Subclinical hepatic encephalopathy (SHE) is currently diagnosed by psychometric tests or neurophysiologic techniques. In view of its sociomedical relevance, simple and reproducible tests for routine diagnosis are required. This study evaluates critical flicker-frequency thresholds for quantification of low-grade hepatic encephalopathy. A total of 115 patients (92 with cirrhosis, 23 controls) were analyzed for HE severity (mental state, computerized psychometric tests), and the threshold frequencies at which light pulses are perceived as fused (fusion frequency) or flickering light (critical flicker frequency [CFF]). CFF was a highly reproducible parameter with little age, day-time, and training dependency. CFFs in cirrhotic patients without HE (HE 0) were not different from those found in noncirrhotic controls. Significantly lower CFFs were found in cirrhotic patients with subclinical or manifest HE, and the various HE groups separated from each other at a high level of significance (P < .01). By using a CFF cut-off value of 39 Hz, a 100% separation of patients with manifest HE from noncirrhotic controls and HE 0 cirrhotic patients was obtained. SHE patients separated from HE 0 cirrhotic patients with high sensitivity (55%) and specificity (100%). The HE severity-dependent differences were found in both, alcoholic and posthepatitic cirrhosis. Statistically significant correlations (P < .01) were found between CFFs and individual psychometric tests. Aggravation of preexisting HE after transjugular intrahepatic portosystemic stent shunt (TIPS) implantation was accompanied by a corresponding decrease of CFF, whereas improvement of HE increased CFF. In conclusion, CFF is a sensitive, simple, and reliable parameter for quantification of low-grade HE severity in cirrhotic patients and may be useful for the detection and monitoring of SHE. H epatic encephalopathy (HE) is a frequent complication of cirrhosis and its appearance indicates poor prognosis. 1-4 HE is usually classified into 4 stages according to the presence and severity of neuropsychiatric symptoms on clinical evaluation. 5 However, a significant proportion of cirrhotic patients, who appear normal on clinical examination, exhibit various quantifiable neuropsychologic deficits and this condition has been termed subclinical hepatic encephalopathy (SHE). 6-10 Whereas detection of overt HE (grade I-IV) is made clinically and does not provide a major diagnostic challenge, diagnosis of SHE is problematic. Psychometric and electrophysiologic tests are currently used for detection of SHE. In addition, proton-magnetic resonance spectroscopy of the brain may bear a not yet fully elaborated diagnostic potential, 11 but is unsuitable for clinical routine. Electrophysiologic tests such as visual-evoked, somatosensory-evoked, or brain stem auditory-evoked potentials suffer from methodologic problems, require sophisticated equipment and analysis, and exhibit a lower sensitivity than psychometric tests. 7,12-14 Psychometric bedside tests, such as the number-connection test...

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prandial venous ammonia concentrations in the OAOne hundred twenty-six patients with cirrhosis, hytreated group showed improvements in comparison perammonemia (ú50 mmol/L), and chronic (persistent) with placebo. In addition, venous fasting blood ammonia hepatic encephalopathy (HE), which developed spontaconcentration (P õ .01), mental state gradation (P õ neously without the existence of known precipitating .001), and PSEI (P õ .01), which includes the mental state factors, were enrolled in a randomized, double-blind, gradation, NCT-A time, and postprandial venous ammoplacebo-controlled clinical trial of intravenously adminnia in this trial, improved to a much higher degree in Hepatic encephalopathy (HE) is one of the major complicapresented are based on the total study sample (intent-to-tions of cirrhosis. Five years after the diagnosis of cirrhosis, treat analysis), which included 63 patients in the placebo the probability of developing at least one episode of this spegroup and 63 patients in the OA group. Of the 126 pa-cific form of decompensated cirrhosis is in the range of 26%. 1 tients, 114 met all the criteria for inclusion and com-Once clinical decompensation has occurred, however, the pleted the trial and treatment as outlined in the protocol prognosis (16% 1 to 22% 2 probability of survival at 5 years) (treated-per-protocol analysis). During baseline, the pla-compared with a survival probability of 55% 2 to 70% 1 in circebo and treatment groups were homogeneous with re-rhotic patients without HE is very poor. 1,2 Therefore, prevengard to mental states, NCT-A performance time, fasting tion and effective treatment of HE may have important progvenous blood ammonia levels, and Child-Pugh criteria. nostic implications in cirrhotic patients. Although a slight improvement occurred in the placeboHyperammonemia 3,4 by a variety of postulated mechagroup, NCT-A performance times (P õ .001) and post-nisms 3-8 is felt to be one of the primary pathogenetic factors in the development of HE. 8 The majority of therapeutic measures currently in use are therefore directed at reducing blood Abbreviations: HE, hepatic encephalopathy; SHE, subclinical hepatic encephalopathy; ammonia levels, 9-13 mainly by diminishing enteric ammonia OA, L-ornithine-L-aspartate; GS, glutamine synthetase; NCT-A, number connection test A; PSEI, portal systemic encephalopathy index.production. Otherwise, it is known that liver and muscle play From the 1 Martin-Luther-University Halle-Wittenberg, Department of Internal Median important part within the ammonia detoxification system, cine, Halle;

Cell culture studies and animal models point to an important role of oxidative/nitrosative stress in the pathogenesis of cerebral ammonia toxicity. However, it is unknown whether oxidative/nitrosative stress in the brain is also characteristic of hepatic encephalopathy (HE) in humans. We therefore analyzed post mortem cortical brain tissue samples from patients with cirrhosis dying with or without HE in comparison with brains from patients without liver disease. Significantly elevated levels of protein tyrosine-nitrated proteins, heat shock protein-27, and 8-hydroxyguanosine as a marker for RNA oxidation were found in the cerebral cortex of HE patients, but not of patients with cirrhosis but without HE. Glutamine synthetase (GS) activity was significantly decreased, whereas GS protein expression was not significantly affected. Protein expression of the glutamate/aspartate cotransporter was up-regulated in HE, whereas protein expression of neuronal and inducible nitric oxide synthases, manganese-dependent and copper/zinc-dependent superoxide dismutase, and glial glutamate transporter-1 were not significantly increased. Conclusion These data indicate that HE in patients with cirrhosis is associated with oxidative/nitrosative stress, protein tyrosine nitration, and RNA oxidation, suggesting a role of oxidative stress in the pathogenesis of HE in patients with cirrhosis.

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Brain edema sufficient to cause intracranial hypertension and brain herniation remains a major cause of mortality in acute liver failure (ALF). Studies in experimental animal models of ALF suggest a role for ammonia in the pathogenesis of both encephalopathy and brain edema in this condition. As part of a series of studies to evaluate the therapeutic efficacy of ammonia-lowering agents, groups of rats with ALF caused by hepatic devascularization were treated with L-ornithine-L-aspartate (OA), an agent shown previously to be effective in reducing blood ammonia concentrations in both experimental and human chronic liver failure. Treatment of rats in ALF with infusions of OA (0.33 g/kg/h, intravenously) resulted in normalization of plasma ammonia concentrations and in a significant delay in onset of severe encephalopathy. More importantly, brain water content was significantly reduced in OA-treated rats with ALF. These protective effects of OA were accompanied by increased plasma concentrations of several amino acids including glutamate, ␥-aminobutyric acid (GABA), taurine, and alanine, as well as the branched-chain amino acids, leucine, isoleucine, and valine. Increased availability of glutamate following OA treatment provides the substrate for the major ammonia-removal mechanism (glutamine synthetase). Plasma (but not cerebrospinal fluid) glutamine concentrations were increased 2-fold (P F .02) in OAtreated rats, consistent with increased muscle glutamine synthesis. Direct measurement of glutamine synthetase activities revealed a 2-fold increase following OA treatment. These findings demonstrate a significant ammonia-lowering effect of OA together with a protective effect on the development of encephalopathy and brain edema in this model of ALF. (HEPATOLOGY 1999;30:636-640.)Brain swelling culminating in increased intracranial pressure and subsequent brain herniation remains the major cause of death in acute liver failure (ALF). Although the pathogenesis of brain edema in ALF has not been fully elucidated, there is a growing body of evidence to suggest that ammonia (either directly or indirectly) plays a predominant role. In experimental animal models of ALF resulting from hepatectomy, 1 hepatic devascularization, 2,3 or toxic liver injury, 4 brain edema is a consistent finding, and brain ammonia frequently reaches millimolar concentrations. Exposure of various brain preparations to millimolar concentrations of ammonia in vitro results in significant cell swelling. 5,6 Furthermore, precipitous increases in blood ammonia concentrations are associated with brain edema in conditions such as Reye' s syndrome 7 and urea cycle enzymopathies. 8 L-Ornithine-L-aspartate (OA) has been proven to be effective in lowering blood ammonia concentrations in both experimental and human chronic liver failure. 9-11 A recent randomized, clinical trial of OA treatment revealed significant reductions in blood ammonia in cirrhotic patients concomitant with a significant improvement of neuropsychiatric symptoms. 10 In view of these findin...