Psychometric Hepatic Encephalopathy Score Research Articles

Cerebral haemodynamics in cirrhotic patients with hepatic encephalopathy

Factors other than elevated levels of ammonia may be implicated in hepatic encephalopathy (HE) pathophysiology, including abnormal cerebral haemodynamics. Transcranial Doppler ultrasonography (TCD) evaluates cerebrovascular structural integrity and reactivity, through pulsatility index (PI) and breath-holding index (BHI) respectively. The aim of this study was to evaluate cerebral haemodynamics by TCD in patients with compensated and decompensated cirrhosis, and patients with and without HE. We studied 90 subjects by TCD measuring PI and BHI in the middle cerebral artery: 30 with cirrhosis and no HE, 30 with cirrhosis and low-grade HE and 30 healthy subjects. Critical flicker frequency, psychometric hepatic encephalopathy score and West-Haven criteria were performed to assess MHE and HE respectively. Pulsatility index increased in decompensated cirrhotics (Child≥7) when compared with compensated cirrhotics and healthy subjects [median (IQR) 1.07 (0.95-1.21) vs 0.90 (0.83-1.05) vs 0.87 (0.78-0.96); P<0.001]. A reverse relationship was observed for BHI among the three groups [0.82 (0.45-1.11) vs 1.20 (0.82-1.52) vs 1.28 (1.06-1.68); P<0.001]. Similar findings were observed in decompensation [model for end-stage liver disease (MELD) score ≥14]. Patients with HE showed higher PI and lower BHI [1.05 (1.00-1.16) and 0.89 (0.59-1.15)], when compared with patients without HE [0.96 (0.83-1.13) and 1.00 (0.60-1.53)] or controls [0.87 (0.78-0.96) and 1.28 (1.06-1.68)] (P<0.001 for PI, and P=0.007 for BHI). In multivariate regression models, only PI predicted HE, but it was outperformed by MELD-sodium and tumour necrosis factor-alpha. These results indicate that cerebral haemodynamics are altered in patients with cirrhosis, in relation to severity of disease and HE. Findings on impaired PI and BHI suggest that structural vascular damage and loss of vascular autoregulation are implicated in the pathophysiology of HE.

Issue Highlights

Issue Highlights

Encéphalopathie hépatique minime : un diagnostic précoce pour améliorer le pronostic

Minimal hepatic encephalopathy (MHE) is the mildest form of the spectrum of hepatic encephalopathy that impairs health-related quality of life. The aim of this study is to evaluate the prevalence of MHE in patients with liver cirrhosis and analyze risk factors. Between September 2011 and December 2012, consecutive cirrhotic patients seen in our department were evaluated. Patients included were screened by the psychometric hepatic encephalopathy score (PHES) battery comprising 5 tests: number connection test A and B, line tracing test, serial dotting test and digit symbol test. Patients included were regularly followed-up for the development of overt hepatic encephalopathy, driving accidents, falls and death. We included 45 cirrhotic patients. Etiology of cirrhosis was viral in half of cases. Child-Pugh score was A in 55.6 %, B in 26.7 % and C in 17.8 %. Median Meld score was 14. According to the PHES score, MHE was detected in 44.4 % of patients. Univariate analysis identified 4 variables significantly associated with the presence of MHE: age ≥ 55 years (P=0.031), poor educational status with years of study< 9 years (P=0.007), MELD score ≥ 15 (P=0.002) and Child-Pugh ≥ 7 (P=0.001). At multivariate analysis, the only independent risk factor of MHE was a MELD score≥15 (OR=15.4; P<0.001). During the follow-up, patients with MHE developed more often overt encephalopathy, falls and driving accidents, and had a lower survival, although the difference was not statically significant. In this preliminary small series, prevalence of MHE in Tunisian cirrhotic patient was 44.4 %. A MELD score ≥ 15 was the only independent risk factor. MHE had a negative impact on the outcome, justifying an early diagnostic. Adequate therapy may improve cognitive function.

P459 RESCUE THERAPY BY AUTOLOGOUS INFUSION OF GRANULOCYTE-COLONY STIMULATING FACTOR-MOBILIZED PERIPHERAL BLOOD CD34-POSITIVE CELLS IN PATIENTS WITH DECOMPENSATED LIVER CIRRHOSIS

has two parts; easier “Off” and a difficult “On” state. Time required to complete both parts, OffTime+OnTime, determines impairment. Aim: To define normative values for EncephalApp and perform sensitivity analyses of the MHE diagnosis in a multi-center US study. Methods: Age-matched healthy controls from three sites (Virginia/ Arkansas/Ohio) and outpatient cirrhotics (Virginia/Ohio) were administered the gold standard (PHES, psychometric hepatic encephalopathy score: 6 tests) and EncephalApp. Results impaired >−4SD than controls was deemed MHE on PHES as recommended while 2SD beyond controls on OffTime+OnTime was considered impaired on EncephalApp. Concordance between sites regarding EncephalApp cut-offs and PHES diagnosis of MHE was performed using Kappa. Sensitivity/specificity of EncephalApp cut-offs compared to PHES was calculated as a whole and in each center using ROC. Results: 134 controls (56 Virginia, 50 Ohio, 28 Arkansas, age 55±7yrs, education 14±2.5 yrs) and 176 cirrhotics (137 Virginia, 39 Ohio, 57±4yrs, education 13±2yrs) were included. Based on control+2SD OffTime+OnTime, EncephalApp cut-offs were 206 seconds for all controls, 202 using Virginia controls only, 211 for Arkansas controls and 209 seconds for Ohio controls only. There was a high concordance of abnormal EncephalApp between these 3 sites (Kappa range 0.80–0.90, Table). The specificity/sensitivity were 81% using PHES as the gold standard at 183 seconds cut-off with AUC of 0.90.

Prolonged N200 is the early neurophysiologic change in the patient with minimal hepatic encephalopathy

Background. In neurophysiological studies, P300, is well known for reflecting early cognitive impairment in minimal hepatic encephalopathy (MHE). Although P300 is investigated extensively, other early event-related potential (ERP) parameters have not been studied in MHE. Methods. The subjects were 21 adult cirrhotic patients without clinical encephalopathy and 29 normal controls. For neuropsychological testing, number connection tests, A and B (NCT-A, NCT-B), the line tracing test, the serial dotting test (SDT), and the digit symbol test (DST) were performed. For ERP testing, auditory oddball paradigms were used. The N100, P200, N200, and P300 parameters were measured. Results. Cirrhosis had longer neuropsychological performance scores on NCT-A, SDT, and DST than the control group. In neurophysiological test, cirrhotic patients showed longer latencies for N100, P200, N200, and P300 than the control group. Although P300 alteration was not seen in patients without MHE compared to the control group (325.4 ± 43.3 vs. 345.21 ± 35.1, p = 0.25), N200 latency was significantly prolonged in cirrhotic patients without MHE compared to the healthy group (242.1 ± 30.3 vs. 259.58 ± 33.3, p = 0.006). N200 also showed good correlation with psychometric hepatic encephalopathy score and critical flicker frequency. Conclusions. N200 is a useful tool for assessing early changes of cognitive dysfunction in cirrhosis. It suggests that slower auditory cortical processing is the first sign of cerebral deterioration in patients with hepatic encephalopathy.

Non invasive blood flow measurement in cerebellum detects minimal hepatic encephalopathy earlier than psychometric tests.

To assess whether non invasive blood flow measurement by arterial spin labeling in several brain regions detects minimal hepatic encephalopathy. Blood flow (BF) was analyzed by arterial spin labeling (ASL) in different brain areas of 14 controls, 24 cirrhotic patients without and 16 cirrhotic patients with minimal hepatic encephalopathy (MHE). Images were collected using a 3 Tesla MR scanner (Achieva 3T-TX, Philips, Netherlands). Pulsed ASL was performed. Patients showing MHE were detected using the battery Psychometric Hepatic Encephalopathy Score (PHES) consisting of five tests. Different cognitive and motor functions were also assessed: alterations in selective attention were evaluated using the Stroop test. Patients and controls also performed visuo-motor and bimanual coordination tests. Several biochemical parameters were measured: serum pro-inflammatory interleukins (IL-6 and IL-18), 3-nitrotyrosine, cGMP and nitrates+nitrites in plasma, and blood ammonia. Bivariate correlations were evaluated. In patients with MHE, BF was increased in cerebellar hemisphere (P = 0.03) and vermis (P = 0.012) and reduced in occipital lobe (P = 0.017). BF in cerebellar hemisphere was also increased in patients without MHE (P = 0.02). Bimanual coordination was impaired in patients without MHE (P = 0.05) and much more in patients with MHE (P < 0.0001). Visuo-motor coordination was impaired only in patients with MHE (P < 0.0001). Attention was slightly affected in patients without MHE and more strongly in patients with MHE (P < 0.0001). BF in cerebellar hemisphere and vermis correlated with performance in most tests of PHES [(number connection tests A (NCT-A), B (NCT-B)and line tracing test] and in the congruent task of Stroop test. BF in frontal lobe correlated with NCT-A. Performance in bimanual and visuomotor coordination tests correlated only with BF in cerebellar hemisphere. BF in occipital lobe correlates with performance in the PHES battery and with CFF. BF in cerebellar hemisphere correlates with plasma cGMP and nitric oxide (NO) metabolites. BF in vermis cerebellar also correlates with NO metabolites and with 3-nitrotyrosine. IL-18 in plasma correlates with BF in thalamus and occipital lobe. Non invasive BF determination in cerebellum using ASL may detect MHE earlier than the PHES. Altered NO-cGMP pathway seems to be associated to altered BF in cerebellum.

Value of Critical Flicker Frequency and Psychometric Hepatic Encephalopathy Score in Diagnosis of Low-Grade Hepatic Encephalopathy

Critical flicker frequency (CFF) and psychometric hepatic encephalopathy score (PHES) analyses are widely used to diagnose hepatic encephalopathy (HE), but little is known about their value in the diagnosis of low-grade HE. The diagnostic values of CFF and PHES were compared using a computerized test battery and West Haven criteria as reference. We performed CFF analysis on 559 patients with cirrhosis and 261 without (controls). Of these 820 patients, 448 were evaluated using a modified PHES system and 148 were also evaluated using the conventional PHES system. CFF distinguished between patients with overt HE and without minimal or overt HE in the entire study population with 98% sensitivity and 94% specificity and in the subgroup of patients who were evaluated by conventional PHES with 97% sensitivity and 100% specificity. Conventional PHES identified patients with overt HE with 73% sensitivity and 89% specificity. CFF distinguished between patients with and without minimal HE with only 37% sensitivity but 94% specificity (entire study population). In the subgroup of patients evaluated by conventional PHES, CFF distinguished between patients with and without minimal HE with 22% sensitivity and 100% specificity; these values were similar to those for conventional PHES (30% sensitivity and 89% specificity). The modified PHES distinguished between patients with and without minimal HE with 49% sensitivity and 74% specificity. The diagnostic agreement values between CFF and conventional or modified PHES in patients with minimal HE were only 54% or 47%, respectively. In an analysis of patients with cirrhosis and controls, CFF distinguished between patients with overt HE and without minimal or overt HE. PHES testing produced a statistically significant difference among groups, but there was considerable overlap between controls and patients with overt HE. PHES, CFF, and a combination of PHES and CFF could not reliably distinguish patients with minimal HE from controls or those with overt HE.

In patients with liver cirrhosis, proinflammatory interleukins correlate with health-related quality of life irrespective of minimal hepatic encephalopathy

Liver cirrhosis is associated with latent systemic inflammatory response syndrome as evidenced by elevated levels of proinflammatory cytokines. It has been proposed that inflammatory mediators play a role in the pathogenesis of minimal and overt hepatic encephalopathy (HE); hence, they may also have an effect on health-related quality of life (HRQL). The aim of this study was to investigate the relationship between serum levels of interleukin-1β (IL-1β), IL-6, and IL-18 and the occurrence of minimal HE and HRQL. Forty-two consecutive patients with liver cirrhosis were prospectively enrolled to the study. Minimal HE was detected by the Psychometric Hepatic Encephalopathy Score (PHES) and critical flicker frequency. HRQL was assessed with Chronic Liver Disease Questionnaire and 36-Item Short Form Health Survey (SF-36) questionnaires. The interleukins studied were determined using colorimetric sandwich enzyme-linked immunosorbent assay. Serum levels of interleukins correlated with liver dysfunction, but did not discriminate patients with minimal HE from those with overt or absent HE. IL-1β and IL-6 showed significant correlations with PHES, but showed no relationship with critical flicker frequency. Serum IL-6 and IL-18 correlated with both physical-related general health and mental component summary evaluated by the SF-36 questionnaire. This study shows that chronic inflammation plays a role in impaired HRQL in patients with cirrhosis irrespective of minimal HE.

Probiotics Prevent Hepatic Encephalopathy in Patients With Cirrhosis: A Randomized Controlled Trial

Hepatic encephalopathy (HE) is associated with a poor prognosis in patients with advanced liver disease. Probiotics alter the intestinal microbiota with non-urease-producing organisms that reduce production of ammonia. We investigated the efficacy of probiotics for the primary prophylaxis of HE. We conducted a prospective trial at a tertiary care referral institute in New Delhi, India, from January 2012 through March 2013, of patients with cirrhosis without overt HE (age, 48.6 ± 11.1 y; 96 men and 64 women); 25 were Child-Turcotte-Pugh (CTP) class A, 51 were CTP class B, and 84 were CTP class C. Subjects were assigned randomly to groups given probiotics (1× 10(8) colony-forming units, 3 times daily; n= 86, 42 with minimal HE) or no test article (control, n=74; 33 with minimal HE). All subjects underwent psychometric analyses, critical flicker fusion (CFF) threshold assessments, glucose hydrogen breath tests to identify small intestinal bacterial overgrowth (SIBO), and lactulose hydrogen breath tests to measure orocecal transit time (OCTT). The primary end point was the development of overt HE. At baseline, subjects in each group had comparable CTP score, model for end-stage liver disease scores, CFF assessments, psychometric hepatic encephalopathy scores, and OCTT. After a mean follow-up period of 38.6 ± 8.80 weeks for patients given probiotics and 40.3 ± 9.8 weeks for controls, 6 patients given probiotics and 7 controls died (P= .81). Three months of probiotic administration significantly reduced levels of arterial ammonia, SIBO, and OCTT; increased psychometric hepatic encephalopathy scores; and increased CFF thresholds, compared with baseline. Seven subjects in the probiotic group and 14 controls developed overt HE (P < .05; hazard ratio for controls vs probiotic group, 2.1; 95% confidence interval, 1.31-6.53). Psychometric hepatic encephalopathy scores, CTP scores, and SIBO correlated with the development of overt HE. In a prospective, randomized controlled trial, probiotics were found to be effective in preventing HE in patients with cirrhosis. Trial registration No: CTRI/2012/07/002807.

Value of computerized inhibitory control test and blood tests in minimal hepatic encephalopathy diagnosis

Background. Minimal hepatic encephalopathy (MHE) can be diagnos­ed by “paper-pencil” tests, computerised inhibitory control or critical flicker frequency tests, but for clinical practice more convenient methods of diagnosis are being searched. The aim of the study was to assess the value of inhibitory control test (ICT) and laboratory blood tests (leucocytes, platelets, hemoglobin, AST, ALT, ALP, GGT, bilirubin, albumin, SPA, INR, glucose, ammonia, IL-6) for MHE diagnosis. Materials and methods. 62 cirrhotic patients without overt hepatic encephalopathy were enrolled in the study. The control group consisted of 53 volunteers without chronic liver diseases. Routine laboratory tests, IL-6 of venous blood samples and ammonia of the capillary blood were extracted after overnight fasting. Ammonia was measured by the micro-diffusion method. IL-6 concentration was detected using the solid phase chemiluminescence immunometer analysis. At the same day all participants performed the PHES (Psychometric Hepatic Encephalopathy Score) battery and ICT under recommended diagnostic standards. Results. MHE was diagnosed in 44/71.0% out of 62 cirrhotic patients while 18/29.0% had no evidence of psychomotor or cognitive disturbances. There was not statistically significant difference in age, gender, education. Patients with MHE had statistically significant differences neither in leukocytes, platelets count nor in ALT, AST, ALP, GGT, IL-6, albumin, SPA, INR, bilirubin concentration in comparison with those without MHE. Patients with MHE perform ICT worse than those without MHE but the differences were not statistically significant. Conclusions. In our study ICT was not approved as a good diagnostic tool for MHE. The IL-6 concentration in the peripheral blood as well as routine biochemical tests seem not useful for MHE diagnosis in cirrhotic patients.

Abnormal baseline brain activity in patients with HBV-related cirrhosis without overt hepatic encephalopathy revealed by resting-state functional MRI

Neurocognitive dysfunction of varying degrees is common in patients with hepatitis B virus-related cirrhosis (HBV-RC) without overt hepatic encephalopathy (OHE). However, the neurobiological mechanisms underlying these dysfunctions are not well understood. We sought to identify changes in the neural activity of patients with HBV-RC without OHE in the resting state by using the amplitude of low-frequency fluctuation (ALFF) method and to determine whether these changes were related to impaired cognition. Resting-state functional MRI data from 30 patients with HBV-RC and 30 healthy controls matched for age, sex, and years of education were compared to determine any differences in the ALFF between the two groups. Cognition was measured with the psychometric hepatic encephalopathy score (PHES), and the relationship between these scores and ALFF variation was assessed. Compared with controls, patients showed widespread lower standardized ALFF (mALFF) values in visual association areas (bilateral lingual gyrus, middle occipital gyrus, and left inferior temporal gyrus), motor-related areas (bilateral precentral gyrus, paracentral lobule, and right postcentral gyrus), and the default mode network (bilateral cuneus/precuneus and inferior parietal lobule). Higher mALFF values were found in the bilateral orbital gyrus/rectal gyrus. In patients, mALFF values were significantly positive correlated with the PHES in the right middle occipital gyrus and bilateral precentral gyrus. Our findings of resting-state abnormalities in patients with HBV-RC without OHE suggest that neurocognitive dysfunction in patients with HBV-RC without OHE may be caused by abnormal neural activity in multiple brain regions.

Serum nitrotyrosine and psychometric tests as indicators of impaired fitness to drive in cirrhotic patients with minimal hepatic encephalopathy

Cirrhotic patients with minimal hepatic encephalopathy (MHE) show impaired driving ability and increased vehicle accidents. The neurological deficits contributing to impair driving and the underlying mechanisms are poorly understood. Early detection of driving impairment would help to reduce traffic accidents in MHE patients. It would be therefore useful to have psychometric or biochemical parameters reflecting driving impairment. The aims of this work were as follows: (i) to shed light on the neurological deficits contributing to impair driving; (ii) to assess whether some psychometric test or biochemical parameter is a good indicator of driving impairment. We assessed in 22 controls, 36 cirrhotic patients without and 15 with MHE, driving performance using a driving simulator (SIMUVEG) and Driver Test. MHE was diagnosed using the psychometric hepatic encephalopathy score (PHES). Psychometric tests assessing different neurological functions (mental processing speed, attention, visuo-spatial and bimanual coordination) were performed. Blood ammonia and parameters related with nitric oxide-cGMP metabolism, IL-6, IL-18 and 3-nitrotyrosine were measured. Patients with MHE showed impaired driving ability correlating with MHE grade, with impaired vehicle lateral control in spite of reduced driving speed. Patients with MHE show psychomotor slowing, longer reaction times, impaired bimanual and visuo-spatial coordination and concentrated attention and slowed speed of anticipation and increased blood ammonia, cGMP, IL-6, IL-18 and 3-nitrotyrosine. Impaired mental processing speed, attention and alterations in visuo-spatial and motor coordination seem main contributors to impaired driving ability in patients with MHE. Increased serum 3-nitrotyrosine is associated with impaired driving ability.

Normalization of the psychometric hepatic encephalopathy score in Polish population. A prospective, quantified electroencephalography study

The psychometric hepatic encephalopathy score (PHES) is recommended as a gold standard in evaluation of minimal hepatic encephalopathy (HE). Normative databases have been collected in few countries, clearly showing differences among studied groups. Thus, the standardization of PHES for selected populations remains necessary. To standardize PHES in a large cohort of Polish healthy subjects and to evaluate the normograms in patients with cirrhosis with quantified electroencephalography (EEG). Three hundred and sixteen (142 males/174 females, aged 44.5±12.1) normal individuals and 50 (31 males/19 females, aged 52.8±12.4) patients with cirrhosis without overt HE were included. Key correction variables of psychometric tests were performed. The multivariate linear regression was used to calculate PHES normograms. Age and education levels were identified as predictors of all tests, therefore age- and education-adjusted normograms were developed. A weighted time-errors regression model for line tracing test (LTT) scoring was used. The PHES ranged between +5 and -15 points and the cut-off between normal and pathological PHES was set on ≤-5 points. By this cut-off level, PHES had a sensitivity of 57% and specificity of 97% to diagnose minimal HE (AUC=0.866±0.028). In patients with cirrhosis, PHES correlated with severity of liver disease (MELD, r=-0.475, P<0.001 and Child-Pugh classification, r=-0.452, P<0.002) and EEG (r=0.547, P<0.002). In patients with impaired EEG, PHES was lower than in individuals with unaltered EEG (P<0.02); however, agreement between these two modalities was limited. Valid Polish PHES normograms, which incorporates w-LTT scoring system have been developed. Future multi-centre international studies are needed to validate widely applicable norms.

Serum natremia affects health-related quality of life in patients with liver cirrhosis: a prospective, single centre study

Introduction. Hyponatremia is associated with high mortality and predicts hepatic encephalopathy but its effect on health-related quality of life remains to be established.Material and methods. In this study we prospectively analyzed the relationship between hyponatremia, clinical features and quality of life in a cohort of 116 patients with cirrhosis. Chronic Liver Disease Questionnaire and Medical Outcomes Study 36-Item Short Form Health Survey were performed to assess quality of life. Evaluation of hepatic encephalopathy included West-Haven criteria, Psychometric Hepatic Encephalopathy Score and Critical Flicker Frequency analysis. Severity of liver disease was assessed with Child-Pugh score and MELD. Univariate and multivariate analysis were implemented to evaluate the influence of analyzed factors on quality of life.Results. Multivariate analysis has identified serum natremia, Psychometric Hepatic Encephalopathy Score, Critical Flicker Frequency and severity of liver disease measured with MELD and Child-Pugh score as independent factors affecting quality of life in patients with cirrhosis. West Heaven criteria failed to show the relationship with quality of life in analyzed subjects. Serum kalemia showed correlation with neither quality of life, hepatic encephalopathy nor severity of the disease.Conclusion. In patients with cirrhosis serum natremia along with severity of liver disease and hepatic encephalopathy exerts a significant effect on patients’ quality of life.

203 ORAL GLUTAMINE CHALLENGE – DOES IT IMPROVE REVEALING MINIMAL HEPATIC ENCEPHALOPATHY IN CIRRHOSIS?

Background and Aims: Minimal hepatic encephalopathy (MHE) is a prevalent asymptomatic condition, whose diagnosis is difficult due to the lack of a gold standard test. Oral glutamine challenge (OGC) has been found to increase blood ammonia in patients with cirrhosis which could lead to significant cognitive impairment. The aim of our study was to evaluate the value of OGC in improving the performance of psychometric tests and arterial blood ammonia for the diagnosis of MHE. Secondary we followed the risk for development of overt hepatic encephalopathy (OHE). Methods: Fifty-four patients (male/female: 34/20; mean age 59.5yrs) with cirrhosis and 13 healthy controls matched by sex and age were included. Follow-up lasted 12 months. MHE was assessed using the psychometric hepatic encephalopathy score (PHES). Arterial ammonia blood concentrations and PHES were evaluated preand post-60 minutes of a 20 g oral glutamine load. Statistical analysis used paired t-test, relative operating characteristics (ROC) and multivariate logistic regression analysis. Results: At baseline, 29 (53.7%) out of 54 patients met the criteria for MHE, while post glutamine challenge, 43 patients (79.63%) had MHE (p < 0.0001). Arterial blood ammonia levels had significantly raised after glutamine challenge in the cirrhotic patients (baseline vs post glutamine: 85.2±20.8mg/dL vs 159.82±66.01mg/dL, p < 0.0001) as compared to controls values which remained unchanged. ROC analysis showed a pathological glutamine tolerance cut-off value of 124mg/dl. For baseline arterial blood ammonia the AUROC was 0.54 (CI: 0.402–0.680, p = 0.58), with no significant change post glutamine challenge (AUROC = 0.53, CI: 0.389–0.667, p = 0.77). In the follow-up 16 patients (29.62%) developed OHE. In multivariate model, MELD score (OR = 1.5187, 95%CI: 1.0690–2.1574, P = 0.0197), but not Child Pugh class, arterial blood ammonia, esophageal varices grading, was a strong independent predictor of OHE. Conclusions: In cirrhotic patients, OGC appears to improve the performance of psychometric tests, but not arterial blood ammonia for the diagnosis of MHE. MELD score has proven to be independently related with OHE in the follow up. Acknowledgements: This work was made possible by the project ‘Doctoral Scholarships for increasing competitiveness in the medical and pharmaceutical field’ POSDRU/88/1.5/S/58965.

A Randomised Double Blind Controlled Trial Comparing Rifaximin Plus Lactulose with Lactulose Alone in Treatment of Overt Hepatic Encephalopathy

Background: Hepatic encephalopathy (HE) is associated with poor prognosis. Probiotics alter gut flora with nonurease producing organism with decrease ammonia production. Present study assessed efficacy of probiotics for primary prophylaxis of HE. Methods: In prospective randomised controlled trial, patients with no history of overt HE were randomised into: group 1 [Probiotics, n=86, one capsule (110 billion CFU) TDS] and group 2 [control, n = 74]. All patients underwent psychometric tests, critical flicker frequency (CFF), glucose hydrogen breath test (GHBT) for small intestinal bacterial overgrowth (SIBO) and lactulose hydrogen breath test (LHBT) for oro-cecal transit time (OCTT). Primary end point was development of overt HE. Results: One hundred and sixty patients (age 48.6 11.1 years, M:F 96:64) were included. 25 (15.6%), 51 (31.9%) and 82 (52.5%) patients were in CTP class A, B and C respectively. Baseline laboratory parameters, CTP score, MELD score, CFF, psychometric hepatic encephalopathy score (PHES) and OCTT were comparable. Forty two patients (48.8%) in group 1 and 33 (44.6%) in group 2 had minimal HE (P=0.88). Mean follow up of Group 1 and Group 2 patients was 38.6 8.80 vs. 40.3 9.8 weeks (P =0.67). Eleven patients (6.9%) were lost during follow up. Six patients (7.5%) in group 1 and 7 (10.1%) in group 2 died (P =0.81). There was significant improvement in arterial ammonia levels, SIBO, OCTT, PHES, CFF andMHE after 3 months of treatment with probiotics. Seven (8.8%) patients in Group 1 and 14 (20.3%) patients in Group 2 developed overt HE (P <0.05, hazard ratio 2.1, 95% CI, 1.31-6.53). MHE, CTP score and SIBO correlated with development of overt HE. Conclusion: Probiotics are effective in primary prophylaxis of HE.

Modulation of neural activation following treatment of hepatic encephalopathy

To measure changes in psychometric state, neural activation, brain volume (BV), and cerebral metabolite concentrations during treatment of minimal hepatic encephalopathy. As proof of principle, 22 patients with well-compensated, biopsy-proven cirrhosis of differing etiology and previous minimal hepatic encephalopathy were treated with oral l-ornithine l-aspartate for 4 weeks. Baseline and 4-week clinical review, blood chemistry, and psychometric evaluation (Psychometric Hepatic Encephalopathy Score and Cognitive Drug Research Score) were performed. Whole-brain volumetric and functional MRI was conducted using a highly simplistic visuomotor task, together with proton magnetic resonance spectroscopy of the basal ganglia. Treatment-related changes in regional BV and neural activation change (blood oxygenation level dependent) were assessed. Although there was no change in clinical, biochemical state, basal ganglia magnetic resonance spectroscopy, or in regional BV, there were significant improvements in Cognitive Drug Research Score (+1.2, p = 0.003) and Psychometric Hepatic Encephalopathy Score (+1.5, p = 0.003) with treatment. This cognitive amelioration was accompanied by changes in blood oxygenation level-dependent activation in the posterior cingulate and ventral medial prefrontal cortex, 2 regions that form part of the brain's structural and metabolic core. In addition, there was evidence of greater visual cortex activation. These structurally interconnected regions all showed increased function after successful encephalopathy treatment. Because no regional change in BV was observed, this implies that mechanisms unrelated to astrocyte volume regulation were involved in the significant improvement in cognitive performance.

Abnormal regional homogeneity of resting‐state brain activity in patients with HBV‐related cirrhosis without overt hepatic encephalopathy

Many studies have reported that cognitive deficits exist in cirrhotic patients without overt hepatic encephalopathy (OHE). However, the neurobiological mechanisms underlying these deficits are still not fully understood. To investigate regional activity abnormalities in patients with hepatitis B virus-related cirrhosis (HBV-RC) without OHE using resting-state functional MRI (Rs-fMRI), and to examine the relationship between regional activity abnormalities and impaired cognition. A newly reported regional homogeneity (ReHo) approach was used to compare the local synchronization of Rs-fMRI signals in 32 patients with HBV-RC without OHE and 32 well-matched healthy controls. Cognition was measured in all patients using psychometric hepatic encephalopathy score (PHES) tests, and the relationship between ReHo variation and PHES was analysed. Relative to healthy controls, the cirrhosis group showed high ReHo in the prefrontal cortex, and widespread low ReHo in visual association areas (left lingual gyrus, middle temporal gyrus and right middle occipital gyrus), motor association areas (bilateral precentral gyrus and paracentral lobule) and the bilateral precuneus. Correlation analysis of the mean ReHo values in different brain areas and PHES in cirrhotic patients revealed a significantly positive correlation in the left lingual gyrus (r = 0.352; P = 0.048), right middle occipital gyrus (r = 0.453; P = 0.009) and bilateral precentral gyrus (left: r = 0.436, P = 0.013; right: r = 0.582, P < 0.001), paracentral lobule (r = 0.485; P = 0.005) and precuneus (r = 0.468; P = 0.007). Our results provide information on the pathophysiological mechanisms underlying cognitive alterations in cirrhotic patients and demonstrate the feasibility of using Rs-fMRI with ReHo analysis as a noninvasive modality with which to detect the progression of cognitive changes in cirrhotic patients.

Comparison of the most favoured methods for the diagnosis of hepatic encephalopathy in liver transplantation candidates

ObjectiveHepatic encephalopathy (HE) is a common complication of liver insufficiency. While there is widespread acceptance of its importance, there is no consensus on how best to diagnose and monitor HE.ObjectiveTo...

Psychometric hepatic encephalopathy score for diagnosis of minimal hepatic encephalopathy in China

To construct normal values for the tests of the psychometric hepatic encephalopathy score (PHES) and to evaluate its usefulness in the diagnosis of minimal hepatic encephalopathy (MHE) among Chinese individuals with cirrhosis. The five tests of PHES, number connection test-A (NCT-A), number connection test-B, serial dotting test, line tracing test and digit symbol test (DST), were administered to all enrolled subjects in a quiet room with sufficient light. Cirrhotic subjects with overt HE were excluded by the West-Haven criteria and a detailed neurological examination. Based on the nomograms of healthy volunteers, the patients were classified as having MHE when their PHES was less than -4. In total, 146 healthy volunteers completed all the PHES tests. Age and education years were confirmed to be predictors of all five tests. In total, 53 patients with liver cirrhosis completed the PHES. Of the patients with liver cirrhosis, 24 (45.3%), 22(41.5%) and 7(13.2%) had Child-Pugh grades A, B and C, respectively. MHE was diagnosed in 26 patients (49.1%). Compared with compensated cirrhotic patients (Child A), decompensated cirrhotic patients (Child B and C) had a higher proportion of MHE (65.5% vs 29.2%). No differences in age and education years were found between the MHE and non-MHE groups. NCT-A and DST were able to diagnose MHE with a sensitivity of 76.9% and a specificity of 96.3% (AUC = 0.866, K = 0.735). The proportion of MHE is associated with liver function. NCT-A and DST are simple tools that can be used for the diagnosis of MHE in China.