Prevention Of Overt Hepatic Encephalopathy Research Articles

WED-319 - Rifaximin plus lactulose is more effective than lactulose alone for the prevention of overt hepatic encephalopathy in patients with or without diabetes

WED-319 - Rifaximin plus lactulose is more effective than lactulose alone for the prevention of overt hepatic encephalopathy in patients with or without diabetes

FRI508 - Simultaneous large spontaneous portosystemic shunt embolization for the prevention of overt hepatic encephalopathy after TIPS: a randomized controlled trial

FRI508 - Simultaneous large spontaneous portosystemic shunt embolization for the prevention of overt hepatic encephalopathy after TIPS: a randomized controlled trial

Concurrent large spontaneous portosystemic shunt embolization for the prevention of overt hepatic encephalopathy after TIPS: A randomized controlled trial.

Large spontaneous portosystemic shunt (SPSS) is associated with increased risk of HE in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). This study aimed to evaluate whether prophylactic embolization of large SPSS at the time of TIPS creation could reduce the incidence of post-TIPS HE in patients with cirrhosis and variceal bleeding. From June 2014 to August 2017, 56 patients with cirrhosis and large SPSS planning to undergo TIPS for the prevention of variceal bleeding were randomly assigned (1:1) to receive TIPS alone (TIPS group, n=29) or TIPS plus simultaneous SPSS embolization (TIPS+E group, n=27). The primary endpoint was overt HE. TIPS placement and SPSS embolization was successful in all patients. During a median follow-up of 24 months, the primary endpoint was met in 15 patients (51.7%) in the TIPS group and six patients (22.2%) in the TIPS+E group (p=0.045). The 2-year cumulative incidence of overt HE was significantly lower in the TIPS+E group compared with the TIPS group (21.2% vs. 48.3%; HR, 0.38; 95% CI, 0.15-0.97; p=0.043). The 2-year incidence of recurrent bleeding (TIPS+E vs. TIPS, 15.4% vs. 25.1%; p=0.522), shunt dysfunction (12.3% vs. 18.6%, p=0.593), death (15.0% vs. 6.9%, p=0.352), and other adverse events was not significantly different between the two groups. In patients with cirrhosis treated with TIPS for variceal bleeding, concurrent large SPSS embolization reduced the risk for overt HE without increasing other complications. Concurrent large SPSS embolization should therefore be considered for prophylaxis of post-TIPS HE.

The Prevalence and Association of Cognitive Impairment with Sleep Disturbances in Patients with Chronic Liver Disease.

Introduction/Aim. The aim of this study was to assess the prevalence of cognitive impairments and their association with sleep patterns in a cohort of patients diagnosed with chronic liver disease (CLD). Material and methods. The present paper is a prospective cohort study, carried out over a period of 12 months, among patients with various stages of CLD. We evaluated the cognitive function through psychometric hepatic encephalopathy score (PHES), while sleep was assessed by actigraphy and two self-reported questionnaires: Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). Results. Seventy-four patients with CLD were considered eligible and were enrolled between December 2020–November 2021. The prevalence of minimal hepatic encephalopathy (MHE) in the entire cohort was 41.9%, and the diagnosis was considered for PHES scores ≤ −3. Patients with cirrhosis recorded significantly lower PHES scores compared to patients with other CLDs but without cirrhosis (−3.19 ± 3.89 vs. 0.19 ± 2.92, p < 0.05). Patients who exhibited MHE suffered from poor sleep, daytime somnolence, disturbed nighttime sleep, and low overall sleep efficacy. Patients diagnosed with MHE and undergoing treatment with lactulose and/or rifaximin for prevention of overt hepatic encephalopathy (HE) showed better results in terms of sleep parameters compared to patients diagnosed with MHE but without treatment. Conclusions. This research increases awareness regarding the connection between sleep features and MHE in patients with cirrhosis and other CLDs. A deeper insight into the subclinical stages of HE and associated sleep disturbances is warranted in future studies.

In patients having transjugular intrahepatic portosystemic shunt, rifaximin prevented overt hepatic encephalopathy.

Bureau C, Thabut D, Jezequel C, et al. The use of rifaximin in the prevention of overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled trial. Ann Intern Med. 2021;174:633-40. 33524293.

The Use of Rifaximin in the Prevention of Overt Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt : A Randomized Controlled Trial.

The efficacy of rifaximin in the secondary prevention of overt hepatic encephalopathy (HE) is well documented, but its effectiveness in preventing a first episode in patients after transjugular intrahepatic portosystemic shunt (TIPS) has not been established. To determine whether rifaximin prevents overt HE after TIPS compared with placebo. Randomized, double-blind, multicenter, placebo-controlled trial. (ClinicalTrials.gov: NCT02016196). 197 patients with cirrhosis undergoing TIPS for intractable ascites or prevention of variceal rebleeding. Patients were randomly assigned to receive rifaximin (600 mg twice daily) or placebo, beginning 14 days before TIPS and continuing for 168 days after the procedure. The primary efficacy end point was incidence of overt HE within 168 days after the TIPS procedure. An episode of overt HE occurred in 34% (95% CI, 25% to 44%) of patients in the rifaximin group (n = 93) and 53% (CI, 43% to 63%) in the placebo group (n = 93) during the postprocedure period (odds ratio, 0.48 [CI, 0.27 to 0.87]). Neither the incidence of adverse events nor transplant-free survival was significantly different between the 2 groups. The study's conclusion applies mainly to patients with alcoholic cirrhosis, who made up the study population. The potential benefit of rifaximin 6 months after TIPS and beyond remains to be investigated. In patients with cirrhosis treated with TIPS, rifaximin was well tolerated and reduced the risk for overt HE. Rifaximin should therefore be considered for prophylaxis of post-TIPS HE. French Public Health Ministry.

Budget impact of optimizing rifaximin-α use for the prevention of recurrent hepatic encephalopathy in The Netherlands

Aims Rifaximin-α as an adjunct to lactulose is reimbursed in the Netherlands for prevention of the third and subsequent episodes of overt Hepatic Encephalopathy (HE) in cirrhotic patients. However, use of rifaximin-α remains limited. This study evaluates the clinical and economic impact of treating all patients eligible under Dutch reimbursement conditions with rifaximin-α as an adjunct to lactulose for the prevention of overt HE in the Netherlands from a hospital and healthcare payer’s perspective. Materials and methods A budget impact analysis was performed following national and international guidelines. Resource use was based on Dutch real-world data. HE-related cost inputs were based on the declaration codes, Dutch cost manual, and actual drug list prices. Several sensitivity and scenario analyses were conducted to assess model robustness. Results Treating eligible HE patients with rifaximin-α in addition to lactulose saves €4,487 and costs €249 per patient over a 5-year period compared with lactulose monotherapy from hospital and healthcare payer’s perspectives, respectively. In the Netherlands, an estimated 38% of the 2,567 eligible patients are currently being treated with rifaximin-α. Optimizing rifaximin-α use by treating all eligible patients with the rifaximin-α + lactulose could save more than 3,000 hospital admissions, almost 15,000 hospital bed days, and 300 deaths over a 5-year period. Despite increased drug costs, treatment is estimated to result in potential cost savings over a 5-year period of 7.2 million euros from a Dutch hospital perspective. The budget impact is 397,770 euros from a healthcare payer’s perspective. Conclusions Next to a clinical perspective, also from an economic perspective, wider prescription of rifaximin-α adhering to guidelines could be beneficial to reduce costs from a hospital perspective. From a healthcare payer’s perspective, costs increase with addition of rifaximin-α due to relative better survival causing relatively higher drug and liver transplantation-related costs.

Lactulose improves cognition, quality of life, and gut microbiota in minimal hepatic encephalopathy: A multicenter, randomized controlled trial.

Lactulose is effective in the treatment and prevention of overt hepatic encephalopathy (OHE), but there are limited data on its use on microbiota in relations to minimal hepatic encephalopathy (MHE) recovery. The present study aimed to assess the efficacy of lactulose in recovery of MHE in aspects of cognitive function, quality of life, and impact on intestinal microbiota. This multicenter, open-label randomized controlled trial was conducted in 11 teaching hospitals in China. Participants were randomly allocated on a 2:1 basis to receive lactulose (Gp-L) or no therapy as control (Gp-NL) for 60 days. The primary endpoint was the MHE reversal rate. Gut microbiota were compared between MHE patients and healthy volunteers, as well as lactulose-responders and non-responders. A total of 98 cirrhotic patients were included in the study, with 31 patients in the Gp-NL group and 67 patients in the Gp-L group. At day 60, the MHE reversal rate in Gp-L (64.18%) was significantly higher than that in Gp-NL (22.58%) (P = .0002) with a relative risk of 0.46 (95% confidence interval 0.32-0.67). Number needed to treat was 2.4. Further, there was significantly more improvement in physical functioning in Gp-L (4.62 ± 6.16) than in Gp-NL (1.50 ± 5.34) (P = .0212). Proteobacteria was significantly higher in MHE patients compared with healthy volunteers (12.27% vs 4.65%, P < .05). Significant differences were found between lactulose responders and non-responders in Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. Treatment with lactulose significantly improves MHE recovery rate, and gut microbiota change in MHE patients can modulate the effectiveness of this therapy. Chinese Clinical Trial Register (ChiCTR) (ID: ChiCTR-TRC-12002342).

Comparative Efficacy of Treatment Options for Minimal Hepatic Encephalopathy: A Systematic Review and Network Meta-Analysis

We aimed to synthesize evidence for most effective treatments for minimal hepatic encephalopathy (HE) and prevention of overt HE in patients with cirrhosis. We performed a systematic search of the PubMed, EMBASE, OvidSP, and Cochrane Central Register of Controlled Trials databases through July 26, 2018, for randomized controlled trials evaluating treatments for minimal HE in patients with cirrhosis, with primary outcomes of reversal of minimal HE or prevention of overt HE. We conducted a meta-analysis and then used network meta-analysis and surface under cumulated ranking (SUCRA) to pool the direct and indirect estimates and rank the different treatments. We appraised study quality using the Grading of Recommendations Assessment, Development and Evaluation system. Our meta-analysis and network meta-analysis included 25 trials, comprising 1563 participants. Agents found to be effective in reversing minimal HE compared with placebo or no treatment included rifaximin (odds ratio [OR], 7.53; 95% predictive interval [PrI], 4.45-12.73; SUCRA, 89.2%; moderate quality), lactulose (OR, 5.39; 95% PrI, 3.60-8.0; SUCRA, 67.2%; moderate quality), the combination of probiotics and lactulose (OR, 4.66; 95% PrI, 1.90-11.39; SUCRA, 52.4%; low quality), L-ornithine L-aspartate (OR, 4.45; 95% PrI, 2.67-7.42; SUCRA, 47.2%; low moderate quality), and probiotics (OR, 3.89; 95% PrI, 2.52-6.02; SUCRA, 34.1%; low quality). Agents found to be effective in preventing episodes of overt HE compared with placebo or no treatment included L-ornithine L-aspartate (OR, 0.19; 95% PrI, 0.04-0.91; SUCRA, 75.1%; high moderate quality), lactulose (OR, 0.22; 95% PrI, 0.09-0.52; SUCRA, 73.9%; moderate quality), and probiotics (OR, 0.27; 95% PrI, 0.11-0.62; SUCRA, 59.6%; low quality). In a meta-analysis of data from 25 trials, we found rifaximin and lactulose to be most effective for reversal of minimal HE in patients with cirrhosis. L-ornithine L-aspartate and lactulose are most effective in the prevention of overt HE. Lactulose was the only agent that was effective in reversing minimal HE, preventing overt HE, reducing ammonia, and improving quality of life, with tolerable adverse effects. International prospective register of systematic reviews ID:107003.

Intravenous and Oral Hyperammonemia Management

Hyperammonemia have significant morbidity and mortality. In this paper, we reviewed the latest research and evidence of both conventional and upcoming oral or intravenous treatments. New updates on the role of oral agents such as rifaximin, PEG, probiotics, glycerol phenylbutyrate, and zinc supplements in the management of both chronic hyperammonemia and overt hepatic encephalopathy have been discussed in this review. We discussed the recent findings on the role of branched-chain amino acids in patients with cirrhosis. Rifaximin role has expanded as mono or combination therapy in patients with hepatic encephalopathy. Probiotics and zinc might play a role in the prevention of overt hepatic encephalopathy. Newer oral agents such as activated carbon seem to be promising. Saline or albumin might play a role in diuretic-induced hyperammonemia but their role is yet to be determined. More research is needed for new interventions and treatment validation.

Assessment of Potential Impact of Demographic and Baseline Disease Characteristics on Rifaximin Monotherapy versus Lactulose Combination Therapy for the Prevention of Overt Hepatic Encephalopathy (OHE) Recurrence

Introduction: Rifaximin 550 mg is indicated for prevention of OHE recurrence in adults. A phase 4, open-label noninferiority trial evaluated the impact of baseline parameters on the efficacy of rifaximin alone vs rifaximin + lactulose for OHE recurrence prevention. Methods: Adults with cirrhosis and a previous OHE episode now in remission (Conn score ≤1) were randomized to rifaximin 550 mg BID alone or rifaximin 550 mg BID + lactulose (self-titrated; 2-3 soft stools/d) for 6 months. Breakthrough HE (Conn score ≥2) was monitored monthly. Time to onset of an OHE episode (primary endpoint) was assessed overall and by baseline parameters: age (< 65 y; ≥65 y), sex, race, prior lactulose use, diabetes status, MELD score, Conn score (0; 1), Child-Pugh class, asterixis grade (0; ≥1), duration of HE remission before study entry (≤90 days; >90 days), time since first diagnosis of advanced liver disease (< 50 months; 50 months), time since first diagnosis of HE (< 15 months; ≥15 months), number of HE episodes during past 6 months (1; >1), and cirrhosis etiology. Noninferiority was demonstrated if the upper limit 2-sided, 95% CI of hazard ratio (HR) of rifaximin to rifaximin + lactulose was < 1.6. Results: 113 patients were treated in the rifaximin alone group; 108 in rifaximin + lactulose group. Overall population mean MELD score was 11.9, 39.8% and 55.7% were Child-Pugh A and B, respectively, and baseline parameters were similar between groups. Breakthrough HE was reported in fewer patients in rifaximin + lactulose (13.9%) vs rifaximin alone (24.8%) groups; rifaximin + lactulose reduced the risk of breakthrough HE over 6 months to a greater degree (rifaximin alone vs combination HR, 2.0; 95% CI, 1.0-3.7; P=0.04). Demographic and baseline characteristics evaluated did not substantially alter the risk profile with rifaximin alone vs rifaximin + lactulose. In some subgroups (ie, Child-Pugh A [HR, 0.7; 95% CI, 0.2-2.4; P=0.6], remission duration >90 days [HR, 0.9; 95% CI, 0.4-2.1; P=0.7], prior 6-month HE episodes >1 [HR, 0.9; 95% CI, 0.3-2.7; P=0.9]), rifaximin alone reduced the risk of breakthrough HE to a greater degree than rifaximin + lactulose (ie, HR < 1); however, differences were not significant. Conclusion: Rifaximin + lactulose therapy appears to be consistently efficacious in prevention of OHE recurrence vs rifaximin alone and was unaltered by baseline characteristics evaluated. These data support the generalizability of the primary endpoint results.

The Effects of Probiotics and Symbiotics on Risk Factors for Hepatic Encephalopathy: A Systematic Review.

Alterations in the levels of intestinal microbiota, endotoxemia, and inflammation are novel areas of interest in the pathogenesis of hepatic encephalopathy (HE). Probiotics and symbiotics are a promising treatment option for HE due to possible beneficial effects in modulating gut microflora and might be better tolerated and more cost-effective than the traditional treatment with lactulose, rifaximin or L-ornithine-L-aspartate. A systematic search of the electronic databases PubMed, ISI Web of Science, EMBASE, and Cochrane Library was conducted for randomized controlled clinical trials in adult patients with cirrhosis, evaluating the effect of probiotics and symbiotics in changes on intestinal microflora, reduction of endotoxemia, inflammation, and ammonia, reversal of minimal hepatic encephalopathy (MHE), prevention of overt hepatic encephalopathy (OHE), and improvement of quality of life. Nineteen trials met the inclusion criteria. Probiotics and symbiotics increased beneficial microflora and decreased pathogenic bacteria and endotoxemia compared with placebo/no treatment, but no effect was observed on inflammation. Probiotics significantly reversed MHE [risk ratio, 1.53; 95% confidence interval (CI): 1.14, 2.05; P=0.005] and reduced OHE development (risk ratio, 0.62; 95% CI: 0.48, 0.80; P=0.0002) compared with placebo/no treatment. Symbiotics significantly decreased ammonia levels compared with placebo (15.24; 95% CI: -26.01, -4.47; P=0.006). Probiotics did not show any additional benefit on reversal of MHE and prevention of OHE development when compared with lactulose, rifaximin, and L-ornithine-L-aspartate. Only 5 trials considered tolerance with minimal side effects reported. Although further research is warranted, probiotics and symbiotics should be considered as an alternative therapy for the treatment and management of HE given the results reported in this systematic review.

Comparative Effectiveness of Different Pharmacological Interventions for the Treatment of Minimal Hepatic Encephalopathy: A Systematic Review With Network Meta-analysis

Background and Aims: Minimal hepatic encephalopathy (MHE) is the mildest presentation of hepatic encephalopathy (HE), which includes a spectrum of neuropsychiatric manifestations ranging from subtle cognitive decline to deep coma. MHE has been shown to impair quality of life, predict overt HE (OHE), and even death. Various treatment modalities including lactulose, rifaximine, probiotics, branched chain amino acids and ammonia scavengers have shown benefit in MHE. However, due to a paucity of comparative studies, a clear consensus on the optimal treatment of MHE is yet to be reached. To address this deficiency, we evaluated the comparative effectiveness of all agents used for treatment of MHE using a network meta-analysis, combining direct and indirect treatment comparisons of all available randomized clinical trials(RCTs). Methods: We performed a systematic search of the PubMed, EMBASE, OvidSP and CENTRAL databases for RCTs of adults with MHE that compared the effectiveness of active interventions [Lactulose, l-Ornithine l-Aspartate (LOLA), rifaximine, pre-/pro-/synbiotics (PPS), branched chain amino acids(BCAA), alone or in combination] with each other or placebo. We used Bayesian network meta-analysis to combine direct and indirect evidence to estimate odds ratios (ORs) between treatments, and used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence. Results: We identified 27 RCTs (2056 participants) comparing 5 different interventions for reversal of minimal HE and 21 RCTs (1162 participants) comparing 4 different interventions to prevent the development of overt HE. In network meta-analysis, in the order of superiority, rifaximine [odds ratio (OR), 8.14; 95% predictive interval (PrI), 4.49–14.74], lactulose (OR, 5.64; 95% PrI, 3.64–8.73), probiotics + lactulose (OR, 4.72; 95% PrI, 1.22–18.28), LOLA (OR, 4.43; 95% PrI, 2.39–8.22), PPS (OR, 4.37; 95% PrI, 2.66–7.19) and BCAA (OR, 2.16; 95% PrI, 1.03–4.56), showed significant improvement in reversal of minimal HE compared to placebo or no intervention. Rifaximin was superior to BCAA (OR, 0.27; 95% PrI, 0.10–0.69), PPS (OR, 0.54; 95% PrI, 0.28–1.03), LOLA (OR, 0.54; 95% PrI, 0.26–1.14), probiotics + lactulose (OR, 0.58; 95% PrI, 0.14–2.38, lactulose (OR, 0.69; 95% PrI, 0.38–1.25) in reversing MHE. In terms of prevention of development of OHE, LOLA (OR 0.16; 95% PrI, 0.04–0.64), lactulose (OR, 0.21; 95% PrI, 0.09–0.48), PPS (OR, 0.25; 95% PrI, 0.11–0.59), but not rifaximine (OR 0.44; 95% PrI, 0.09–2.04), significantly reduced the risk when compared to placebo or no treatment. However, none of the agents were found to be superior to the others in prevention of OHE. Conclusion: There is a moderate quality evidence to suggest that rifaximine followed by lactulose are the most effective interventions for reversal of MHE. For prevention of development of OHE, LOLA (low quality) followed by lactulose (moderate quality) were most effective. Lactulose is the only agent that is effective both in improving reversal of minimal HE and reducing the risk of development of overt HE (Figure 1, Figure 2).Figure 2SUCRA plots of the under the cumulative ranking curves for all treatments in (a) minimal HE reversal network and (b) development of overt HE network.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The authors have none to declare.

A Meta-analysis on the Role of Probiotics in the Prevention of Overt Hepatic Encephalopathy

Overt hepatic encephalopathy (OHE) is a strong predictor of subsequent episodes of OHE, hospitalizations and mortality. Latest practice guidelines have yet to recommend any treatment for the primary prophylaxis of OHE. Lactulose has been the mainstay of treatment only for secondary prophylaxis, but its use suffers from side effects. Probiotics in recent trials have been found to be effective in preventing the occurrence of OHE without the side effects associated with lactulose. Comprehensive literature search of PubMed, Cochrane Central Register of Controlled Trials, EMBASE and reference lists was done. Studies on adults with liver cirrhosis, without OHE at the time of enrollment, with at least 1 month follow-up period, were included. The authors independently reviewed each included trial. Quality of included studies was assessed using the Cochrane Collaboration’s tool for evaluating risk of bias. Seven studies were included in the meta-analysis. Probiotics significantly reduced the development of OHE (RR (CI 95%): 0.49[0.37,0.65], P<0.00001), regardless of history of prior OHE. As primary prophylaxis and secondary prophylaxis, probiotics significantly reduced the development of OHE (Primary: RR (CI 95%): 0.52[0.28,0.95], P=0.03; Secondary: RR (95% CI): 0.64[0.48,0.85], P=0.002). Probiotics did not provide any mortality benefit, whether given as primary or secondary prophylaxis (Overall: RR (CI 95%): 0.79[0.53,1.19], P=0.26; Primary: RR (CI 95%): 0.80[0.30,2.14], P=0.67; Secondary: RR (CI 95%): 0.77[0.49,1.23], P=0.68). Probiotics, whether as primary or secondary prophylaxis, are effective in preventing OHE in patients with liver cirrhosis. Role of probiotics in reducing mortality is still uncertain. Studies with larger sample sizes and longer duration are recommended.

PWE-101 A single centre experience of rifaximin in the prevention of recurrent hepatic encephalopathy

Introduction Rifaximin is a non-absorbable, broad spectrum antibiotic that is used for the treatment and prevention of overt hepatic encephalopathy (HE). It acts locally in the gut to reduce intestinal flora, including ammonia-producing species, with hyperammonaemia considered to play a central role in the pathogenesis of HE. Our aim was to assess the tolerability and efficacy of rifaximin at preventing HE-related hospital admissions at our transplant unit. Method Medical records for all patients who were commenced on rifaximin for recurrant HE at our transplant unit between March 2012 and August 2014 were evaluated. Patient demographics, concurrent therapy, MELD, UKELD and number of hospital admissions were collected 6 months prior to initiation of rifaximin therapy and then 6 months following treatment. Continuous variables are presented as median (interquartile range). Results 23 patients with HE (median age 64 (53–68) years; 14 males) were commenced on Rifaximin. Nine had ALD, 8 had NASH, 2 had PBC, and one each had alpha-1 antitrypsin deficiency, PSC, Hepatitis C and secondary biliary cirrhosis. MELD and UKLED at commencement were 13 (11–21) and 55 (50–58) respectively. All were prescribed lactulose and 6 had tried neomycin and 1 metronidazole. Of the 23 patients, six died and one was transplanted within six months of starting treatment, one was discharged back to the local hospital. Treatment was withdrawn in one patient due to diarrhoea (non-infective). Thus, 14 patients were included in the final analysis. The number of hospital admissions for overt HE fell significantly between the six months prior to and the six months after commencing rifaximin, from 2 (1–3) to 0(0–1.25), p = 0.003. There was no observed change in the MELD or UKELD scores during the six months of treatment (12.5 vs 12, p = 0.9 and 51 vs 51, p = 0.2 respectively). In one patient, the HE improved to the extent that she was able to be removed from the transplant waiting list. Three of the 14 patients were being treated for recurrent HE post TIPSS insertion. In this subgroup of patients, there was no reduction in the number of hospital admissions with HE (2 vs 2, p = 0.4). None of the patients developed C difficile infection. Conclusion Rifaximin is effective at reducing the number of hospital admissions in patients with recurrent HE. We would recommend a trial of treatment with rifaximin in patients who are being considered for liver transplant because of recurrent HE, with otherwise well preserved hepatic synthetic function. We did not observe a benefit of rifaximin at preventing hospital admissions in patients with post-TIPSS recurrent HE. Rifaximin is well tolerated and proved to be safe. Disclosure of interest None Declared.

A Model for Predicting Development of Overt Hepatic Encephalopathy in Patients With Cirrhosis

Overt hepatic encephalopathy (HE) affects patients' quantity and quality of life and places a burden on families. There is evidence that overt HE might be prevented pharmacologically, but prophylaxis would be justified and cost effective only for patients at risk. We aimed to identify patients with cirrhosis at risk for overt HE. We collected data from October 2009 through December 2012 for 216 consecutive patients with cirrhosis (based on liver biopsy, 96 patients with minimal HE), admitted to the Gastroenterology Unit at the University of Rome. Patients were followed up and evaluated for an average of 14.7 ± 11.6 months; development of overt HE was recorded. We analyzed end-stage liver disease scores, shunt placement, previous overt or minimal HE, psychometric hepatic encephalopathy score (PHES), and levels of albumin, bilirubin, creatinine, and sodium to develop a prediction model. We validated the model in 112 patients with cirrhosis seen at the University of Padua and followed up for 12 ± 9.5 months. During the follow-up period, 68 patients (32%) developed at least 1 episode of overt HE. Based on multivariate analysis, the development of overt HE was associated with previous HE, minimal HE (based on PHES), and level of albumin less than 3.5 g/dL (area under curve [AUC], 0.74). A model that excluded minimal HE but included albumin level and previous HE also identified patients who would develop overt HE (AUC, 0.71); this difference in AUC values was not statistically significant (P = .104). Both models were validated in the independent group of patients (3 variables: AUC, 0.74; 95% confidence interval, 0.66-0.83; and 2 variables: AUC, 0.71; 95% confidence interval, 0.63-0.78). We developed and validated a model to identify patients with cirrhosis at risk for overt HE based on previous HE, albumin levels, and PHES. If PHES was not available, previous HE and albumin levels still can identify patients at risk. Psychometric evaluation is essential for patients with no history of HE. These findings should aid in planning studies of pharmacologic prevention of overt HE.

Management of Hepatic Encephalopathy in the Hospital

Hepatic encephalopathy (HE) develops in up to 50% of patients with cirrhosis and is a feature of decompensated cirrhosis. With the goal of reviewing the evidence for treatment and prevention of overt hepatic encephalopathy, pubmed was searched using search terms hepatic encephalopathy AND treatment, limited to human studies from January 1, 2003, through December 1, 2013, and supplemented by key references. The inpatient incidence of HE is approximately 23,000 annually, and management of these patients is common for internists and subspecialists. Treatment of the hospitalized patient with HE has changed in recent years. Treatment entails 2 phases: induction and maintenance of remission. Most cases of significant HE are precipitated by infection, gastrointestinal bleeding, medications, or other culprits. All patients should be evaluated for secondary triggers of HE, and treatment should be initiated with a nonabsorbable disaccharide (ie, lactulose) in most patients. Rifaximin (off label) can be added in patients not responding to lactulose. Neomycin is a less preferred alternative to rifaximin owing to its adverse effect profile. Other therapies, including zinc, L-ornithine-L-aspartate, and branched-chain amino acids, can be considered for patients not responding to disaccharides and nonabsorbable antibiotics. Large portosystemic shunts may be embolized in patients with medically refractory recurrent or severe HE with otherwise well-compensated cirrhosis. Molecular Adsorbent Recirculating System is now available for patients with severe HE who do not respond to medical therapy. It is critically important that patients hospitalized with significant HE continue maintenance therapy at the time of dismissal to prevent further episodes. Patients with a first-time episode of HE can be administered lactulose, and careful instructions should be provided to patients and caregivers about dose titration to achieve 3 bowel movements daily. Patients with recurrent HE episodes despite lactulose use benefit from the addition of rifaximin, which decreases the frequency of recurrent HE episodes and related hospitalizations. Last, patients and their families should be counseled about the risk of motor vehicle accidents, which require mandatory reporting to the Department of Motor Vehicles in some states.

Update on Management of Patients With Overt Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a multifactorial neuropsychiatric disease that affects patients with cirrhosis. We review the clinical impact, pathogenesis, evaluation, management, and prevention of overt HE in patients with cirrhosis. Articles published between January 1960 and November 2012 were acquired through a MEDLINE search of different combinations of the terms hepatic encephalopathy, pathophysiology, treatment, prophylaxis, prevention, prognosis, and recurrence. The Healthcare Cost and Utilization Project database was used to obtain prevalence and cost information related to hospitalizations of patients with HE. The literature describes significant morbidity and mortality of HE in patients with cirrhosis. Overt HE develops in 30% to 45% of patients with cirrhosis and is associated with a substantial pharmacoeconomic burden, particularly HE-related hospitalizations. The development of HE in patients with cirrhosis portends a worsened prognosis and is incorporated into the Child-Pugh classification of the severity of liver disease. In the hospitalized patient, the development of HE is associated with precipitating events (eg, gastrointestinal bleeding, dehydration, infection), and in some patients, its course is characterized by frequent and severe relapses. In addition, hospitalized patients with overt HE have a 3.9-fold increased mortality risk. Patient management employs nonabsorbable disaccharides, the nonsystemic antibiotic rifaximin, or both, to treat acute HE episodes and prevent HE relapse. In open-label trials, use of the nonabsorbable disaccharide lactulose reduced the risk of overt HE recurrence in patients compared with no-lactulose control groups for ≤ a median of 14 months. In a randomized, placebo-controlled trial, rifaximin 550 mg twice daily was more effective in maintaining HE remission compared with placebo and was associated with a reduction in HE-related hospitalizations. Recent advances in treatment and preventative therapies may reduce the personal, societal, and economic impact of this disorder.

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.