Episodes Of Overt Hepatic Encephalopathy Research Articles

Medically-Tailored Meals for Patients with Cirrhosis and Hepatic Encephalopathy: The BRAINFOOD proof-of-concept trial

Background and AimsGuidelines recommend that patients with Hepatic Encephalopathy (HE) receive a high-protein diet (roughly 1 g/kg actual body weight). Concommitant sodium restriction, low health literacy, and food insecurity limit patients’ ability to meet this goal. We aimed to determine the feasibility of home-delivered high protein medically tailored meals (MTM) for patients with a recent episode of overt HE. MethodWe enrolled patients with prior overt HE on active HE therapy in a 6 month trial of MTM. All received 12 weeks of 21 home-delivered meals/week with protein snacks (mid-day and bedtime). Patients completed follow-up at week 24. The primary outcome was feasibility. Additional outcomes included change in protein and micronutrient intake (measured using 24-hour dietary recalls performed by dieticians), cognitive function (animal naming test, ANT; encephalapp stroop), physical function (liver frailty index, LFI), and quality of life (SF-8). Healthcare utilization was also assessed. Results10 patients competed the study with >90% of MTM consumed. Protein intake rose from 74.6+25.1g at baseline to 93.8+24.3g on MTM (p=0.04). Branched-chain amino acids also increased – valine 3.73+1.26g to 5.17+1.28, isoleucine 3.32+1.18 to 4.69+1.55, leucine 5.83+2.00 to 7.49+2.07, all p<0.001. LFI improved from 4.42±0.32 to 3.96±0.82 by the end of the MTM phase (p=0.03). SF-8 quality of life scores improved from 55.5±15.5 at baseline to 64.7±18.3 after the MTM phase, to 64.4±19.1 at the end of the study (p=0.1). EncephalApp-Stroop time improved from 227±94 to 194±58s by the end of the MTM phase (p=0.08). ANT scores were similarly non-significantly improved. ConclusionHome delivered MTM are feasible, increase protein consumption, and may improve patient well-being. A randomized trial is needed.

Proton pump inhibitor use and risk of hepatic encephalopathy: a multicenter study

Background & AimsData on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting, and data from multicenter studies are scarce. The aim of this study was to dissect the potential association between PPI use and minimal (MHE) and overt HE (OHE). MethodsData from patients with cirrhosis recruited at seven centers across Europe and the US were analyzed. MHE was defined by the Psychometric Hepatic Encephalopathy Score (PHES). PPI use was recorded on the day of testing with PHES. Patients were followed for OHE development and death/liver transplantation (LTx). Results1160 patients with a median MELD of 11 were included (Child-Pugh stages: A 49%/B 39%/C 11%). PPI use was noted in 58% of the patients. Median follow-up time was 18.1 months, during which 230 (20%) developed an OHE episode, and 224 (19%) reached the composite endpoint of death/LTx. In multivariable analyses, PPI use was neither associated with the presence of MHE at baseline nor OHE development during follow-up. These findings were consistent in subgroup analyses of patients with Child-Pugh A or B cirrhosis and after excluding patients with a history of OHE. PPI use was also not associated with a higher risk of OHE, neither in patients with an indication for treatment nor in patients without an indication. ConclusionsPPI use is not associated with a higher risk of HE in patients with liver cirrhosis. On the basis of these findings, a prescription should currently not be prohibited in case of a generally accepted indication. Impact and implicationsData on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting. In this study, PPI use was not associated with a higher risk of minimal HE at baseline or overt HE during follow-up in patients with liver cirrhosis. On the basis of these findings, a prescription of a PPI by a physician should currently not be prohibited in case of a generally accepted indication.

Population characteristics, healthcare pathways and outcomes of patients with cirrhosis hospitalized with overt hepatic encephalopathy in France: A study of the French Hospital‐Discharge Database

Hepatic encephalopathy (HE) is a severe complication of cirrhosis, independently associated with a poor survival. The objectives of this study were to describe the prevalence of overt hepatic encephalopathy (OHE) requiring hospitalization, and the healthcare pathways and outcomes of patients hospitalized for OHE in France. Data from the French Hospital‐Discharge Database (Programme de Medicalisation des Systemes d'information, PMSI) within the 5-year period from 2014 to 2018 were analysed. Since the disease lacks a PMSI code in the ICD-10, an identification algorithm was developed. The analysis identified 57,191 patients with OHE including 48,566 patients (85 %) who had been hospitalized twice or more during the study period. Each year, an average of over 20,000 patients were hospitalized in France for OHE as the primary or secondary reason for hospitalization. Among these patients, between 11,500 and 13,500 had been hospitalized at least twice in that year with an average of 3.4 hospitalisations per year. 25 % of admissions occurred following consultation at the emergency unit. Among hospitalisations, 15 % involved admission to the critical care resuscitation unit or intensive care. For all patients identified as suffering from OHE and hospitalized, the 5-year mortality was 46.5 % (26,621 patients). This pioneering study revealed that, in France, despite a probable underestimation of OHE episodes due to the lack of specific PMSI coding, the prevalence of OHE was very high, with frequent recurrences and readmissions, and high mortality.

Multiple ammonia-induced episodes of hepatic encephalopathy provoke neuronal cell loss in bile-duct ligated rats

Hepatic encephalopathy (HE) is defined as a reversible syndrome and therefore should resolve following liver transplantation (LT). However, neurological complications have been reported in up to 47% of LT recipients, which have been documented to be associated with a history of overt HE pre-LT. We hypothesise that multiple episodes of HE lead to permanent cell injury and exacerbate neurological dysfunction. Our goal was to evaluate the impact of cumulative HE episodes on neurological status and brain integrity in rats with chronic liver disease. Episodes of overt HE (loss of righting reflex) were induced following injection of ammonium acetate in bile duct ligation (BDL) rats (BDL-Ammonia) every 4 days starting at week 3 post-BDL. Neurobehaviour was evaluated after the last episode. Upon sacrifice, plasma ammonia, systemic oxidative stress, and inflammation markers were assessed. Neuronal markers including neuron-specific nuclear antigen and SMI311 (anti-neurofilament marker) and apoptotic markers (cleaved caspase-3, Bax, and Bcl2) were measured. Total antioxidant capacity, oxidative stress marker (4-hydroxynonenal), and proinflammatory cytokines (tumour necrosis factor-alpha and interleukin-1β) were measured in brain (hippocampus, frontal cortex, and cerebellum). Proteomic analysis was conducted in the hippocampus. In hippocampus of BDL-Ammonia rats, cleaved caspase-3 and Bax/Bcl2 ratio were significantly increased, whereas NeuN and SMI311 were significantly decreased compared with BDL-Vehicle rats. Higher levels of oxidative stress-induced post-translational modified proteins were found in hippocampus of BDL-Ammonia group which were associated with a lower total antioxidant capacity. Ammonia-induced episodes of overt HE caused neuronal cell injury/death in BDL rats. These results suggest that multiple bouts of HE can be detrimental on the integrity of the brain, translating to irreversibility and hence neurological complications post-LT. Hepatic encephalopathy (HE) is defined as a reversible neuropsychiatric syndrome resolving following liver transplantation (LT); however, ∼47% of patients demonstrate neurological impairments after LT, which are associated with a previous history of overt HE pre-LT. Our study indicates that multiple episodes of overt HE can cause permanent neuronal damage which may lead to neurological complications after LT. Nevertheless, preventing the occurrence of overt HE episodes is critical for reducing the risk of irreversible neuronal injury in patients with cirrhosis.

Development and validation of the AMMON-OHE model to predict risk of overt hepatic encephalopathy occurrence in outpatients with cirrhosis

Neuropsychological and psychophysical tests are recommended to assess the risk of overt hepatic encephalopathy (OHE), but their accuracy is limited. Hyperammonaemia is central in the pathogenesis of OHE, but its predictive utility is unknown. In this study, we aimed to determine the role of neuropsychological or psychophysical tests and ammonia, and to develop a model (AMMON-OHE) to stratify the risk of subsequent OHE development in outpatients with cirrhosis. This observational, prospective study included 426 outpatients without previous OHE from three liver units followed for a median of 2.5 years. Psychometric hepatic encephalopathy score (PHES) <-4 or critical flicker frequency (CFF) <39 was considered abnormal. Ammonia was normalized to upper limit of normal (AMM-ULN) at the respective reference laboratory. Multivariable frailty competing risk and random survival forest analyses were performed to predict future OHE and to develop the AMMON-OHE model. External validation was carried out using 267 and 381 patients from two independent units. Significant differences were found in time-to-OHE (log-rank p <0.001) according to PHES or CFF and ammonia, with the highest risk in patients with abnormal PHES plus high AMM-ULN (hazard ratio 4.4; 95% CI 2.4-8.1; p <0.001 compared with normal PHES and AMM-ULN). On multivariable analysis, AMM-ULN but not PHES or CFF was an independent predictor of the development of OHE (hazard ratio 1.4; 95% CI 1.1-1.9; p= 0.015). The AMMON-OHE model (sex, diabetes, albumin, creatinine and AMM-ULN) showed a C-index of 0.844 and 0.728 for the prediction of a first episode of OHE in two external validation cohorts. In this study, we developed and validated the AMMON-OHE model, comprising readily available clinical and biochemical variables that can be used to identify outpatients at the highest risk of developing a first episode of OHE. In this study, we aimed to develop a model to predict which patients with cirrhosis are at risk of developing overt hepatic encephalopathy (OHE). Using data from three units and including 426 outpatients with cirrhosis, we developed the AMMON-OHE model - comprising sex, diabetes, albumin, creatinine and ammonia levels - which demonstrated good predictive ability. The AMMON-OHE model performs better than PHES and CFF to predict the first episode of OHE in outpatients with cirrhosis. This model was validated in 267 and 381 patients from two independent liver units. The AMMON-OHE model is available online for clinical use.

Prediction and prevention of the first episode of overt hepatic encephalopathy in patients with cirrhosis.

Hepatic encephalopathy (HE) is one of the most important complications of patients with liver cirrhosis. In addition, HE is associated with a dismal prognosis and has detrimental effects on patients' quality of life. Thus, it is of pivotal importance to identify patients at high risk for overt HE (OHE) in whom primary prophylaxis may be justified. In this narrative review, we aim to provide insight into predictors and prediction tools for a first-time episode of OHE and to scrutinize the current level of evidence of primary prophylaxis. In recent decades, several cognitive tests, composite scores, and blood-based biomarkers have been demonstrated to be predictive of a first-time episode of OHE. Among the best validated are the established tests for minimal HE, such as the Psychometric Hepatic Encephalopathy Score, determination of the critical flicker frequency, Stroop EncephalApp, or the Animal Naming Test. Individualized risk stratification using blood-based biomarkers and cross-sectional imaging (sarcopenia and spontaneous portosystemic shunts) is coming to the fore, but validation in larger multicenter cohorts is often lacking. On the basis of current evidence, a recommendation for primary prophylaxis of a first episode of OHE cannot be made in general. Only 2 studies have investigated the prevention of a first-time OHE episode as the primary endpoint. In this narrative review, we provide a concise overview of the current evidence levels on prediction tools and pharmacological prevention of a first episode of OHE. In addition, we give an outlook on future research targets to improve knowledge on this important topic.

FRI492 - A network meta-analysis of numbers needed to treat to prevent an episode of overt hepatic encephalopathy in patients with cirrhosis treated for at least 6 months with lactulose alone, or lactulose plus rifaximin-alpha

FRI492 - A network meta-analysis of numbers needed to treat to prevent an episode of overt hepatic encephalopathy in patients with cirrhosis treated for at least 6 months with lactulose alone, or lactulose plus rifaximin-alpha

Pharmacokinetics/pharmacodynamics of L-ornithine phenylacetate in overt hepatic encephalopathy and the effect of plasma ammonia concentration reduction on clinical outcomes.

Hepatic encephalopathy (HE) is a serious neurocognitive complication of liver dysfunction, often associated with elevated plasma ammonia. Ornithine phenylacetate (OP), a potent ammonia scavenger, is being evaluated for the treatment of acute/overt HE. The pharmacokinetics and pharmacodynamics of OP in patients with HE were characterized in this phase IIb study (NCT01966419). Adult patients hospitalized with an overt HE episode, cirrhosis, and plasma ammonia above the upper limit of normal (ULN) who failed to improve after 48 hours’ standard care were randomly assigned to continuous intravenous OP (10, 15, or 20 g/day, based on Child–Turcotte–Pugh score) or matching placebo for 5 days. Plasma levels of ornithine and phenylacetic acid (PAA) and plasma/urinary levels of phenylacetylglutamine (PAGN) (primary metabolite of PAA) were regularly assessed; plasma ammonia level was the primary pharmacodynamic variable. PAA demonstrated dose‐dependent pharmacokinetics; ornithine and PAGN levels increased with dose. PAGN urinary excretion represented ~50%–60% of administered PAA across all doses. Mean reduction in plasma ammonia with OP at 3 hours postinfusion was significantly greater versus placebo (p = 0.014); and time to achieve plasma ammonia less than or equal to the ULN was significantly reduced (p = 0.028). Achievement of clinical response based on HE stage was associated with a greater reduction in mean plasma ammonia level (p = 0.009). OP effects on plasma ammonia were consistent with its proposed mechanism of action as a primary ammonia scavenger, with a significant association between reduced plasma ammonia and improvement in HE stage. OP should be further evaluated as a promising treatment for hyperammonemia in patients with overt HE.

The improvement in body composition including subcutaneous and visceral fat reduces ammonia and hepatic encephalopathy after transjugular intrahepatic portosystemic shunt.

BackgroundSarcopenia and myosteatosis have been associated to a poor prognosis of cirrhosis and to a higher incidence of hepatic encephalopathy (HE). The prognostic implications of visceral and subcutaneous adiposity are less known.AimTo evaluate the modifications of visceral and subcutaneous adipose tissue after TIPS and to investigate their relationships with the modification of muscle mass and with the incidence of post‐TIPS HE.Patients and Methods35 cirrhotic patients submitted to TIPS were retrospectively studied. The modification of skeletal muscle index (SMI), muscle attenuation (myosteatosis), subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI), assessed by CT‐scan and plasma ammonia were evaluated before and after a mean follow‐up of 19 ± 15 months after TIPS. The number of episodes of overt HE was also recorded.ResultsDuring the follow‐up, the mean SMI and muscle attenuation increased significantly; SATI significantly increased while VATI significantly decreased, although not uniformly in all patients. By comparing the patients with or without improvement in their nutritional status after TIPS, MELD remained stable while the number of episodes of overt HE was significantly lower in the patients with improved SMI and in the patients with improved SATI. Finally, inverse correlation was observed between the variation of ammonia and SATI (r = −.40; P < .05).ConclusionIn addition to muscle mass, adipose tissue is modified after TIPS. The improvement of subcutaneous adipose tissue as well as of sarcopenia and myosteatosis is associated to the amelioration of cognitive impairment independently of liver function. The correlation between adipose tissue and ammonia modification may suggest an active role of the adipose tissue in the inter‐organ ammonia trafficking.

Transjugular Intrahepatic Portosystemic Shunt Creation for the Prevention of Gastric Variceal Rebleeding in Patients with Hepatocellular Carcinoma: A Multicenter Retrospective Study

PurposeTo evaluate the effectiveness and safety of transjugular intrahepatic portosystemic shunt (TIPS) creation for the prevention of gastric variceal rebleeding in patients with hepatocellular carcinoma (HCC). Materials and MethodsThis multicenter retrospective study included 126 cirrhotic patients (mean age, 54.1 ± 10.2 years; 110 men) with HCC who underwent TIPS creation for the prevention of gastric variceal rebleeding. Of these, 110 (87.3%) patients had gastroesophageal varices and 16 (12.7%) patients had isolated gastric varices. Thirty-five (27.8%) patients had portal vein tumor thrombus. ResultsTIPS creation was technically successful in 124 (98.4%) patients. Rebleeding occurred in 26 (20.6%) patients during the follow-up period. The 6-week and 1-year actuarial probabilities of patients remaining free of rebleeding were 98.3% ± 1.2% and 81.2% ± 3.9%, respectively. Forty-nine (38.8%) patients died during the follow-up period. The 6-week and 1-year actuarial probabilities of survival were 98.4 ± 1.1% and 65.6 ± 4.4%, respectively. Two (1.6%) patients had major procedure-related complications, including acute liver failure (n = 1) and intra-abdominal bleeding (n = 1). Thirty-three (26.2%) patients had at least 1 episode of overt hepatic encephalopathy during the follow-up period. Shunt dysfunction occurred in 15 (11.9%) patients after a median follow-up time of 11.4 months (range, 1.4–41.3 months). Lung metastasis occurred in 3 (2.4%) patients, 3.9–32.9 months after TIPS creation. ConclusionsTIPS creation may be effective and safe for the prevention of gastric variceal rebleeding in patients with HCC.

Development and Validation of a Clinical-Genetic Risk Score to Predict Hepatic Encephalopathy in Patients With Liver Cirrhosis.

We aimed to define the impact of the genetic background on overt hepatic encephalopathy (HE) in patients with liver cirrhosis by developing a combined clinical-genetic risk score. Patients suffering from liver cirrhosis from the outpatient clinics of 4 hospitals (n = 600) were included and followed up for at least 5 years until HE bouts, liver transplant, or death. Patients were genotyped for 60 candidate single nucleotide polymorphisms together with the microsatellite in the promoter region of the gene GLS. Single nucleotide polymorphisms rs601338 (FUT2), rs5743836 (TRL9), rs2562582 (SLC1A3), rs313853 (SLC1A5), and GLS microsatellite did predict independently the incidence and severity of overt HE and were included as genetic score. Competing risk analysis revealed that bilirubin (subhazard ratio [sHR] 1.30 [1.15-1.48], P < 0.001), albumin (sHR 0.90 [0.86-0.93], P < 0.001), genetic score (sHR 1.90 [1.57-2.30], P < 0.001), and previous episodes of overt HE (sHR 2.60 [1.57-4.29], P < 0.001) were independently associated to HE bouts during the follow-up with an internal (C-index 0.83) and external validation (C-index 0.74). Patients in the low-risk group had 5% and 12% risk of HE at 1 (log-rank 92.1; P < 0.001) and 5 (log-rank 124.1; P < 0.001) years, respectively, whereas 36% and 48% in the high-risk group. The genetic background influenced overt HE risk and severity. The clinical-genetic HE Risk score, which combined genetic background together with albumin, bilirubin, and previous episodes of overt HE, could be a useful tool to predict overt HE in patients with cirrhosis.

Clinical, neuropsychological and neurophysiological indices and predictors of hepatic encephalopathy (HE)

Background & aims The occurrence of overt hepatic encephalopathy (HE) marks a significant progression in the natural history of liver disease. The aims of the present study were: 1) to describe a large cohort of patients with cirrhosis in terms of neuropsychological/neurophysiological HE indices, and 2) to test if the severity of liver disease and/or any such indices [Psychometric Hepatic Encephalopathy Score (PHES), Scan test, electroencephalography (EEG)] predicted mortality/HE risk in a subgroup of such cohort. Method 461 patients with cirrhosis (59±10 years; 345 males) were included; information on previous overt HE episodes was available in 407. Follow up information on mortality/HE-related hospitalization in 134/127, respectively. Information on previous overt HE episodes and both mortality and HE-related hospitalization over the follow up in 124. Results Patients with a history of overt HE (60%) had poorer liver function, worse neuropsychiatric indices, higher ammonia levels and higher prevalence of portal-systemic shunt. The risk of HE-related hospitalization over the follow up was higher in patients with higher MELD score and worse Scan performance. Mortality was higher in those with higher MELD. Amongst patients without a history of overt HE, those with worse PHES had higher HE risk. Amongst patients with a history, those with higher MELD, better PHES and worse Scan performance had higher HE risk. Conclusions In patients without previous overt HE episodes, neuropsychological and neurophysiological tests predict HE, while in those with previous overt HE episodes, HE development largely depends on the severity of liver dysfunction.

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.

Clinical, neuropsychological and neurophysiological indices and predictors of hepatic encephalopathy (HE).

The occurrence of overt hepatic encephalopathy (HE) marks a significant progression in the natural history of liver disease. The aims of the present study were to: 1) describe a large cohort of patients with cirrhosis in terms of neuropsychological or neurophysiological HE indices, and 2) test if the severity of liver disease and/or any such indices [Psychometric Hepatic Encephalopathy Score (PHES), Scan test, electroencephalography (EEG)] predicted mortality/HE risk in a subgroup of such cohort. Four hundred and sixty-one patients with cirrhosis (59±10years; 345 males) were included; information on previous overt HE episodes was available in 407. Follow-up information on mortality/HE-related hospitalization in 134/127 respectively. Information on previous overt HE episodes and both mortality and HE-related hospitalization over the follow-up in 124. Patients with a history of overt HE (60%) had poorer liver function, worse neuropsychiatric indices, higher ammonia levels and higher prevalence of portal-systemic shunt. The risk of HE-related hospitalization over the follow-up was higher in patients with higher MELD score and worse Scan performance. Mortality was higher in those with higher MELD. Among patients without a history of overt HE, those with worse PHES had higher HE risk. Among patients with a history, those with higher MELD, better PHES and worse Scan performance had higher HE risk. In patients without previous overt HE episodes, neuropsychological and neurophysiological tests predict HE, while in those with previous overt HE episodes, HE development largely depends on the severity of liver dysfunction.

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.

S1013 Lack of Colonic Microbial Cross-Resistance to Other Antibiotics in Patients Treated With Rifaximin Alone vs Rifaximin Plus Lactulose for Reducing the Risk of Overt Hepatic Encephalopathy (OHE) Recurrence

INTRODUCTION: Rifaximin is a nonsystemic antibiotic indicated for reducing the risk of OHE recurrence in adults. The risk of bacterial antibiotic resistance to rifaximin and cross-resistance to other antibiotics is thought to be low, possibly because of minimal systemic absorption. Data are limited on the potential impact of concomitant lactulose. This phase 4 substudy assessed rifaximin ± lactulose on antibiotic susceptibility of fecal bacteria in patients with cirrhosis and a history of overt HE. METHODS: Adults with cirrhosis and history of ≥1 OHE episode during previous 6 months, currently in OHE remission (Conn score ≤1) were randomized to receive open-label rifaximin 550 mg twice daily (BID) or rifaximin 550 mg BID + lactulose (titrated to 2-3 soft stools/d) for 6 months. Stool samples were collected at screening (baseline) and month 6/end of treatment (EOT). Patients were randomly selected for the fecal microbiota antibiotic susceptibility substudy. Bacteria were cultured using standard techniques; susceptibility to several antibiotics, depending on bacterium, was tested by broth or agar dilution methods; and minimum inhibitory concentrations (MIC) were determined. Control strains were included per lab SOP practices. RESULTS: Sixty-four patients (mean age, 55.8 y; 64.1% male) were included (rifaximin: n = 31; rifaximin + lactulose: n = 33). Overall, 376 bacterial isolates were identified: Enterobacteriaceae (36.2%), Enterococcaceae (27.7%), Bacteroidaceae (25.5%) families, Staphylococcaceae (7.2%), and Clostridiaceae (3.5%). Patients in each group had a similar distribution of bacterial families and species at baseline and EOT. Cross resistance to other antibiotics rarely developed (Table 1). CONCLUSION: Rifaximin ± lactulose for up to 6 months did not lead to clinically relevant changes to fecal microbial antibiotic susceptibility profiles. There was no indication of clinically relevant antibiotic resistance with the addition of lactulose to rifaximin therapy for the prevention of OHE recurrence. These data support the clinical safety profile of rifaximin + lactulose in adults with cirrhosis.Table 1

S1014 The Modest Differential Effects of Rifaximin Alone vs Rifaximin Plus Lactulose on Intestinal Microbial Diversity and Composition in Patients With Cirrhosis

INTRODUCTION: Rifaximin, a nonsystemic antibiotic, is indicated in the United States for reducing the risk of overt hepatic encephalopathy (OHE) recurrence in adults and may be used alone or in combination with lactulose. This analysis employed genomic characterization to assess the impact of daily rifaximin alone or rifaximin + lactulose treatment on stool microbiota in patients with a history of OHE. METHODS: In a randomized, open-label trial, patients aged ≥18 y with cirrhosis and history of ≥1 OHE episode during the prior 6 months, currently in HE remission (Conn score ≤1), received rifaximin 550 mg twice daily (BID) or rifaximin 550 mg BID + lactulose (titrated to 2–3 soft stools/d) for 6 months. Stool samples were collected at screening (baseline) and month 6/end of treatment (EOT). Patients were randomly selected for the stool microbiota sequencing analysis substudy. Genomic characterization of microbiota was achieved using 16S rRNA bacterial deep gene sequencing. Metrics included stool microbiota richness (number of bacterial species in a sample, adjusted for different numbers of sequences observed from each sample), evenness (relative abundance of different species [range, 0–1; 1 = complete evenness]), and Shannon diversity index (richness and evenness [overall community complexity]). RESULTS: Sixty-six adults (mean age, 56.0 y; 68.2% male; mean body mass index, 31.7 kg/m2) were randomly selected for stool microbiota analysis (rifaximin alone [n = 34]; rifaximin + lactulose [n = 32]; demographics evenly matched). At baseline, measures of richness and evenness of stool microbiota and Shannon diversity index were similar for rifaximin alone and rifaximin + lactulose groups (Table 1). Stool microbiota richness did not significantly change from baseline to EOT in either group; no significant difference was observed between groups. Significant decreases from baseline to EOT were seen in evenness of stool microbiota and Shannon diversity index in the rifaximin alone group (P < 0.005 for both measures); greater reductions in these parameters were observed in the rifaximin alone group versus the rifaximin + lactulose group (P < 0.05 for both measures). CONCLUSION: Modest effects on stool microbiota diversity and evenness, with no effects on the absolute number of species, were observed in the rifaximin alone group. Concomitant lactulose may offset these effects, but further research is needed. Overall, data support that overall effects to stool microbiota during rifaximin treatment are modest in scope.Table 1

Incidence and Bedside Predictors of the First Episode of Overt Hepatic Encephalopathy in Patients With Cirrhosis.

Hepatic encephalopathy (HE) is associated with marked increases in morbidity and mortality for patients with cirrhosis. We aimed to determine the risk of and predictors for HE in contemporary patients. We prospectively enrolled 294 subjects with Child A-B (70% Child A) cirrhosis and portal hypertension without previous HE from July 2016 to August 2018. The primary outcome was the development of overt HE (grade >2). We assessed the predictive power of model for end-stage liver disease-sodium (MELD-Na) score, the Inhibitory Control Test, the Sickness Impact Profile score, and the Bilirubin-Albumin-Beta-Blocker-Statin score. We also derived a novel predictive model incorporating MELD-Na score, impact of cirrhosis on daily activity (Likert 1-9), frailty (chair-stands per 30 seconds), and health-related quality of life (Short-Form 8, 0-100). The cohort's median age was 60 years, 56% were men, and the median MELD-Na score was 9. During a follow-up of 548 ± 281 days, 62 (21%) had incident overt HE with 1-year probability of 14% ± 2%, 10% ± 2%, and 25% ± 5% for Child A and B. The best model for predicting the risk of overt HE included MELD-Na, Short-Form 8, impact on activity rating, and chair-stands within 30 seconds. This model-MELDNa-Actvity-Chairstands-Quality of Life Hepatic Encephalopathy Score-offered an area under the receiver operating curve (AUROC) for HE development at 12 months of 0.82 compared with 0.55, 0.61, 0.70, and 0.72 for the Inhibitory Control Test, Sickness Impact Profile, Bilirubin-Albumin-Beta-Blocker-Statin, and MELD-Na, respectively. The AUROC for HE-related hospitalization was 0.92. This study provides the incidence of HE in a well-characterized cohort of contemporary patients. Bedside measures such as activity, quality of life, and physical function accurately stratified the patient's risk for overt HE.

Risk of recurrent hepatic encephalopathy in patients with liver cirrhosis: a German registry study

Patients with hepatic encephalopathy (HE) show low quality of life, recurrent hospitalizations and an increased mortality. We aimed to assess the natural course of patients after a recent episode of overt HE and to identify risk factors for HE recurrence in Germany. Fifteen sites took part in a prospective, observational study including patients with liver cirrhosis who had been hospitalized for HE within 3 months before recruitment. Clinical data, psychometric hepatic encephalopathy score (PHES) and critical flicker frequency were assessed quarterly for 1 year. Primary endpoint was HE recurrence requiring hospitalization, all-cause-mortality was treated as a competing risk factor. From January 2014 to March 2016, a total of 115 patients were recruited. Overall 14 premature deaths were documented. For 78 subjects follow-up data were available in accordance with the protocol. After a median of 118 days, more than half of the per-protocol cohort was readmitted to hospital due to HE (N = 34) or died (N = 11). The risk for hospitalization was significantly increased in patients who had been recruited by liver transplant centers (P = 0.003), had had frequent HE relapses prior to recruitment (P = <0.0001) or an abnormal PHES result of <-4 (P = 0.044). Abnormal PHES results barely missed level of significance as an independent risk factor for re-hospitalization in a multivariable competing risk model (P = 0.093). Patients with a history of HE are at high risk for the development of recurrent overt HE demanding hospitalization. The PHES test may aid in detection, monitoring and risk stratification of recurrent HE.

Validation of a Simple Quality-of-Life Score for Identification of Minimal and Prediction of Overt Hepatic Encephalopathy.

Minimal hepatic encephalopathy (MHE) is underdiagnosed because most clinics refrain from psychometric testing. Diagnostic activities need to go up so patients with MHE can get the treatment their condition requires. The sickness impact profile questionnaire for covert hepatic encephalopathy (SIPCHE) score is based on quality‐of‐life outcomes and has been proposed as a simple, patient‐administered diagnostic score for grade 1 and MHE. Validate the SIPCHE for MHE identification and overt hepatic encephalopathy (OHE) prediction. 110 patients with liver cirrhosis (age 60 years, Model for End‐Stage Liver Disease score of 11.4, 80% blue‐collar) provided information for SIPCHE scoring: gender, age, and four SIP statements: “I do not maintain balance (physically),” “I act irritable or impatient with myself,” “I am not doing any of the usual physical recreation or activities,” and “I am eating much less than usual.” MHE was diagnosed using an abnormal continuous reaction time test and/or portosystemic encephalopathy syndrome test score. Patients were followed for 2.7 years on average. SIPCHE score positivity had high sensitivity (82%) but low specificity (38%) for MHE detection. Patients with an abnormal SIPCHE had a higher incidence of OHE during follow‐up (35% vs. 14%, P = 0.05). OHE prediction sensitivity was 87% and exclusion sensitivity was 85%. The patients with an abnormal SIPCHE had twice as many subsequent episodes of OHE, and despite their high mortality, also a higher risk. An abnormal SIPCHE had a high sensitivity and low specificity for MHE identification. An abnormal SIPCHE was associated with a more than doubled risk of OHE, even with death as a competing event. SIPCHE could be used as a high‐sensitivity, low‐cost, surrogate marker of MHE in clinics without availability of psychometric tests and allow more patients to benefit from anti‐MHE treatment.