bluuebunny/crossref_metadata_2025 huggingface dataset:
P: 6 Interaction of Pre-dementia Mild Cognitive Impairment and Hepatic Encephalopathy in Elderly Patients With Cirrhosis: A Multi-Center Study
Authors: Xie Jessie , Acharya Chathur , Vargas Hugo , Duarte-Rojo Andres , Wade James B. , Thacker Leroy R. , Kelly Megan , Fagan Andrew , White Melanie B. , Flud Christopher , Garcia-Saenz-de-Sicilia Mauricio , Bajaj Jasmohan S.
Published: September 2019

BACKGROUND:

Patients with cirrhosis are growing older and the overlap between hepatic encephalopathy (HE) & pre-dementia mild cognitive impairment (MCI) is unclear. HE affects visuospatial/psychomotor speed while MCI affects memory. Aim: Determine the performance of elderly cirrhotics on tests for HE and dementia and their impact on quality of life (QOL).

METHODS:

Outpatient cirrhotics and controls ages 65–95 years were recruited at 4 centers. Subjects had to have MMSE > 25, no current HE or dementia to be eligible. All subjects got tests for HE (psychometric hepatic encephalopathy score, PHES: 5 tests & low score = poor, EncephalApp, OffTime + OnTime, high score = poor) and QOL: Sickness Impact profile (SIP, high score = poor QOL). Cirrhotics also got tests for MCI; RBANS (tests immediate memory, delayed memory, language, visuo-spatial & attention). A neuro-psychologist evaluated results and divided cirrhotics into (A) unimpaired (B) MCI only (C) HE only & (D) (MCI/HE overlap). Demographics, MELD, alcohol etiology, and SIP were compared. Finally, age, gender and education-adjusted norms were created for PHES and EncephalApp based on the controls. Presence of MHE and sensitivity of EncephalApp for MHE diagnosis were evaluated.

RESULTS:

109 cirrhotics and 100 non-cirrhotic subjects were included. Demographics/education levels were statistically similar between centers. Controls were older than cirrhotics (74.9 ± 6.6 vs 70.5 ± 4.4, P < 0.05) and had similar education/gender distribution. Despite this, controls performed better than cirrhotics on all tests (PHES 2.9 ± 12.4 vs −4.5 ± +4.5, P < 0.001, EncephalApp Off+On 181.4 ± +71.9 vs 218.2 ± +80.0, P = 0.03) and had a better QOL (SIP total 3.8 ± +7.1 vs 7.9 ± +9.5, Psych 3.3 ± +8.4 vs 7.2 ± +11.1, Phys 3.0 ± +6.2 vs 6.7 ± +9.5, all P < 0.001). Within cirrhosis subgroups (Table 1), demographics, MELD/alc & MMSE were similar. Pts with both MCI/HE had worse cognition on all tests, which translated into a worse QOL compared to other groups. Presence of HE, with/without MCI, contributed towards poor QOL. Norms for PHES/EncephalApp: Adjusting for age, gender & education, 17% (n = 17) patients were positive for MHE on PHES compared to controls. On EncephalApp, 49% (n = 47) patients were positive. AUC for EncephalApp using PHES as the gold standard was 0.86 (0.78-0.95 CI).

CONCLUSIONS:

In this multi-center study, adjusted norms defining the high sensitivity of EncephalApp to diagnose HE in older individuals were created. Presence of HE regardless of MCI contributed towards poor cognition and QOL in patients >65 years.
P: 7 Identifying Overt Hepatic Encephalopathy Using Administrative Data in the ICD-10 Era: A Study to Validate Diagnostic Algorithms
Authors: Korovaichuk Sophia , Tapper Elliot B.
Published: September 2019

BACKGROUND:

Administrative datasets are necessary in order to study the outcomes of patients with hepatic encephalopathy (HE) at the population-level. Validated algorithms using ICD-9 diagnostic codes have facilitated prior studies but are now invalid given the switch to ICD-10 in 2015. To date, no study has validated any diagnostic coding algorithm for HE using ICD-10 codes.

METHODS:

From 2016–2017 at the University of Michigan outpatient liver clinic, we prospectively enrolled 300 persons with Child A-B cirrhosis and portal hypertension with no current or prior history of HE. All patients were followed for up to 3 years. Each patient was assessed every 3 months for clinical developments (including new overt HE, falls, hospitalizations, and liver cancer) and recorded all medications taken. Overt HE was defined as disorientation that was clinically defined as HE by the patient's hepatologist. We surveyed all ICD-10 billing codes generated for each patient during follow up. We sought to evaluate the sensitivity and specificity of codes and medications for the presence of HE: K72.90 (hepatic failure), K72.91 (hepatic failure with coma), G93.40 (encephalopathy, NOS), G93.49 (Other encephalopathy), and prescription of lactulose or rifaximin.

RESULTS:

Overall our cohort was aged 60 (52–66) years, 56.3% male, and 70% Child class A. All patients had portal hypertension, 76% had varices, and 41% had a history of ascites (predominantly well controlled). The median MELD-Na score was 9 (IQR, 7–13). Overall 68 out of 301 patients (22%) developed overt HE during follow-up. Only 1 patient was assigned the code K72.91, whereas codes G930.40 and G93.49 were not coded in our claims data. These 3 codes offered 0% sensitivity and specificity for HE. Conversely, the ICD-code K72.90 had moderate sensitivity (41.2%) and high specificity (97.9%), positive predictive value (PPV) 84.8%, and negative predictive value (NPV) 85.1%. Recorded lactulose and or rifaximin use was highly sensitive (94.1%) and specific (98.3%), PPV 87.7%, NPV 98.3%.

CONCLUSION:

In this prospective study, we define the performance of diagnostic codes for the identification of HE in the electronic health record study. Medications specific for HE therapy outperformed diagnostic codes.
P: 10 Hepatic Encephalopathy Is Reversible in the Long-term after Liver Transplantation
Authors: Hopp Anna-Elisabeth , Dirks Meike , Petrusch Carlotta , Goldbecker Annemarie , Tryc Anita Blanka , Barg-Hock Hannelore , Strassburg Christian , Klempnauer Jürgen , Weissenborn Karin , Pflugrad Henning
Published: September 2019

BACKGROUND:

Cognitive dysfunction caused by hepatic encephalopathy in patients with acute or chronic liver failure improves within the first year after liver transplantation. However, cognitive restitution seems to be incomplete in a subset of patients. Furthermore, a new-onset cognitive decline after liver transplantation was described. This prospective study analyzed whether a history of hepatic encephalopathy before liver transplantation had an impact on the long-term outcome of cognitive function after liver transplantation and if patients who underwent liver transplantation up to 5 five years before showed worse cognitive function than adjusted healthy controls.

METHODS:

34 patients with liver cirrhosis on the waiting list for liver transplantation underwent a psychometric test battery and questionnaires assessing health-related quality of life 3.4 ± 3.1 months (T1) before liver transplantation. Further 33 patients were included directly after liver transplantation. After transplantation all patients (n = 67) underwent psychometric testing and completed questionnaires at 8.9 ± 3.6 months (T2) and at 62.1 ± 12.2 months (T3) thereafter. The psychometric test battery consisted of the Portosystemic Encephalopathy Syndrome-Test which provides the psychometric hepatic encephalopathy score (PHES), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Inhibitory Control Test and the Critical Flicker Frequency. All patients were asked to complete the self-reporting questionnaires Hospital Anxiety and Depression Scale, Beck Depression Inventory, Fatigue Impact Scale and Short Form 36 health survey to assess health-related quality of life. Patients were divided into 2 groups: Patients with and without hepatic encephalopathy before liver transplantation. Test results were compared to those of 55 adjusted healthy controls.

RESULTS:

Patients tested before liver transplantation performed significantly worse than controls in the psychometric tests (RBANS total scale mean 92.6 ± 13.3 vs 99.9 ± 12.0, P < 0.001; PHES median 0 (interquartile range (IQR) −3; 1) vs 1 (IQR 0; 2), P < 0.01). About 1 year after liver transplantation patients with a history of hepatic encephalopathy still showed cognitive impairment compared to controls (RBANS total scale mean 89.5 ± 15.6 vs 99.9 ± 12.0, P = 0.001; PHES median 0 (IQR −2; 1) vs 1 (IQE 0; 2), P < 0.01) while patients without a history of hepatic encephalopathy did not. 5 years after liver transplantation both patient groups did not differ from healthy controls (Table 1). Health-related quality of life improved significantly in both patient groups after transplantation.

CONCLUSIONS:

Cognitive impairment associated to hepatic encephalopathy seems to be reversible within 5 years after liver transplantation.
P: 14 Non-alcoholic Fatty Liver Disease Alters Expression of Genes Governing Hepatic Nitrogen Conversion
Authors: Lykke Eriksen Peter , Vilstrup Hendrik , Rigbolt Kristoffer , Suppli Malte Palm , Sørensen Michael , Veidal Sanne Skovgård , Knop Fillip Krag , Thomsen Karen Louise
Published: September 2019

BACKGROUND:

We recently showed that the functional capacity for ureagenesis is deficient in patients with NAFLD. The aim of this study was to assess the expression of urea cycle and related genes to elucidate whether there may be a gene regulatory basis to the functional problem.

METHODS:

Liver mRNA expression analyses within the gene pathway governing hepatic nitrogen conversion were performed in 20 non-diabetic, biopsy-proven NAFLD patients (8 simple steatosis; 12 non-alcoholic steatohepatitis (NASH)), and compared with 12 obese and 14 lean healthy control persons. The relationship between gene expressions and functional capacity for ureagenesis was described.

RESULTS:

Gene expression of most urea cycle-related enzymes were downregulated in NAFLD vs. both control groups and markedly so for the urea cycle flux-generating carbamoyl phosphate synthetase (CPS1) (∼3.5-fold, P < 0.0001). In the NASH patients, the reduction of CPS1 expression paralleled the deficit in functional ureagenesis (P = 0.03). Additionally, the expression of several genes involved in amino acid uptake and degradation, and the glucagon receptor gene, were downregulated in NAFLD. Conversely, gene expression of glutamine synthetase (GS) increased more than 1.5-fold (P ≤ 0.03), inversely related to CPS1 expression (P = 0.004).

CONCLUSIONS:

NAFLD downregulated the expression of urea cycle-related genes. Downregulation of the urea cycle flux-generating enzyme CPS1 correlated with loss of functional capacity for urea synthesis in patients with NASH. On gene level, these changes coincided with an increase in the major ammonia scavenging enzyme GS. The effects seemed to be related to a fatty liver as such rather than NASH or obesity. The findings support that gene regulatory mechanisms are involved in the deficient urea synthesis of NAFLD, but it remains unexplained how the hepatocyte fat accumulation exerts these
P: 19 Predictive Value of Induced Hyperammonaemia and Neuropsychiatric Profiling in Relation to the Occurrence of Post-tips Hepatic Encephalopathy (HE)
Authors: Senzolo Marco , Zarantonello Lisa , Formentin Chiara , Orlando Costanza , Beltrame Raffaello , Vuerich Anna , Angeli Paolo , Burra Patrizia , Montagnese Sara
Published: September 2019

BACKGROUND:

Hepatic encephalopathy (HE) occurs in 20%–50% of patients after transjugular intrahepatic portosystemic shunt (TIPS). While indices such as an older age, a history of overt HE and severe liver failure have been associated with post-TIPS HE, it remains difficult to identify patients at risk. The aim of this study was to evaluate the predictive value of a large set of clinical, laboratory and neuropsychiatric parameters, both at baseline and after the induction of hyperammonaemia, in relation to the development of post-TIPS HE for 12 months in a group of well-characterised TIPS candidates.

METHODS:

18 TIPS candidates (58 ± 8 yrs, MELD 11 ± 3; 13 refractory ascites, 1 hydrothorax, 4 uncontrolled bleeding) underwent neurophysiological [Electroencephalography (EEG)], neuropsychological [Psychometric Hepatic Encephalopathy Score (PHES) and Scan test], capillary ammonia and subjective sleepiness assessment both at baseline and after the induction of hyperammonaemia by an oral amino acid challenge (AAC).

RESULTS:

At baseline, 3 (17%) patients had abnormal EEG, 1 (5%) abnormal PHES, and 6 (33%) abnormal Scan performance; fasting capillary ammonia concentrations were 199 ± 88 μg/dL and subjective sleepiness 2.5 ± 1.2 (1–9 scale). Post-AAC, 3 (17%) patients had abnormal EEG, none abnormal PHES, and 3 (17%) abnormal Scan performance. Post-AAC, patients exhibited the expected increase in ammonia [F(4, 56) = 2.7213, P = 0.038] and subjective sleepiness [F(4, 52) = 5.4002, P = 0.001]. Six months after TIPS, 3 patients had had an HE-related hospitalization. Compared to their counterparts who had not, they showed significantly lower, pre-AAC fasting ammonia concentrations (96 ± 93 vs. 225 ± 58 μg/dL, P = 0.017). They also showed worse PHES and Scan performance at baseline, as well as worse Scan performance and slower EEG post-AAC. Twelve months post-TIPS, 5 patients had had an HE-related hospitalization, and comparisons between the two groups confirmed the findings at 6 months.

CONCLUSIONS:

TIPS candidates, who are by definition at low risk of HE, seem to encompass two different populations: i) those who are well and have not had overt HE because their ammonia levels are near-normal, ii) those who are well and have not had overt HE despite hyperammonaemia, either because of habituation or a personal inclination not to exhibit the HE phenotype. Fasting ammonia may be a promising and easily obtained parameter for future validation and inclusion in models for the prediction of post-TIPS HE.
P: 20 EID-UL-AZHA (Muslim's Festival of Sacrifice): Increased Frequency of Spontaneous Encephalopathy, Whether This Is Secondary to Consumption of High Protein Diet?
Authors: Bhatti Rehmatullah
Published: September 2019

BACKGROUND:

Protein restricted diet once was the cornerstone of the management of Hepatic encephalopathy, latter no evidence showed significant benefits. However sub group of cirrhotics are intolerant to dietary proteins, especially animal proteins. We compared precipitants of encephalopathy and effect of animal proteins consumption during the festival of EID-UL-AZHA

METHODS:

A retrospective comparative cross sectional study was conducted and analyzed hospital data of AIMS (Asian institute of medical sciences, Hyderabad, Pak.). Patients of cirrhosis were enrolled with clinically diagnosed hepatic encephalopathy in two groups. Group A was categories with patients admitted 15 days before EID-Ul-AZHA and Group B includes patients admitted on EID UL AZHA day and up to 15 days afterward. Patients with neurological deficit and suspected CNS infection were excluded. Patient of both groups were assessed to compare precipitant factors for encephalopathy that includes infections, electrolytes imbalance, upper GI bleed, constipation, AKI and drugs. Dietary history regarding normal protein diet and high protein diet (animal proteins > 1.5 g/kg/day) were also collected and compared in both groups.

RESULTS:

Out of 378 screened patients, 92 were presented with encephalopathy. All patients were Muslims with mean age 54.36 ± 11 yrs. Majority 66.3% were males and 33.7% were females. Precipitating factors were identified in 70.2% and 62.9% in group A and B respectively. Precipitating factor remain unidentified in 29.8% patients in group A and 37.1% in group B. 98.2% patients in group A were taking usual diet, only 1.8% consumed high (animal) protein diet, while in group B 51.4% patients were on usual diet and 48.6% consumed high (animal) protein diet. A comparable rise in frequency of spontaneous hepatic encephalopathy (without an identified precipitating factors) was observed in group B and 76.9% patients out of them were consuming high (animal) protein diet.

CONCLUSIONS:

A comparable rise in frequency spontaneous hepatic encephalopathy was observed during and/or post event of EID-UL-AZHA, majority had consumed high (animal) proteins. Consumption of meat (animal proteins) could be the possible contributing factor. Generally protein restriction is not recommended in cirrhotics but, still in sub group of cirrhotics who are protein intolerant, protein restriction or substitution of source of protein is inevitable. A further multicenter study is necessary at a larger scale to find out characteristic of patients who are intolerant to animal proteins.
P: 25 Muscle Alterations Are Associated With Minimal and Overt Hepatic Encephalopathy in Patients With Liver Cirrhosis
Authors: Nardelli Silvia , Lattanzi Barbara , Merli Manuela , Gioia Stefania , Ridol Lorenzo , Riggio Oliviero
Published: September 2019

BACKGROUND:

Muscle alterations (myosteatosis and sarcopenia) are frequent in cirrhosis and related to some complications included overt hepatic encephalopathy. The aim of our study was to investigate the relationship between muscle alterations and minimal hepatic encephalopathy (MHE) and their role on the risk of overt HE.

METHODS:

64 cirrhotics were submitted to Psychometric Hepatic Encephalopathy Score (PHES) and to Animal Naming Test (ANT) to detect MHE. CT scan was used to analyse the skeletal muscle index (SMI) and attenuation. The incidence of the first episode of HE, taking into account the competing risk nature of the data, was estimated.

RESULTS:

Myosteatosis was observed in 24 patients (37.5%), sarcopenia in 37 (58%) and MHE in 32 (50%). Both myosteatosis (62.5 vs 12.5%; P < 0.001) and sarcopenia (84 vs 31%; P < 0.001) were more frequent in patients with MHE. The variables independently associated to the presence of MHE were: sarcopenia, previous overt HE and myosteatosis. Thirty-one (48%) patients developed overt HE during 16.1 ± 13 months; myosteatosis was detected in 68% and sarcopenia in 84% of them. Sarcopenia and myosteatosis were also independently associated to the development of overt HE. Venous ammonia was significantly higher in sarcopenic patients (62.6 ± 17.7 vs 41.4 ± 16.1 μg/dl; P < 0.001) and in myosteatosic patients (65.2 ± 19.2 vs 46.7 ± 17.1 μg/dl; P < 0.001) and inversely correlated to both parameters. Survival was significantly lower in malnourished patients compared with patients without myosteatosis or sarcopenia (P < 0.001).

CONCLUSIONS:

Myosteatosis and sarcopenia, probably by reducing the handling of ammonia in the muscle, are independently associated to MHE and to the risk of overt HE in cirrhotics. In malnourished patients, the amelioration of nutritional status may be a possible goal to decrease both the prevalence oh MHE and the incidence of overt HE.
P: 32 Liver Transplant Is Associated With Improvement in Cognition, Tandem Gait and Risk of Falls
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:

Cirrhosis is associated with poor health related quality of life (HRQOL), cognitive and physical frailty (CF/PF), that manifest as covert/overt hepatic encephalopathy (CHE/OHE) and with incoordination and falls respectively. Tandem gait (TG; heel-toe) walking is a marker of PF. We aimed to determine the impact of LT on CF, abnormal TG, falls and HRQOL, in decompensated cirrhosis.

METHODS:

We prospectively enrolled pts from the active LT wait list from 2011–2016. All pts underwent complete neurological examination, cognitive testing by the psychometric hepatic encephalopathy score (PHES), and HRQOL assessment using sickness impact profile (SIP, physical/psychosocial domains). All pts were followed up at 6 & 12 months post-LT at which point repeat testing was done. Cognitive frailty (prior OHE/CHE) & physical frailty (abnormal TD) and falls were analyzed pre/post-LT.

RESULTS:

61 pts completed all visits. The median (IQR) time to LT was 54 (16, 112.5) days. Majority were men (51, 84%), with HCV etiology (21, 34%). Pre-LT: Thirty (49%) had abnormal TD, 37 (61%) had CHE, 20 (32.7%) with CHE + abnormal TD, 38 (62%) had prior OHE & 9 (14.7%) had falls. The abnormal vs normal TD pts had similar ages, sex, education level and MELD scores. Comparison showed the abnormal TD group had higher OHE (76% vs 48%, P = 0.03) and worse physical SIP score [24 (12.5, 39) vs 13.8 (3.2, 20.5), P = 0.008]. On multivariable analysis with abnormal TD as dependent variable physical SIP score was significant [OR 1.05 (1.006–1.09), P = 0.02]. On multivariable analysis with CHE+ abnormal TD as dependent variable physical SIP score [OR 1.12 (1.06–1.25), P = 0.02] and PHES scores were significant [OR 0.8 (0.68–0.96), P = 0.02]. Post-LT 6/12 months: Six pts had ACR that was managed with standard treatment and all pts were controlled on calcineurin inhibitors and mycophenolate at post-LT visits. There was a sustained improvement in PHES, SIP scores, falls and TD abnormalities post-LT more at 12 compared to 6 months in all pts (Table 1). Post-LT analysis showed that pts with abnormal pre-LT TD had a worse PHES score at 6 month [−4 (−5, 0) vs −0.5 (−3, 1.25), P = 0.0064] and higher cognitive impairment on PHES [12 (40%) vs 3 (10%), P = 0.007] compared to those with normal pre-LT TD.

CONCLUSIONS:

After LT, there is a sustained improvement in CF, abnormal TG and HRQOL from 6 through 12 months, which is accompanied by a lower rate of falls.
P: 35 Hepatic Encephalopathy Is an Independent Risk Factor for the Occurrence of Infection in Cirrhotic Patients With Acute Decompensation
Authors: Alabsawy Eman , Shalimar  , Agarwal Banwari , Jalan Rajiv
Published: September 2019

BACKGROUND:

Hepatic encephalopathy (HE) in cirrhotic patients increases mortality with worsening of HE grade 1. Infection is important in the pathogenesis and a common reason for progression to HE and death in these patients 2. However, HE role as a predisposing factor to infection in patients with acute decompensation (AD) is not known. It's recently shown that CNS injury leads to secondary immunodeficiency, and significantly increases susceptibility to infection (Pneumonia is the commonest serious complication with stroke 3), with development of the so known CNS injury-induced immunodepression (CIDS). But those studies focused only on organic brain injuries, like stroke, TBI and SCI4. Our study aims to determine whether HE is associated with the development of new infections in cirrhotic patients with AD.

METHODS:

Patients were identified at two institutions (AIIMS & UCL) as part of ongoing prospective studies of AD. Culture positive Infections and severity of HE (classified by West Haven Criteria) were measured on the day of admission, and new culture positive infections were assessed for up to 28 days after admission. Organ failures were defined as CLIF-organ failure score. Cox-proportional hazard analysis was used to assess predictors of infection.

RESULTS:

759 cirrhotic patients with AD were included with a median age of 45 years, and varying degrees of HE; grade 0/1 (n = 452), grade 2–4 (n = 307). On day 0, Patients classified into 4 groups; no HE no infection (n = 359), overt HE no infection (n = 222), no HE with infection (n = 93), overt HE with infection (n = 85). OFs (Liver, Renal, Brain, Coagulation, Respiratory, and Circulatory) and ACLF grades were measured on Day 0, with ACLF grade 0, 1, 2, and 3 (n = 242, 99, 206, and 212 respectively). On univariate and multivariate analyses, Overt HE (with no baseline infection) was independently predictive of new infections (1.639 and 1.608; P = 0.006, and 0.016 respectively). Furthermore, age and circulatory failure were also independent risk factors for infection (P = 0.001, and 0.017 respectively). Overall, HE was higher in non-survivors (n = 191) compared to survivors (n = 116).

CONCLUSIONS:

The results of this study show for the first time that, in AD patients, overt HE not only associated with higher mortality but is also an independent risk factor for infection. We also showed that Age and Circulatory failure are independent risk factors for infections. That would make them, after further studies, an indication for prophylactic antibiotics.
P: 43 A Sensitive and Convenient Protocol for Determining Brain Water Content in Rats using a Moisture Analyzer
Authors: Madrigal Carlota , Llanes Ana , Bryan Sofia , Bañares Juan , Martín-Guerra Rocío , Franco Carolina , Puerto Marta , Rubio Carmen , Bañares Rafael , Vaquero Javier
Published: September 2019

BACKGROUND:

Brain water content represents a major endpoint in studies of hepatic encephalopathy and liver failure.1 However, none of the current methods for evaluating brain water content fulfills the ideal requirements of a measuring technique, being complex, expensive, lengthy, qualitative or insensitive.2 Our AIM was to evaluate a novel protocol for measuring brain water content using a moisture analyzer in a rodent model of hyponatremia-induced brain edema.

METHODS:

Female Sprague-Dawley rats (248 ± 41 g bw) undergoing a 3-hour protocol for inducing hyponatremia-related brain edema (HypoNa group) were compared with a group of normonatremic rats (Control group). All rats were anesthetized with sevoflurane and mechanically ventilated. Body temperature was maintained at 37 ºC and major physiological parameters (heart rate, oxygen saturation, mean arterial pressure) were monitored. Acute hyponatremia was induced by administering desmopressin (DDAVP 1 ug/rat s.c.) and two i.p. injections of 140 mmol/L glucose solution (an injection of 12% of b.w. at the beginning and of 6% of b.w. 30 minutes later). At the end of the experiments, blood was collected from aorta, the rats were decapitated, and the brain was quickly dissected. Frontal cortex was immediately frozen and stored in liquid nitrogen. The frontal cortex was pulverized frozen with a metal mortar, and the frozen powder was placed in a moisture analyzer (MB120, Ohaus Corporation) between two glass-fiber filters for measuring water content by the wet-to-dry weight method. Dry weight (g) was determined when there was no change in 1 mg for 3 minutes.

RESULTS:

Compared with the Control group, rats in the HypoNa group presented lower sodium (134.0 ± 1.0 vs. 104.8 ± 1.0 mmol/L, P < 0.0001), calcium (1.27 ± 0.04 vs. 1.15 ± 0.03 mmol/L, P < 0.05), and effective osmolality (281.2 ± 2.10 vs. 229.8 ± 3.8 mOsm/L, P < 0.0001), and a trend to increased concentrations of potassium (4.10 ± 0.15 vs. 4.75 ± 0.40 mmol/L, P = 0.25) and lactate (2.23 ± 0.38 vs. 6.23 ± 2.18 mmol/L, P = 0.22) in plasma. Frontal cortex water content was higher in the HypoNa group (Control: 82.20 ± 0.74 vs. HypoNa: 85.01 ± 0.97 %, P < 0.01). Measuring time of water content using the moisture analyzer was <15 minutes per sample.

CONCLUSIONS:

These results suggest that the present protocol using a moisture analyzer is a convenient and sensitive method for measuring brain water content in rats.
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.