bluuebunny/crossref_metadata_2025_split huggingface dataset:
P: 30 Relation Between Mortality and Psychometric Test Results in Patients Awaiting Liver Transplantation
Authors: Wirries Ann-Katrin , Pflugrad Henning , Tryc Anita Blanka , Barg-Hock Hannelore , Klempnauer Jürgen , Goldbecker Annemarie , Strassburg Christian , Weissenborn Karin 
Published: September 2019

BACKGROUND:
Hepatic encephalopathy is a common severe complication of liver cirrhosis that, however, so far is not considered as an indication for organ allocation to patients on the transplant waiting list. Multiple psychometric tests have been developed to detect hepatic encephalopathy. However, there is only rare data about the predictive value of psychometric test results regarding mortality in patients with liver cirrhosis. This retrospective analysis of prospective data determined the predictive value of the Inhibitory Control Test (ICT), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Portosystemic Encephalopathy Syndrome-Test and the Critical Flicker Frequency (CFF) assessment in regard to mortality in patients on the waiting list for liver transplantation.

METHODS:
143 patients awaiting liver transplantation were included. They underwent a test battery including the Inhibitory Control Test, the Repeatable Battery for the Assessment of Neuropsychological Status, the Portosystemic Encephalopathy Syndrome-Test which provides the psychometric hepatic encephalopathy score (PHES) and the Critical Flicker Frequency assessment at study inclusion. The PHES was available for all patients (n = 143), the RBANS scores for n = 115, the ICT results for n = 99, and the CFF results for n = 136 patients. Basic characteristics (age, gender, underlying liver disease, accompanying diseases) and Model for End-stage Liver Disease (MELD) -Score at the time of study inclusion were documented. Follow-up was done for 5 years. Patients who either received a liver transplantation or dropped out of the study during the observation period were censored. The five-year survival rate was analyzed with the Kaplan-Meier curve.

RESULTS:
Patients with abnormal PHES had a significantly higher mortality risk than patients with a normal PHES (P < 0.0001). Also patients with an abnormal RBANS result had a significantly higher risk to die than patients with a normal RBANS result (P = 0.018), but the difference was less significant compared to the PHES. Mortality risk did not significantly differ between patients with normal or abnormal CFF or ICT results. (CFF: P = 0.412; ICT: P = 0.202). In a binary logistic regression analysis the MELD-Score and diabetes were independent prognostic factors for mortality risk (MELD: P = 0.003; diabetes: P = 0.008). The MELD-Score turned out to have significant impact on the test results regarding the PHES (P < 0.0001), but not concerning the other tests (CFF: P = 0.903; RBANS: P = 0.065; ICT: P = 0.139).

CONCLUSIONS:
An abnormal PHES result is an indicator for an increased mortality risk, though less predictive than the MELD-Score.
P: 31 The Natural History of Cirrhosis After the Development of Hepatic Encephalopathy
Authors: Louissaint Jeremy , Tapper Elliot B. 
Published: September 2019

BACKGROUND:
Hepatic encephalopathy (HE) is a watershed moment in the natural history of cirrhosis portending decreased quality of life and worsening prognosis. Recent strides in the management of HE have been made to decrease symptom burden and readmissions. The impact of these interventions requires a contemporary re-examination of the natural history of HE and its clinical implications.

METHODS:
We examined data from a 20% random sample of US Medicare enrollees with cirrhosis and continuous Part D prescription coverage from 2008–2014. Those with a diagnosis of HE prior to or within 3 months after the diagnosis of cirrhosis was made were excluded. Incident HE was defined by ICD-9 code 572.2 and/or the initiation of a prescription for an HE-specific treatment (Neomycin, Lactulose, or Rifaximin). Outcomes included transplant-free survival and hospital-days or 30-day readmissions per person-year. Multivariate analysis was performed for survival (hazard ratios, HR, Cox regression) and hospital utilization (incidence rate ratios, IRR, negative binomial regression).

RESULTS:
Among 186,160 Medicare-enrollees (median age 65 years) with cirrhosis, 49,164 experienced HE (26.4%). The median survival following cohort entry of those who did and did not develop HE was 5.78 and 3.4 years, respectively (P < 0.001). Multivariate analysis identified decreased survival with older age (HR 1.02, CI: 1.02–1.03), male sex (HR 1.21, CI: 1.19–1.24), ESRD (HR 1.08, CI: 1.01–1.14), and increasing Charlson Comorbidity Index (HR 1.2–1.42, CI: 1.17–1.48). Cirrhosis etiologies of HCV and alcohol were associated with improved survival (HR 0.87 CI: 0.85–0.90 and HR 0.82 CI: 0.79–0.85, respectively) while NAFLD was linked to increased mortality after HE (HR 1.07, CI: 1.02–1.12). Hospital-days per person year were 11.8 in patients with HE compared to 2.9 in those without (P < 0.001). Factors that were inversely associated with hospital utilization were Rifaximin use (HR 0.40, CI: 0.39–0.42) and gastroenterology consultation (HR 0.73, CI: 0.67–0.80). Rifaximin use was associated with decreased hospital-days (IRR 0.35, CI: 0.33–0.37) and fewer 30-day readmissions (HR 0.18, CI: 0.08–0.40), while gastroenterology consultation was associated only with a decreased risk of 30-day readmissions (HR 0.71: CI: 0.57–0.88) but not overall hospitalizations.

DISCUSSION:
The outcomes after HE in this contemporary Medicare-insured population are poor. The development of HE increases hospitalization utilization and worsens survival with few, potentially modifiable, targets for prospective study intervention.
P: 40 Potassium Deficiency Compromises Urea Synthesis and Markedly Increases Ammonia in Rats
Authors: Mikkelsen Anne Catrine B. , Thomsen Karen Louise , Aamann Luise , Vilstrup Hendrik , Aagaard Niels Kristian 
Published: September 2019

BACKGROUND:
Potassium deficiency decreases gene expression, synthesis of proteins, and growth in plants, bacteria, rodents and humans.1–4 The effect of hypokalemia on liver protein synthesis is scarcely described. Early studies have established an association between hypokalemia and development of hepatic encephalopathy in chronic liver disease.5,6 We investigated the effects of potassium deficiency on synthesis of liver proteins including urea cycle enzymes and the regulation of urea synthesis in rats.

METHODS:
Female Wistar rats were fed a K+-free diet for 13 days. Half of the rats were then repleted with K+ for one week following depletion. K+-depleted and -repleted rats were compared to free-fed and pair-fed controls. We examined the urea cycle enzyme mRNAs and proteins in liver tissue, the in vivo Capacity of Urea-Nitrogen Synthesis (CUNS) and plasma ammonia concentrations. Also, we measured hepatic albumin gene and protein expression, and potassium levels in plasma, liver, kidney and muscle tissues.

RESULTS:
The diet induced hypokalemia of 1.9 ± 0.4 mmol/L compared to pair-fed controls (3.6 ± 0.2 mmol/L). Muscle and kidney tissue potassium concentrations were decreased, but unchanged in liver tissue. Gene expression of albumin and two out of five urea cycle enzymes were moderately decreased, whereas protein expressions of albumin, the urea cycle enzymes, and glutamine synthetase were normal. However, CUNS was reduced by 33%. Plasma ammonia concentrations were eight-fold elevated to 235 (95% CI: 194–287) µmol/L compared to pair-fed controls 29 (95% CI: 26–32) µmol/L. Repletion of potassium normalized the changes.

CONCLUSIONS:
Hypokalemia markedly increased plasma ammonia concentrations. The capacity for urea synthesis was impaired, but only moderately so, and further studies are needed to fully explain the causes of hyperammonemia.
P: 45 Increased Iba-1 Expression in an Autopsied Brain Samples of ALF & Chronic Liver Disease Patients With Hepatic Encepahlopathy
Authors: Chopra Madhu , Vasishta Rakesh K. , Chakraborti Anuradha , Duseja Ajay , Chawla Yogesh , Dhiman Radha K. 
Published: September 2019

BACKGROUND:
Systemic inflammation both in acute liver failure (ALF) and patients with cirrhosis and hepatic encephalopathy (HE) leads to microglial activation and an increase in oxidative stress. Iba-1 has been found to be a highly specific marker expressed in microglial cells in animal models. We studied Iba-1 expression in the brains of patients with ALF and CLF with hepatic encephalopathy and the control patients without any neurological disease.

METHODS:
Autopsied frontal cortex samples were obtained from 5 patients with ALF due to viral hepatitis (HEV, HBV flare) or toxic liver injury (ATT induced) or mushroom poisoning. 7 patients with cirrhosis and HE and 7 controls were obtained. Expression of Iba-1 mRNA was investigated by real-time PCR using appropriate molecular probes and protein expression was assessed using immunohistochemistry using commercially available polyclonal antibodies and measure the intensity with the help of H-score.

RESULTS:
Iba-1 immunostaining highlights the microglial cells in the grey matter of the brain in ALF patients (H-score = 2000) as compared to the patients with cirrhosis and HE (H-score = 450) and to controls (H-score = 300). ALF grey matter specifically highlights the microglial nodule, and faint cytoplasmic hue is also noted in the neurons. Gene expression studies show the increased fold change in Iba-1 in ALF (fold change = 4.08, P = 0.11) and in patients with cirrhosis and HE (fold change = 1.1, P = 0.84) patients when compared with controls, though not statistically significant.

CONCLUSIONS:
These results demonstrated the increased microglial activation as well as the number of microglial cells in the ALF patients that can contribute to neuroinflammation.
P: 46 Ammonia Is an Independent Biomarker of Poor Outcomes in Patients With Advanced Cirrhosis on the Transplant Waiting List
Authors: Alexandrin Gonçalo , Domingues Tiago D. , Bernal William , Shawcross Debbie L. 
Published: September 2019

BACKGROUND:
Ammonia plays a pivotal role in the development of hepatic encephalopathy (HE) and brain oedema in acute liver failure and is a poor prognostic biomarker. However, its utility as a prognostic biomarker in patients with cirrhosis remains unclear as there is no direct correlation with hyperammonemia and the manifestation of HE per se. It has recently been demonstrated that blood ammonia levels correlate with organ failure and are an independent risk factor for mortality in patients with cirrhosis and acute decompensation. The aim of this study was to determine whether ammonia levels in patients with advanced cirrhosis awaiting liver transplantation influence waiting list outcomes.

METHODS:
A retrospective observational study of 300 sequential cirrhotic adult patients listed for liver transplantation between January 2015 and December 2018 was undertaken. All patients had an arterial ammonia measured at the time of assessment for transplant. All patients were closely followed up until death or transplantation. The main outcomes were hospital admissions (and number of organ failures), infection and mortality. Chronic Liver Failure-Sequential Organ Failure Assessment criteria were used to determine the presence of organ failures. For the transplanted patients, post-op complications were recorded.

RESULTS:
200 (66.7%) were male with mean age of 54.29 ± 10.4. Mean follow-up time was 722.6 days. 266 (88.7%) patients were transplanted, 15 (5.0%) were de-listed for being too sick for transplant or following clinical improvement, 14 (4.7%) died on the list and 5 (1.6%) were still active on list. 97 (32.3%) patients were hospitalized on the waiting list and 60 (20%) had evidence of at least one infection. On multivariate analysis, ammonia correlated with hospitalisation (P < 0.001), infection (P < 0.001) and all-cause mortality (P = 0.00135). Of the patients that had at least one hospital admission, ammonia was an independent predictor of the presence of acute-on-chronic liver failure (ACLF) (P = 0.01811). For the transplanted patients, ammonia levels correlated with the presence of post-op complications (P < 0.001).

CONCLUSIONS:
In this retrospective study, arterial ammonia at the time of listing for liver transplantation was an independent predictor of hospitalisation, ACLF, infection and mortality. These data suggest that blood ammonia may be an important determinant of wait-list survival and further prospective studies are warranted.
P: 47 Risk of Recurrent Hepatic Encephalopathy (HE) in Patients With Liver Cirrhosis: A German Registry Study
Authors: Gabriel Maria M. , Kircheis Gerald , Hardtke Svenja , Markwardt Daniel , Buggisch Peter , Mix Heiko , Grüngreiff Kurt , Welzel Tanja , Kälsch Julia , Hartmann Heinz , Gerbes Alexander , Weber Kristina , Wedemeyer Heiner , Weissenborn Karin 
Published: September 2019

BACKGROUND:
Patients with Hepatic Encephalopathy (HE) show a low quality of life, recurrent hospitalizations and an increased mortality. We aimed to assess the natural course of patients after a recent HE-episode under the conditions of the German health system, as respective data were not available.

METHODS:
Fifteen sites from Germany - 8 of them liver transplant (LT) centers - took part in an observational prospective study including cirrhotic patients who had been hospitalized due to an acute episode of HE within 3 months before recruitment. Age < 18 years, no liver cirrhosis, malignancies and current hospitalization were exclusion criteria. Demographic and clinical data, health related quality of life (HRQoL) score SF-36, psychometric hepatic encephalopathy score (PHES) and critical flicker frequency (CFF) were assessed and monitored quarterly for one year. Primary endpoint was a novel clinical manifestation of HE necessitating hospital admission. Secondary endpoints were the combined endpoint of hospital admission for a novel HE episode and/or death, the dynamics of the West Haven Criteria (WHC) as well as changes in CFF, PHES and SF-36.

RESULTS:
A total of 115 patients were recruited. Fourteen patients (12.4 %) died during the study period due to complications of liver cirrhosis other than HE. For 67 subjects follow-up data were available in accordance with the protocol. After a median of 113 days half of the per protocol cohort (N = 34) was re-admitted due to a recurrent manifestation of HE. The patient groups with and without re-hospitalization differed significantly regarding recruitment sites (LT centers vs no LT centers) (P = 0.005), interval from discharge to recruitment (P = 0.007), history of more than 4 HE relapses prior to recruitment (P = 0.029), SF-36 mental score (P = 0.046) and PHES ≤ −3 (P = 0.004), whereas CFF, clinical (e.g. MELD score, WHC grade) and laboratory data did not differ. Of note, CFF performance was correct only in about half of both, the total and the per protocol group. Patients with incorrect CFF performance had worse PHES results than those with valid CFF measurement. Multiple logistic regression analysis revealed a PHES test result of ≤−3 as an independent risk factor for re-hospitalization (P = 0.046).

CONCLUSIONS:
Mortality in our cohort is comparatively low. Despite advanced treatment strategies, patients with a history of HE are still sincerely jeopardized to develop recurrent clinical HE. The PHES test appears useful for detection, monitoring and stratification of recurrent HE. Patients with PHES ≤−3 at baseline had an increased risk of deterioration.
P: 48 Nonselective Beta-blocker Use Is Associated With Increased Hepatic Encephalopathy-Related Readmissions in Patients With Cirrhosis
Authors: Amin Fallahzadeh Mohammad , Bizzarri Daniel , Saracino Giovanna , Rahimi Robert S. 
Published: September 2019

BACKGROUND:
Hepatic Encephalopathy (HE) is a reversible syndrome of impaired brain function that is associated with frequent hospitalizations and decreased survival in cirrhotic patients. Nonselective beta-blockers (NSBB) are the mainstay of pharmacologic treatment for portal hypertension and prevention of variceal bleeding. Due to their effects on hepatic blood flow, we hypothesized that NSBB use would decrease portal flow, leading to increased HE related hospitalizations independent of liver disease severity. This study was done to assess the effect of NSBB use on HE-related readmissions.

METHODS:
We examined all the patients with cirrhosis admitted at Baylor University Medical Center between January 2013 and July 2018. The outcome measure of HE-related readmissions was analyzed in patients taking NSBB vs. patients not taking NSBB using cox proportional hazard regression model. The model was adjusted for age, sex, Model for End-Stage Liver Disease (MELD) score, selective beta-blocker (SBB) use, ascites, and history of esophageal varices (EV) and transjugular intrahepatic portosystemic shunt (TIPS). The Kaplan-Meier method and log-rank test were used to compare the cumulative incidence of HE-related readmissions between the aforementioned groups.

RESULTS:
There were 393 patients in this study with a mean age of 58.1 ± 10.2 years and a male predominance. The mean MELD score was 19.6 ± 7.7. The median time between the first admission and future readmission was 1.9 months with interquartile range of 4.8 months. The cumulative incidence of HE-related readmissions was significantly higher in patients taking NSBB compared with patients who were never prescribed NSBB (P < 0.001) (Figure 1). This effect was not seen for patients who were taking SSBs. In multivariate analysis, after adjusting for age, sex, MELD score, SBB use, ascites, history of EV and TIPS, NSBB use was independently associated with increased risk of HE-related re-hospitalizations; Hazard ratio was 2.82 (95% confidence interval: 1.81–4.41).

CONCLUSIONS:
NSBB use is independently associated with increased HE-related readmissions in patients with cirrhosis, regardless of liver disease severity. Thus, NSBBs should be used cautiously in patients who have experienced a prior HE episode. However, further prospective studies are needed to determine the impact of NSBB on portal hypertension complications.
P: 50 Developing a New Animal Model of Episodic Hepatic Encephalopathy
Authors: Tamnanloo Farzaneh , Ochoa-Sanchez Rafael , Tremblay Mélanie , Rose Christopher F. 
Published: September 2019

BACKGROUND:
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, a major complication of chronic liver disease (CLD/cirrhosis). The primary cause of hospital admissions for cirrhotic patients is an overt episode of HE. Precipitating factors of HE frequently lead to an increase in blood ammonia. Patients who have experienced multiple episodes of HE are associated with persisting neurological complications post-liver transplantation. Currently, the impact of HE episodes on neurological integrity is unknown. We hypothesize that multiple episodes of HE will accelerate and/or intensify neurological deterioration. To date, an animal model of episodic HE is lacking. Therefore, our goal was to characterize an animal model of episodic HE (precipitated with ammonia) and to evaluate the impact of cumulative episodes on neurological status in cirrhotic rats.

METHODS:
Animal model of CLD and HE: 6-week bile-duct ligation (BDL) rats, and Sham-operated controls were used. BDL and Sham rats were divided in two groups, episodic and non-episodic. Injection (i.p) of ammonium acetate was used to induce episodes of overt HE (pre-coma; loss of righting reflex) every 4 days starting 3-weeks post-BDL surgery (total 5 episodes). Saline was injected as vehicle for non-episodic groups. Two days following the last HE episode, we assessed motor-coordination (RotaRod), anxiety (elevated plus maze, EPMT), as well as short-term and long-term memory (novel object recognition) in all groups. Upon sacrifice, plasma ammonia was measured.

RESULTS:
The concentration of ammonia required to induce an episode of overt HE in BDL rats lessened with each subsequent episode, ranging from 7 to 4.5 mmol/kg. Short-term memory (P < 0.05) and motor-coordination (P < 0.05) were impaired in both non-episodic and episodic BDL groups compared to respective Sham-operated controls. Long-term memory impairment (P = 0.06) and increased anxiety (+60.0%, P < 0.05) were exclusively found in episodic BDL rats compared to non-episodic BDL rats. Moreover, there was an increase in blood ammonia (+30.4%, P = 0.06) in episodic compared to non-episodic BDL rats, suggesting that although episodic-BDL rats recover from each HE episode, baseline (pre-episode) ammonia remain higher than non-episodic BDL rats.

CONCLUSIONS:
Cumulative HE episodes escalate neurological impairments in cirrhotic-BDL rats. Thus, this new episodic HE model represents a good approach to explore the pathological mechanism arising from multiple episodes, as well as further investigate whether higher hyperammonemia and/or increased brain sensitivity to ammonia is responsible for more complex neurological manifestations in episodic-BDL rats. Moreover, this model is an excellent platform to investigate novel therapies to prevent/treat episodic HE.
P: 52 Visual Analysis of the EEG Performs Better Than Standard Spectral Analysis in the Clinical Setting
Authors: Garciá-Garciá Raquel , Morgan Marsha Y. , Jackson Clive D. 
Published: September 2019

BACKGROUND:
The electroencephalogram (EEG) provides objective information useful for detecting and monitoring hepatic encephalopathy (HE); its acquisition does not require patient co-operation and there are no learning effects. The ISHEN guideline (Guérit et al, 2009) states that 'the EEG classification based on visual pattern recognition, although informative, does not allow reliable grading' and that 'quantitative (computer-based) analysis may improve the reliability of EEG assessment'. However, this recommendation was rated as weak and uncertain. This study aims to compare the performance of visual and spectral analysis of the EEG for the diagnosis of any degree of HE.

METHODS:
The study population comprised of 137 healthy controls (53% men: mean [range] age 39 [17–75] yr) and 226 patients with cirrhosis (66% men; mean age 54.8 [26–80] yr) classified, based on clinical status and PHES results, as neuropsychologically unimpaired (n = 127) or as having minimal (n = 21) or overt (n = 78) HE. A researcher with no previous experience received basic training in EEG analysis. She was asked to select 60 to 100 sec of recording, preferably from the P3-P4 montage, from the 403 anonymized patient/control EEG records and to estimate the visual wave frequency in a representative epoch, marking her selection. Spectral analysis of the EEG was undertaken on the same 60 to 100 sec of recording and the mean dominant frequency (MDF) and %theta power obtained (Jackson et al, 2016). The performances of the visual and spectral assessment of the EEG for the diagnosis of any degree of HE were compared.

RESULTS:
The diagnostic performance for the diagnosis of any degree of HE was comparable between the visual assessment of background activity (ROC: threshold 8.75 Hz; AUC 0.84; sensitivity 77.4%; specificity 74.5%) and the spectral %theta power (ROC: threshold 23%; AUC 0.81; sensitivity 74.8%; specificity 78.4%). However, the visually assessed background activity provided better separation of the patients in relation to their neuropsychiatric status that either of the spectral variable. Thus, significant differences were observed in the visual background activity between all patient groups and healthy controls and between patients with minimal and overt HE, whereas significant differences in spectral variables were only observed in the patients with overt HE (Figure 1).

CONCLUSIONS:
The ISHEN statement that 'visual assessment of the EEG, does not allow reliable grading' and that 'quantitative analysis may improve the reliability of EEG assessment is not supported by the findings in this study.