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The pathogenesis of hepatic encephalopathy (HE) is not fully understood yet. Hyperammonemia due to liver failure and subsequent disturbance of cerebral osmolytic balance is thought to play a pivotal role in the emergence of HE. The aim of this in-vivo MR spectroscopy study was to investigate the levels of γ-aminobutyric acid (GABA) and its correlations with clinical symptoms of HE, blood ammonia, critical flicker frequency, and osmolytic levels. Thirty patients with minimal HE or HE1 and 16 age-matched healthy controls underwent graduation of HE according to the West-Haven criteria and including the critical flicker frequency (CFF), neuropsychometric testing and blood testing. Edited proton magnetic resonance spectroscopy ((1)H MRS) was used to non-invasively measure the concentrations of GABA, glutamate (Glu), glutamine (Gln), and myo-inositol (mI) - all normalized to creatine (Cr) - in visual and sensorimotor cortex. GABA/Cr in the visual area was significantly decreased in mHE and HE1 patients and correlated both to the CFF (r = 0.401, P = 0.013) and blood ammonia levels (r = -0.434, P = 0.006). Visual GABA/Cr was also strongly linked to mI/Cr (r = 0.720, P < 0.001) and Gln/Cr (r = -0.699, P < 0.001). No group differences or correlations were found for GABA/Cr in the sensorimotor area. Hepatic encephalopathy is associated with a regional specific decrease of GABA levels in the visual cortex, while no changes were revealed for the sensorimotor cortex. Correlations of visual GABA/Cr with CFF, blood ammonia, and osmolytic regulators mI and Gln indicate that decreased visual GABA levels might contribute to HE symptoms, most likely as a consequence of hyperammonemia.

Neuropsychological and psychophysical tests are recommended to assess the risk of overt hepatic encephalopathy (OHE), but their accuracy is limited. Hyperammonaemia is central in the pathogenesis of OHE, but its predictive utility is unknown. In this study, we aimed to determine the role of neuropsychological or psychophysical tests and ammonia, and to develop a model (AMMON-OHE) to stratify the risk of subsequent OHE development in outpatients with cirrhosis. This observational, prospective study included 426 outpatients without previous OHE from three liver units followed for a median of 2.5 years. Psychometric hepatic encephalopathy score (PHES) <-4 or critical flicker frequency (CFF) <39 was considered abnormal. Ammonia was normalized to upper limit of normal (AMM-ULN) at the respective reference laboratory. Multivariable frailty competing risk and random survival forest analyses were performed to predict future OHE and to develop the AMMON-OHE model. External validation was carried out using 267 and 381 patients from two independent units. Significant differences were found in time-to-OHE (log-rank p <0.001) according to PHES or CFF and ammonia, with the highest risk in patients with abnormal PHES plus high AMM-ULN (hazard ratio 4.4; 95% CI 2.4-8.1; p <0.001 compared with normal PHES and AMM-ULN). On multivariable analysis, AMM-ULN but not PHES or CFF was an independent predictor of the development of OHE (hazard ratio 1.4; 95% CI 1.1-1.9; p = 0.015). The AMMON-OHE model (sex, diabetes, albumin, creatinine and AMM-ULN) showed a C-index of 0.844 and 0.728 for the prediction of a first episode of OHE in two external validation cohorts. In this study, we developed and validated the AMMON-OHE model, comprising readily available clinical and biochemical variables that can be used to identify outpatients at the highest risk of developing a first episode of OHE. In this study, we aimed to develop a model to predict which patients with cirrhosis are at risk of developing overt hepatic encephalopathy (OHE). Using data from three units and including 426 outpatients with cirrhosis, we developed the AMMON-OHE model – comprising sex, diabetes, albumin, creatinine and ammonia levels – which demonstrated good predictive ability. The AMMON-OHE model performs better than PHES and CFF to predict the first episode of OHE in outpatients with cirrhosis. This model was validated in 267 and 381 patients from two independent liver units. The AMMON-OHE model is available online for clinical use. [Display omitted] • Neither PHES nor CFF are independent predictors of a first episode of OHE. • Ammonia levels above the upper limit of normal are independently associated with the risk of developing OHE. • The best model to predict a first episode of OHE (the AMMON-OHE model) includes sex, diabetes, albumin, creatinine and ammonia. • The AMMON-OHE model performs better than PHES and CFF to predict the first episode of OHE in outpatients with cirrhosis. • The AMMON-OHE model showed good predictive accuracy in two separate external validation cohorts. [ABSTRACT FROM AUTHOR]

Introduction: Minimal hepatic encephalopathy (MHE) represents one of the most overlooked complications of liver cirrhosis. Aim of the study: To compare the utility and efficacy of different MHE diagnostic modalities. Material and methods: This case-control study was conducted on hepatitis C virus (HCV)-related compensated cirrhotic patients. The Psychometric Hepatic Encephalopathy Score (PHES) was used to assign patients to MHE and controls. All patients were subjected to plasma ammonia, serum 3-nitrotyrosine (3-NT), critical flicker frequency (CFF), and the modified inhibitory control test (ICT). Results: CFF was significantly lower in the control group (38.5, 40 Hz, p = 0.003). The unweighted lures on ICT were 8.7, 4.9 in MHE and controls (p < 0.001). Moreover, ammonia was higher in the MHE group (89, 61.5 µmol/l, p < 0.001). 3-NT was also higher in the MHE group (31.5, 13.7 nmol/l, p < 0.001) respectively. CFF at cutoff < 39 Hz had sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 57.5%, 77.5%, 71.9% and 64.6%, respectively; in modified ICT, at cutoff > 5 unweighted lures the values were 87.5%, 80%, 81.4% and 86.5%, respectively; in ammonia, at cutoff ≥ 76.45 µmol/l the values were 65%, 72.5%, 70.3% and 67.4%, respectively; for 3-NT at cutoff ≥ 14.15 nmol/l the values were 85%, 82.5%, 82.9% and 84.6%, respectively. The accuracy for MHE diagnosis was 67.5%, 83.3%, 68.8%, 83.8% relying on CFF, 3-NT, ammonia, and ICT respectively. On multivariate analysis, CFF < 39 Hz (OR = 10.2, p = 0.04), modified ICT > 5 unweighted lures (OR = 43.2, p = 0.002), and serum 3-NT levels ≥ 14.15 nmol/l (OR = 50.4, p < 0.001) were independent predictors of MHE. Conclusions: 3-NT and ICT are advantageous to reveal MHE in compensated liver cirrhosis, while CFF can be only used as adjuncts, with humble merits of ammonia [ABSTRACT FROM AUTHOR]

Background: Minimal hepatic encephalopathy (MHE) is viewed as mild neuro-cognitive abnormalities in cirrhotics without overt encephalopathy. Diagnostic strategies for MHE include portosystemic encephalopathy (PSE) syndrome test, critical flicker frequency test (CFF), computerised tests like Inhibitory control test, Scan test etc. We compared critical flicker frequency test with standard PSE syndrome test. Methods: Fifty patients with cirrhotics of liver without overt encephalopathy were studied. PSE syndrome test was done with the standard charts. PSE score was calculated from the normal distribution tables. CFF was tested with manual CFF tool. Results: Their mean age (years) was 46 ± 12.8; there were 45 males. Of these 22, 21 and 7 patients belonged to Child’s A, B and C categories. PSE score detected MHE in 40%, of which 35% were in Child’s A and 65% in Child’s B/C. CFF was normal (>39HZ) in 36% patients and abnormal (<39HZ) in 64% patients. Mean ammonia levels were significantly higher in abnormal CFF (70.87 ± 14.38) as compared normal CFF (32.21 ± 7.9) group (P < 0.001). The sensitivity of CFF for detecting MHE was 85%, specificity 52%, positive predictive value 56% and negative predictive value 85%. Thus, CFF appears to be a good test for excluding MHE. Conclusions: CFF test is highly sensitive (85%) with high negative predictive value (85%). It is a useful test to rule out MHE. The test is simple, quick and in-expensive and can be performed in the outpatient settings. [ABSTRACT FROM AUTHOR]

Introduction. Blood ammonia-measurements are often performed in the emergency departments to diagnose or rule out hepatic encephalopathy (HE). However, the utility and correct interpretation of ammonia levels is a matter of discussion. At this end the present prospective study evaluated whether blood ammonia levels coincide with HE which was also established by the West Haven criteria and the critical flicker frequency, respectively.Material and methods. In 59 patients with known cirrhosis ammonia-levels were determined and patient were additionally categorized by the West-Haven criteria and were also evaluated psychophysiologically using the critical flicker frequency, CFF for the presence of HE.Results. When false positive and false negative results were collapsed the determination of blood ammonia levels alone resulted in 40.7% in a misdiagnoses of HE compared to the West-Haven criteria (24/59 when using West-Haven criteria, 95% confidence interval [CI], 28.1% to 54.3%) and 49.2% when compared with the results of the CFF (29/59, when using CFF, 95% CI, 35.9% to 62.5%).Discussion. Ammonia blood levels do not reliably detect HE and the determination of blood ammonia can not be regarded a useful screening test for HE. Its use as sole indicator for a HE in the Emergency Department may frequently result in frequent misinterpretations.

Background Hepatic encephalopathy ( HE) is a serious complication of liver cirrhosis. Recently, a microsatellite in the promoter region of the phosphate-activated glutaminase ( GLS ) gene was associated with the risk of HE. The aim of the present study was to investigate, using the critical flicker frequency ( CFF) test, whether the described GLS variant increases the risk of developing HE in patients with cirrhosis. Methods We recruited 158 patients (66% men; mean age 59 years, range 23-86) with liver cirrhosis. Mean model for end-stage liver disease score was 13.8 (range 5-35); 48% of patients presented with Child-Pugh score B or C. The presence and severity of HE were determined by the CFF test, with frequencies ≤39 Hz denoting cases. GLS variants were genotyped by sequencing the microsatellite in the promoter region and were classified as short, long or short-long forms (depending on the length of the macrosatellite alleles). Results In total, 53% of patients had abnormal CFF results (i.e. ≤39 Hz; range for entire cohort 26-57). The GLS microsatellite distribution amongst patients was short form (20%), long form (32%) and short-long form (48%) and was consistent with Hardy-Weinberg equilibrium. CFF values differed significantly between groups ( P = 0.043). Carriers of the GLS long microsatellite had a significantly higher risk of HE according to multivariate analyses (odds ratio 3.23, 95% confidence interval 1.46-7.13, P = 0.004). Conclusion CFF results were significantly lower amongst carriers of the GLS long microsatellite. Our findings support the role of the GLS long microsatellite in the development of HE; this could be important for identifying susceptible patients and for the prevention of this condition. [ABSTRACT FROM AUTHOR]

Minimal hepatic encephalopathy (MHE) is intermittently present in up to 2/3 of patients with chronic liver disease. It impairs their daily living and can be treated. However, there is no consensus on diagnostic criteria except that psychometric methods are required. We compared two easy-to-perform reproducible bedside methods: the critical flicker frequency (CFF) and continuous reaction times (CRT) tests. A CFF <39 Hz and CRT-index <1.9 (index: the ratio 50/(90 minus 10) percentiles of reaction times) indicates cerebral dysfunction. 154 patients with acute or chronic liver disease with out overt hepatic encephalopathy (HE) underwent both tests at the same occasion. Both tests were abnormal in 20% of the patients and both tests were normal in 40% of the patients. In more than 1/3 the two tests were not in agreement as CFF classified 32% and CRT-index classified 48% of the patients as having MHE ( p < 0.005). The two tests were weakly linearly correlated (r = 0.14, p < 0.001) and neither test correlated with the metabolic liver function measured by the Galactose Elimination Capacity (GEC), nor with the blood ammonia concentration. Both tests identified a large fraction of the patients as having MHE and cleared only 40%. The two tests did not show concordant results, likely because they describe different aspects of MHE: the CFF gives a measure of astrocytic metabolic state and hence pathogenic aspects of MHE, whereas the CRT measures a composite key performance, viz. the ability of reacting appropriately to a sensory stimulus. The choice of test depends on the information needed in the clinical and scientific care and study of the patients. [ABSTRACT FROM AUTHOR]

Introduction: Hepatic encephalopathy (HE) is a complication of liver disease. Several treatments have been introduced but onlyl-ornithine–l-aspartate (LOLA) shows proven efficacy. This double-blind, randomized, placebo-controlled trial evaluated the effect of LOLA on postural control in cirrhotics. Methods: Forty patients were randomized to either LOLA or a placebo. HE was evaluated by psychometric testing (PSE Syndrome Test) and critical flicker frequency (CFF). Posturography [equilibrium score (ES)] provided information regarding postural control. Peripheral blood was analysed for ammonia concentration (NH3) and the partial pressure of ammonia (pNH3). Results: Both groups were comparable regarding baseline variables. Posturography and PSE Syndrome Test improved in both groups; improvement was greater in the LOLA group (ES: 5.3%; PSE: 1.9) compared with the placebo (ES: 3.9%; PSE: 1.3) but did not reach significance (ES: P=0.3; PSE: P=0.5). CFF remained unchanged during treatment and between groups ( P=NS). NH3 decreased in the LOLA group (Δ: −15 μmol/L) and slightly increased in the placebo group (Δ: 11.1 μmol/L), but the differences did not reach statistical significance ( P=0.07). pNH3 remained largely unchanged (LOLA Δ: −1.2 × 10−5 mmHg vs. placebo Δ: −0.3 × 10−5 mmHg; P=0.21). Conclusion: In the LOLA group, an improvement of posturographic control and PSE Syndrome Test was observed, but a similar improvement was also achieved by the placebo. In LOLA, ammonia levels tended to decrease while they tended to increase in the placebo group. LOLA might augment the improvement achieved by intravenous fluids alone but a larger cohort will be needed to show this effect with statistical significance. [ABSTRACT FROM AUTHOR]