Episodes Of Hepatic Encephalopathy Research Articles

Relative Sarcopenia With Excess Adiposity Predicts Survival After Transjugular Intrahepatic Portosystemic Shunt Creation.

OBJECTIVE. The purpose of this study was to assess the impact of relative sarcopenia with excess adiposity on mortality after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS. In this single-institution retrospective study, patients underwent abdominal CT scans within 100 days before or 30 days after TIPS creation. Subcutaneous and visceral adipose tissue and muscle were segmented at the L3 vertebral level. Relative sarcopenia with excess adiposity was defined as the lowest sex-specific quartile of muscle area divided by muscle plus adipose. Dates of death, liver transplantation, TIPS occlusion, and hepatic encephalopathy (HE) after TIPS creation were identified. Mortality was evaluated using competing risks survival analysis. Number of HE episodes and time to first episode were analyzed using negative binomial regression and competing risks survival analysis, respectively. RESULTS. A total of 141 patients (91 men; mean age, 56 years) were included in this study. In univariate analyses, Model for End-Stage Liver Disease (MELD) score (hazard ratio [HR], 1.09 per point; CI, 1.05-1.13; p < 0.001) and relative sarcopenia with excess adiposity (HR, 2.70; CI, 1.55-4.69; p < 0.001) were significant risk factors for shorter survival after TIPS. In multivariate analysis, both MELD score (HR, 1.09; CI, 1.03-1.15; p = 0.003) and relative sarcopenia with excess adiposity (HR, 2.65; CI, 1.56-4.51; p < 0.001) were significant predictors of worse survival. The C-index at 30 days was 0.71 for MELD score, 0.72 for relative sarcopenia with excess adiposity, and 0.80 for a model including both. There was no association between relative sarcopenia with excess adiposity and number of HE episodes (incidence rate ratio, 1.08; CI, 0.49-2.40; p = 0.84) or time to first HE episode (HR, 0.89; CI, 0.51-1.54; p = 0.67). CONCLUSION. Relative sarcopenia with excess adiposity is a risk factor for mortality after TIPS and contributes additional prognostic information beyond MELD score.

The additive value of sarcopenia, myosteatosis and hepatic encephalopathy in the predictivity of model for end-stage liver disease

BackgroundSince the use of the Model for End-Stage Liver Disease (MELD) score for establishing the prognosis of cirrhotic patients has been introduced, questions have been raised whether complications of liver cirrhosis would provide additional information. Myosteatosis, sarcopenia and hepatic encephalopathy (HE) are frequent in cirrhosis and may affect prognosis.Aim of the study was analyzing if these factors are independently related to survival and may improve the accuracy of MELD. Methods249 cirrhotics that underwent abdominal CT-scan were enrolled. For each patient, information about previous episodes of HE and muscle alterations were obtained. Patients were followed until transplantation or death. ResultsHistory of HE, MELD, sarcopenia and myosteatosis were independently associated with mortality. The MELD-Sarco-Myo-HE score added accuracy to the MELD score alone for 6- and 3-months mortality. By removing HE, as the only not quantifiable parameter of the model, no relevant decrease in accuracy for 6- and 3-months mortality detection was observed. ConclusionsThe accuracy of MELD in predicting 3- and 6-months mortality may be improved by considering the muscle alterations. A model considering the above parameters may classify more accurately over 30% of the patients.

Predictive value of induced hyperammonaemia and neuropsychiatric profiling in relation to the occurrence of post-TIPS hepatic encephalopathy.

Hepatic encephalopathy (HE) occurs in 20-50% of patients after transjugular intrahepatic portosystemic shunt (TIPS) placement. Older age, HE history and severe liver failure have all been associated with post-TIPS HE but it remains difficult to identify patients at risk. The aim of the present pathophysiological, pilot study was to assess the role of induced hyperammonaemia and associated neuropsychological and neurophysiological changes as predictors of post-TIPS HE. Eighteen TIPS candidates with no overt HE history (56 ± 8yrs., MELD 11 ± 3) underwent neurophysiological [Electroencephalography (EEG)], neuropsychological [Psychometric Hepatic Encephalopathy Score (PHES) and Scan tests], ammonia and sleepiness assessment at baseline and after the induction of hyperammonaemia by an oral amino acid challenge (AAC). Pre-AAC, 17% of patients had abnormal EEG, 5% abnormal PHES, and 33% abnormal Scan performance. Post-AAC, 17% had abnormal EEG, 0% abnormal PHES, and 17% abnormal Scan performance. Pre-AAC, ammonia concentrations were 201 ± 73μg/dL and subjective sleepiness 2.5 ± 1.2 (1-9 scale). Post-AAC, patients exhibited the expected increase in ammonia/sleepiness. Six months post-TIPS, 3 patients developed an episode of HE requiring hospitalization; these showed significantly lower pre-AAC fasting ammonia concentrations compared to patients who did not develop HE (117 ± 63 vs. 227 ± 57μg/dL p = 0.015). They also showed worse PHES/Scan performance pre-AAC, and worse Scan performance post-AAC. Findings at 12months follow-up (n = 5 HE episodes) were comparable. In conclusion, baseline ammonia levels and both pre- and post-AAC neuropsychiatric indices hold promise in defining HE risk in TIPS candidates with no HE history.

Assessment of integrated specialty pharmacy services as a medication optimization strategy for rifaximin in hepatic encephalopathy patients

Background: Lactulose non-adherence has been identified as a factor for recurrent episodes of hepatic encephalopathy (HE). Treatment guidelines recommend adding rifaximin (Xifaxan1) to lactulose for ongoing management after an overt HE recurrence on lactulose alone to reduce the risk of further episodes and HE-related hospitalizations. Clinical observations suggested that rifaximin therapy is not initiated in patients upon HE-related hospital discharge where indicated. Aims: Integrate the CHI Health Specialty Pharmacy medication access coordinator (MAC) into the cascade of care of patients during an HE-related hospitalization to optimize access to and initiation of rifaximin upon discharge. Methods: Retrospective assessment of integrated MAC assistance in the CHI Health gastroenterology clinic from 26 September 2018 to 31 March 2019. Hospitalized patients were identified using TheraDoc2 reporting. Inclusion criteria: rifaximin ordered during an HE-related hospital admission at CHI Health. Exclusion criteria: discharge care assignment to an alternative physician group or facility. Primary outcome: the percentage of patients initiated on rifaximin upon hospital discharge via the integrated MAC. Secondary outcomes: cases requiring benefits verification and financial assistance, and number of rifaximin prescriptions acquired by the CHI Health Specialty Pharmacy. Results: A total of 40 patients met the inclusion criteria during the assessed timeframe. Thirty-one patients were excluded, 27 to other groups and 4 to facilities. Integrated MAC assistance was utilized for the remaining 9 patients and 100% were initiated on rifaximin upon discharge. Of those, 4 required benefits prior authorizations, 2 qualified for manufacturer patient assistance and 3 received sample medication. CHI Health Specialty Pharmacy acquired 2 rifaximin prescriptions. Conclusions: Integrated MAC assistance in a health-system gastroenterology clinic optimizes rifaximin access and initiation in patients following an HE-related hospitalization. It is anticipated that more patients going forward will qualify for MAC assistance due to a reduction in the community physician groups providing care at CHI Health. Further evaluation is warranted to determine whether medication optimization results in improved adherence and reduced readmissions in this population.

P: 50 Developing a New Animal Model of Episodic Hepatic Encephalopathy

BACKGROUND: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, a major complication of chronic liver disease (CLD/cirrhosis). The primary cause of hospital admissions for cirrhotic patients is an overt episode of HE. Precipitating factors of HE frequently lead to an increase in blood ammonia. Patients who have experienced multiple episodes of HE are associated with persisting neurological complications post-liver transplantation. Currently, the impact of HE episodes on neurological integrity is unknown. We hypothesize that multiple episodes of HE will accelerate and/or intensify neurological deterioration. To date, an animal model of episodic HE is lacking. Therefore, our goal was to characterize an animal model of episodic HE (precipitated with ammonia) and to evaluate the impact of cumulative episodes on neurological status in cirrhotic rats. METHODS: Animal model of CLD and HE: 6-week bile-duct ligation (BDL) rats, and Sham-operated controls were used. BDL and Sham rats were divided in two groups, episodic and non-episodic. Injection (i.p) of ammonium acetate was used to induce episodes of overt HE (pre-coma; loss of righting reflex) every 4 days starting 3-weeks post-BDL surgery (total 5 episodes). Saline was injected as vehicle for non-episodic groups. Two days following the last HE episode, we assessed motor-coordination (RotaRod), anxiety (elevated plus maze, EPMT), as well as short-term and long-term memory (novel object recognition) in all groups. Upon sacrifice, plasma ammonia was measured. RESULTS: The concentration of ammonia required to induce an episode of overt HE in BDL rats lessened with each subsequent episode, ranging from 7 to 4.5 mmol/kg. Short-term memory (P &lt; 0.05) and motor-coordination (P &lt; 0.05) were impaired in both non-episodic and episodic BDL groups compared to respective Sham-operated controls. Long-term memory impairment (P = 0.06) and increased anxiety (+60.0%, P &lt; 0.05) were exclusively found in episodic BDL rats compared to non-episodic BDL rats. Moreover, there was an increase in blood ammonia (+30.4%, P = 0.06) in episodic compared to non-episodic BDL rats, suggesting that although episodic-BDL rats recover from each HE episode, baseline (pre-episode) ammonia remain higher than non-episodic BDL rats. CONCLUSIONS: Cumulative HE episodes escalate neurological impairments in cirrhotic-BDL rats. Thus, this new episodic HE model represents a good approach to explore the pathological mechanism arising from multiple episodes, as well as further investigate whether higher hyperammonemia and/or increased brain sensitivity to ammonia is responsible for more complex neurological manifestations in episodic-BDL rats. Moreover, this model is an excellent platform to investigate novel therapies to prevent/treat episodic HE.

P: 1 Genetic Fingerprint of Hepatic Encephalopathy Risk in Liver Cirrhosis

BACKGROUND: To determine the impact of genetic factors on the development of hepatic encephalopathy (HE) in patients with liver cirrhosis. METHODS: Patients suffering from compensated liver cirrhosis [n = 434; estimation cohort (n = 294) and validation cohort (n = 140)] were included. Patients were followed up for five years until HE bouts, liver transplant, or death. Methods: Patients were genotyped for 62 candidate SNPs (genes involved in the pathophysiology of HE: inflammation, ammonia and glutamine metabolism, intestinal barrier integrity and oxidative stress) by using OpenArray custom plates. Likewise, a haplotype formed by four SNPs within GLS plus the length of a microsatellite in the promoter region of GLS were determined (Romero-Gómez et al. Ann Intern Med 2010). Statistical analysis was performed by Cox regression and Kaplan-Meier for continuous and categorical data. Significant variables, and those known as weighted prognostic indicators, were entered into multivariable models by competing risks, according to Fine and Gray's method. RESULTS: In the estimation cohort, competing risks analysis showed GLS mutations, FUT2-(rs601338), TLR9-(rs5743836), SLC1A3-(rs2562582) and SLC1A5-(rs313853), together with MELD, albumin, sodium and previous episodes of HE as variables independently associated to HE development. Those genes encode for proteins involved in maintenance of intestinal barrier integrity by host-microbial interactions (FUT2), pro-inflammatory response triggered by pathogens (TLR-9) and glutamine transport (SLC1A3 and SLC1A5). Combining these genetic factors according to number of alleles at risk, three levels of risk patients were defined: low, mid or high risk [sHR: 1; 6.5 (1.8–22.9) P = 0.004; 27.1 (7.5–96.8) P &lt; 0.001, respectively] (C-index = 0.82). This regression model performed in a similar manner in the validation cohort [sHR: 1; 4.2 (1.2–14.3) P = 0.024; 10.0 (2.7–36.7) P &lt; 0.001] (C-index = 0.78). Cumulative survival free of HE after 5 years was also influenced by this genetic fingerprint: 95.3%, 77.0% and 42.5% for the low, mid and high-risk groups (log-Rank 53.1; P &lt; 0.001) in the estimation, and 85.2%, 56.0% and 40.0% (log-Rank 14.1; P &lt; 0.001) in the validation cohort, respectively (Figure 1). CONCLUSIONS: Combination of unfavorable variants could predict HE. This genetic fingerprint could be implemented in clinical practice for decision making in the management of cirrhotic patients. Besides, this work emphasizes the role of these pathways in the pathophysiology of HE and brings out novel genes as potential therapeutic targets.

P: 47 Risk of Recurrent Hepatic Encephalopathy (HE) in Patients With Liver Cirrhosis: A German Registry Study

BACKGROUND: Patients with Hepatic Encephalopathy (HE) show a low quality of life, recurrent hospitalizations and an increased mortality. We aimed to assess the natural course of patients after a recent HE-episode under the conditions of the German health system, as respective data were not available. METHODS: Fifteen sites from Germany - 8 of them liver transplant (LT) centers - took part in an observational prospective study including cirrhotic patients who had been hospitalized due to an acute episode of HE within 3 months before recruitment. Age &lt; 18 years, no liver cirrhosis, malignancies and current hospitalization were exclusion criteria. Demographic and clinical data, health related quality of life (HRQoL) score SF-36, psychometric hepatic encephalopathy score (PHES) and critical flicker frequency (CFF) were assessed and monitored quarterly for one year. Primary endpoint was a novel clinical manifestation of HE necessitating hospital admission. Secondary endpoints were the combined endpoint of hospital admission for a novel HE episode and/or death, the dynamics of the West Haven Criteria (WHC) as well as changes in CFF, PHES and SF-36. RESULTS: A total of 115 patients were recruited. Fourteen patients (12.4 %) died during the study period due to complications of liver cirrhosis other than HE. For 67 subjects follow-up data were available in accordance with the protocol. After a median of 113 days half of the per protocol cohort (N = 34) was re-admitted due to a recurrent manifestation of HE. The patient groups with and without re-hospitalization differed significantly regarding recruitment sites (LT centers vs no LT centers) (P = 0.005), interval from discharge to recruitment (P = 0.007), history of more than 4 HE relapses prior to recruitment (P = 0.029), SF-36 mental score (P = 0.046) and PHES ≤ −3 (P = 0.004), whereas CFF, clinical (e.g. MELD score, WHC grade) and laboratory data did not differ. Of note, CFF performance was correct only in about half of both, the total and the per protocol group. Patients with incorrect CFF performance had worse PHES results than those with valid CFF measurement. Multiple logistic regression analysis revealed a PHES test result of ≤−3 as an independent risk factor for re-hospitalization (P = 0.046). CONCLUSIONS: Mortality in our cohort is comparatively low. Despite advanced treatment strategies, patients with a history of HE are still sincerely jeopardized to develop recurrent clinical HE. The PHES test appears useful for detection, monitoring and stratification of recurrent HE. Patients with PHES ≤−3 at baseline had an increased risk of deterioration.

P: 48 Nonselective Beta-blocker Use Is Associated With Increased Hepatic Encephalopathy-Related Readmissions in Patients With Cirrhosis

BACKGROUND: Hepatic Encephalopathy (HE) is a reversible syndrome of impaired brain function that is associated with frequent hospitalizations and decreased survival in cirrhotic patients. Nonselective beta-blockers (NSBB) are the mainstay of pharmacologic treatment for portal hypertension and prevention of variceal bleeding. Due to their effects on hepatic blood flow, we hypothesized that NSBB use would decrease portal flow, leading to increased HE related hospitalizations independent of liver disease severity. This study was done to assess the effect of NSBB use on HE-related readmissions. METHODS: We examined all the patients with cirrhosis admitted at Baylor University Medical Center between January 2013 and July 2018. The outcome measure of HE-related readmissions was analyzed in patients taking NSBB vs. patients not taking NSBB using cox proportional hazard regression model. The model was adjusted for age, sex, Model for End-Stage Liver Disease (MELD) score, selective beta-blocker (SBB) use, ascites, and history of esophageal varices (EV) and transjugular intrahepatic portosystemic shunt (TIPS). The Kaplan-Meier method and log-rank test were used to compare the cumulative incidence of HE-related readmissions between the aforementioned groups. RESULTS: There were 393 patients in this study with a mean age of 58.1 ± 10.2 years and a male predominance. The mean MELD score was 19.6 ± 7.7. The median time between the first admission and future readmission was 1.9 months with interquartile range of 4.8 months. The cumulative incidence of HE-related readmissions was significantly higher in patients taking NSBB compared with patients who were never prescribed NSBB (P &lt; 0.001) (Figure 1). This effect was not seen for patients who were taking SSBs. In multivariate analysis, after adjusting for age, sex, MELD score, SBB use, ascites, history of EV and TIPS, NSBB use was independently associated with increased risk of HE-related re-hospitalizations; Hazard ratio was 2.82 (95% confidence interval: 1.81–4.41). CONCLUSIONS: NSBB use is independently associated with increased HE-related readmissions in patients with cirrhosis, regardless of liver disease severity. Thus, NSBBs should be used cautiously in patients who have experienced a prior HE episode. However, further prospective studies are needed to determine the impact of NSBB on portal hypertension complications.

P: 37 Probiotics Combined With Rifaximin for the Treatment of Chronic Hepatic Encephalopathy: A Longitudinal In Vivo 1H-MRS Study of Brain Metabolism Using BDL Rats

BACKGROUND: Chronic hepatic encephalopathy (HE) is a severe complication of chronic liver disease (CLD), and finding the right treatment to reduce HE episodes before liver transplant remains a challenge. Both rifaximin (non-absorbable antibiotic) and probiotics are currently used to reduce HE symptoms, but their precise effect on brain metabolites has never been studied. Our aims were: 1) to assess in vivo and longitudinally the effect of the combination of probiotics and rifaximin on bile duct ligated (BDL) rats in different brain regions; and 2) to compare these results with both non-treated (n = 17) and rifaximin-only treated rats (n = 12).1,2 METHODS: In vivo 1H-MRS at 9.4 Tesla combined with biochemical tests (plasma NH4+, bilirubin) and microbiota analysis were performed on adult Wistar rats (n = 9) before BDL3,4 (week 0) and at weeks 2, 4, 6 and 8 after surgery. Evolution of metabolites was studied using the SPECIAL sequence (TE = 2.8 ms) in the hippocampus (2 × 2.8 × 2 mm3) and cerebellum (2.5 × 2.5 × 2.5 mm3). Metabolite concentrations were estimated using LCModel and water as internal reference. Probiotics administration (VIVOMIXX®, 60 billion bacteria/kg of rat) started two weeks before BDL-surgery until the end of the study. Rifaximin (15.7 mg/kg/day = 'human-dose') was administered twice daily starting two weeks after BDL-surgery. RESULTS: All rats displayed the characteristic rise in plasma bilirubin, regardless of treatment group, as well as a similar ammonium increase (Figure 1a). The characteristic pattern of chronic HE was observed (Figure 1e): a gradual increase of brain glutamine followed by a gradual decrease in the other brain osmolytes (myo-inositol, taurine, total choline) and a later decrease of glutamate and creatine. The combination of probiotics and rifaximin improved some of the neuro-metabolic changes associated with CLD at early stages of HE (week 4) in the cerebellum: the 'probiotics + rifaximin' group showed a lower rise of brain glutamine (+33% vs +66%, Figure 1c) and a smaller decrease of creatine (−4% vs −14%). In the hippocampus, rats receiving both probiotics and rifaximin exhibited a smaller increase in brain glutamine even at week 8 after BDL compared to non-treated rats (+99% vs +136%, Figure 1d) and a smaller decrease in brain myo-inositol and glutamate (−20% vs −30% and −7% vs −13%, respectively). Also, bifidobacteria concentration was slightly higher in the 'probiotics+rifaximin' group at week 8 (Figure 1b). Finally, the administration of rifaximin associated with this probiotic showed more beneficial effects than rifaximin only, and both could be used to maintain a balanced microbiota and may provide opportunities for reducing the spread of antibiotic resistances. CONCLUSIONS: To conclude, some promising changes were induced in the neurometabolic profile of BDL-rats who were treated with this specific probiotic and rifaximin (glutamine, myo-inositol, creatine and glutamate).

P: 3 Clinical Value of Asterixis in a Large Population of Well-characterised Patients With Cirrhosis and Varying Degree of Hepatic Encephalopathy

BACKGROUND: Current guidelines for the diagnosis of overt hepatic encephalopathy (HE) include the clinical sign asterixis, which has also been used as an outcome in clinical trials. Limited information is available on the ability of physicians to detect/grade asterixis, and the relationship between asterixis and other HE indices. The aim of the study was to retrospectively assess the clinical value of asterixis in a large population of well-characterised patients with varying degree of HE. METHODS: Asterixis was sought for/graded in 374 consecutive patients with cirrhosis (59 ± 8 yrs, 280 males; MELD 14 ± 5, Pugh 7.9 ± 2.0) by trainees in Internal Medicine (n = 16), attending the Padova HE clinic between 2011 and 2019. Patients were asked to stretch their arms, extend their wrist and spread their fingers, and observed for 1 min. Asterixis was qualified as absent, rare, frequent or continuous. All underwent neuropsychiatric examination as per local protocols, including electroencephalography (EEG) and a set of neuropsychological tests [Animal Naming Test (ANT); Psychometric Hepatic Encephalopathy Score (PHES); computerised simple (sRT), choice (cRT) and Scan (ScanRT) reaction times]. Laboratory indices (venous ammonia, CRP, sodium) were recorded, together with presence/absence of previous HE episodes and spontaneous/surgical portal-systemic shunts. Patients were followed up for 24 months in relation to the development of HE-related hospitalizations. RESULTS: 280/59/33/2 patients were qualified as having no/rare/frequent/continuous asterixis, thus those with frequent and continuous asterixis were grouped for purposes of subsequent analyses. Associations were observed between the presence/degree of asterixis and the presence of overt HE on the day of study (χ2 = 55, P &lt; 0.001), a history of HE (χ2 = 21, P &lt; 0.001), and the presence of portal-systemic shunts (χ2 = 11.8, P = 0.019). Significant differences in neuropsychiatric HE indices were observed between patients with different degrees of asterixis. Some were prominent between patients with/without the sign, regardless of its frequency (PHES, ScanRT), while for others the relationship was linear (ANT, sRT, cRT, spectral EEG parameters). Significant differences in laboratory indices of liver failure/HE were also observed between patients with different degrees of asterixis. Again, some were prominent between patients with/without the sign (Pugh, CRP), while for others the relationship was linear (MELD, ammonia). Finally, the likelihood of developing HE-related hospitalisations over the follow up period was significantly higher in patients with asterixis (Cox-Mantel P = 0.028). CONCLUSIONS: Asterixis is reliably detected/graded by specialist trainees in a tertiary referral liver centre, and shows significant associations with established neuropsychological, neurophysiological and laboratory HE indices, as well as the likelihood of developing HE-related hospitalisations over time.

P: 38 Rifaximin Reduces the Incidence of Spontaneous Bacterial Peritonitis, Variceal Bleeding and All-cause Admissions in Patients on the Liver Transplant Waiting List

BACKGROUND: Rifaximin reduces the risk of overt hepatic encephalopathy (HE) in patients with advanced chronic liver disease (ACLD) and is associated with significant reductions in hospitalisations and 30‐day readmissions. This study examined clinical outcomes of patients listed for liver transplantation with a diagnosis of HE on rifaximin compared to those naïve to the drug. METHODS: Patient records of those listed for liver transplantation over a 2-year period were retrospectively reviewed. Patients were included if they had at least two episodes of overt HE resulting in hospitalisation or were encephalopathic at the time of assessment. Information collected included patient demographics, aetiology of liver disease, disease severity scoring at transplant listing, concomitant medications and medical co-morbidities. Emergency admissions whilst on the waiting list for complications of ACLD in addition to requirement for prioritisation (UKELD score ≥63), duration on the waiting list (days) and mortality on the waiting list were recorded. Univariate and multivariate regression analyses were performed on acute admission and complication data (related to sepsis, acute variceal bleeding (AVB), HE and complications of ascites) with rifaximin use as the independent variable. RESULTS: Of the 622 patients listed for transplantation, 101 were listed with HE. 66 patients were treated with rifaximin and 35 were naïve at listing. Median MELD score was similar (15 [14–16)] rifaximin-treated and 16 [14–18] rifaximin-naïve). The use of lactulose was not significantly different between groups. Patients on the waiting list treated with rifaximin had an independent association with reduced all-cause admissions (P = 0.037), episodes of spontaneous bacterial peritonitis (P = 0.008) and AVB (P = 0.026). Mean length of hospital stay was 9 (95% CI 6–12) in the rifaximin-treated group vs 14 days (95% CI 7–21) in the rifaximin-naïve group. Multivariate regression analysis demonstrated that rifaximin was independently associated with an increase in days to readmission (adjusted effect estimate 71, 95% CI 3–140 days, P = 0.037) and reduced likelihood of requirement for prioritisation on the waiting list (odds ratio 0.29; 95% CI 0.89–0.93, P = 0.037). CONCLUSION: Rifaximin prescribed for HE in patients listed for liver transplantation improved outcomes on the waiting list with a significant reduction in admissions related to spontaneous bacterial peritonitis, ascites and AVB and indicating potential beneficial impacts of rifaximin beyond HE in ACLD.

P: 26 The Modification of Quantity and Quality of Muscle Mass Improves the Cognitive Impairment After TIPS

BACKGROUND: Hepatic encephalopathy (HE) is the major complication of transjugular intrahepatic portosystemic shunt (TIPS). In cirrhotic patients, a correlation between sarcopenia and hepatic encephalopathy has been suggested. AIM: to evaluate the evolution of the skeletal muscle quantity and quality at CT scan and of the patients' cognitive impairment (both overt and minimal HE) before and after TIPS. PATIENTS AND METHODS: 27 cirrhotic patients submitted to TIPS were studied. The modification of Skeletal Muscle Index (SMI), muscle attenuation, HE and plasma ammonia were evaluated before and after a mean follow-up of 9.8 ± 4 months after TIPS. RESULTS: During the follow-up, the mean SMI and muscle attenuation increased significantly, although not uniformly in all patients. PHES (Psychometric Hepatic Encephalopathy Score) and ammonia improved significantly in the patients with amelioration in SMI &gt;10% (n = 16) and not in those without (n = 11) (PHES: −1.6 ± 2 vs −4.8 ± 2.1; P = 0.0005; ammonia: 48.5 ± 28.7 vs 96 ± 31.5 μg/dl; P = 0.0004). Moreover, the prevalence of minimal HE (12.5% vs 73%, P = 0.001) as well as the number of episodes of overt HE during the follow-up were significantly reduced in the patients with improved SMI. MELD remained stable or worsened after TIPS and was not significantly different between the groups with or without SMI improvement. CONCLUSION: The amelioration of muscle wasting and HE independent of liver function observed after TIPS supports the causal relationship between muscle wasting and HE.

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.

Uncommon Movement Disorders in Chronic Hepatic Disease with Response to Rifaximin

<strong>Background:</strong> Chronic hepatic disease can present with extrapyramidal symptoms. We describe two cases that presented with highly unusual movement disorders: ballism and gait freezing. <strong>Case report:</strong> Patient 1 is a 42-year-old man with previous episodes of hepatic encephalopathy (HE) who presented with upper limb dystonia and generalized chorea that progressed to ballism. Patient 2 is a 55-year-old woman who presented with pronounced gait freezing. In both patients, features of HE and acquired hepatocerebral degeneration coexisted. They improved markedly, though transiently, with rifaximin. <strong>Discussion:</strong> Ammonia-reducing treatments should be considered in patients presenting with movement disorders due to chronic liver disease.

Muscle Alterations Are Associated With Minimal and Overt Hepatic Encephalopathy in Patients With Liver Cirrhosis.

Muscle alterations (myosteatosis and sarcopenia) are frequent in cirrhosis and related to some complications including overt hepatic encephalopathy (HE). The aim of our study was to investigate the relationship between muscle alterations and minimal HE (MHE) and their role in the risk of overt HE. Sixty-four patients with cirrhosis were administered the Psychometric Hepatic Encephalopathy Score and animal naming test to detect MHE. Computed tomography was used to analyze the skeletal muscle index and attenuation. The incidence of the first episode of HE, taking into account the competing risk nature of the data, was estimated. Myosteatosis was observed in 24 patients (37.5%), sarcopenia in 37 (58%), and MHE in 32 (50%). Both myosteatosis (62.5% versus 12.5%, P<0.001) and sarcopenia (84% versus 31%, P<0.001) were more frequent in patients with MHE. The variables independently associated with the presence of MHE were sarcopenia, previous overt HE, and myosteatosis. Thirty-one (48%) patients developed overt HE over 16.1±13 months; myosteatosis was detected in 68% and sarcopenia in 84% of them. Sarcopenia and myosteatosis were also independently associated with the development of overt HE. Venous ammonia was significantly higher in patients with sarcopenia (62.6±17.7 versus 41.4±16.1 μg/dL, P<0.001) and in patients with myosteatosis (65.2±19.2 versus 46.7±17.1 μg/dL, P<0.001) and inversely correlated to both parameters. Survival was significantly lower in malnourished patients compared to patients without myosteatosis or sarcopenia (P<0.001). Conclusion: Myosteatosis and sarcopenia, probably by reducing the handling of ammonia in the muscle, are independently associated with MHE and the risk of overt HE in patients with cirrhosis; in malnourished patients, the amelioration of nutritional status may be a goal to decrease both the prevalence of MHE and the incidence of overt HE.

Rifaximin reduces the incidence of spontaneous bacterial peritonitis, variceal bleeding and all-cause admissions in patients on the liver transplant waiting list.

SummaryBackgroundRifaximin reduces the risk of overt hepatic encephalopathy (HE) and is associated with significant reductions in hospitalisations and 30‐day readmissions.AimTo examine the outcomes of patients listed for liver transplantation with a diagnosis of HE on rifaximin compared to those naïve to the drug.MethodsPatient records of those listed for liver transplantation over a 2‐year period were retrospectively reviewed. Patients were included if they had at least two episodes of overt HE resulting in hospitalisation or were encephalopathic at the time of assessment.ResultsOf the 622 patients listed for transplantation, 101 had HE. Sixty‐six patients were treated with rifaximin and 35 were naïve at listing. The use of concurrent lactulose was not significantly different between groups. Median MELD score was similar (15 [14‐16)] rifaximin‐treated and 16 [14‐18] rifaximin‐naïve). Patients on the waiting list treated with rifaximin had reduced all‐cause admissions, episodes of spontaneous bacterial peritonitis and variceal bleeding. Mean length of stay was 9 days (95% CI 6‐12) in the rifaximin‐treated group vs 14 (95% CI 7‐21) in the rifaximin‐naïve group. Multivariate regression analysis demonstrated that rifaximin was independently associated with an increase in average days to readmission (adjusted effect estimate 71, 95% CI 3‐140 days) and reduced likelihood of requirement for prioritisation on the waiting list (odds ratio 0.29; 95% CI 0.89‐0.93).ConclusionRifaximin prescribed for HE in patients listed for liver transplantation improved outcomes with significant reduction in admissions related to spontaneous bacterial peritonitis, ascites and variceal bleeding.

Cerebral water content mapping in cirrhosis patients with and without manifest HE.

Hepatic encephalopathy (HE) is a frequent and debilitating complication of cirrhosis and its pathogenesis is not definitively clarified. Recent hypotheses focus on the possible existence of low-grade cerebral edema due to accumulation of osmolytes secondary to hyperammonemia. In the present study we investigated increases in cerebral water content by a novel magnetic resonance impedance (MRI) technique in cirrhosis patients with and without clinically manifest HE. We used a 3T MRI technique for quantitative cerebral water content mapping in nine cirrhosis patients with an episode of overt HE, ten cirrhosis patients who never suffered from HE, and ten healthy aged-matched controls. We tested for differences between groups by statistical non-parametric mapping (SnPM) for a voxel-based spatial evaluation. The patients with HE had significantly higher water content in white matter than the cirrhosis patients (0.6%), who in turn, had significantly higher content than the controls (1.7%). Although the global gray matter water content did not differ between the groups, the patients with HE had markedly higher thalamic water content than patients who never experienced HE (6.0% higher). We found increased white matter water content in cirrhosis patients, predominantly in those with manifest HE. This confirms the presence of increasing degrees of low-grade edema with exacerbation of pathology. The thalamic edema in manifest HE may lead to compromised basal ganglia-thalamo-cortical circuits, in accordance with the major clinical symptoms of HE. The identification of the thalamus as particularly inflicted in manifest HE is potentially relevant to the pathophysiology of HE.

Neurological Complications Occurring After Liver Transplantation: Role of Risk Factors, Hepatic Encephalopathy, and Acute (on Chronic) Brain Injury.

Orthotopic liver transplantation (LT) remains the only way to definitively cure patients with the most severe liver diseases. Because the survival rate is now fairly high, important questions about neurological sequelae or quality of life after LT have emerged. Indeed, LT represents a peculiar situation because up to 30% of patients present with neurological symptoms after LT compared with only 4% after cardiac transplant and 0.5% after renal transplant. These postoperative neurological symptoms have long been interpreted as sequelae of hepatic encephalopathy (HE). However, postoperative decompensation of an unknown cerebral condition due to the pathophysiology of cirrhosis or undiagnosed neurodegenerative disorders or aging constitute other possibilities that are underrecognized. Some patients who undergo LT for acute liver failure and patients with cirrhosis without episodes of HE and without any previous cerebral alteration also display post-LT neurological symptoms. This latter situation speaks in favor of a direct adverse effect of either general anesthesia, the surgical procedure, or factors related to the postoperative intensive care unit (ICU) environment. The role of inflammation, which has been described in the ICU setting, could also be a crucial determinant. In this review, we will discuss the neurological complications associated with LT, the neurocognitive complications after LT, and how to assess the LT-related neurological or neurocognitive complications. Furthermore, we will review the various hypotheses surrounding post-LT neurocognitive impairment and will conclude with recommendations for future directions.

Emergency Transjugular Intrahepatic Portosystemic Shunt: an Effective and Safe Treatment for Uncontrolled Variceal Bleeding

BackgroundUncontrolled variceal bleeding (VB) remains a great challenge for clinical treatment. Emergency transjugular intrahepatic portosystemic shunt (TIPS) is a salvage procedure, but unsatisfactory clinical outcomes and a high incidence of complications have been reported. This study aimed to investigate the effect and safety of emergency TIPS performed in our institution during recent years. MethodsFifty-eight consecutive cirrhotic patients with uncontrolled VB who underwent emergency TIPS from March 2009 to November 2017 in our hospital were followed until the last clinical evaluation, liver transplantation (LT), or death. ResultsOverall, 5, 36, and 17 patients belonged to Child-Pugh class A, B, and C, respectively. TIPS was successfully performed in 57 (98.3%) patients at 89.5 h (mean) after initial bleeding. After TIPS, bleeding ceased in 52 (91.2%) patients, and 51 (89.5%) patients had a portal pressure gradient below 12 mmHg. Only one (1.8%) major procedure-related complication occurred without any clinical consequences, and no procedure-related deaths occurred. During follow-up, 55 hepatic encephalopathy (HE) episodes occurred in 19 (33.3%) patients, and the median time of the first HE episode was 3.1 months. Seven (12.3%) patients experienced shunt dysfunction after 8.7 months (median). The 6-week, 1-year, and 2-year variceal rebleeding rates were 10.5%, 17.1%, and 20.0%, respectively. The LT-free survival rates at 6 weeks, 1 year, and 2 years were 87.7%, 81.8% and 73.6%, respectively. ConclusionOur study highlights the fact that emergency TIPS could be effective for patients with liver cirrhosis and uncontrolled VB with few potential complications.

The modification of quantity and quality of muscle mass improves the cognitive impairment after TIPS.

Hepatic encephalopathy (HE) is the major complication of transjugular intrahepatic portosystemic shunt (TIPS). In cirrhotic patients, a correlation between sarcopenia and HE has been suggested. To evaluate the evolution of the skeletal muscle quantity and quality at CT scan and of the patients' cognitive impairment (both overt and minimal HE) before and after TIPS. Twenty-seven cirrhotic patients submitted to TIPS were studied. The modification of Skeletal Muscle Index (SMI), muscle attenuation, HE and plasma ammonia were evaluated before and after a mean follow-up of 9.8±4months after TIPS. During the follow-up, the mean SMI and muscle attenuation increased significantly, although not uniformly in all patients. Psychometric Hepatic Encephalopathy Score (PHES) and ammonia improved significantly in the patients with amelioration in SMI >10% (n=16) and not in those without (n=11) (PHES: -1.6±2 vs -4.8±2.1; P=0.0005; ammonia: 48.5±28.7 vs 96±31.5μg/dL; P=0.0004). Moreover, the prevalence of minimal HE (12.5% vs 73%, P=0.001) as well as the number of episodes of overt HE during the follow-up were significantly reduced in the patients with improved SMI. Model for end-stage liver disease remained stable or worsened after TIPS and was not significantly different between the groups with or without SMI improvement. The amelioration of muscle wasting and HE independent of liver function observed after TIPS supports the causal relationship between muscle wasting and HE.