiologic tests did not predict the patient response. Two patients underwent transplantation after neurologic improvement was produced by plasmapheresis; however, despite plasmapheresis, 4 patients progressed to brain death. Our data demonstrate that plasmapheresis may transiently improve the encephalopathy of acute hepatic failure but is not curative alone. Therefore, plasmapheresis may be a useful adjunct in the treatment of liver failure, potentially improving the pretransplantation status of the patient.     

Cognitive event-related potential in hepatic encephalopathy

A study of auditory P300 was performed on 24 patients with cirrhosis of the liver: 13 patients with hepatic encephalopathy (HE grade 1–2) and 11 patients without clinical encephalopathy (HE grade 0). The patients were also assessed using spontaneous EEG and neuropsychological methods: Mini Mental State, Digit Span and Number Connection Test. The P3 latency was found to be significantly increased in all patients (100%) with HE grade 1–2 and in 6 patients (54.5%) with HE grade 0. The clinical value of using the P300 latency in the hepatic encephalopathy is subsequently discussed.     

Electron microscopy in human hepatic encephalopathy

Summary Electron microscopic post mortem examination of the lenticular nuclei of two human cases who died in hepatogenic coma is reported. Lesions were found to be swelling and vacuolation of astrocytes. In addition an excess of lipofuscin and lipid like substances were present in the same cells. No changes were found in myelinated fibres, neurons and small blood vessels.This study was supported by CIC 80 from Universidad de Concepción.     

Brain monoamines in human hepatic encephalopathy

Summary Dopamine (DA) serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), and tryptophan (Trp) were assayed spectrofluorometrically in various brain regions of 10 patients with acute hepatic coma, in 3 cases of uremic coma, 4 cases of diabetic coma, in three patients with liver cirrhosis without coma, and in 5 cases of hepatic coma treated by parenteral nutrition withi-valine a branched-chain amino acid. The results were as follows: 1. In all types of coma, brain DA showed a mild general decrease, the average reduction being 20 to 30% of the controls. 2. In hepatic and other metabolic comata, brain 5-HT and 5-HIAA were generally increased, most significantly in the brainstem tegmentum and parts of the limbic system. 3. Brain Trp was significantly increased in hepatic coma, with the highest elevation in the brainstem tegmentum. 4. In liver cirrhosis without coma, brain 5-HT was within normal range, while Trp and 5-HIAA were elevated in the brainstem, their increase being much less than in untreated hepatic coma. 5. In hepatic coma treated by parenterali-valine, brain Trp showed slight elevation similar to non-comatose cirrhosis, while 5-HIAA showed almost normal values, and 5-HT was even decreased in most brain areas.These preliminary results in human postmortem brains confirm previous CSF and brain findings in experimental and human hepatic and uremic encephalopathies, indicating considerable derangement in central monoamine neurotransmitters which are attributed, at least in part, to amino acid imbalance in plasma and brain. Increased 5-HT synthesis or turn-over in the ascending serotonergic brainstem systems might represent one biochemical substrate of clinical disorders of consciousness in hepatic failure and other metabolic catastrophes. Manipulation of plasma and hence brain amino acids may influence neurological symptoms of hepatic encephalopathy by changing the brain neurotransmitter profile.     

The role of astrocytes in hepatic encephalopathy

The Alzheimer type II astrocyte change is the distinctive morphologic alteration in brain of humans and experimental animals succumbing to hepatic encephalopathy (HE). Whether this change is a primary event in the pathogenesis of HE or whether it is secondary to injury of some other component(s) of the CNS has not been clarified. Studies in a rat model of HE have revealed early reactive changes in astrocytes characterized by cytoplasmic hypertrophy. During the later phases, degenerative changes ensue corresponding to the Alzheimer type II change observed by light microscopy. In view of the role of astrocytes in ammonia detoxification and the importance of ammonia in the pathogenesis of HE, we have suggested that the initial astrocytic changes are the morphological correlates of ammonia detoxification. We have speculated that the later degenerative alterations could lead to failure by astrocytes to carry out key functions (e.g., neurotransmitter uptake, ion regulation, and the like) and contribute to the development of the encephalopathy. Recently, the potential involvement of astrocytes in HE has been further investigated, using primary astrocyte cultures. Exposure of cultures to ammonia at clinically relevant concentrations has shown morphologic changes closely resembling those observed in experimental HE in vivo. These deleterious effects can partly be prevented by raising cyclic AMP levels in cells. Other potential toxins (octanoic acid, phenol) have shown pathologic changes as well. Although some alterations were common to all three, they each possessed distinctive pathological effects. A synergistic interaction has also been demonstrated with these toxins. Functional studies of ammonia-treated astrocytes have shown the following: With low doses or short-term exposure, the uptakes of K⁺, glutamate, and GABA remained unchanged or slightly increased, whereas with higher doses or longer treatment, those activities diminished. A fall in ATP values occurred with prolonged ammonia treatment. Preliminary findings have shown no significant derangements in the beta-adrenergic receptor, except for a slight decrease in receptor affinity. However, cyclic AMP production was diminished following stimulation with isoproterenol. A slight rise in the number of benzodiazepine receptors was found. These studies indicate that profound changes occur in astrocytes following exposure to ammonia and other putative toxins. It is proposed that toxins and factors involved in the precipitation of HE do so by affecting astroglial properties. Derangements in such properties may lead to glial dysfunction (primary gliopathy), resulting in an encephalopathic state.     

Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy

Summary. The increase of the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin (5-HT). To study the role of tryptophan on the increased brain 5-HT metabolism in HE, we attempted to monitor brain levels of tryptophan in rats with thioacetamide-induced acute liver failure by intravenous infu-sion of branched-chain amino acids (BCAA). The effect of this treatment on 5-HT synthesis and metabolism was investigated in five brain areas. BCAA-infusions (1 and 2 gm/kg/24 h) increased the ratio BCAA/aromatic amino acids in plasma two- and fourfold, respectively, and lowered both plasma and brain levels of tryptophan. At the higher BCAA-dose all parameters suggesting an altered brain 5-HT metabolism (increased brain levels of 5-HT and 5-HIAA, increased 5-HIAA/5-HT ratio) were almost completely normalized. These results provide further evidence for the role of tryptophan in the elevation of brain 5-HT metabolism and for a potential role of BCAA in the treatment of HE. Received December 17, 1997; accepted March 19, 1998     

Ammonia: Key factor in the pathogenesis of hepatic encephalopathy

There is substantial clinical and experimental evidence to suggest that ammonia toxicity is a major factor in the pathogenesis of hepatic encephalopathy associated with subacute and chronic liver disease. Ammonia levels in patients with severe liver disease are frequently found to be elevated both in blood and cerebrospinal fluid (csf). Hepatic encephalopathy results in neuropathological damage of a similar nature (Alzheimer type II astrocytosis) to that found in patients with congenital hyperammonemia resulting from inherited defects of urea cycle enzymes. Following portocaval anastomosis in the rat, blood ammonia concentration is increased 2-fold, and brain ammonia is found to be increased 2–3-fold. Administration of ammonia salts or resins to rats with a portocaval anastomosis results in coma and in Alzheimer type II astrocytosis. Since the CNS is devoid of effective urea cycle activity, ammonia removal by brain relies on glutamine formation. Cerebrospinal fluid and brain glutamine are found to be significantly elevated in cirrhotic patients with encephalopathy and in rats following portocaval anastomosis. In both cases, glutamine is found to be elevated in a region-dependent manner. Several mechanisms have been proposed to explain the neurotoxic action of ammonia. Such mechanisms include: (i) Modification of blood-brain barrier transport; (ii) alterations of cerebral energy metabolism; (iii) direct actions on the neuronal membrane; and (iv) decreased synthesis of releasable glutamate, resulting in impaired glutamatergic neurotransmission.