bluuebunny/crossref_metadata_2025_split huggingface dataset:
P: 23 Prospective Study on Mortality of Acute on Chronic Liver Failure and Its Predictors
Authors: Bhatti Rehmatullah 
Published: September 2019

BACKGROUND:
Acute on chronic liver failure (ACLF) is a well recognized entity, characterized by an acute liver insult in patients with underlying chronic liver disease leading to sudden deterioration of liver function and a high mortality. We aimed to determine hospital, 28 days and 12 weeks mortality of ACLF, its predictors and precipitating factors

METHODS:
We conducted a prospective descriptive study at AIMS (Asian institute of medical sciences, Hyderabad, Pak.) from January 2018 to December 2018. We enrolled patients of ACLF as defined by Asian Pacific Association for the Study of Liver (APASL, 2014) and collected data to determine cause, precipitating acute insult, organ failure, ACLF grade MELD, and CTP scores. Patients were followed to determine hospital, 28 days and 12 weeks mortality and its predictors.

RESULTS:
Total patients were 117 with mean age of 40.9 +- 13.9 years (range 12–85). Majority were males 86 (73.5%) and 31 (26.5%) were females. Majority of patients 55 (47%) were Hepatitis B Virus (HBV) positive, among them 24 (43.6%) were with HDV co-infection. The most common precipitating acute insult was SEPSIS 65 (55.6). Others were drug induce liver injury (DILI) 8 (6.8%), HEV acute hepatitis 7 (5.9), HDV superinfection 5 (4.3%), HBV flair 4 (3.4%), alcohol binge drinking 4 (3.4%), surgery 2 (1.7%), acute PVT 2 (1.7%), Upper GI Bleed 1 (0.9%) and 20 (17.1%) were unknown. Hospital mortality was 49 (41.9%), 28 days 71 (60.7%) and 12 weeks mortality was 103 (88.0%). Organ failure (P = 0.002), ACLF grade (P = 0.002), encephalopathy (P = 0.001), MELD (P = 0.01) and AKI (P = 0.02) were found to be predictors of mortality.

CONCLUSIONS:
Acute-on-chronic liver failure (ACLF) is an acute deterioration of liver function superimposed on Chronic Liver Disease with a high mortality. In our study HBV infection was the commonest cuase of CLD, and sepsis was the commonest acute insult. We found high hospital, 28 days and 12 weeks mortality. Organ failure, ACLF grade, encephalopathy, MELD score and AKI were found to be predictors of mortality of ACLF.
P: 29 Contributors to Balance Impairment in Adults With Cirrhosis and Hepatic Encephalopathy
Authors: Murphy Susan L. , Richardson James K. , Blackwood Jennifer A. , Martinez Beanna A. , Runyan Emily J. , Park Megan L. , Louissaint Jeremy , Tapper Elliot B. 
Published: September 2019

BACKGROUND:
Falls are common and associated with significant morbidity for persons with cirrhosis and hepatic encephalopathy. In order to intervene with targeted rehabilitation efforts to reduce and prevent falls, a better understanding of mechanisms underlying balance deficits is needed. To this end, unipedal stance time (UST) is a useful measure of balance as it requires the integration of sensory, neurocognitive, and muscular factors.

METHODS:
We prospectively enrolled 119 outpatients with cirrhosis and history of hepatic encephalopathy from the hepatology clinic at Michigan Medicine. The primary outcome was UST. Each patient was evaluated for demographic and clinical factors [Child Turcotte Pugh (CTP) class, MELD score], physical function (grip-strength and hip-strength using lateral plank time), neurocognitive factors [Numbers Connection Test (NCT) A and B, recognition reaction time accuracy - ability to catch or inhibit catching an instrumented stick under 'lights on' and 'lights off' conditions within 400 ms], and sensory factors (lower limb vibratory sensation and visual contrast). Falls self-efficacy, perceived ability to perform different tasks without falling, was also assessed. We evaluated bivariate Pearson correlations and developed a linear regression model to identify significant contributors to balance impairment.

RESULTS:
Participants were 50% female, aged 62.9 + 7.3 years, 80% CTP A, 18% CTP B, 2% CTP C, with MELD 11 + 5. The mean UST was 12.7 + 9.9 seconds (median = 9.42 seconds, IQR = 19.26). In bivariate analyses, UST was most highly correlated with lateral plank time (r = 0.61), followed by recognition reaction time accuracy [total, percent correct in lights on, and in lights off conditions (r = 0.47, r = .36, r = .33)] and NCT A and B tests (each r = 0.27). In multivariable regression, 54% of variance in UST was explained by significant factors of plank time, recognition reaction time accuracy, falls self-efficacy, age, and CTP. Based on standardized beta coefficients, plank time, CTP of B or C, and recognition reaction time accuracy were the strongest predictors. For every second increase of plank time, UST increases by 0.26 seconds on average. If classified by CTP of B or C, UST decreases by 5.8 seconds. For each additional percent correct on recognition reaction time accuracy, UST increases by 0.12 seconds.

CONCLUSIONS:
The strongest factors associated with diminished balance, as indicated by UST, in this high fall-risk cirrhosis population are hip strength, clinical disease severity, and neurocognitive capacity. These findings support a rehabilitation approach that targets strengthening as well as neurocognitive training to address balance impairment.
P: 38 Rifaximin Reduces the Incidence of Spontaneous Bacterial Peritonitis, Variceal Bleeding and All-cause Admissions in Patients on the Liver Transplant Waiting List
Authors: Tranah Thomas , Salehi Shayon , Heaton Nigel , Heneghan Michael , Aluvihare Varuna , Patel Vishal , Shawcross Debbie 
Published: September 2019

BACKGROUND:
Rifaximin reduces the risk of overt hepatic encephalopathy (HE) in patients with advanced chronic liver disease (ACLD) and is associated with significant reductions in hospitalisations and 30‐day readmissions. This study examined clinical outcomes of patients listed for liver transplantation with a diagnosis of HE on rifaximin compared to those naïve to the drug.

METHODS:
Patient records of those listed for liver transplantation over a 2-year period were retrospectively reviewed. Patients were included if they had at least two episodes of overt HE resulting in hospitalisation or were encephalopathic at the time of assessment. Information collected included patient demographics, aetiology of liver disease, disease severity scoring at transplant listing, concomitant medications and medical co-morbidities. Emergency admissions whilst on the waiting list for complications of ACLD in addition to requirement for prioritisation (UKELD score ≥63), duration on the waiting list (days) and mortality on the waiting list were recorded. Univariate and multivariate regression analyses were performed on acute admission and complication data (related to sepsis, acute variceal bleeding (AVB), HE and complications of ascites) with rifaximin use as the independent variable.

RESULTS:
Of the 622 patients listed for transplantation, 101 were listed with HE. 66 patients were treated with rifaximin and 35 were naïve at listing. Median MELD score was similar (15 [14–16)] rifaximin-treated and 16 [14–18] rifaximin-naïve). The use of lactulose was not significantly different between groups. Patients on the waiting list treated with rifaximin had an independent association with reduced all-cause admissions (P = 0.037), episodes of spontaneous bacterial peritonitis (P = 0.008) and AVB (P = 0.026). Mean length of hospital stay was 9 (95% CI 6–12) in the rifaximin-treated group vs 14 days (95% CI 7–21) in the rifaximin-naïve group. Multivariate regression analysis demonstrated that rifaximin was independently associated with an increase in days to readmission (adjusted effect estimate 71, 95% CI 3–140 days, P = 0.037) and reduced likelihood of requirement for prioritisation on the waiting list (odds ratio 0.29; 95% CI 0.89–0.93, P = 0.037).

CONCLUSION:
Rifaximin prescribed for HE in patients listed for liver transplantation improved outcomes on the waiting list with a significant reduction in admissions related to spontaneous bacterial peritonitis, ascites and AVB and indicating potential beneficial impacts of rifaximin beyond HE in ACLD.
P: 39 Modulation of the Urea Cycle Function by Toll-like Receptor 4 Signaling: A Potential Novel Therapeutic Target for Hyperammonemia and Hepatic Encephalopathy
Authors: Kerbert Annarein J. C. , Sharifi Yalda , Sheikh Mohammed , Engelmann Cornelius , Andreola Fausto , Jalan Rajiv 
Published: September 2019

BACKGROUND:
Lipopolysaccharide (LPS) and ammonia act synergistically in mediating the severity of hepatic encephalopathy (HE) in cirrhosis. Although LPS results in neuroinflammation, it is not clear whether it induces hyperammonemia (HA) contributing to HE. This study addressed the following questions: 1) Does LPS worsen HA in cirrhosis? 2) Does treatment with an antagonist (TAK242) of the LPS receptor, toll-like receptor 4 (TLR4), prevent HA? 3) Is a TLR4 knock-out (TLR4-/-) animal protected from HA? 4) If so, what is the underlying mechanism? Do they have a more effective urea cycle?

METHODS:
Study 1: Sprague Dawley rats were treated with LPS (0.025 mg/kg, ip.) 4 weeks after bile duct ligation (BDL). 4 groups of rats were studied: sham (n = 4), BDL (n = 4), BDL+LPS (n = 6) and BDL+TAK242 (10 mg/kg ip.) 3 hours before LPS injection (n = 7). Study 2: 4 groups of mice were studied: wild type control (WTC, n = 7), WT with HA (WTH, n = 10), TLR4-/- control (TLR4-/-C, n = 10) and TLR4-/- with HA (TLR4-/-H, n = 10). HA was induced by adding 0.28M ammonium chloride to drinking water for 3 days. For both studies, plasma ammonia and liver gene expression (qPCR, data shown as 2^-ΔΔCT compared to sham/WT) of the 5 urea cycle enzymes (UCEs) were assessed. For study 2, protein expression of the key, rate-limiting enzyme carbamoyl phosphate synthetase 1 (CPS1) was also assessed (Western Blot, immunohistochemistry).

RESULTS:
Study 1: There was a stepwise increase in plasma ammonia throughout sham, BDL and BDL+LPS groups (P < 0.001). Pre-treatment with TAK242 prior to LPS injection in BDL rats was associated with a reduction in plasma ammonia (P < 0.01, Figure 1a) and a higher coma-free survival rate (100% vs. 15%). Gene expression of all UCEs showed a stepwise decrease throughout sham, BDL and BDL+LPS (all P < 0.05), which was prevented by TAK242 (all P < 0.05). This was most pronounced for CPS1, for which expression levels in the TAK242-treated group were restored to that of the sham animals (Figure 1b). Study 2: In TLR4-/- mice, the increase in plasma ammonia was less compared to WT mice (P < 0.001). Although no significant changes were found for gene expression of UCEs between groups, protein expression of CPS1 was significantly higher in TLR4-/- mice as compared to WT mice, as shown by both Western Blot and immunohistochemistry.

CONCLUSIONS:
These data suggest that TLR4 signaling contributes to the development of hyperammonemia by modulating the urea cycle function. Inhibition of TLR4 with TAK242 offers a potential novel therapy for HA and HE in cirrhosis.
P: 41 Precipitants of Hepatic Encephalopathy, In-hospital Mortality and Its Predictors
Authors: Ali Mashooque , Hassan Adil , Iqbal Javed , Bughio Ubedullah , Bhatti Rehmatullah , Ali Mohsin , Sadik Muhammad 
Published: September 2019

BACKGROUND:
Hepatic encephalopathy (HE) is a common complication of liver dysfunction, including acute liver failure and liver cirrhosis. HE presents as a spectrum of neuropsychiatric symptoms ranging from subtle fluctuating cognitive impairment to coma. It is a significant contributor of morbidity in patients with liver disease. Common culprits include gastrointestinal bleeding, infection, constipation, hypokalemia, hyponatremia, and medications such as opiates and benzodiazepines. This study aim to evaluate the change in common precipitants of HE, in-hospital mortality and its predictors.

METHODS:
This descriptive study was conducted in Hepatology division of Asian Institute of Medical Sciences, Hyderabad, Pakistan from October 2018 to April 2019. A total of 82 cirrhotic patients with HE were included in the study. Frequency of precipitating factors were determined and in-hospital mortality was evaluated.

RESULTS:
A total of 82 cirrhotic patients with mean age 52.31 years, with males 62.2%. Common etiology for cirrhosis was HCV 64.63%, 56.09% were CTP B, 36.58% patients had MELD in between 11-15. According to West Haven criteria most common grades were Grade II 52.43%, Grade III 17% and Grade IV 16%. Most common precipitants were hyponatremia 18%, constipation 12%, hypokalemia 5%, infections 10%, variceal upper GI bleeding 4%, 24% had mixed precipitants and in 27% patients no precipitant found. 42.7% had Acute Kidney Injury (AKI) mostly associated with electrolyte imbalance. 70.7% were improved and discharged, 11% were expired, 18.3% discharged on request. AKI, SBP and Shock were associated with high mortality.

CONCLUSIONS:
Electrolyte imbalance, constipation and infections were leading causes of HE. AKI was independent predictor of HE and in-hospital mortality along with SBP and shock.
P: 56 Evaluation of Cognitive Dysfunction in Animal Models and Relatability to Human Disease
Authors: Cabrera-Pastor Andrea , Llansola Marta , Montoliu Carmina , Felipo Vicente 
Published: September 2019

ABSTRACT:
Animal models are essential to investigate the mechanisms responsible for the cognitive and motor alterations in minimal or clinical hepatic encephalopathy (HE). The characterization of these mechanisms allows identifying new therapeutic targets which modulation may improve neurological function in patients. Animal models also allow testing if treatments directed to modulate these targets improve cognitive and motor function. These studies require evaluation of cognitive and motor function in animal models. It is important to understand which tests can be performed in rodents, which cognitive and motor aspects are evaluated by the tests and how they can be related to cognitive and motor dysfunction in the patients. The earliest alterations in patients with minimal HE (MHE) include attention deficits, psychomotor slowing, impairment of visuo-motor and bimanual coordination, of working memory, spatial memory, long-term memory, spatial orientation, verbal learning, concentration, balance and equilibrium, associated with increased falls. To understand the mechanisms involved in each type of cognitive and motor alteration in MHE the behavioral tests in animal models should be designed to evaluate these neurological alterations by procedures that maximize the translatability to the human situation and the utility to evaluate treatments to improve cognitive and motor impairment. Many functions are evaluated in humans using pencil or computerized tests such as number connection tests, repetition of series of words or numbers, naming colors, and other actions which can't be reproduced exactly in animal models. Functions such as verbal learning can't be evaluated in animal models. However, a good number of cognitive and motor processes impaired in patients with MHE may be evaluated in rodents using appropriate behavioral tests. For example, a combination of properly designed tests in the radial maze, Morris water maze, object recognition and object location allows evaluating with high sensitivity working memory, reference memory and distinguishing the spatial and non-spatial components of working and reference memory. These components are altered in rats with MHE and different mechanisms are involved in the impairment of different components. Also, there are pharmacological treatments that restore selectively working or reference memory and spatial or non-spatial learning and memory in rats with MHE. There are also appropriate test to assess some motor alterations: hypokinesia, fine motor coordination or balance. Studies based on proper use of animal models will accelerate the advance in understanding the mechanisms involved in MHE and will open new therapeutic approaches to improve quality of life and life span of the patients.
P: 58 Prediction of Overt Hepatic Encephalopathy by the Continuous Reaction Time Method and the Portosystemic Encephalopathy Syndrome Test in Patients With Cirrhosis
Authors: Wernberg Charlotte , de Muckadell O. Schaffalitzky , Vilstrup Hendrik , Lauridsen Mette Munk 
Published: September 2019

BACKGROUND:
Predicting overt hepatic encephalopathy (OHE) is of major importance because the condition is unpleasant, requires hospitalization, and partly preventable. The risk is related to pre-existing discrete cognitive defects, and a number of psychometric tests are validated for detection of such defects. For clinical practice it is recommended to apply two different tests. We used the Continuous Reaction Time test (CRT) and the Porto Systemic Encephalopathy Test (PSE), and examined their single and combined value for prediction of OHE in cirrhosis patients.

METHODS:
We studied 130 mentally unimpaired cirrhosis patients by the two tests and followed them up for on average 38.5 months. The CRT measures velocity and stability in motor reaction times to 150 repeated auditory. The PSE is a paper-and-pencil test measuring the duration of completing 5 tasks. We collected data on episodes of OHE during follow-up. The clinical course was analysed in patient groups according to the outcome of each test and of both tests together. No anti-HE treatment was initiated except for OHE.

RESULTS:
We observed 74 OHE events. The PHES was abnormal in 47 and predicted 31 OHE episodes among 14 patients (PPV = 29%, NPV of 75%, sens. 40%, spec. 65%). The CRT test was abnormal in 74/130 and predicted 54 OHE episodes among 23 patients (PPV = 31%, NPV = 78%, sens. 65%, spec. 46%). One or both tests were abnormal in 87/130 and predicted 60 OHE episodes among 27 patients (PPV = 31%, NPV = 81%, sens. 77%, spec. 40%). 43/130 had two normal tests but 8 experienced OHE and had 14 OHE-admissions.

CONCLUSIONS:
The combined use of PSE and CRT test identified 77% of patients who later experienced OHE while ruling out future OHE with an NPV of 81%.
P: 61 Attenuation of Neurological Symptoms of Type C Hepatic Encephalopathy by Selective Ablation of Neuronal FXR Expression
Authors: Grant Stephanie , Williams Elaina , Petrescu Anca , McMillin Matthew , Frampton Gabriel , DeMorrow Sharon 
Published: September 2019

BACKGROUND:
Hepatic encephalopathy (HE) describes the neurological deficits that result from liver impairment. Liver disease is associated with an increase of circulating bile acids that can cross the blood brain barrier and activate FXR receptors in neurons. We have previously demonstrated that aberrant bile acid signaling via activation of neuronal FXR contributes to HE pathogenesis in rodent models of acute liver failure. However, a role for FXR-mediated bile acid signaling in HE due to chronic liver cirrhosis is undefined.

METHODS:
Neuron-specific FXR knockout mice were generated by crossing Floxed FXR mice (FXRfl) with SNAP-25 cre recombinase mice. The resulting mice were designated FXRΔneu. C57Bl/6 (WT), FXRfl, and FXRΔneu were treated with carbon tetrachloride (CCl4; 1 ml/kg) by oral gavage twice per week for 12 weeks. Neurobehavioral indices and neuromuscular deficits were assessed by open field test, rotarod, grip strength test and gait analysis. After 12 weeks, tissue was collected and liver damage was assessed by serum chemistry and H&E staining. Total bile acid content was assessed in the cortex and cerebellum using colorimetric assays. The expression of ASBT, FXR, and its downstream effector SHP was assessed by qPCR and immunofluorescence. Microglia activation was assessed by Iba1 immunofluorescence. The expression of proinflammatory cytokines were assessed by qPCR and EIA. In parallel, total bile acids, ASBT and FXR expression were assessed in brain tissue from cirrhotic patients with HE, compared to cirrhotics without HE and age- and gender-matched controls that had been collected and banked by the Australian Brain Bank Network.

RESULTS:
Total bile acid content was elevated in the cortex and cerebellum in CCl4-treated WT mice and in cirrhotic patients with HE, compared to cirrhotics without HE and non-liver impaired controls. Furthermore, ASBT, FXR and SHP expression were increased in the frontal cortex of mice and humans with HE, but not in non-HE control samples. WT and FXRfl mice treated with CCl4 had significant deficits observed in every neurobehavioral and neuromuscular test performed, as well as marked microglia activation and increased proinflammatory cytokine expression compared to vehicle-treated mice. These neurological deficits and neuroinflammation were attenuated in FXRΔneu mice after CCl4 treatment, even though liver damage was comparable in all genotypes of mice used.

CONCLUSIONS:
These data indicate that neuronal expression of FXR plays an important role in the development of HE. Specific targeting of FXR activation in the brain may be a potential therapeutic target for the management of HE.
P: 63 Animal Naming Test Is Highly Accurate and Reliable for Diagnosis of Minimal Hepatic Encephalopathy in Outpatients With Cirrhosis
Authors: Taneja Sunil , Agarwal Ankit , Chopra Madhu , Duseja Ajay , Dhiman Radha K. 
Published: September 2019

BACKGROUND:
Background and Aims: Minimal hepatic encephalopathy (MHE) is the mildest form in the spectrum of hepatic encephalopathy that impairs health-related quality of life. PHES remains the gold standard for the diagnosis of this condition. Animal naming test (ANT) is reliable and sensitive tool for diagnosis of MHE and can also predict overt episodes of HE. We compared usefulness of PHES and ANT for the diagnosis of MHE and for the prediction of the development of overt episodes of HE.

METHODS:
Between July 2017 to June 2018, one hundred and three consecutive patients with liver cirrhosis without overt HE were subjected to PHES and ANT evaluation. MHE was diagnosed when the PHES was ≤−5. Receiver-operating characteristic (ROC) curve was used to determine the optimum cut-off of ANT value for the diagnosis of MHE. The best sensitivity and specificity was found at <14. Patients were followed-up every 3-6 months till October 2018.

RESULTS:
Thirty-seven (35.9%) patients had MHE as assessed by altered PHES. ANT (<14) was present in 36 (34.95%) patients with MHE with sensitivity of 89.19% and specificity of 95.7%, PPV of 91.67%, NPV of 94.03% and diagnostic accuracy of 93.20%. The area under the curve for diagnosis of MHE was 0.978 (95% CI 0.954–1.0). MHE patients had significantly lower ANT as compared to non MHE patients and controls (10.81 ± 0.324 vs 15.27 ± 0.147 vs 15.78 ± 0.192, respectively, P = 0.01). MHE patients had lower hand grip strength compared to non-MHE patients and the control group (Males: 26 vs 30 vs 38, Females 25 vs 28 vs 28, P > 0.05). PHES significantly correlated with Child-Pugh (r = −0.421, P = 0.001) and model for end-stage liver disease (MELD) (r = −0.345, P = 0.001) scores. ANT correlated with PHES (r = 0.752, P = 0.001) and also with Child-Pugh (r = −0.408, P = 0.001) and MELD (r = −0.318, P = 0.001) scores. During follow-up, 14 patients in MHE group and 4 in non-MHE group developed overt episodes of HE (P = 0.001). Out of 37 patients with abnormal PHES 14 patients developed overt HE on follow up and out of 36 patients with abnormal ANT 14 patients developed overt HE on follow up. 33 patients had both PHES and ANT abnormal. 4 patients had PHES abnormal and ANT normal. 3 patients had PHES normal and ANT abnormal.

CONCLUSIONS:
ANT is a highly accurate and reliable test for the diagnosis of MHE and prediction of overt episodes of HE in outpatients of cirrhosis as compared to PHES and correlates well with the Child-Pugh and MELD scores.