bluuebunny/crossref_metadata_2025_split huggingface dataset:
P: 44 Non-canonical Inflammasome as a Driver of Hepatic Encephalopathy in a Mouse Model of Acute-on-Chronic Liver Failure
Authors: Soffientini U. , Beaton N. , Weiss E. , Baweja S , Habtesion A. , Paradis V. , Hall A. , Luong T. , Nadar A. , Sarin S. K. , Williams R. , Chokshi S. , Py B. F. , Moreau R. , Jalan R. , Mehta G. 
Published: September 2019

BACKGROUND:
Hepatic encephalopathy (EH) is a key feature of Acute-on-chronic liver failure, a common cause of mortality in cirrhosis. ACLF is characterized by multi-organ failure and disease progression is associated with elevated levels of circulating bacterial endotoxin (LPS), and increased non-apoptotic hepatocyte cell death. The non-canonical inflammasome is a LPS-sensing pathway, mediated by caspase-11 which, when activated, leads to cleavage of the cytoplasmic protein Gasdermin D (GSDMD) and subsequent pyroptosis - a form of non-apoptotic cell death. The aim of this study was to determine the role of the non-canonical inflammasome in the onset of EH in cirrhosis and ACLF.

METHODS:
Cirrhosis was induced in male C57BL mice by CCl4 gavage, twice weekly for 10 weeks. Subsequently, mice underwent i.p injection of LPS to induce ACLF. Brain tissue water content, plasma ALT and creatinine were measured by standard techniques. GSDMD cleavage was assessed by Western blot for full length and N-terminus protein. Caspase-11 activation was measured by colorimetric assay in liver protein extract. Mice deficient in Caspase11 showed protection against EH upon induction of ACLF, in the form of reduced brain swelling, and levels of circulating ALT and creatinine.

RESULTS:
All CCl4 + LPS mice showed features of ACLF following LPS injection, with increases in brain water (79.9 ± 0.2 vs 78.9 ± 0.1%, P < 0.01), plasma ALT (102.0 ± 8.9 vs 79.2 ± 6.2 IU/ml, P = 0.05) and creatinine (48.9 ± 5.6 vs 34.8 ± 1.3 umol/L, P < 0.05) at 4 hours compared to control (Figure 1a). Cleavage of hepatic GSDMD (ratio N-terminus: full length GSDMD 7.7 vs 2.1, P < 0.001) and activation of caspase-11 (2 fold induction, P < 0.05) (Figure 1b) was seen in the ACLF group at 4 hours compared to control. Caspase11-/- mice were protected against ACLF, with reduced brain water (78.9 ± 0.2% vs 78.3 ± 0.2%, P < 0.05), plasma ALT (530 ± 144 vs 172 ± 18 IU/ml, P = 0.05) and creatinine (17.9 ± 1.4 vs 13.7 ± 1.0 µmol/L, P < 0.05) at 4 hours after LPS injection compared to wild-type controls (Figure 1c).

CONCLUSIONS:
This study demonstrates non-canonical inflammasome activation and as a feature of ACLF concomitant to HE, resulting in activation of the target protein GSDMD in the liver. The non-canonical inflammasome activity is enhanced in cirrhosis, and deletion of Caspase-11 is shown to be protective against the onset of HE in ACLF.
P: 51 Aminoglycosides and Metronidazole for the Prevention and Treatment of Hepatic Encephalopathy in Adults With Cirrhosis
Authors: Jeyaraj Rebecca , Vadera Sonam , Low Zhi Yang , Gluud Lise Lotte , Morgan Marsha Y. 
Published: September 2019

BACKGROUND:
The EASL/AASLD guidelines stipulate that both neomycin and metronidazole may be used as alternatives for the treatment of overt HE, whereas the Italian guidelines state that these antibiotics are currently not recommended, mainly because of their potential systemic toxicity. This study aims to evaluate the utility of aminoglycosides and metronidazole vs. placebo, non-absorbable disaccharides (NAD) and other active treatment, for the management of HE in adults with cirrhosis.

METHODS:
Electronic/manual searches of the literature were undertaken for relevant RCTs. The results of the meta-analyses are presented as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CIs). Bias control was assessed using the CHBG domains and the certainty of the evidence using GRADE.

RESULTS:
Twenty RCTs evaluated aminoglycosides including neomycin (n = 15) paromomycin (n = 4), and ribostamycin (n = 1). Treatment periods ranged from 3 to 168 days. Comparators included: placebo (n = 2), NADs (n = 7), other antibiotics viz. rifaximin, erythromycin and ciproxin (n = 9) and BCAAs (n = 2). All but one trial was at 'high risk of bias'; the certainty of the evidence was low or very low for all outcomes. Twenty trials, with 1110 participants, reported mortality data, although there were no events in 12 trials. No differential beneficial or harmful effects were found in any of the trials (RR 1.10, 95% CI 0.89 to 1.42, I2 6%, P = 0.39). Seventeen trials, with 1025 participants reported data on HE. No differential beneficial or harmful effects were found in any of the trials (RR 0.89, 95% CI 0.57 to 1.39, I2 69%, P = 0.62). Twenty trials, with 1110 participants, reported 778 serious adverse events (SAEs), although there were no events in eight trials. Use of the aminoglycosides was associated with more SAEs including pneumonia and renal failure (RR 1.46, 95% CI 0.99 to 2.16, I2 0%, P = 0.06) (Figure 1). One RCT evaluated metronidazole vs. rifaximin. Treatment was administered for three days as an adjunct to oral lactulose, LOLA and thrice daily enemata. Both regimens were equally as effective; no adverse events were reported.

CONCLUSIONS:
Although no significant differences were observed between the effects of aminoglycosides and other interventions, in relation to death and HE, in patients with cirrhosis, their use may be associated with an increased risk of serous adverse events. The utility of metronidazole for the management of HE can not be evaluated on the basis of the available literature. Neither drug should be used routinely in this setting.
P: 54 Diagnosis of Covert Hepatic Encephalopathy Is Influenced by Multiple Non-cognitive Variables That Varies by Testing Strategy
Authors: Acharya Chathur , White Melanie B. , Fagan Andrew , Sterling Richard K. , Stravitz R. Todd , Puri Puneet , Fuchs Michael , Luketic Velimir , Sanyal Arun J. , Wade James B. , Gilles HoChong , Heuman Douglas M. , Tinsley Felicia , Matherly Scott , Lee Hannah , Siddiqui Mohammad S. , Bajaj Jasmohan S. 
Published: September 2019

BACKGROUND:
Covert hepatic encephalopathy (CHE) is a serious complication on cirrhosis that manifests as an amnestic cognitive dysfunction. Diagnosis is based on examining cognitive functions, but results are influenced by multiple non-cognitive factors such as sleep and medications but data regarding the influence of other non-cognitive covariates is limited. We aimed to examine the potential non-cognitive variables that could influence testing on the psychometric hepatic encephalopathy score (PHES) and the encephalapp stroop.

METHODS:
Patients between ages 20-75 years were enrolled from clinic between 2012–2018. Those with severe uncontrolled psychiatric comorbidities were excluded as were those actively abusing alcohol or drugs. All patients underwent testing for CHE based on 2 testing strategy as recommended by the AASLD/EASL guidelines. Demographics and details of comorbidities were collected. CHE was diagnosed based on published norms. Appropriate t tests and logistic regression were done. Dependent variable was CHE on PHES and Stroop.

RESULTS:
We enrolled a total of 257 patients with mean age 61.1 ± 8.3, 72% were males, HCV was he predominant etiology 96 (37.3%). Median BMI was 29 (26, 34). Median education was 13 (12, 16) years. Median MELD was 11 (7.25, 15) with median childs score of 6 (5, 8). Charlson comorbidity score (CCI) was 5 (4, 6). Eighty five (33%) had a history of prior OHE and were on lactulose (13), rifaximin (9) or both (63), 95 (37%) had ascites with 58 (61%) controlled on diuretics and 17 (18%) had a h/o SBP. 41 (16%) had a h/o variceal bleeding. In terms of comorbidities 34.2% had Diabetes Mellitus, 58% had Hypertension, 11% had Coronary artery disease, 14% had hypothyroidism, 2% had CHF, 2.3% had COPD, 30% had depression and 87% were controlled on medications. 2.3% had post traumatic stress disorder (PTSD) and were on medications. 14% were on chronic narcotic medications. On cognitive testing 109 (42.4%) had CHE with a median PHES score of −3 (−7, 0) whereas 206 (80%) tested positive on encephalapp stroop. On univariable analysis hypertension was found to be significant only for stroop. On multivariable analysis age and prior OHE were predictive for both tests but for the Encephalapp stroop hypertension was found to be independently predictive (Table 1).

CONCLUSION:
The diagnosis of CHE can be influenced by other non-cognitive variables and these vary between individual testing strategies probably due to the differential effects that these systemic conditions have on cerebral/subcortical functions. Physicians must take into consideration these covariates while interpreting CHE testing based on these 2 tests.
P: 62 Neurometabolism in Grey Matter of Children With Chronic Liver Disease or Portosystemic Shunting: A 1H-MRS Study at 7T
Authors: Cudalbu Cristina , Xin Lijing , Lachat Sarah , Valenza Nathalie , Zangas-Gehri Florence , McLin Valérie 
Published: September 2019

BACKGROUND:
Neurocognitive deficits in children with chronic liver disease (CLD) or congenital porto-systemic shunts (CPSS) are incompletely understood. Understanding the molecular underpinnings by non-invasive means could inform management. Aims To characterize the neurometabolic profile in the grey matter (GM) of children with CLD or CPSS and analyze correlations with neurocognitive and biological results.

METHODS:
Children aged 8–14 were enrolled if they presented with CLD or CPSS. Short-echo-time (16 ms) using 1H-MRS at 7T in GM dominated medial prefrontal cortex was performed, and neurocognitive testing and routine labs were obtained within 3 months of each other following informed consent.

RESULTS:
5 patients (8–14 y) including 4 with CLD (2 girls), 1 with CPSS (1 girl), and 4 controls (10–14 y, 2 girls) underwent 1H-MRS. Causes of CLD: congenital disorder of glycosylation (1), progressive familial intrahepatic cholestasis type-2 (1), portal obliterative venopathy (1), autoimmune hepatitis (1). Mean plasma ammonium in patients was 26 umol/l, mean serum bilirubin was in normal range and mean platelet count was 201 G/L (59–346). The 3 patients with CLD showed scores in average or above average on Total Intellectual Quotient measures (WISC-IV). One of the 3 scored below average on the working memory sub-scale of the WISC-IV (<1, 65 SD), while the intellectual profiles were homogenous and above average for the 2 others patients. One of these 2 scored below average on 6/10 parameters on the Conners Continuous Performance Test, suggesting attention deficit. The other two were in range. The patient with CPSS displayed Total Intellectual Quotient below average (<1, 65 SD on the WISC-IV), with additional deficits (<1, 65 SD) in executive and attentional functioning as well as expressive and receptive language. 1H-MRS results: 13 metabolites were reliably quantified. Figure 1 illustrates the differences between CLD and CPSS: the expected increase of brain glutamine and decrease of brain osmolytes (inositol, taurine, total choline) together with a previously unreported decrease in the neurotransmitters glutamate, GABA and N-acetylaspartate. No statistically significant differences were observed between the CLD patients and controls.

CONCLUSIONS:
In patients with compensated CLD, there were no significant neurometabolic alterations as assessed by high resolution 1H-MRS. In CPSS, however, neurometabolic changes were clear, and likely related to measurably impaired neurocognitive functioning. Together, these results suggest that in CPSS (type B encephalopathy) the brain is likely exposed to a higher load of neurotoxic substances than in patients who have some degree of portal flow (type C).
P: 64 Multimodal Approach Including MR-spectroscopy for the Diagnosis of Minimal Hepatic Encephalopathy
Authors: Weiss Nicolas , Hermann Bertrand , Rudler Marika , Bouzbib Charlotte , Galanaud Damien , Mallet Maxime , Duvoux Christophe , Coilly Audrey , Francoz Claire , Plessier Aurélie , Thabut Dominique 
Published: September 2019

BACKGROUND:
There is no gold-standard for the diagnosis of hepatic encephalopathy (HE) and especially in case of minimal HE (MHE) where the value of paraclinical examinations is debated. MR-spectroscopy has been proposed as a valuable diagnostic tool for the diagnosis of HE by showing increased glutamate/glutamine peak and decreased myoinositol and choline peaks. However, access to MRI is difficult and few data on real life experience has been reported. We studied the interest of a multimodal approach combining clinical, neuropsychological, biological and MR-spectroscopy in the diagnosis of MHE.

METHODS:
We conducted a retrospective study in a single tertiary university hospital in Paris, France, where all out-patients referred to a specific hepato-neurology consultation dedicated to the diagnostic of MHE underwent a clinical examination, psychometric tests (Critical Flicker Frequency-CFF, Psychometric Hepatic Encephalopathy Score-PHES), ammonemia and cerebral MRI with spectroscopy (MRS). Patients were classified as having MHE or not by consensus between two experts.

RESULTS:
We included 56 patients between February 2013 and April 2016. Median age was 57 years [49–63]. Forty-four (79%) had a cirrhosis (etiology: alcohol 35%, NASH 9%, viral 23%, alcoholic and non-alcoholic steatohepatitis 26%, other 7%) with a median MELD of 10 [7–12]. Twelve (21%) had non-cirrhotic portal hypertension (Budd-Chiari 33%, extra-hepatic portal hypertension 33%, idiopathic portal hypertension 16%, portal agenesia 9% and nodular regenerative hyperplasia 9%). According to the experts, 57% had an MHE, whereas 43% hadn't. Among the clinical informations, only the presence of a portosystemic shunt (TIPS or surgical) was associated with MHE. A venous ammonemia >50 μmol/l, MRI T1 hyperintensity of the basal ganglia and an MRS HE profil suggestive of HE were all statistically associated with the diagnosis of MHE (P < 0.0001). The best diagnostic performance was achieved by combining MRS with either MRI T1 hyperintensity (AUC = 0.93) or ammonemia (AUC = 0.91).

CONCLUSION:
A multimodal approach combining clinical data, ammonemia and cerebral MRI with MRS seems to have good accuracy for the diagnosis of MHE. Further prospective studies are mandatory.
P: 66 Increased Levels of Xenobiotics in Plasma of Cirrhotic Patients With Neurological Symptoms, a Metabolomic Study
Authors: Weiss Nicolas , Saint Hilaire Pierre Barbier , Colsch Benoit , Attala Suleiman , Schaefer Augustin , Rudler Marika , Bouzbib Charlotte , Lamari Foudil , Sedel Frédéric , Junot Christophe , Thabut Dominique 
Published: September 2019

BACKGROUND:
Encephalopathy is a classical complication of liver disease and/or portosystemic shunts. Its pathophysiology is not completely elucidated; mechanisms include the role of elevated ammonia levels in association with systemic inflammation. An impairment of blood-brain barrier (BBB) permeability is also hypothetized. Metabolomics enables to detect a wide range of metabolites without any a priori. In a recent metabolomic study including patients who underwent cerebrospinal fluid (CSF) collection, our group outlined that xenobiotics/drugs that usually are not able to cross BBB were retrieved in the CSF, suggesting a potential neurological toxicity of drugs. CSF collection is invasive. To describe the xenobiotics present in the plasma of cirrhotic patients, using the same metabolomic approach.

METHOD:
We conducted a retrospective study of plasma samples in the Hepatological ICU. Plasma samples from cirrhotic patients displaying encephalopathy were compared to plasma from cirrhotic patients without neurological symptoms, and to plasma from healthy controls. Liquid chromatography coupled to high-resolution mass spectrometry was performed and thenafter the metabolic fingerprints were compared to database and between the different groups.

RESULTS:
Plasma samples were obtained from 12 cirrhotic patients with encephalopathy (age 59 [40–68], MELD 20 [16–31], alcohol 58%), 13 cirrhotic patients without encephalopathy (age 56 [55–64], MELD 17 [14–29], alcohol 38%) and 9 healthy controls. Among 495 identified metabolites, 25 corresponded to xenobiotics or its derivatives. Fluoxetine was detected with a more than 200 fold increase, aminosalicylic acid with a more than 10 fold increase and benzyl alcohol (present in cough pills and antiseptics) with a 3 fold increase in cirrhotic patients with encephalopathy as compared to cirrhotic patients. In cirrhotic patients with or without encephalopathy, propranolol was detected with a more than 8500 fold increase, acetaminophen with a 40 fold increase, penicillamine and ampicillin both with a 2 fold increase as compared to healthy controls. Interestingly, several substances which were not expected to have systemic diffusion were detected in cirrhotic patients and in healthy controls: eugenol, isoeugenol (used in mouth bathing solution), triethanolamine (trolamin, used in cutaneous creams) and resorcinol monoacetate (used in mouth bathing solution and in cutaneous creams).

CONCLUSION:
Cirrhotic patients, especially those with neurological symptoms, display dramatically increased levels of several xenobiotics in plasma. These results confirm that PK/PD parameters of commonly used drugs are highly modified in those patients. This suggests a potential role of xenobiotics in the pathophysiology of encephalopathy in patients with liver diseases
P: 69 Sarcopenia Pre- and Post-liver Transplantation: Implication for Hepatic Encephalopathy
Authors: Nguyen Mimosa , Huard Geneviève , Tang An , Rose Christopher F. , Bemeur Chantal 
Published: September 2019

BACKGROUND:
Muscle wasting (sarcopenia) and hepatic encephalopathy affect 30 to 70% of cirrhotic patients. The presence of sarcopenia may be associated with a worst prognosis and complications, including hepatic encephalopathy, in cirrhotic patients awaiting and after liver transplantation (LT). To this day, few studies have evaluated and followed muscle mass (in terms of quantity and quality) after LT. The goal of this study was to assess the association between the evolution of sarcopenia and the prognosis of cirrhotic patients, including hepatic encephalopathy and neurological complications, before and after LT.

METHODS:
In total, 94 cirrhotic patients who underwent LT at the Montreal University Hospital Center - Liver Unit were included. Sarcopenia was assessed at the third lumbar level vertebrae using a computed tomography scan (CT-scan). The diagnostic of sarcopenia was based on previously established sex-specific cut-off values of skeletal muscle index. Patients were classified into two groups: (1) persistent or newly developed sarcopenia after LT (Sarc+); (2) resolved sarcopenia or absence of sarcopenia before and after LT (Sarc-). Muscle quality (myosteatosis) was assessed by calculating intramuscular adipose tissue content. The prognostic factors were collected 6 months before and during 1 year after LT through medical records and included the number of complications, the presence of hepatic encephalopathy and the episodes of infections, the length of stay, and the frequency of readmissions.

RESULTS:
Sarcopenia persisted or was newly developed (Sarc+) in 62% of the patients (n = 58). It remained absent or was resolved after LT in 38% of the patients (n = 35). Muscle quality was significantly decreased post-LT (P = 0.034). The group Sarc+ experienced more complications pre-LT (P = 0.012) and post-LT (P < 0.001), infections post-LT (P = 0.006) and readmissions (P = 0.048) compared to the group Sarc-. The length of stay was longer for the group Sarc+ as opposed to the group Sarc- (P < 0.001). Hepatic encephalopathy was present in 83% of patients pre-LT whereas 17% experienced persistent neurological complications post-LT.

CONCLUSIONS:
Persistent and newly developed sarcopenia after LT appear to have negative outcomes on the prognosis of patients. Interventional strategies to optimize, increase or preserve muscle mass could help to improve post-operative recovery as well as the quality of life in patients who have undergone LT.
P: 70 Quality of Life Assessment May Aid in the Diagnosis of Minimal Hepatic Encephalopathy and Prediction of Overt Hepatic Encephalopathy
Authors: Munk Lauridsen Mette , Vilstrup Hendrik , Schaffalitzky de Muckadell Ove B. , Heuman Douglas M. , Bajaj Jasmohan S. 
Published: September 2019

BACKGROUND:
Minimal hepatic encephalopathy (MHE) impinges on quality of life (QoL), is associated with a high risk of overt hepatic encephalopathy (OHE) and is often treatable by simple means. Still, MHE is rarely systematically diagnosed and treated likely because dedicated psychometric tests give the impression of being resource heavy and thus scare off many clinicians. Simple, patient-administered QoL questionnaires e.g. sickness impact profile (SIP), could improve diagnostic rates. This approach was tested in a US-based study introducing SIPCHE score (formula of 4 SIP statements, gender and age). We here aim at externally validate SIPCHE score in a cirrhotic cohort using continuous reaction time (CRT) test and portosystemic hepatic encephalopathy score (PHES) for MHE diagnosis.

METHODS:
110 cirrhotic patients without OHE (age 60 years, MELD 11.4, 80% blue-collar) completed cognitive testing and SIP. Abnormal CRT and/or PHES diagnosed MHE. SIP consists of 136 questions inquiring about QoL and standardized QoL scores were compared in MHE and non-MHE patients. The SIPCHE (US cut point >0) was applied and predictive values were calculated. We followed the patients for 2.7 years on average and registered OHE episodes.

RESULTS:
The SIPCHE was abnormal in 82/110 patients and was in agreement with the psychometric tests in 73/110 cases (66%). The SIPCHE indicated MHE in 58/71 of the patients with MHE according to 2-test psychometry (positive predictive value = 71%, sensitivity = 82%, AUUROC 0.63). The SIPCHE was false positive in 24/39 non-MHE patients (specificity 38%, NPV 53%). A normal SIPCHE did not exclude MHE in our population as 13/28 (46%) with a normal SIPCHE score had MHE according to the CRT and PSE tests. In our cohort using a cut point of >−0.40, in stead of >0, sligthly improved correct classification to 72% of patients. Only 4/28 (14%) with a normal baseline SIPCHE experienced OHE, while 29/82 (35%) with abnormal SIPCHE experienced OHE (P = 0.05). Accordingly, the SIPCHE positive predictive value for a future HE episode is this 87% (likelihood ratio 2.4).

CONCLUSIONS:
In conclusion, the idea of a patient-reported outcome score as an addition to standard psychometry is appealing. The US derived SIPCHE score is able to identify the majority of patients with MHE and future OHE episodes, but lacks diagnostic specificity. We suggest that development of regional SIPCHE scores could be useful. In future studies using the SIPCHE as a measure of patients-experienced effect of MHE treatment would be of interest.