Episodes Of Overt Hepatic Encephalopathy Research Articles

Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis.

BackgroundRifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear.AimTo study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design.MethodsAdults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM.ResultsOf 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P < 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P < 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments.ConclusionsThis analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting.

Ammonia-induced senescence in cultured rat astrocytes and in human cerebral cortex in hepatic encephalopathy.

Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis and is due to a low-grade cerebral edema associated with oxidative/nitrosative stress. Recent reports suggest that cognitive impairment in cirrhotic patients may not resolve completely after an attack of manifest HE. As astrocyte dysfunction is central to the pathogenesis of HE and astrocytes are critically involved in synaptic plasticity, we tested for sustained impairment of astrocyte function by analyzing expression levels of senescence biomarkers in ammonia-treated cultured rat astrocytes and in postmortem brain samples from cirrhotic patients with or without HE. NH4 Cl time- and dose-dependently inhibited proliferation of cultured astrocytes by up to 45% (5 mmol/L, 72 h) and strongly increased senescence-associated β-galactosidase activity. Inhibition of astrocyte proliferation by ammonia was mediated by a l-methionine sulfoximine-, oxidative stress-, and p38(MAPK) -dependent activation of p53 associated with enhanced transcription of cell cycle inhibitory genes GADD45α and p21. Mitochondria and the nucleus were identified as sources of oxygen radical formation after prolonged NH4 Cl exposure. Concurrently, NH4 Cl (5 mmol/L) treatment inhibited both epidermal growth factor- and brain-derived neurotrophic factor (BDNF)-induced proliferation as well as BDNF-mediated astrocyte morphology changes through downregulation of the respective growth factor receptors epidermal growth factor receptor and truncated tyrosine receptor kinase B. Increased mRNA expression levels of senescence-associated genes were also found in post mortem brain samples from patients with liver cirrhosis with HE, but not in those without HE. The data suggest that ammonia toxicity and HE are associated with premature astrocyte senescence, which may impair neurotransmission and contribute to persistence of cognitive disturbances after resolution of episodes of overt HE.

Mo1022 Effect of Body Mass Index (BMI) on Functional Status of Patients With Cirrhosis Based on the Six-Minute Walk Test (6mwt)

Background & Aims: Hepatic encephalopathy (HE) represents a spectrum of neurocognitive impairment seen in cirrhotic patients and is considered to be fully reversible with treatment, however recent evidence suggests otherwise. This longitudinal study was carried out to evaluate the persistence of cognitive impairment in cirrhotics with prior overt HE (OHE) episode despite treatment. Methods: Of 213 patients screened, 107 patients who met the eligibility criteria were enrolled and 102 patients completed the study (52 patients without prior OHE episode and 50 patients with prior OHE). Among 102 patients included in the study, 86 were men and 16 were women; 67 (65.7%) patients had alcoholic etiology and 35 (34.3%) had non-alcoholic etiology (hepatitis B virus 6 patients, hepatitis C virus 4 patients, cryptogenic 14 patients, miscellaneous 11 patients). All patients underwent psychometric hepatic encephalopathy score (PHES) evaluation at 3 separate visits (Day 1, Day 3 and between 30 and 60 days, median 34). PHES ≤5 was considered abnormal and diagnostic of minimal HE (MHE). One point improvement in PHES between first and second evaluation was considered as a measure of learning. Results: Thirty-four (33.3%) of patients with cirrhosis of liver had MHE; 20 (40%) with prior episode and 14 (26.9%) without prior episode of OHE had MHE. Patients with previous OHE episode showed learning impairment in PHES on repetition on 3rd day [Day 1, mean -3.70 (95% confidence intervals -4.71 -2.68) versus Day 3, -4.02 (-5.06-2.97); P = 0.084] as compared to patients without prior OHE episode [Day 1, -2.26 (-3.13 -1.40) versus Day 3, -0.44 (-1.24 0.35); P <0.0001] irrespective of having MHE or not. In this study, 57 patients were learners, i.e., 1point improvement in PHES (55.8%) and 45 patients were non-learners (44.2%). Univariate analysis demonstrated that Child-Turcotte-Pugh score, lactulose and/or rifaximin therapy, presence of MHE and previous OHE episode were associated with learning impairment. Multivariate analysis demonstrated that only presence of previous episode of OHE (adjusted odds ratio [95%, confidence interval; 38.398, 9.192 160.4]; p <0.0001) significantly affected learning. Conclusions: This study conclusively demonstrated learning impairment in cirrhotic patients with previous episode of OHEdespite normalmental status. Improvement in PHES on repetition can be used as a measure of learning in future studies.

Persistence of cognitive impairment after resolution of overt hepatic encephalopathy.

Hepatic encephalopathy (HE) represents a spectrum of neurocognitive impairment seen in cirrhotic patients and is considered to be fully reversible with treatment; however, recent evidence suggests otherwise. This longitudinal study was carried out to evaluate the persistence of cognitive impairment in cirrhotics with prior overt HE (OHE) episode despite treatment. Of the 213 patients screened, 107 patients who met the eligibility criteria were enrolled and 102 patients completed the study (52 patients without prior OHE episode and 50 patients with prior OHE). All patients underwent psychometric hepatic encephalopathy score (PHES) evaluation at three separate visits (day 1, day 3, and between 30 and 60 days). A one-point improvement in PHES between the first and second evaluation was considered as a measure of learning. Patients with a previous OHE episode showed learning impairment in PHES on repetition on day 3 (P=0.084), whereas patients without a previous OHE episode demonstrated learning effect (P<0.0001) irrespective of whether they had minimal HE (MHE) or not. Univariate analysis demonstrated that Child-Turcotte-Pugh score, lactulose and/or rifaximin therapy, the presence of MHE, and a previous OHE episode were associated with learning impairment. Multivariate analysis demonstrated that only the presence of a previous episode of OHE (adjusted odds ratio 38.398; 95% confidence interval 9.192-160.4; P<0.0001) significantly affected learning. This study conclusively demonstrated learning impairment in cirrhotic patients with a previous episode of OHE despite normal mental status. Improvement in PHES on repetition may be a measure of learning.

P451 COST EFFECTIVENESS OF RIFAXIMIN-a IN THE REDUCTION OF RECURRENCE OF OVERT HEPATIC ENCEPHALOPATHY

Introduction: Hepatic encephalopathy (HE) is associated with high morbidity and mortality. Rifaximin-α is effective in reducing the recurrence of episodes of overt HE. The aim was to characterise the cost effectiveness of rifaximin-α versus standard care (lactulose). Methods: This economic evaluation used a Markov state transition model. The outcome was the incremental cost effectiveness ratio (ICER), derived from estimates of the cost/quality adjusted life years. The payer perspective was that of UK National Health Service. Outcome data were from two trials of rifaximin-α. Population outcome data were from a complementary study of patients with liver cirrhosis treated within the NHS. Cost data (GBP£2012) were derived from published sources. Health-related utility was estimated indirectly from disease-specific trial QoL data. The time horizon was five years. Costs and benefits were discounted at 3.5%. Extensive sensitivity analysis was carried out. Results: The average cost of the included elements of care was £15,476 in the rifaximin-α arm and £4,486 in the lactulose arm, a difference of £10,990. The corresponding values for benefit was 2.36 QALYs, and 1.83 QALYs per person, respectively; a difference of 0.53 units. This translated into a base-case ICER of £20,852/QALY. Key parameters that impacted the ICER included the event-free survival pattern, ranging from an ICER of £13,919 using an exponential model, to £21,425/QALY using a log-logistic model. Evaluation to 10 years resulted in an ICER of £19,122/QALY. Conclusion: Rifaximin-α in patients with liver cirrhosis was cost effective compared to standard care, reducing episodes of overt hepatic encephalopathy.

Pre-transjugular intrahepatic portosystemic shunts (TIPS) prediction of post-TIPS overt hepatic encephalopathy: The Critical Flicker Frequency is more accurate than psychometric tests

Transjugular intrahepatic portosystemic shunts (TIPS) is a second-line treatment because of an increased incidence of overt hepatic encephalopathy (OHE). A better selection of patients to decrease this risk is needed and one promising approach could be the detection of minimal hepatic encephalopathy (MHE). The aim of the present prospective study was to determine whether pre-TIPS minimal hepatic encephalopathy was predictive of post-TIPS OHE and to compare Psychometric Hepatic Encephalopathy Sum Score(PHES) and the Critical Flicker Frequency (CFF) in this setting. From May 2008 to January 2011, 54 consecutive patients treated with TIPS were included. PHES and CFF were performed 1 to 7 days before and after TIPS at months 1, 3, 6, 9, and 12 or until liver transplantation or death. Before TIPS, MHE was detected by PHES and CFF in 33% and 39% of patients, respectively. After the TIPS procedure, 19 patients (35%) experienced a total of 64 episodes of OHE. OHE developed significantly more often inpatients for whom an indication for TIPS had been refractory ascites, with a history of OHE or of renal failure, lower hemoglobin level, or MHE as diagnosed by CFF. Post-TIPS OHE was more accurately predicted by CFF than by PHES. Absence of MHE at CFF had a good negative predictive value (91%) for the risk of post-TIPS recurrent OHE, defined as the occurrence of three or more episodes of OHE or of one episode which lasted more than 15 days. The absence of pre-TIPS history of OHE and a CFF value equal to or greater than 39 Hz had a 100% negative predictive value for post-TIPS recurrent OHE. Aiming to decrease the rate of post-TIPS HE, the use of CFF could help selecting patients for TIPS.

The thalamus in cirrhotic patients with and without hepatic encephalopathy: A volumetric MRI study

Background & aimsThe thalamus is a major relay and filter station in the central neural system. Some previous studies have suggested that the thalamus maybe implicated in the pathogenesis of hepatic encephalopathy. The aim of our study was to investigate changing thalamic volumes in cirrhotic patients with and without hepatic encephalopathy. MethodsNeuropsychological tests and structural MR scanning were performed on 24 cirrhotic patients, 23 cirrhotic patients with minimal hepatic encephalopathy, 24 cirrhotic patients during their first episode of overt hepatic encephalopathy, and 33 healthy controls. Voxel-based morphometry analysis was performed to detect gray matter morphological changes. The thalamus and whole brain volume were extrapolated. A receiver operating characteristic curve analysis of thalamic volumes was used to discriminate patients with minimal hepatic encephalopathy from those with hepatic cirrhosis. ResultsThalamic volume increased in a stepwise manner in patients with progressively worse stages of hepatic encephalopathy compared to healthy subjects. Additionally, a comparison of gray matter morphometry between patients with Child–Pugh grades A, B, or C and controls revealed a progression in thalamic volumes in parallel with the degree of liver failure. Moreover, thalamic volume was significantly correlated with the number connection test A time and digit-symbol test score in cirrhotic patients with minimal hepatic encephalopathy (r=0.659, P=0.001; r=−0.577, P=0.004; respectively). The area under the receiver operating characteristic curve was 0.827 (P=0.001). ConclusionsA significantly increased thalamic volume may be provide an objective imaging measure for predicting seizures due to minimal hepatic encephalopathy in cirrhotic patients.

Probiotics in liver diseases

Alterations in intestinal microbiota and inflammatory response play a key role in disease progression and development of complications in liver diseases, mainly in cirrhosis and non-alcoholic steatohepatitis. Probiotics can be useful to delay disease progression and to prevent development of complications due to their ability to modulate intestinal flora, intestinal permeability and inflammatory response. Several studies have shown the efficacy of probiotics in the treatment of minimal hepatic encephalopathy and the prevention of episodes of overt hepatic encephalopathy. Probiotics have also been observed to prevent postoperative bacterial infections and to improve liver damage in non-alcoholic steatohepatitis. However, more studies are needed in order to confirm the efficacy and safety of probiotics in patients with liver diseases, and to better understanding of the mechanisms implicated in their effects.

Dynamic Changes of Intrinsic Brain Activity in Cirrhotic Patients after Transjugular Intrahepatic Portosystemic Shunt: A Resting-State fMRI Study

PurposeThe majority of cirrhotic patients who underwent transjugular intrahepatic portosystemic shunt (TIPS) experienced the first post-TIPS hepatic encephalopathy (HE) episode within the first three months after TIPS insertion. However, so far, little is known about the exact neuro-pathophysiological mechanism of TIPS's effects on brain function. We aimed to investigate the dynamics of brain function alteration of post-TIPS patients using resting-state functional MRI (rs-fMRI).Materials and MethodsSixteen cirrhotic patients who were scheduled for TIPS and 16 healthy controls were included in the rs-fMRI scans. Ten patients repeated the MRI study in a median 8-day follow-up interval following TIPS and seven in a median 3-month follow-up. The amplitude of low frequency fluctuation (ALFF), an index reflecting the spontaneous brain activity, was compared between patients before TIPS and healthy controls as well as patients pre- and post- TIPS.ResultsCompared with healthy controls, patients showed decreased ALFF in frontal and parietal regions and increased ALFF in insula. Patients who underwent the median 8-day follow-up fMRI examinations showed decreased ALFF in posterior cingulate cortex (PCC)/precuneus and increased ALFF in anterior cingulate cortex (ACC). Of 10 patients in this group, 9 had moderate to large increase rate of ALFF value (>20%, mean 49.19%) in ACC, while only one patient with the smallest increase rate of ALFF value (<10%) in ACC, who experienced three episodes of overt HE during the 3-month follow-up. In the median 3-month follow up observation, patients displayed persistently decreased ALFF in PCC, ACC and medial prefrontal cortex (MPFC), while no increased regional ALFF was observed.ConclusionTIPS insertion alters cirrhotic patients' ALFF patterns in the resting state, which may imply different short-term and moderate-term effects on cirrhotic patients, i.e., both impairment and compensatory mechanism of brain functions in peri-TIPS and continuous impairment of brain function 3 months following TIPS.

Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: An open labeled randomized controlled trial of lactulose versus no lactulose

Development of overt hepatic encephalopathy (HE) is associated with poor prognosis in patients with cirrhosis. Lactulose is used for the treatment of HE. There is no study on the prevention of overt HE using lactulose in patients who never had HE earlier. Consecutive cirrhotic patients who never had an episode of overt HE were randomized to receive lactulose (Gp-L) or no lactulose (Gp-NL). All patients were assessed by psychometry (number connection test [NCT-A and B], figure connection test if illiterate [FCT-A and B], digit symbol test [DST], serial dot test [SDT], line tracing test [LTT]) and critical flicker frequency test (CFF) at inclusion and after 3 months. These patients were followed every month for 12 months for development of overt HE. Of 250 patients screened, 120 (48%) meeting the inclusion criteria were randomized to Gp-L (n = 60) and Gp-NL (n = 60). Twenty (19%) of 105 patients followed for 12 months developed an episode of overt HE. Six (11%) of 55 in the lactulose (Gp-L) group and 14 (28%) of 50 in the Gp-NL (P = 0.02) developed overt HE. Ten (20%) of 50 patients in Gp-NL and five (9%) of 55 patients in the Gp-L group died, P = 0.16. Number of patients with minimal hepatic encephalopathy (MHE) were comparable in two groups at baseline (Gp-L vs Gp-NL, 32:36, P = 0.29). Lactulose improved MHE in 66% of patients in Gp-L. Taking a cutoff < 38 Hz sensitivity and specificity of CFF in predicting HE were 52% and 77% at baseline and 52% and 82% at 3 months of treatment. On multivariate analysis, Child's score and presence of MHE at baseline were significantly associated with development of overt HE. Lactulose is effective for primary prevention of overt hepatic encephalopathy in patients with cirrhosis.

Lactulose in the treatment of hepatic encephalopathy: New evidence for an old modality

See article in J. Gastroenterol. Hepatol. 2012; 27: 1329–1335.

Changes in cerebral blood flow after transjugular intrahepatic portosystemic shunt can help predict the development of hepatic encephalopathy: An arterial spin labeling MR study

Background and purposeCerebral blood flow (CBF) changes after transjugular intrahepatic portosystemic shunt (TIPS) are still unclear. Our aim is to assess the TIPS-induced CBF changes and their potential clinical significance using the arterial spin labeling (ASL) perfusion magnetic resonance imaging. Materials and methodsNine cirrhotic patients underwent ASL 1–8 days before and 4–7 days after TIPS. CBF was calculated at each voxel and mean CBF values were computed in the whole brain, gray matter and white matter. Changes of CBFs before and after TIPS were compared by paired t-test. ResultsVoxel-wise results showed CBF diffusely increased in patients after TIPS, but no region with significant decrease in CBF was found, nor was any significant mean CBF difference detected in the whole brain, gray matter and white matter. Six patients out of nine showed a global CBF increase of 9–39%; one patient presented a global CBF decrease of 6%; another two showed a global CBF decrease of 16% and 31% respectively. Follow-up studies showed that the two patients with greatly decreased global CBF suffered from multiple episodes of overt hepatic encephalopathy (OHE) after TIPS and one died of OHE. ConclusionsCBF derived from noninvasive ASL MRI could be used as a useful biomarker to predict the development of OHE through consecutively tracking CBF changes in patients with inserted TIPS. Increased CBFs in many cortical regions could be common effects of the TIPS procedure, while decreased global CBF following TIPS might indicate the development of OHE.

The Diagnosis and Treatment of Minimal Hepatic Encephalopathy

The subtype of hepatic encephalopathy (HE) called minimal hepatic encephalopathy (MHE) is highly prevalent (22-74%) among patients with liver dysfunction. MEH is defined as HE without grossly evident neurologic abnormalities, but with cognitive deficits that can be revealed by psychometric testing. This article is based on relevant original publications and reviews in English and German (1970-2011) that were retrieved by a selective key-word-based search in the Medline and PubMed databases. Despite its mild manifestations, MHE impairs patients' quality of life and their ability to work. It impairs driving ability and is associated with a higher rate of motor vehicle accidents. Furthermore, patients with MHE fall more often and are more likely to undergo progression to overt HE. The main pathophysiological mechanism of MHE is hyperammonemia leading to astrocyte dysfunction. Psychometric tests are the standard instruments for establishing the diagnosis; further, supportive diagnostic tools include neurophysiological tests and imaging studies. Recent randomized and controlled trials have revealed that treatment with lactulose or rifaximin therapy improves the quality of life of patients with MHE. Rifaximin was also found to improve driving performance in a simulator. A combination of these two drugs prevents the recurrence of episodic HE over a 6-months follow-up period. Moreover, small-scale trials have revealed that some dietary supplements can improve the cognitive deficits of MHE. Clinical trials have shown that patients with MHE and patients who have had an episode of overt HE in the past can benefit from drug treatment.

Primary Prophylaxis of Hepatic Encephalopathy in Patients with Cirrhosis: An Open Labeled Randomized Controlled Trial of Lactulose versus No Lactulose

Purpose: Development of hepatic encephalopathy (HE) is associated with poor prognosis in patients with cirrhosis. Lactulose is used for the treatment of HE. There is no study on the prevention of HE using lactulose in patients who never had HE earlier. Methods: Consecutive cirrhotic patients who never had an episode of HE were randomized to receive lactulose (Gp-L) or no lactulose (Gp-NL). All patients were assessed by psychometry [(number connection test (NCT-A and B), figure connection test if illiterate (FCT-A and B), digit symbol test (DST), serial dot test (SDT), line tracing test (LTT)] and critical flicker frequency test (CFF) at inclusion and after 3 months. These patients were followed monthly for development of overt HE. Results: Of 250 patients screened, 120(48%) meeting the inclusion criteria were randomized to Gp-L(n=60) and Gp-NL(n=60). Minimal hepatic encephalopathy (MHE) was present in (10/22, 45%) in Child A, (37/68, 54%) in Child B and (21/30, 70%) in Child C patients. Number of patients with MHE were comparable in two groups at baseline (Gp-L vx Gp-NL, 32:36, p=0.29). Lactulose improved MHE in 66% of patients in Gp-L. Patients diagnosed to have MHE had CFF significantly lower than those who did not had MHE in Gp-L (38.4±3.2 vs. 40.5±2.4 Hz, p=0.001) and in Gp-NL (38.8±2.8 vs. 41.7±3.2Hz, p=0.001). Twenty one (20%) of 105 patients followed over a median follow up of 12 mo developed an episode of overt HE. Six (11%) of 55 in the lactulose (Gp-L) group and 15(30%) of 50 in the Gp-NL (p=0.02) developed HE. Ten (20%) of 50 patients in Gp-NL and 5(9%) of 55 patients in Gp-L group died, p=0.16 Taking a cutoff < 38Hz sensitivity and specificity of CFF in predicting HE at baseline (52% and 77%) and at 3 month of treatment was (52% and 82%). On multivariate analysis CTP score and presence of MHE at baseline is significantly associated with development of HE. Conclusion: Lactulose is effective for primary prevention of hepatic encephalopathy in patients with cirrhosis.

159 Severity of Chronic Cognitive Impairment in Cirrhosis Increases With Number of Episodes of Overt Hepatic Encephalopathy

159 Severity of Chronic Cognitive Impairment in Cirrhosis Increases With Number of Episodes of Overt Hepatic Encephalopathy

Persistence of Cognitive Impairment After Resolution of Overt Hepatic Encephalopathy

In patients with cirrhosis, hepatic encephalopathy (HE) has acute but reversible as well as chronic components. We investigated the extent of residual cognitive impairment following clinical resolution of overt HE (OHE). Cognitive function of cirrhotic patients was evaluated using psychometric tests (digit symbol, block design, and number connection [NCT-A and B]) and the inhibitory control test (ICT). Improvement (reduction) in ICT lures and first minus second halves (DeltaL(1-2)) were used to determine learning of response inhibition. Two cross-sectional studies (A and B) compared data from stable cirrhotic patients with or without prior OHE. We then prospectively assessed cognitive performance, before and after the first episode of OHE. In study A (226 cirrhotic patients), 54 had experienced OHE, 120 had minimal HE, and 52 with no minimal HE. Despite normal mental status on lactulose after OHE, cirrhotic patients were cognitively impaired, based on results from all tests. Learning of response inhibition (DeltaL(1-2) > or =1) was evident in patients with minimal HE and no minimal HE but was lost after OHE. In study B (50 additional patients who developed > or =1 documented OHE episode during follow-up), the number of OHE hospitalizations correlated with severity of residual impairment, indicated by ICT lures (r = 0.5, P = .0001), digit symbol test (r = -0.39, P = .002), and number connection test-B (r = 0.33, P = .04). In the prospective study (59 cirrhotic patients without OHE), 15 developed OHE; ICT lure response worsened significantly after OHE (12 before vs 18 after, P = .0003), and learning of response inhibition was lost. The 44 patients who did not experience OHE did not have deteriorations in cognitive function in serial testing. In cirrhosis, episodes of OHE are associated with persistent and cumulative deficits in working memory, response inhibition, and learning.

Rifaximin has a Favorable Long-Term Safety Profile for Maintenance of Remission from Overt Hepatic Encephalopathy

Purpose: The minimally absorbed, gut-selective antibiotic rifaximin (550 mg twice daily [BID]) was effective in maintaining remission from overt hepatic encephalopathy (HE) in a randomized, double-blind, placebo-controlled, 6-month trial (RCT). This protective effect was sustained in a longterm, ongoing, open-label maintenance study (OLM). The safety profile of rifaximin as demonstrated in the RCT and OLM is described here. Methods: Patients (n=299) with cirrhosis and a history of ≥2 overt HE episodes (Conn score [CS] ≥2) within 6 months before screening and in remission (CS ≤ 1) were enrolled in the RCT. Patients who completed the RCT were permitted to rollover into the OLM. New patients who met eligibility requirements and had ≥1 HE episodes of CS ≥2 within the previous 12 months were also enrolled in the OLM. All patients had a CS ≤2 at enrollment. Results: A total of 336 patients were treated with rifaximin (550 mg BID) in the RCT and OLM for up to 840 days (mean: 274 days). Of these, 257 patients were on rifaximin for ≥ 6 months and 114 patients for ≥1 year. Most patients in the RCT and OLM received concomitant lactulose therapy. During treatment with rifaximin, the overall profile of adverse events (AEs) was consistent with expectations for patients with liver cirrhosis and a history of overt HE. In the RCT, the pattern of AEs was similar between the rifaximin (N=140) and placebo (N=159) groups, with AEs experienced by 80% of patients in each group. Fewer patients in the rifaximin group than the placebo group experienced severe AEs (26% vs. 31%), drugrelated AEs (19% vs. 21%), serious AEs (36% vs. 40%), and AEs leading to discontinuation (21% vs. 28%). Rifaximin did not adversely affect mortality, which occurred in 7% of patients in each group. The safety profile of rifaximin during long-term treatment (N=336) was similar to that in the RCT. When normalized for exposure duration, long-term treatment and increased exposure did not adversely impact the safety profile. Adverse event rates, including discontinuation rates and deaths were all lower during long term rifaximin therapy compared with the RCT rifaximin group. Clinical laboratory results were consistent with the cirrhotic population under study. Laboratory findings did not show hepatotoxic or nephrotoxic drug effects. Conclusion: The rates and spectrum of AEs were similar in patients on rifaximin therapy (plus lactulose) when compared with patients who received placebo (i.e., lactulose alone). The favorable long-term safety profile of rifaximin together with its previously demonstrated long-term efficacy in the maintenance of remission of HE support its preventive role in this potentially disabling complication of cirrhosis. Disclosure: Sheikh - Salix, grant; Bass - Salix: consultant, speaker bureau; Sanyal - Salix: consultant, research support; Poordad - Salix: grant/research, speaker bureau, advisory board; Mullen - Salix: grant, consultant, speaker bureau; Sigal - Salix: consultant, research support; Frederick - Salix: consultant, advisory board; Bhandari - Salix: consultant; Vemuru - Salix: consultant; Huang - Salix: employee; Merchant - Salix: employee; Shaw - Salix: employee; Bortey - Salix: employee; Forbes - Salix: employee. This research was supported by an industry grant from Salix Pharmaceuticals, Inc.

Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy

Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy

Hyponatremia Is a Risk Factor of Hepatic Encephalopathy in Patients With Cirrhosis: A Prospective Study With Time-Dependent Analysis

The aim of this study was to investigate whether hyponatremia is a risk factor of overt hepatic encephalopathy (HE) in cirrhosis. A total of 61 patients with cirrhosis were evaluated prospectively for 1 year and all episodes of overt HE were recorded. Predictive factors of HE were analyzed using a conditional model (Prentice, Williams, and Peterson) for recurrent events to assess the relationship between HE and time-dependent covariates. The effects of hyponatremia on the brain concentration of organic osmolytes were analyzed in 25 patients using 1 H-magnetic resonance spectroscopy. Twenty-eight of the 61 patients developed 57 episodes of overt HE during follow-up. Among a number of clinical and laboratory variables analyzed, the only independent predictive factors of overt HE were hyponatremia (serum sodium < 130 mEq / l), history of overt HE, serum bilirubin,and serum creatinine. Hyponatremia was associated with low brain concentration of organic osmolytes, particularly myo-inositol (MI). Furthermore, patients with low brain MI levels had a higher probability of development of overt HE compared with that of patients with high brain MI levels. In patients with cirrhosis, the existence of hyponatremia is a major risk factor of the development of overt HE. Treatment of hyponatremia may be a novel therapeutic approach to preventing HE in cirrhosis.

Low Cerebral Oxygen Consumption and Blood Flow in Patients With Cirrhosis and an Acute Episode of Hepatic Encephalopathy

It is unclear whether patients with hepatic encephalopathy (HE) have disturbed brain oxygen metabolism and blood flow. We measured cerebral oxygen metabolism rate (CMRO(2)) by using (15)O-oxygen positron emission tomography (PET); and cerebral blood flow (CBF) by using (15)O-water PET in 6 patients with liver cirrhosis and an acute episode of overt HE, 6 cirrhotic patients without HE, and 7 healthy subjects. Neither whole-brain CMRO(2) nor CBF differed significantly between cirrhotic patients without HE and healthy subjects, but were both significantly reduced in cirrhotic patients with HE (P < .01). CMRO(2) was 0.96 +/- 0.07 mumol oxygen/mL brain tissue/min (mean +/- SEM) in cirrhotic patients with HE, 1.34 +/- 0.08 in cirrhotic patients without HE, and 1.35 +/- 0.05 in healthy subjects; and CBF was 0.29 +/- 0.01 mL blood/mL brain tissue/min in patients with HE, 0.47 +/- 0.02 in patients without HE, and 0.49 +/- 0.03 in healthy subjects. CMRO(2) and CBF were correlated, and both variables correlated negatively with arterial ammonia concentration. Analysis of regional values, using individual magnetic resonance co-registrations, showed that the reductions in CMRO(2) and CBF in patients with HE were essentially generalized throughout the brain. The observations imply that reduced cerebral oxygen consumption and blood flow in cirrhotic patients with an acute episode of overt HE are associated with HE and not cirrhosis as such, and that the primary event in the pathogenesis of HE could be inhibition of cerebral energy metabolism by increased blood ammonia.