Nutritional aspects of prehabilitation in adults with cirrhosis awaiting liver transplant.

Malnutrition, sarcopenia (low muscle mass), and physical frailty have gained increasing recognition in candidates for liver transplant (LT) as these conditions can impact postoperative functional capacity. Multidimensional prehabilitation programs have been proposed as a safe intervention in adults awaiting LT but the nutritional pillar of prehabilitation has been understudied. This review summarizes the nutritional recommendations for prehabilitation for individuals with cirrhosis awaiting LT. Three major aspects of nutritional prehabilitation are discussed: (1) Assess: Evaluate nutritional status and assess for malnutrition, sarcopenia, and frailty to guide the nutritional prehabilitation intervention intensity, increasing across universal, targeted, and specialist levels; (2) Intervene: Prescribe a nutritional prehabilitation intervention to meet established nutrition guidelines in cirrhosis with a targeted focus on improving nutritional status and muscle health; (3) Reassess: Follow-up based on the required intensity of nutritional care with as needed intervention adjustment. Topics covered in the review include nutritional care levels for prehabilitation, energy prescriptions across body mass index strata, detailed considerations around protein intake (amount, distribution, and quality), carbohydrate and fat intake, other nutritional considerations, and the potential role of dietary supplements and nutraceuticals. Future research is warranted to more accurately evaluate energy needs, evaluate emerging dietary supplementation strategies, and establish the role of nutraceuticals alongside food-based interventions. While the general principles of nutritional prehabilitation are ready for immediate application, future large-scale randomized controlled trials in this space will help to quantify the benefit that can be gained by transitioning the LT approach from passive "transplant waitlist time" to active "transplant preparation time."

Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting.

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

Predictors of Respiratory Failure Development in a Multicenter Cohort of Inpatients With Cirrhosis.

INTRODUCTION: Hospitalized patients with cirrhosis can develop respiratory failure (RF), which is associated with a poor prognosis, but predisposing factors are unclear. METHODS: We prospectively enrolled a multicenter North American cirrhosis inpatient cohort and collected admission and in-hospital data (grading per European Association for the Study of Liver-Chronic Liver Failure scoring system, acute kidney injury [AKI], infections [admission/nosocomial], and albumin use) in an era when terlipressin was not available in North America. Multivariable regression to predict RF was performed using only admission day and in-hospital events occurring before RF. RESULTS: A total of 511 patients from 14 sites (median age 57 years, admission model for end-stage liver disease [MELD]-Na 23) were enrolled: RF developed in 15%; AKI occurred in 24%; and 11% developed nosocomial infections (NI). At admission, patients who developed RF had higher MELD-Na, gastrointestinal (GI) bleeding/AKI-related admission, and prior infections/ascites. During hospitalization, RF developers had higher NI (especially respiratory), albumin use, and other organ failures. RF was higher in patients receiving albumin (83% vs 59%, P < 0.0001) with increasing doses (269.5 ± 210.5 vs 208.6 ± 186.1 g, P = 0.01) regardless of indication. Admission for AKI, GI bleeding, and high MELD-Na predicted RF. Using all variables, NI (odds ratio [OR] = 4.02, P = 0.0004), GI bleeding (OR = 3.1, P = 0.002), albumin use (OR = 2.93, P = 0.01), AKI (OR = 3.26, P = 0.008), and circulatory failure (OR = 3.73, P = 0.002) were associated with RF risk. DISCUSSION: In a multicenter inpatient cirrhosis study of patients not exposed to terlipressin, 15% of patients developed RF. RF risk was highest in those admitted with AKI, those who had GI bleeding on admission, and those who developed NI and other organ failures or received albumin during their hospital course. Careful volume monitoring and preventing nosocomial respiratory infections and renal or circulatory failures could reduce this risk.

Development and Evaluation of a Patient Cirrhosis Knowledge Assessment.

BACKGROUND AND AIMS: Self-management skills improve outcomes for patients with cirrhosis. While education programs exist to teach these skills, there are limited patient assessments to evaluate their efficacy. We aimed to develop and evaluate cirrhosis knowledge assessments for patients with compensated and decompensated cirrhosis. METHODS: Across two institutions, a 4-stage process was undertaken: first, we developed a comprehensive set of questions regarding cirrhosis self-management. Second, the questions underwent critical review by patients and hepatology providers. Third, patients with cirrhosis answered these questions before and after a written educational tool. Questions were updated based on results. Fourth, patients answered the updated questions before and after a video educational tool. Binomial test or paired sample t-test was used to compare pre- and post-tests depending on question type. RESULTS: In phase 3, 134 patients completed pre- and post-tests. 44% were decompensated, 81% were diagnosed with cirrhosis at least 3 years, and 52% were 60-75 years. 95% of single-answer questions were answered correctly by at least 70% of patients in the pre-test. None of the answers improved significantly with education. After phase 3, 6 questions were removed and 6 questions were edited to increase challenge. In phase 4, 96 patients (42 compensated, 54 decompensated) completed pre- and post-tests. In the compensated assessment, 3 questions improved after education and the summative score increased (7.9 to 9.0, P < 0.001). In the decompensated assessment, 4 questions improved after education and the summative score increased (7.0 to 7.7, P = 0.004). CONCLUSION: Through a rigorous process, we created and evaluated cirrhosis knowledge assessments for patients with compensated and decompensated cirrhosis. Further validation is required and then these assessments can be used to improve patient education.

Liver transplantation in the patient with physical frailty.

Frailty is a decline in functional reserve across multiple physiological systems. A key component of frailty is sarcopenia, which denotes a loss of skeletal muscle mass and impaired contractile function that ultimately result in physical frailty. Physical frailty/sarcopenia are frequent and contribute to adverse clinical outcomes before and after liver transplantation. Frailty indices, including the liver frailty index, focus on contractile dysfunction (physical frailty), while cross-sectional image analysis of muscle area is the most accepted and reproducible measure to define sarcopenia. Thus, physical frailty and sarcopenia are interrelated. The prevalence of physical frailty/sarcopenia is high in liver transplant candidates and these conditions have been shown to adversely impact clinical outcomes including mortality, hospitalisations, infections, and cost of care both before and after transplantation. Data on the prevalence of frailty/sarcopenia and their sex- and age-dependent impact on outcomes are not consistent in patients on the liver transplant waitlist. Physical frailty and sarcopenic obesity are frequent in the obese patient with cirrhosis, and adversely affect outcomes after liver transplantation. Nutritional interventions and physical activity remain the mainstay of management before and after transplantation, despite limited data from large scale trials. In addition to physical frailty, there is recognition that a global evaluation including a multidisciplinary approach to other components of frailty (e.g., cognition, emotional, psychosocial) also need to be addressed in patients on the transplant waitlist. Recent advances in our understanding of the underlying mechanisms of sarcopenia and contractile dysfunction have helped identify novel therapeutic targets.

An Evaluation of Online Cirrhosis-related Information Intended for Patients and Caregivers.

With nearly 70% of American adults seeking online health information,1 the internet represents a powerful space to provide patients with evidence-based, usable education about their chronic conditions. Although effective patient-oriented communication recommendations are available, the accessibility, reliability, and accuracy of online health content is largely unmonitored or evaluated. In a complex chronic disease, such as cirrhosis, understanding the online information landscape specific to patients can provide insight into resources that are available to support their self-management behaviors and to fill knowledge gaps.

Admission Serum Metabolites and Thyroxine Predict Advanced Hepatic Encephalopathy in a Multicenter Inpatient Cirrhosis Cohort.

BACKGROUND & AIMS: Grades 3 to 4 hepatic encephalopathy (advanced HE), also termed brain failure, is an organ failure that defines acute-on-chronic liver failure. It is associated with poor outcomes in cirrhosis but cannot be predicted accurately. We aimed to determine the admission metabolomic biomarkers able to predict the development of advanced HE with subsequent validation. METHODS: Prospective inpatient cirrhosis cohorts (multicenter and 2-center validation) without brain failure underwent admission serum collection and inpatient follow-up evaluation. Serum metabolomics were analyzed to predict brain failure on random forest analysis and logistic regression. A separate validation cohort also was recruited. RESULTS: The multicenter cohort included 602 patients, of whom 144 developed brain failure (105 only brain failure) 3 days after admission. Unadjusted random forest analysis showed that higher admission microbially derived metabolites and lower isoleucine, thyroxine, and lysophospholipids were associated with brain failure development (area under the curve, 0.87 all; 0.90 brain failure only). Logistic regression area under the curve with only clinical variables significantly improved with metabolites (95% CI 0.65-0.75; P = .005). Four metabolites that significantly added to brain failure prediction were low thyroxine and maltose and high methyl-4-hydroxybenzoate sulfate and 3-4 dihydroxy butyrate. Thyroxine alone also significantly added to the model (P = .05). The validation cohort including 81 prospectively enrolled patients, of whom 11 developed brain failure. Admission hospital laboratory thyroxine levels predicted brain failure development despite controlling for clinical variables with high specificity. CONCLUSIONS: In a multicenter inpatient cohort, admission serum metabolites, including thyroxine, predicted advanced HE development independent of clinical factors. Admission low local laboratory thyroxine levels were validated as a predictor of advanced HE development in a separate cohort.

Role of Oral Health, Frailty, and Minimal Hepatic Encephalopathy in the Risk of Hospitalization: A Prospective Multi-Center Cohort of Outpatients With Cirrhosis.

BACKGROUND & AIMS: Hospitalizations are a sentinel event in cirrhosis; however, the changing demographics in patients with cirrhosis require updated hospitalization prediction models. Periodontitis is a risk factor for liver disease and potentially progression. The aim of this study was to determine factors, including poor oral health, associated with 3-month hospitalizations in a multi-center cohort of outpatients with cirrhosis. METHODS: North American Consortium for Study of End-stage Liver Disease (NACSELD-3), a new study cohort, recruits outpatients with cirrhosis. Cirrhosis details, demographics, minimal hepatic encephalopathy (MHE), frailty, and comorbid conditions including oral health were collected. All patients were followed for 3 months for nonelective hospitalizations. Multi-variable models were created for this outcome using demographics, cirrhosis details, oral health, MHE, frailty, and comorbid conditions with K-fold internal validation using 25%/75% split. RESULTS: A total of 442 outpatients (70% men; 37% compensated; Model for End-stage Liver Disease-Sodium, 12; 42% ascites; and 33% prior HE) were included. MHE was found in 70%, frailty in 10%; and both in 8%. In terms of oral health, 15% were edentulous and 10% had prior periodontitis. Regarding 3-month hospitalizations, 14% were admitted for mostly liver-related reasons. These patients were more likely to be decompensated with higher cirrhosis complications, MHE, frailty and periodontitis history. Multi-variable analysis showed prior periodontitis (P = .026), composite MHE + frailty score (P = .0016), ascites (P = .004), prior HE (P = .008), and hydrothorax (P = .004) were associated with admissions using the training and validation subsets. CONCLUSIONS: In a contemporaneous, prospective, multi-center cohort study in outpatients with cirrhosis, poor oral health is significantly associated with 3-month hospitalizations independent of portal hypertensive complications, MHE, and frailty. Potential strategies to reduce hospitalizations should consider oral evaluation in addition to MHE and frailty assessment in practice pathways.

Frailty is associated with increased risk of cirrhosis disease progression and death.

BACKGROUND AND AIMS: The Liver Frailty Index (LFI) is a well-studied tool that evaluates frailty in patients with cirrhosis. Consisting of grip strength, chair stands, and balance testing, the LFI has been associated with increased mortality in patients awaiting liver transplant. We aimed to extend our understanding of frailty in cirrhosis by exploring the relationship between the LFI and the risk of (1) cirrhosis progression, (2) mortality, and (3) unplanned hospitalizations, in both compensated and decompensated disease. APPROACH AND RESULTS: Adult patients with cirrhosis from four centers in North America and one in India were included. Frailty was measured at baseline using the LFI and categorized as robust (LFI < 3.2), prefrail (LFI 3.2-4.5), and frail (LFI > 4.5). Progression of cirrhosis was defined by an increase in clinical stage, ranging from 1 to 5, from baseline using the D'Amico classification. Factors associated with progression, mortality, and hospitalizations were evaluated using multivariate regression models, with transplant as a competing risk. In total, 822 patients with cirrhosis were included. Average Model for End-Stage Liver Disease (MELD) score was 15.5 ± 6.0. In patients with compensated cirrhosis, being frail versus robust was associated with increased risk of progression to the next cirrhosis stage or to death (HR, 2.45; 95% CI, 1.14-5.29) and with an increased risk of unplanned hospitalizations (2.32; 95% CI, 1.13-4.79), after adjusting for age, sex, and MELD score. Similar HRs were observed in patients with decompensated cirrhosis. CONCLUSIONS: Frailty was an independent predictor of cirrhosis progression or death and unplanned hospitalization across patients with compensated and decompensated cirrhosis. Future studies are needed to evaluate the possibility of slowing cirrhosis disease progression by reversing or preventing frailty.

Accuracy and Precision of Point-of-Care International Normalized Ratio in Patients With Liver Disease.

OBJECTIVE: To determine if the CoaguChek XS Pro Point-of-Care (POC) device can accurately and precisely measure the international normalized ratio (INR) compared with the gold standard laboratory INR in pediatric and adult patients with liver disease. METHODS: This prospective cohort study included 15 pediatric patients without liver disease, 13 pediatric patients with liver disease, and 17 adult patients with liver disease. The accuracy of the POC INR values was determined using the correlation and Bland-Altman limits of agreement. The accuracy of the coagulometer INR was assessed by calculating the proportion of POC INR measurements that were ≤15% of their corresponding laboratory INR. RESULTS: A comparison of INR measurements showed an excellent correlation in pediatric patients without liver disease ( r = 0.82), pediatric patients with liver disease ( r = 0.89), and adult patients with liver disease ( r = 0.96). Fourteen (93%) POC INR values were ≤15% in pediatric patients without liver disease from its paired laboratory INR. All 13 paired measurements were ≤15% in pediatric patients with liver disease. In adult patients with liver disease, 12 (71%) POC INR values were ≤15% of their paired laboratory INR. CONCLUSIONS: In patients with liver disease, the CoaguChek XS Pro provides an accurate measure of the INR compared to laboratory INR measurements.

Home-based intensive nutrition therapy improves frailty and sarcopenia in patients with decompensated cirrhosis: A randomized clinical trial.

BACKGROUND AND AIM: The majority of patients with decompensated cirrhosis suffer from malnutrition, a potentially modifiable contributor to frailty and sarcopenia. The present study investigated the impact of a 6-month dietician-supported home-based intensive nutrition therapy (HINT) intervention on objective frailty and sarcopenia metrics in patients with decompensated cirrhosis. METHODS: One hundred adult patients with decompensated cirrhosis, frailty, and sarcopenia at baseline were randomized 1:1 to receive standard medical therapy (SMT) plus HINT (intervention) versus SMT (control) alone. The primary outcome was an improvement in frailty as measured by the liver frailty index (LFI). Secondary outcome measures included sarcopenia metrics, liver disease severity scores, hospitalization, and death. RESULTS: The LFI improved more in the intervention arm as compared with controls (0.8 vs 0.4; P < 0.001). Baseline and end-of-study skeletal muscle index (SMI) was available in a subset of 32 male patients, with greater improvements seen in the intervention arm compared with controls (6.36 vs 0.80; P = 0.02). Patients in the intervention arm had less hospitalizations over the 6-month follow-up (19 [38%] vs 29 [58%]; P = 0.04). On subgroup analysis, in the 64% of patients who were adherent to calorie and protein intake targets at 6 months, significant improvement was seen in liver disease severity scores and survival (P < 0.05). CONCLUSION: In patients with decompensated cirrhosis, frailty, and sarcopenia, a 6-month dietitian-supported home-based intensive outpatient nutrition therapy was associated with statistically and clinically relevant improvement in frailty. The subgroup of adherent patients showed improvement in their liver disease scores and reduction in mortality. These findings support the key role of food as medicine in the management of cirrhosis.

Exploring participant perceptions of a virtually supported home exercise program for people with multiple myeloma using a novel eHealth application: a qualitative study.

INTRODUCTION: Supervision, tailoring, and flexibility have been proposed as key program elements for delivering successful exercise programs for people with multiple myeloma (MM). However, no studies to date have evaluated the acceptability of an intervention employing these components. The aim of this study was to determine the acceptability of a virtually supported exercise program and eHealth application for people with MM. METHODS: A qualitative description approach was used. One-on-one interviews were conducted with participants who completed the exercise program. Content analysis was used to analyze verbatim transcripts from interviews. RESULTS: Twenty participants were interviewed (64.9 ± 6.7 years of age, n = 12 females). Participants had positive perceptions of the exercise program. Two themes emerged related to strengths/limitations: One Size Does Not Fit All (sub-themes: Supportive & Responsive Programming and Diverse Exercise Opportunities), and App Usability. Supportive and Responsive Programming was a main strength of the program, characterized as programming that was tailored, involved active support, and delivered by appropriate personnel. The inclusion of Diverse Exercise Opportunities was also regarded as a strength, as it accommodated the preferences of all participants. Related to App Usability, participants felt the app was simple and user friendly but had a few less intuitive components. CONCLUSION: The virtually supported exercise program and eHealth application were acceptable for people with MM. Programs should employ tailoring, active support, and appropriate personnel to bolster acceptability and include both supervised and flexible exercise formats. eHealth apps should be simple to use so technology proficiency is not a barrier to participation.

Using a Patient-Completed Food Frequency Questionnaire to Determine Mediterranean Diet Score in People with Inflammatory Bowel Disease.

Purpose: To examine the level of agreement between a patient-completed food frequency questionnaire (FFQ) and assessment of usual intake by a registered dietitian (RD) to score adherence to a Mediterranean diet (MedD) in patients with inflammatory bowel disease (IBD).Methods: Patients with IBD completed a short FFQ and were subsequently interviewed by an RD. A 12-item MedD score (MDS), adapted from the Mediterranean Diet Adherence Screener (MEDAS), was calculated from the FFQ and RD assessments. To determine agreement between individual items, Cohen's kappa coefficients were calculated. Absolute agreement between assessment methods was quantified using a one-way random intra-class correlation coefficient for a single measure.Results: Forty-six patients with IBD participated. The mean FFQ-MDS was 4.59 (standard deviation [SD] = 1.65), and mean RD-MDS was 4.83 (SD = 1.53). Kappa coefficients for individual MEDAS items ranged from 0.41 to 0.78 (p < 0.01) between the FFQ- and RD-MDS. Most items demonstrated moderate to substantial agreement. The intra-class correlation coefficient for absolute agreement between the summed FFQ-MDS and RD-MDS was 0.71 (95% confidence interval: 0.52-0.83, p < 0.001), indicating moderate reliability.Conclusions: This patient-completed FFQ may be a promising tool in clinical practice and research and would benefit from additional evaluation to validate its use in patients with IBD.

Predicted estimates of resting energy expenditure have limited clinical utility in patients with cirrhosis.

BACKGROUND & AIMS: Malnutrition is associated with adverse clinical outcomes in patients with cirrhosis. Accurate assessment of energy requirements is needed to optimize dietary intake. Resting energy expenditure (REE), the major component of total energy expenditure, can be measured using indirect calorimetry (mREE) or estimated using prediction equations (pREE). This study assessed the usefulness of predicted estimates of REE in this patient population. METHODS: Individual mREE data were available for 900 patients with cirrhosis (mean [±1 SD] age 55.7±11.6 years-old; 70% men; 52% south-east Asian) and 282 healthy controls (mean age 36.0±12.8 years-old; 52% men; 18% south-east Asian). Metabolic status was classified using thresholds based on the mean ± 1 SD of the mREE in the healthy controls. Comparisons were made between mREE and pREE estimates obtained using the Harris-Benedict, Mifflin, Schofield and Henry equations. Stepwise regression was used to build 3 new prediction models which included sex, ethnicity, body composition measures, and model for end-stage liver disease scores. RESULTS: The mean mREE was significantly higher in patients than controls when referenced to dry body weight (22.4±3.8 cf. 20.8±2.6 kcal/kg/24 hr; p <0.001); there were no significant sex differences. The mean mREE was significantly higher in Caucasian than Asian patients (23.1±4.4 cf. 21.7±2.9 kcal/kg/24 hr; p <0.001). Overall, 37.1% of Caucasian and 25.3% of Asian patients were classified as hypermetabolic. The differences between mREE and pREE were both statistically and clinically relevant; in the total patient population, pREE estimates ranged from 501 kcal/24 hr less to 548 kcal/24 hr more than the mREE. Newly derived prediction equations provided better estimates of mREE but still had limited clinical utility. CONCLUSIONS: Prediction equations do not provide useful estimates of REE in patients with cirrhosis. REE should be directly measured. LAY SUMMARY: People with cirrhosis are often malnourished and this has a detrimental effect on outcome. Provision of an adequate diet is very important and is best achieved by measuring daily energy requirements and adjusting dietary intake accordingly. Prediction equations, which use information on age, sex, weight, and height can be used to estimate energy requirements; however, the results they provide are not accurate enough for clinical use, particularly as they vary according to sex and ethnicity.

Outcomes of Exercise Interventions in Patients With Advanced Liver Disease: A Systematic Review of Randomized Clinical Trials.

INTRODUCTION: Frailty and sarcopenia are common complications of advanced liver disease. Owing to associated morbidity/mortality, there have been targeted efforts to prevent and/or improve both by enrolling these patients in focused exercise programs. This review systematically analyzes the data of randomized clinical trials (RCTs) on anthropometric, physical fitness, quality-of-life, and safety outcomes of exercise interventions in patients with advanced liver disease. METHODS: Two authors independently searched trials on PubMed and EMBASE from inception up to November 18, 2021. A third independent arbitrator adjudicated all disagreements. We qualitatively summarized these outcomes as follows: (i) muscular fitness (maximal inspiratory/expiratory pressures, muscle size, muscle strength, and bioimpedance testing), (ii) cardiorespiratory fitness (cardiopulmonary exercise testing and 6-minute walk distance), (iii) quality of life, and (iv) others (safety or frailty indices). RESULTS: There were 11 RCTs (4 home-based interventions) with 358 participants. Interventions ranged from 8 to 14 weeks and included cycling, walking, resistance exercises, balance and coordination training, and respiratory exercises. All described outcomes compared preintervention with postintervention measurements. Nine studies showed statistically significant improvements in at least 1 physical fitness variable. Ten studies showed statistically significant improvements in at least 1 muscular fitness variable. Six studies showed statistically significant improvements in at least 1 quality-of-life variable. Attrition rates ranged from 5% to 36%, and adherence rates ranged very widely from 14% to 100%. Only 1 study reported frailty indices. Notably, no complications of portal hypertension were seen in intervention groups in the 9 studies that reported these data. DISCUSSION: A review of 11 RCTs with 358 participants with advanced liver disease demonstrates that exercise interventions can have favorable outcomes on muscular/cardiorespiratory fitness and quality of life. Although attrition and adherence varied, these interventions seem to be safe in patients with cirrhosis and are well tolerated.

The Assessment of Driving Fitness Using an On-Road Evaluation in Patients With Cirrhosis.

INTRODUCTION: The association between cirrhosis and driving performance is of particular clinical relevance because of the life-threatening safety issues both for the driver with cirrhosis and the general public. Study aims were to assess (i) driving competency through the use of an in-office computerized battery and on-road driving assessment (DriveABLE) and (ii) the association between minimal hepatic encephalopathy (MHE), in-office paper-pencil tools, and additional measures (e.g., frailty, depression, cognitive testing) with unsafe driving. METHODS: Patients were prospectively recruited from 2 tertiary care liver clinics. In-office tests and in-office and on-road assessments of driving competence were completed. The χ 2 test and 1-way analysis of variance were used to analyze differences among those with and without MHE. Logistic regression was used to evaluate predictors of an indeterminate/fail result on the in-office computerized driving assessment battery (DriveABLE Cognitive Assessment Tool [DCAT]). RESULTS: Eighty patients participated with a mean age of 57 years, 70% male, 75% Child-Pugh B/C, and 36% with a history of overt hepatic encephalopathy. Thirty percent met MHE criteria on both the psychometric hepatic encephalopathy score and the Stroop app tests. Only 2 patients (3%) were categorized as "unfit to drive" in the on-road driving test, one with MHE and the other without. Fifty-eight percent of the patients were scored as indeterminate/fail on the DCAT. This corresponded to a higher mean number of on-road driving errors (5.3 [SD 2.1] vs 4.2 [SD 1.6] in those who passed the DCAT, P = 0.01). Older age (odds ratio 1.3; confidence interval 1.1, 1.5; P = 0.001) and MHE by Stroop/psychometric hepatic encephalopathy score (odds ratio 11.0; confidence interval 2.3, 51.8; P = 0.002) were independently predictive of worse performance on the DCAT. DISCUSSION: Worse performance in in-office testing was associated with worse scores on a computerized driving assessment battery and more on-road driving errors, but in-office tools were insufficient to predict on-road driving failures. A diagnosis of MHE should not be used alone to restrict driving in patients with cirrhosis. At-risk patients require on-road driving tests under the supervision of driving regulatory agencies. Future studies should continue to refine and evaluate in-office or at-home testing to predict driving performance.

Association of serum metabolites and gut microbiota at hospital admission with nosocomial infection development in patients with cirrhosis.

Cirrhosis is complicated by a high rate of nosocomial infections (NIs), which result in poor outcomes and are challenging to predict using clinical variables alone. Our aim was to determine predictors of NI using admission serum metabolomics and gut microbiota in inpatients with cirrhosis. In this multicenter inpatient cirrhosis study, serum was collected on admission for liquid chromatography-mass spectrometry metabolomics, and a subset provided stool for 16SrRNA analysis. Hospital course, including NI development and death, were analyzed. Metabolomic analysis using analysis of covariance (ANCOVA) (demographics, Model for End-Stage Liver Disease [MELD] admission score, white blood count [WBC], rifaximin, and infection status adjusted) and random forest analyses for NI development were performed. Additional values of serum metabolites over clinical variables toward NI were evaluated using logistic regression. Stool microbiota and metabolomic correlations were compared in patients with and without NI development. A total of 602 patients (231 infection admissions) were included; 101 (17%) developed NIs, which resulted in worse inpatient outcomes, including intensive care unit transfer, organ failure, and death. A total of 127 patients also gave stool samples, and 20 of these patients developed NIs. The most common NIs were spontaneous bacterial peritonitis followed by urinary tract infection, Clostridioides difficile, and pneumonia. A total of 247 metabolites were significantly altered on ANCOVA. Higher MELD scores (odds ratio, 1.05; p < 0.0001), admission infection (odds ratio, 3.54; p < 0.0001), and admission WBC (odds ratio, 1.05; p = 0.04) predicted NI (area under the curve, 0.74), which increased to 0.77 (p = 0.05) with lower 1-linolenoyl-glycerolphosphocholine (GPC) and 1-stearoyl-GPC and higher N-acetyltryptophan and N-acetyl isoputreanine. Commensal microbiota were lower and pathobionts were higher in those who developed NIs. Microbial-metabolite correlation networks were complex and dense in patients with NIs, especially sub-networks centered on Ruminococcaceae and Pseudomonadaceae. NIs are common and associated with poor outcomes in cirrhosis. Admission gut microbiota in patients with NIs showed higher pathobionts and lower commensal microbiota. Microbial-metabolomic correlations were more complex, dense, and homogeneous among those who developed NIs, indicating greater linkage strength. Serum metabolites and gut microbiota on admission are associated with NI development in cirrhosis.

The Prediction of In-Hospital Mortality in Decompensated Cirrhosis with Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a condition in cirrhosis associated with organ failure (OF) and high short-term mortality. Both the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) and North American Consortium for the Study of End-Stage Liver Disease (NACSELD) ACLF definitions have been shown to predict ACLF prognosis. The aim of this study was to compare the ability of the EASL-CLIF versus NACSELD systems over baseline clinical and laboratory parameters in the prediction of in-hospital mortality in admitted patients with decompensated cirrhosis. Five NACSELD centers prospectively collected data to calculate EASL-CLIF and NACSELD-ACLF scores for admitted patients with cirrhosis who were followed for the development of OF, hospital course, and survival. Both the number of OFs and the ACLF grade or presence were used to determine the impact of NACSELD versus EASL-CLIF definitions of ACLF above baseline parameters on in-hospital mortality. A total of 1031 patients with decompensated cirrhosis (age, 57 ± 11 years; male, 66%; Child-Pugh-Turcotte score, 10 ± 2; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) were enrolled. Renal failure prevalence (28% versus 9%, P < 0.001) was more common using the EASL-CLIF versus NACSELD definition, but the prevalence rates for brain, circulatory, and respiratory failures were similar. Baseline parameters including age, white cell count on admission, and MELD score reasonably predicted in-hospital mortality (area under the curve, 0.76). The addition of number of OFs according to either system did not improve the predictive power of the baseline parameters for in-hospital mortality, but the presence of NACSELD-ACLF did. However, neither system was better than baseline parameters in the prediction of 30- or 90-day outcomes. The presence of NACSELD-ACLF is equally effective as the EASL-CLIF ACLF grade, and better than baseline parameters in the prediction of in-hospital mortality in patients with cirrhosis, but not superior in the prediction of longer-term 30- or 90-day outcomes.

Admission Urinary and Serum Metabolites Predict Renal Outcomes in Hospitalized Patients With Cirrhosis.

BACKGROUND AND AIMS: Acute kidney injury (AKI) has a poor prognosis in cirrhosis. Given the variability of creatinine, the prediction of AKI and dialysis by other markers is needed. The aim of this study is to determine the role of serum and urine metabolomics in the prediction of AKI and dialysis in an inpatient cirrhosis cohort. APPROACH AND RESULTS: Inpatients with cirrhosis from 11 North American Consortium of End-stage Liver Disease centers who provided admission serum/urine when they were AKI and dialysis-free were included. Analysis of covariance adjusted for demographics, infection, and cirrhosis severity was performed to identify metabolites that differed among patients (1) who developed AKI or not; (2) required dialysis or not; and/pr (3) within AKI subgroups who needed dialysis or not. We performed random forest and AUC analyses to identify specific metabolite(s) associated with outcomes. Logistic regression with clinical variables with/without metabolites was performed. A total of 602 patients gave serum (218 developed AKI, 80 needed dialysis) and 435 gave urine (164 developed AKI, 61 needed dialysis). For AKI prediction, clinical factor-adjusted AUC was 0.91 for serum and 0.88 for urine. Major metabolites such as uremic toxins (2,3-dihydroxy-5-methylthio-4-pentenoic acid [DMTPA], N2N2dimethylguanosine, uridine/pseudouridine) and tryptophan/tyrosine metabolites (kynunerate, 8-methoxykyunerate, quinolinate) were higher in patients who developed AKI. For dialysis prediction, clinical factor-adjusted AUC was 0.93 for serum and 0.91 for urine. Similar metabolites as AKI were altered here. For dialysis prediction in those with AKI, the AUC was 0.81 and 0.79 for serum/urine. Lower branched-chain amino-acid (BCAA) metabolites but higher cysteine, tryptophan, glutamate, and DMTPA were seen in patients with AKI needing dialysis. Serum/urine metabolites were additive to clinical variables for all outcomes. CONCLUSIONS: Specific admission urinary and serum metabolites were significantly additive to clinical variables to predict AKI development and dialysis initiation in inpatients with cirrhosis. These observations can potentially facilitate earlier initiation of renoprotective measures.

Prognosis of hospitalized patients with cirrhosis and acute kidney disease.

BACKGROUND: The prognosis of acute kidney disease (AKD), defined as a glomerular filtration rate of <60 ml/min/1.73 m2 or a rise in serum creatinine (sCr) of <50% for <3 months, is not clearly known. AIM: To study the prevalence, predictive factors and clinical outcomes in hospitalized cirrhotic patients with AKD. METHODS: The North American Consortium for the Study of End-Stage Liver Disease prospectively enrolled hospitalized decompensated cirrhotic patients. Patients were separated into those with normal renal function (controls or C), AKD or stage 1 AKI as their worst renal dysfunction per International Club of Ascites definition and compared. Parameters assessed included demographics, laboratory data, haemodynamics, renal and patient outcomes. RESULTS: 1244 patients with cirrhosis and ascites (C: 704 or 57%; AKD: 176 or 14%; stage 1 AKI: 364 or 29%) with similar demographics were enrolled. AKD patients had similar baseline sCr but higher hospital admission in the previous 6 months, and higher peak sCr, compared to controls, with their peak sCr being lower than that in stage 1 AKI patients (all P < .0001). The in-hospital and 30-day survival for AKD patients were intermediary between that for controls and stage 1 AKI patients (96% vs 91% vs 86%, P < .0001). The strongest predictors for AKD development while in hospital were the presence of a second infection (OR: 2.44) and diabetes (OR: 1.53). CONCLUSIONS: Patients with AKD had intermediate outcomes between stage 1 AKI and controls. AKD patients, especially those with diabetes and a second infection, need careful monitoring and prompt treatment for AKD to prevent negative outcomes.