Frailty is prevalent in end-stage liver disease and predicts higher waitlist and posttransplant mortality. Despite association of frailty with poor clinical outcomes, evidence-based interventions to reverse frailty remain scarce.

In this pilot study, we tested the feasibility of a novel home-based frailty intervention using home exercise equipment, a smartphone application, and remote frailty assessments to create a dynamic and personalized exercise program for patients with cirrhosis evaluated for liver transplantation.

Fifty-four patients (mean 57.2 [±9.9] y, 59% men) enrolled in the study, with a mean Model for End-Stage Liver Disease-Na 16.9 (±5.8; 70% decompensated). The mean baseline Liver Frailty Index (LFI) was 3.59 (±0.60). The mean follow-up time was 259 (±190) d and the mean change in LFI at the end of the intervention was -0.11 (3.59 versus 3.48, P  = 0.05), representing a clinically meaningful improvement in frailty previously associated with increased survival. In comparison, the retrospective control group, which had similar demographics and clinical characteristics as the intervention group, did not show a significant change in LFI (3.97 versus 3.91, P  = 0.57). Fifty-six percent of patients were adherent (fully or partially) to recommended levels of exercise, and adherence rates declined from 1 to 3 mo after enrollment, underscoring the need to maintain patient engagement in exercise.

This study shows that a home-based frailty intervention is feasible. The intervention led to significant improvement in frailty, which was not seen in the retrospective control group. Future studies, including randomized controlled trials, are necessary to further assess the efficacy of the intervention and also determine its impact on downstream clinical outcomes.

Frailty is a syndrome that can inform clinical treatments and interventions for older adults. Although implementation of frailty across medical subspecialties has the potential to improve care for the aging population, its uptake has been heterogenous. While frailty assessment is highly integrated into certain medical subspecialties, other subspecialties have only recently begun to consider frailty in the context of patient care. In order to advance the field of frailty-informed care, we aim to detail what is known about frailty within the subspecialties of internal medicine. In doing so, we highlight cross-disciplinary approaches that can enhance our understanding of frailty, focusing on ways to improve the implementation of frailty measures, as well as develop potential interventional strategies to mitigate frailty within these subspecialties. This has important implications for the clinical care of the aging population and can help guide future research.

To quantify the potential of fully automated CT-based body composition metrics and clinical frailty data in predicting liver transplant recipient postoperative outcomes.

AI-enabled body composition tools were applied to pre-transplant abdominal CT scans in a retrospective cohort of first-time deceased-donor liver transplant recipients. Clinical frailty data (Fried frailty score) was obtained from an established transplant database. Age- and sex-corrected hazard ratios (HRs) were analyzed according to highest-risk quartiles compared with the other three quartiles combined. Area under the receiver operating characteristic curve (ROC AUC) analysis in univariate and multivariate scenarios was also performed.

598 liver transplant recipients (median age, 56 years [IQR, 49-61]; 383 men/215 women) were included from 2005 to 2021. Mean clinical follow-up interval after transplant was 8.6 ± 4.5 years, with 224 deaths (mean interval, 5.3 ± 3.9 years post-transplant) and 246 graft failures (mean interval, 4.7 ± 4.0 years post-transplant) observed. Univariate HRs for post-transplant survival included 1.53 (95% CI, 1.14-2.06) for muscle attenuation, 1.66 (95% Cl, 1.24-2.22) for aortic Agatston score, 1.35 (1.02-1.80) for SAT area, and 1.82 (1.35-2.46) for liver volume. For those meeting the frailty criteria, HR was 2.14 (1.08-4.22). Multivariate 10-year AUC for predicting mortality was 0.675 using liver volume, aortic Agatston score, and muscle attenuation. 10-year univariate AUC for clinical frailty assessment was 0.601 but increased to 0.878 when combined with CT measures.

Automated CT measurements of muscle density (myosteatosis), aortic calcification, subcutaneous fat, and liver volume are predictive of mortality in liver transplant recipients. Frailty was likewise predictive. Combining CT and clinical frailty assessment was complementary.

Question What is the prognostic value of pre-transplant CT-based body composition measures for deceased-donor liver transplant outcomes, and how do they correlate with frailty assessment? Findings Increased post-transplant mortality was associated with pre-transplant increased liver volume, increased abdominal aortic Agatston score, decreased skeletal muscle attenuation, and decreased subcutaneous adipose tissue area. Clinical relevance Pre-transplant AI-enabled body composition measures have predictive value for post-transplant survival, offering a novel and objective diagnostic tool to identify high-risk transplant recipients that are complementary to clinical assessments.

Falls are a major threat to the well-being of patients with cirrhosis. We are performing a clinical trial to determine whether lactulose, TeleTai-Chi, or their combination will reduce falls in HE and improve health-related quality of life (HRQOL) among patients with cirrhosis.

Patients with cirrhosis and portal hypertension without HE will be enrolled in 3 US states and followed participants for 24 weeks. In stage 1 (12 wk), participants will be randomized to receive either lactulose therapy or enhanced usual care. In stage 2 (12 wk), participants will be randomized to either TeleTai-Chi or usual care. The primary outcome is a hierarchical composite: Injurious falls, noninjurious falls, incident HE, and death/transplantation. Secondary outcomes include cognitive function, days-alive and out-of-hospital, and HRQOL. After completion of the interventions, participants will be followed for 48 weeks for health and financial outcomes.

Our study has a central institutional review board with individual site IRB review. Dissemination includes the publication of study findings and patient-focused educational webinars.

Frailty is associated with multiple morbidities. However, its effect on chronic liver diseases remains largely unexplored. This study evaluated the association of frailty with the risk of incident metabolic dysfunction-associated steatotic liver disease (MASLD), cirrhosis, liver cancer, and liver-related mortality.

A total of 339,298 participants without prior liver diseases from the UK Biobank were included. Baseline frailty was assessed by physical frailty and the frailty index, categorizing participants as non-frail, prefrail, or frail. The primary outcome was MASLD, with secondary outcomes, including cirrhosis, liver cancer, and liver-related mortality, confirmed through hospital admission records and death registries.

During a median follow-up of 11.6 years, 4,667 MASLD, 1,636 cirrhosis, 257 liver cancer, and 646 liver-related mortality cases were identified. After multivariable adjustment, the risk of MASLD was found to be higher in participants with prefrailty (physical frailty: hazard ratio [HR] 1.66, 95% CI 1.40-1.97; frailty index: HR 2.01, 95% CI 1.67-2.42) and frailty (physical frailty: HR 3.32, 95% CI 2.54-4.34; frailty index: HR 4.54, 95% CI 3.65-5.66) than in those with non-frailty. Similar results were also observed for cirrhosis, liver cancer, and liver-related mortality. Additionally, the frail groups had a higher risk of MASLD, which was defined as MRI-derived liver proton density fat fraction >5%, than the non-frail group (physical frailty: odds ratio 1.64, 95% CI 1.32-2.04; frailty index: odds ratio 1.48, 95% CI 1.30-1.68).

Frailty was associated with an increased risk of chronic liver diseases. Public health strategies should target reducing chronic liver disease risk in frail individuals.

While frailty is common and associated with a poor prognosis in people with MASLD (metabolic dysfunction-associated steatotic liver disease) and advanced chronic liver diseases, its impact on the subsequent risk of these outcomes remains largely unexplored. Our study showed that frailty was associated with increased risks of MASLD, cirrhosis, liver cancer, and liver-related mortality. This finding suggests that assessing frailty may help identify a high-risk population vulnerable to developing chronic liver diseases. Implementing strategies that target frailty could have major public health benefits for liver-related disease prevention.

Frailty is one of the most common symptoms in patients with cirrhosis. Many researchers have identified it as a prognostic factor for patients with cirrhosis. However, no quantitative meta-analysis has evaluated the prognostic value of frailty in patients with cirrhosis.

This systematic review and meta-analysis aimed to assess the prognostic significance of frailty in patients with cirrhosis.

The systematic review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations. We conducted a comprehensive search of the literature using databases such as PubMed, Cochrane Library, Embase, and Web of Science, as well as China National Knowledge Infrastructure, encompassing the period from inception to 22 December 2023. Data were extracted for frailty to predict adverse outcomes in patients with cirrhosis. RevMan (version 5.3) and R (version 4.2.2) were used to assess the extracted data.

A total of 26 studies with 9597 patients with cirrhosis were included. Compared with patients having low or no frailty, the frail group had a higher mortality rate (relative ratio, RR=2.07, 95% CI 1.82-2.34, P<.001), higher readmission rate (RR=1.50, 95% CI 1.22-1.84, P<.001), and lower quality of life (RR=5.78, 95% CI 2.25-14.82, P<.001). The summary receiver operator characteristic (SROC) curve of frailty for mortality in patients with cirrhosis showed that the false positive rate (FPR) was 0.25 (95% CI 0.17-0.34), diagnostic odds ratio (DOR) was 4.17 (95% CI 2.93-5.93), sensitivity was 0.54 (95% CI 0.39-0.69), and specificity was 0.73 (95% CI 0.64-0.81). The SROC curve of readmission showed that the FPR, DOR, sensitivity, and specificity were 0.39 (95% CI 0.17-0.66), 1.38 (95% CI 0.64-2.93), 0.46 (95% CI 0.28-0.64), and 0.60 (95% CI 0.28-0.85), respectively.

This meta-analysis demonstrated that frailty is a reliable prognostic predictor of outcomes in patients with cirrhosis. To enhance the prognosis of patients with cirrhosis, more studies on frailty screening are required.

Low skeletal muscle mass is an independent risk factor for increased mortality in patients with acute-on-chronic liver failure (ACLF). However, no study has evaluated the temporal changes in muscle mass during the course of ACLF. Therefore, this study aimed to investigate the dynamic changes in muscle mass and their prognostic role in patients with ACLF.

A retrospective analysis was conducted on consecutive patients with ACLF who underwent two or more abdominal computed tomography examinations within 90 days of admission. The percentage change rates of the skeletal muscle index at the third lumbar vertebra (L3-SMI) were calculated as (L3-SMIfinal - L3-SMIinitial)/(L3-SMIinitial) × 100%.

A total of 154 patients with ACLF were included. During the course of ACLF, the percentage change rates of L3-SMI at 2-7, 8-14, 15-30, 31-60, and 61-90 days were - 0.83 ± 4.43, -3.76 ± 4.40, -7.30 ± 5.89, -10.10 ± 7.45, and - 5.53 ± 9.26, respectively. Significant reductions in L3-SMI were noted in patients with severe conditions compared to other patients at 2-7 days and 15-30 days. Moreover, the rate of decrease in L3-SMI in patients with a lower respiratory quotient (RQ) was significantly greater than that in patients with a normal RQ at 2-7 days and 15-30 days. Additionally, high muscle loss (HR 2.059; 95% CI 1.122-3.780, p = 0.020), rather than pre-existing sarcopenia (HR 1.430; 95% CI 0.724-2.826, p = 0.303) at baseline, was independently associated with 90-day mortality.

Deterioration in muscle mass is associated with disease severity and poor nutritional status and serves as a more effective predictor of adverse short-term outcomes in patients with ACLF. These findings underscore the importance of dynamic evaluation of muscle loss and emphasize the necessity of reversing muscle loss in patients with ACLF.

Hepatocellular carcinoma (HCC) patients with advanced symptoms or liver failure are often ineligible for transplantation, leading only to symptom control. Additionally, various factors lead to other HCC stage patients remaining in natural history.

To describe the demographic of untreated HCC patients and to analyze survival-influencing factors.

single-center retrospective observational study examining HCC patients diagnosed from 2015 to 2021 who received symptom control as their primary treatment. Baseline characteristics and survival data were collected and analyzed.

Of 685 HCC patients, 26% (n=181) remained in natural history, median age 71 years, 82% male patients, 93% with cirrhosis, 53% with previous decompensation. At a mean follow-up of 9.98 months, the mortality rate was 84%. While 49.8% of patients were BCLC-D stage, other reasons for remaining in natural history included frailty (25.4%) comorbidities (16%), and patient's treatment refusal (8%). Independent survival factors were BCLC stage, previous decompensation and diagnosis within the screening program, with 37% of untreated patients detected through surveillance.

Liver function, BCLC stage and functional status influence survival in natural HCC history. A significant 37% diagnosed through screening indicates inclusion criteria refinement necessity to avoid overdiagnosis and optimize resources.

Liver cirrhosis is a progressive disease with high mortality. Gut microbiota derangement, increased gut permeability, bacterial translocation and chronic inflammation all drive disease progression. This trial aims to investigate whether faecal microbiota transplantation (FMT) may improve the disease course in patients with acute decompensation of liver cirrhosis.

In this Danish, multicentre, randomised, double-blinded, placebo-controlled trial, 220 patients with acute decompensation of liver cirrhosis and a Child-Pugh score≤12 will be randomised (1:1) to oral, encapsulated FMT or placebo in addition to standard of care. Before the intervention, the patients will be examined and biological samples obtained, and this is repeated at 1 and 4 weeks and 3, 6 and 12 months after the intervention. The primary outcome is the time from randomisation to new decompensation or death. Secondary endpoints include mortality, number of decompensation events during follow-up and changes in disease severity and liver function.

The Central Denmark Region Research Ethics Committee approved the trial protocol (no. 1-10-72-302-20). The results will be published in an international peer-reviewed journal, and all patients will receive a summary of the results.

ClinicalTrials.gov study identifier NCT04932577.

Background: Liver cirrhosis is associated with significant nutritional challenges, including malnutrition, sarcopenia, and frailty, which impact clinical outcomes. The severity of these issues may vary between inpatient and outpatient settings, but there is a limited understanding of how these conditions manifest in these populations. This study aims to compare the nutritional status, dietary intake, and frailty in outpatients and inpatients with liver cirrhosis and to explore potential sex-specific differences. Methods: This prospective observational study enrolled 195 patients with liver cirrhosis from the Gastroenterology ward and Outpatient Clinic of Policlinico Umberto I, Sapienza University of Rome, between May 2023 and July 2024. Nutritional status was assessed using anthropometric measurements, dietary recall, and food frequency questionnaires. Sarcopenia was evaluated using the SARC-F questionnaire and handgrip strength. Frailty was assessed using the Liver Frailty Index (LFI). Data on clinical characteristics, comorbidities, and disease severity were also recorded. Results: The inpatient group (n = 69) had significantly lower BMI, mid-upper arm circumference, and triceps skinfold compared to outpatients (n = 126). Inpatients exhibited higher frailty, with 73.9% classified as frail according to the LFI, compared to 39.6% in outpatients (p < 0.001). Dietary intake revealed that 91% of inpatients had an energy intake deficit compared to 76% of outpatients (p = 0.009). Protein intake was inadequate in 84% of inpatients versus 61% of outpatients (p < 0.001). Sex-specific analysis showed that females had a higher prevalence of sarcopenia than males (64.4% vs. 38.2%, p < 0.001) and experienced more significant protein deficits (74.3% vs. 57.6%, p = 0.021). Females also had higher LFI score (4.77 ± 0.88 vs. 4.45 ± 0.91, p = 0.034). Multivariate analysis showed that CTP, LFI, and protein deficit are independently associated with hospitalization. Conclusions: Inpatients with liver cirrhosis are at higher risk for malnutrition, frailty, and inadequate nutrient intake compared to outpatients, emphasizing the need for targeted nutritional interventions in hospital settings. Additionally, females with cirrhosis are more prone to sarcopenia and frailty, requiring gender-specific approaches to nutrition.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, and 85% to 90% of cases of HCC occur in patients with underlying liver disease. This makes it a complex illness to treat, because disease burden occurs not only from the cancer, but also potential decompensation of the underlying liver disease. Palliative care is multifaceted care that addresses physical, spiritual, and psychosocial needs of patients and can provide support for their caregivers. It can help in advance care planning and hospice support. Early integration of palliative care can improve patient qualify of life and patient/caregiver satisfaction.

Sarcopenia is highly prevalent in patients with liver cirrhosis (LC), adversely affecting their quality of life and life expectancy. Exercise and nutrition represent common interventions to ameliorate sarcopenia in these patients, although there exists inconsistency in the reported effectiveness of these strategies. This study seeks to assess the impact of exercise and nutrition on sarcopenia in LC patients through a systematic review and meta-analysis.

The research protocol was preregistered on PROSPERO, and adherence to PRISMA reporting guidelines was maintained throughout the systematic review process. Controlled vocabularies via Emtree, MeSH, and CINAHL Subject Heading were searched in five databases without any language limitation. The final analysis included only studies with a randomized controlled trial (RCT) design published by December 2021. The quality of these studies was assessed by the Cochrane ROB 2.0 version, and the meta-analysis was conducted using Review Manager 5.4 version.

A total of 262 studies were screened, and seven RCT studies involving 206 subjects were included in the meta-analysis. Exercise interventions encompassed muscle-strengthening, cardiopulmonary enhancement, and increased walking steps, while nutrition interventions included protein, branched-chain amino acids (BCAAs), carbohydrates, and vitamins. Most interventions had a duration of 8-12 weeks. Significant improvements in skeletal muscle index [mean difference (MD): 0.53, P=0.01, 95% confidence interval (CI): -0.10, 0.96, I2=0%] and albumin (MD: 0.16, P=0.04, 95% CI: 0.01, 0.31, I2=0%) were observed in the experimental group when interventions extended for 12 months. Various indicators, such as thigh circumference, midarm circumference, and sit-to-stand, showed significant improvements within the experimental groups following interventions.

Exercise and nutrition interventions demonstrate efficacy in improving sarcopenia in LC patients, with more pronounced effects observed with interventions lasting 12 months or longer. Skeletal muscle index and albumin levels in patients with LC can be positively influenced by exercise and nutrition strategies. Emphasizing a healthy diet and regular exercise is crucial for preventing sarcopenia in patients with LC.

We analyzed early outcomes regarding the impact of our integrated alcohol-associated liver disease (ALD) clinic on patients with ALD and alcohol use.

We conducted a retrospective study of patients with ALD who were evaluated in our integrated clinic from May 1, 2022, to December 31, 2023. Primary outcomes included differences in baseline clinical/demographic data between patients who accepted versus declined an appointment and changes in the severity of ALD, alcohol consumption, functional status, hospital utilization, and remission in alcohol use disorder for evaluated patients.

Patients who declined appointments (n=66) had higher median no-show rates (15.0 [8.0,30.0] vs. 8.5 [3.25,15.0], p<0.001), social vulnerability index (0.53 [0.26,0.79] vs. 0.38 [0.17,0.63], p=0.033), and proportions of cirrhosis (78.8% vs. 59.8%, p=0.017) versus evaluated patients. Comparison of baseline to first follow-up visit for evaluated patients (n=102) demonstrated significant reductions in median AST (59.5 [41.75, 89] vs. 44.5 [33.5, 56.25], p<0.001), alanine-aminotransferase (33.5 [20,45.25] vs. 26.5 [18.75,33.0], p=0.017), total bilirubin (1.6 [0.7,3.3] vs. 1 [0.5,1.9], p=0.001), phosphatidylethanol (263 [35, 784] vs. 0 [0, 163], p<0.001), MELD-3.0 and Sodium scores for patients with alcohol-associated hepatitis and cirrhosis (16 [11, 18.75] vs. 12 [9, 14], p<0.001), 14 [9.25, 17.75] vs. 11 [8.5, 14], p<0.001), and Child-Turcotte-Pugh scores for patients with cirrhosis (9 [6, 10.5] vs. 7 [6, 9], p<0.001). The proportion of patients with active-severe alcohol use disorder significantly decreased (85.2% vs. 51.9%, p<0.001). Additionally, patients had significant reductions in emergency department utilization (incidence rate ratio of 0.64 emergency department visits/month (p=0.002) and 0.71 hospital admissions/month (p=0.025). However, after considering the false discovery rate, the reduction in hospitalization admissions/month was not statistically significant (False Discovery Rate adjusted p=0.056).

Our integrated approach led to reductions in liver injury, degree of liver decompensation, alcohol use, and ED utilization, and remission in AUD in a population of both non-transplant ALD and post-transplant patients.

In chronic diseases, there have been issues with low levels of participant adherence and retention during well-supported lifestyle behaviour change interventional studies. Theoretically informed, the objective was to explore the types of challenges participants are experiencing to inform future designs.

We conducted an exploratory descriptive study in an adult cirrhosis population after the first 4-6 weeks of a 12-week semi-supervised nutrition and exercise online program.

Participants in the parent feasibility study, assessing the nutrition and exercise intervention (Heal-Me), were eligible for this nested study. Heal-Me is a multimodal program that is tailorable to a participant's abilities through regular interaction with the study's registered dietician and exercise specialist. Interviews (~60 min) with participants were recorded then analysed descriptively, guided by the capability, opportunity and motivational behaviour change model.

The 20 participants preferred the expert-led group online nutrition and exercise classes over independent activities such as protein tracking and the exercise videos. Social gamification (e.g., weekly polls on favourite things like movies or sports teams) contributed to the group experience. All except one person required program tailoring to address preferences, abilities and new onset health events. Findings led to the inclusion of 4 behaviour change techniques to the initial 17, whereas 2 others were expanded.

While program tailoring, awareness of cirrhosis nutrition and regular interactions with staff influenced participant retention and adherence in the first 4-6 weeks of the online program.

Patients with an indication for transplantation of abdominal organs often suffer from terminal organ failure with a relevant number of comorbidities. This can be complicated by acute and underlying disease-related events or age-related comorbidities. The diagnostic assignment of symptoms is difficult and the available treatment options have to be adapted. During the evaluation, the waiting time for suitable donor organs and immediately prior to surgery, the treatment team, consisting of the referring physician and the interdisciplinary transplantation team needs to decide whether the transplantation can be performed.

Dysgeusia is a distortion of the sense of taste whose prevalence and relationship with nutritional status in Metabolic dysfunction-associated Steatotic Liver Disease (MASLD)-related advanced chronic liver disease (ACLD) have never been systematically explored.

200 MASLD patients [60 ≤ F3 fibrosis, 70 compensated ACLD (cACLD), and 70 decompensated (dACLD)] were enrolled. At baseline, the Child-Pugh (CP) score was determined. Dietary habits, body composition, and frailty were evaluated. The European Working Group (EWGSOP2) criteria defined sarcopenia. Dysgeusia was assessed by the Dysgeusia-Total-Score (DTS). A visual analog scale identified appetite impairment (VASAI). During a 6-month follow-up, liver-related decompensation events (LRDEs) were recorded.

The prevalence of dysgeusia increased with the liver disease progression, appearing significantly higher in ACLD compared with ≤ F3 (65.7% vs 5%, p:0.003), as well as in dACLD compared to cACLD patients (58.5 vs 7.1% p < 0.0001). On 41 dACLD patients presenting dysgeusia, 37 (90.2%) showed a significant impairment of appetite levels. In dACLD, the CP score was positively correlated with both DTS (R:0.742) and VASAI (R:0.704), as well as DTS was directly correlated with VASAI (R:0.765) (all p < 0.0001). Compared with dACLD patients without dysgeusia, dysgeusia-affected dACLD patients presented a lower daily protein intake (g/kg/die) (1.55 ± 0.192 vs 1.34 ± 0.15, p < 0.0001). Sarcopenia (70.7 vs 41.3%) and frailty (69.29 vs 37.9%) were significantly more prevalent in dysgeusia-affected dACLD individuals (both p < 0.0001). These patients showed a higher risk of LRDEs occurrence during the follow-up [HR:2.205; C.I. 95%:1.186-4.099; p:0.01]. Logistic regression analysis revealed dysgeusia (aOR: 3.32), appetite impairment (aOR:1.32), sarcopenia (aOR: 3.75), and frailty (aOR:3.03) significantly associated with this outcome (all p < 0.0001).

Dysgeusia appears predominant in MASLD-dACLD and, via appetite impairment, in a close relationship with malnutrition, sarcopenia, and frailty, negatively influencing patients' outcomes.

This study informs how mean arterial pressure (MAP) impacts acute kidney injury (AKI) recovery among all patients hospitalized with cirrhosis, regardless of etiology.

We identified incident AKI episodes among subjects in our cohort of patients with decompensated cirrhosis. AKI was defined as a ≥50% increase in creatinine from an outpatient baseline (≥7 days prior) that required hospitalization. Linear mixed effects models were completed to determine the impact between AKI recovery, MAP, and time. To determine the impact of MAP on AKI reversal, we completed time-dependent Cox regression models with time beginning at the time of peak creatinine and ending at death, discharge, or AKI reversal, among those hospitalized with AKI and those with persistent AKI (≥48 h) We identified 702 hospitalized patients with cirrhosis with AKI. We found those with AKI reversal had, on average, higher MAP (2.1 mm Hg, p <0.05) and a greater increase in MAP over time (0.1 mm Hg per hour, p <0.001). Among all 702 hospitalized patients with AKI and adjusted for confounders, each 5 mm Hg increase in MAP was associated with 1.07× the hazard of AKI reversal ( p <0.01). Similarly, among those with persistent AKI after adjusting for confounders, each 5 mm Hg increase in MAP was associated with a 1.19× greater likelihood of AKI reversal ( p <0.001).

Our data demonstrate that MAP significantly increases the likelihood of AKI recovery regardless of severity or injury or AKI phenotype. We believe these data highlight the importance of MAP as a clinical tool to promote kidney function recovery among patients with cirrhosis hospitalized with AKI.

Among patients with decompensated cirrhosis, serum creatinine (sCr) is biased by sex, frailty, and hepatic synthetic function, while Cystatin C (cysC) is not. We found that sCr would better associate with waitlist mortality and that the difference between cysC and sCr (cysCsCr diff ) would quantify this bias and be independently associated with outcomes. We measured cysC levels at ambulatory liver transplant visits among 525 consecutive patients seen at our center. We defined the cysCsCr diff as the difference between cysC minus sCr. We compared demographics and clinical characteristics in patients with low, intermediate, and high cysCsCr diff , divided by tertile. We used Cox regression to compare the association between sCr and cysC and waitlist mortality and demonstrate the independent association between cysCsCr diff and waitlist mortality. In Cox regression, cysC was significantly more associated with waitlist mortality than sCr ( p < 0.001). We found that as compared to those with a low cysCsCr diff , those with an intermediate or high cysCsCr diff were more likely to be female, have ascites, have higher frailty, and have higher MELD 3.0 scores ( p < 0.05 for all). Compared to those with a low cysCsCr diff , we found that those in the intermediate and high groups were more likely to die during follow-up (low: 6% vs. intermediate: 8% vs. high: 11%, p = 0.007). We found that after adjusting for the components of the MELD 3.0 score, each 1-point increase in the cysCsCr diff was associated with 1.72× (1.27-2.32) the hazard of waitlist mortality. Our study demonstrates that not only is cysC more associated with waitlist mortality than sCr, but that cysCsCr diff represents a novel independent metric associated with waitlist mortality.

Physical frailty increases susceptibility to stressors and has been associated with increased mortality among liver transplant candidates. However, evidence about this population's frailty prevalence and mortality is inconsistent and needs to be clarified. This study aimed to quantitatively synthesize the prevalence of frailty and the role of frailty on mortality in liver transplant candidates.

All eligible studies published in Embase, PubMed, Scopus, and Web of Science from inception until March 5, 2024, were included. The pooled prevalence and hazard ratio (HR) corresponding to 95 % confidence intervals (CI) in mortality estimates were conducted. The random-effects model was used for the calculations.

A total of 17 studies containing 4509 patients with liver transplant waitlist candidates were included. The prevalence of frailty in liver transplant waitlist candidates was 32 % (95 % CI = 25-38; p < 0.01). In this population, frailty was associated with an increased hazard ratio for mortality (8 studies) (HR = 2.49; 95 % CI = 1.77-3.51; p < 0.01). Furthermore, subgroup analysis showed that frailty was associated with a higher mortality in the USA (HR = 4.03; 95 % CI = 1.77-3.51; p < 0.01) compared with the non-USA area (HR = 2.03; 95 % CI = 1.51-2.72; p < 0.01).

Our results suggest that frailty is prevalent in patients awaiting liver transplants, which strongly predicts waitlist mortality among this population. These findings highlight the importance of frailty in the decision of transplantation and in designing studies that consider frailty. Reducing the severity or impact of frailty on this population may improve prognosis.

Perception of the ascites burden and its effects on quality of life may be different between sexes. This study assessed sex differences in perception of ascites burden and its impact on health-related quality of life (HRQoL) in patients with recurrent or refractory ascites.

The North American Consortium for the Study of End-stage Liver Disease prospectively enrolled outpatients with cirrhosis and large ascites requiring repeat large volume paracenteses. Demographics, laboratory results, comorbidities, medications, frailty measurements, and self-reported questionnaires related to functional status, physical activities, and HRQoL (generic = Short Form 36 and ascites specific = Ascites Questionnaire) were compared between sexes.

In total, 392 men (59.6 ± 10.7 years) and 184 women (59.5 ± 11.1 years) with predominantly alcohol-related liver disease (51% and 43%, respectively) and median Model for End-Stage Liver Disease-Na: 13 were enrolled. Both groups had similar comorbidities and cirrhosis complications, ascites duration and severity, and frailty scores ( P = 0.94). Women had more symptoms related to their ascites (Ascites Questionnaire score = 66 ± 21 vs 60 ± 21 in men, P = 0.001) (higher value = feeling worse). 35% of women felt depressed vs 22% of men ( P = 0.0009), with lower mental but not physical functioning components of Short Form 36 ( P = 0.019). Women continued to conduct their daily activities as adequately as men as indicated by Duke Status Activity Index ( P = 0.27) and Godin Leisure Activity Index ( P = 0.47).

Women with cirrhosis and ascites experienced worse emotional HRQoL than men without difference in daily function. Our analyses underscore the differences in the lived experience of women vs men with cirrhosis and highlight the need for patient-reported metrics to provide patient-centered care.

Frailty in cirrhosis or advanced chronic liver disease (ACLD) is a relevant prognostic factor. In the present study, we aimed to analyze potential biomarkers associated with frailty and its improvement in patients with ACLD. We analyzed the serum of outpatients with ACLD who participated in a previous study (Román, Hepatol Commun 2024) in which frailty was assessed using the liver frailty index (LFI), and patients who were frail or prefrail were randomized to a multifactorial intervention (home exercise, branched-chain amino acids, and probiotics) or control for 12 months. We determined a biomarker battery of inflammation, bacterial translocation, and liver damage in blood and urine and blood metabolomics by 1H-NMR. Thirty-seven patients were included. According to the LFI, 32 patients were frail or prefrail, and 5 were robust. At baseline, LFI correlated with LBP, sCD163, mtDNA, FGF-21, urinary NGAL, urinary claudin-3, and the metabolites mannose, ethanol, and isoleucine. During the study, patients in the intervention group showed an improvement in LFI and a decrease in CRP, LBP, sCD163, and ccK18 compared to the control group. Metabolomics showed a decrease in dimethyl sulfone and creatinine and an increase in malonate, ornithine, isoleucine, and valine in the intervention group. We conclude that frailty in patients with ACLD is associated with biomarkers of systemic inflammation, bacterial translocation, and liver damage, and alterations of amino acid and short-chain fatty acid metabolism.

Understanding patients' degree of frailty is crucial for tailoring clinical care for older adults based on their physiologic reserve and health needs ("frailty-guided clinical care"). Two prerequisites for frailty-guided clinical care are: (1) access to frailty information at the point of care and (2) evidence to inform decisions based on frailty information. Recent advancements include web-based frailty assessment tools and their electronic health records integration for time-efficient, standardized assessments in clinical practice. Additionally, database frailty scores from administrative claims and electronic health records data enable scalable assessments and evaluation of the effectiveness and safety of medical interventions across different frailty levels using real-world data. Given limited evidence from clinical trials, real-world database studies can complement trial results and help treatment decisions for individuals with frailty. This article, based on the Thomas and Catherine Yoshikawa Award lecture I gave at the American Geriatrics Society Annual Meeting in Long Beach, California, on May 5, 2023, outlines our group's contributions: (1) developing and integrating a frailty index calculator (Senior Health Calculator) into the electronic health records at an academic medical center; (2) developing a claims-based frailty index for Medicare claims; (3) applying this index to evaluate the effect of medical interventions for patients with and without frailty; and (4) efforts to disseminate frailty assessment tools through the launch of the eFrailty website and the forthcoming addition of the claims-based frailty index to the Centers for Medicare and Medicaid Services Chronic Conditions Data Warehouse. This article concludes with future directions for frailty-guided clinical care.

With the growth of the older adult population, the number of older adults waitlisted for and undergoing kidney and liver transplantation has increased. Transplantation is an important and definitive treatment for this population. We present a contemporary review of the unique preoperative, intraoperative, and postoperative issues that patients older than 65 y face when they undergo kidney or liver transplantation. We focus on geriatric syndromes that are common in older patients listed for kidney or liver transplantation including frailty, sarcopenia, and cognitive dysfunction; discuss important considerations for older transplant recipients, which may impact preoperative risk stratification; and describe unique challenges in intraoperative and postoperative management for older patients. Intraoperative challenges in the older adult include using evidence-based best anesthetic practices, maintaining adequate perfusion pressure, and using minimally invasive surgical techniques. Postoperative concerns include controlling acute postoperative pain; preventing cardiovascular complications and delirium; optimizing immunosuppression; preventing perioperative kidney injury; and avoiding nephrotoxicity and rehabilitation. Future studies are needed throughout the perioperative period to identify interventions that will improve patients' preoperative physiologic status, prevent postoperative medical complications, and improve medical and patient-centered outcomes in this vulnerable patient population.

In obese patients, metabolic dysfunction-associated steatotic liver disease is becoming a leading etiology of end-stage liver disease and HCC. Simultaneous liver transplantation and sleeve gastrectomy (LT-SG) have been proposed in the United States, but the safety and efficacy of the procedure have not been widely explored in Europe. Between January 2016 and December 2022, morbidly obese patients listed for liver transplantation at Tor Vergata University were enrolled in the LT-SG study. Primary outcomes were (1) safety expressed as 30- and 90-day overall survival and (2) major postoperative complications (Clavien-Dindo >IIIa). The secondary outcome was efficacy expressed as a 3-year %excess body mass index (BMI) loss. Eleven patients were enrolled in the study. The median BMI at transplantation was 42 (IQR 38-48). Indications of LT-SG were HCC (63.6%) and cirrhosis (36.4%). In 54% of cases, donors had high-risk characteristics (eurotransplant donor risk index >1.6). The 30- and 90-day overall survival were 63.6% and 54.5%, respectively. All deaths occurred in patients with P-SOFT >15 or in patients who had at least 3 of the following characteristics: >60 years, BMI >45, metabolic syndrome, MELD >25 or eurotransplant donor risk index >1.6. The 6 months, 1, 2, and 3 years %excess BMI loss was 73%, 60%, 50%, and 43%, respectively. LT-SG is a complex procedure that may carry excess risk in an unselected population. It should be considered only in highly selected patients. Standard donors are recommended, and prioritization of severely obese patients on the waiting list should be considered.

Improvement in the nutritional status of patients with acute-on-chronic liver failure (ACLF) may lead to reduction in morbidity and mortality. This study assessed the impact of dietician-supported outpatient intensive nutrition therapy (OINT) on survival and frailty in patients with alcohol-related ACLF METHODS: Seventy patients with alcohol-related ACLF (Asia Pacific Association for the Study of the Liver [APASL] criteria) and frailty were randomized 1:1 to receive standard medical therapy (SMT) plus OINT (intervention) vs SMT (control) alone. The primary outcome was an improvement in survival at 3 months. Secondary outcome measures included improvement in frailty, prognostic scores, and hospitalization.

There was a significant improvement in overall survival in the OINT group as compared with the SMT group after 3 months of follow up (91.4% [standard error (SE), 4.7%] vs 57.1% [SE, 8.4%]; P < .00). On Cox regression model, inclusion in the intervention arm, baseline skeletal muscle index (SMI), and APASL ACLF Research Consortium (AARC score) were independent predictors of survival (P < .05). The liver frailty index (LFI) score also significantly improved in the OINT as compared with SMT (Δ-0.93; 95% confidence interval, -0.71 to 1.13 vs Δ -0.33; 95% confidence interval, -0.44 to 0.72; P < .00). The disease severity including MELD, MELD-Na, and AARC score showed a significant improvement in the OINT group as compared with the SMT group (P < .05). The patients in OINT group had lesser number of hospitalizations 6 (17%) vs 16 (45.7%) (P = .01) as compared with the SMT group.

Outpatient intensive nutrition therapy significantly improves survival, frailty, and disease severity with a reduction in number of hospitalizations and supports the key role of nutrition in treatment of patients with alcohol-related ACLF.

ctri.nic.in/ CTRI/2022/01/039735.

Physical frailty is a critical determinant of mortality in patients with cirrhosis and can be objectively measured using the Liver Frailty Index (LFI), which is potentially modifiable. We aimed to identify LFI cut-points associated with waitlist mortality. Ambulatory adults with cirrhosis without HCC awaiting liver transplantation from 9 centers from 2012 to 2021 for ≥3 months with ≥2 pre-liver transplantation LFI assessments were included. The primary explanatory variable was the change in LFI from first to second assessments per 3 months (∆LFI); we evaluated clinically relevant ∆LFI cut-points at 0.1, 0.2, 0.3, and 0.5. The primary outcome was waitlist mortality (death or delisting for being too sick), with transplant considered as a competing event. Among 1029 patients, the median (IQR) age was 58 (51-63) years; 42% were female; and the median lab Model for End-Stage Liver Disease-Sodium at first assessment was 18 (15-22). For each 0.1 improvement in ∆LFI, the risk of overall mortality decreased by 6% (cause-specific hazard ratio: 0.94, 95% CI: 0.92-0.97, p < 0.001). ∆LFI was associated with waitlist mortality at cut-points as low as 0.1 (cause-specific hazard ratio: 0.63, 95% CI: 0.46-0.87) and 0.2 (HR: 0.61, 95% CI: 0.42-0.87). An improvement in LFI per 3 months as small as 0.1 in the pre-liver transplantation period is associated with a clinically meaningful reduction in waitlist mortality. These data provide estimates of the reduction in mortality risk associated with improvements in LFI that can be used to assess the effectiveness of interventions targeting physical frailty in patients with cirrhosis.

Obesity is associated with increased morbidity in patients with advanced liver disease, but it is particularly challenging for these patients to preserve skeletal muscle mass during weight loss and accelerating sarcopenia is a concern. Alternate-day modified fasting (ADMF) may be particularly effective for weight loss in patients with concomitant cirrhosis and obesity due to preservation of fat-free mass (FFM).

A weight loss program featuring either ADMF or a continuous low-calorie diet (LCD) was evaluated in a 24-week randomized clinical trial in 20 adult patients with Child-Pugh Class A cirrhosis and obesity. Participants were randomized to either ADMF (n = 11) or LCD (n = 9). Both groups received a remotely delivered exercise program. Body composition, sarcopenia measures, and functional outcomes were assessed pre-post.

Thirteen participants completed the intervention (Age = 57 ± 10; BMI = 37.7 ± 5.8 kg/m2). The median body weight lost in ADMF was 13.7 ± 4.8 kg (13.9% of initial body weight), while LCD lost 9.9 ± 6.9 kg (10.7% of initial body weight). Total body fat percentage decreased in both groups (ADMF: -4.1 ± 4.0%; LCD = -2.8 ± 1.4%). Fat-free mass accounted for 34 ± 20% of total weight loss in ADMF and 38 ± 10% in LCD. Functional measures, such as timed chair stands, improved in both groups.

This pilot study demonstrates the feasibility of the ADMF and LCD interventions to produce significant weight loss while improving body composition in patients with cirrhosis and obesity. Further research is needed to validate these findings in larger cohorts and to assess changes in muscle quality and visceral fat.

ClinicalTrials.gov Identifier: NCT05367596.

Sarcopenia and myosteatosis are common in patients with cirrhosis. This study aimed to determine the prevalence of these muscle changes, their interrelations and their prognostic impact over a 12-month period.

We conducted a prospective multicentre study involving 433 patients. Sarcopenia and myosteatosis were evaluated using computed tomography scans. The 1-year cumulative incidence of relevant events was assessed by competing risk analysis. We used a Fine-Gray model adjusted for known prognostic factors to evaluate the impact of sarcopenia and myosteatosis on mortality, hospitalization, and liver decompensation.

At enrolment, 166 patients presented with isolated myosteatosis, 36 with isolated sarcopenia, 135 with combined sarcopenia and myosteatosis and 96 patients showed no muscle changes. The 1-year cumulative incidence of death in patients with either sarcopenia and myosteatosis (13.8%) or isolated myosteatosis (13.4%) was over twice that of patients without muscle changes (5.2%) or with isolated sarcopenia (5.6%). The adjusted sub-hazard ratio for death in patients with muscle changes was 1.36 (95% CI 0.99-1.86, p = 0.058). The cumulative incidence of hospitalization was significantly higher in patients with combined sarcopenia and myosteatosis than in patients without muscle changes (adjusted sub-hazard ratio 1.18, 95% CI 1.04-1.35). The cumulative incidence of liver decompensation was greater in patients with combined sarcopenia and myosteatosis (p = 0.018) and those with isolated sarcopenia (p = 0.046) than in patients without muscle changes. Lastly, we found a strong correlation of function tests and frailty scores with the presence of muscle changes.

Myosteatosis, whether alone or combined with sarcopenia, is highly prevalent in patients with cirrhosis and is associated with significantly worse outcomes. The prognostic role of sarcopenia should always be evaluated in relation to the presence of myosteatosis.

This study investigates the prognostic role of muscle changes in patients with cirrhosis. The novelty of this study is its multicentre, prospective nature and the fact that it distinguishes between the impact of individual muscle changes and their combination on prognosis in cirrhosis. This study highlights the prognostic role of myosteatosis, especially when combined with sarcopenia. On the other hand, the relevance of sarcopenia could be mitigated when considered together with myosteatosis. The implication from these findings is that sarcopenia should never be evaluated individually and that myosteatosis may play a dominant role in the prognosis of patients with cirrhosis.

Physical frailty is associated with increased mortality and poor quality of life (QoL) before and after liver transplantation (LT). Evidence is lacking on how to tailor exercise and behavioural techniques in this patient population.

Home-based EXercise and motivAtional programme before and after Liver Transplantation (EXALT) is a phase 2b, open-label, two-centre randomised controlled clinical trial designed to investigate whether a remotely monitored 'home-based exercise and theory-based motivation support programme (HBEP)' before and after LT improves QoL in LT recipients. Adult patients awaiting a primary LT will be assessed for eligibility at two LT centres (Birmingham, Royal Free London). Participants will be randomly assigned (1:1) to receive either an HBEP while on the LT waiting list through to 24 weeks after LT (Intervention) or a patient exercise advice leaflet (Control). Using a standard method of difference in means (two-sided significance level 0.05; power 0.90) and accounting for a 35% attrition/withdrawal rate, a minimum of 133 patients will be randomised to each treatment group. The primary outcome measure will be assessed using intention-to-treat analysis of the difference in the Physical Component Score of Short form-36 version 2.0 health-related QoL questionnaire between the groups at 24 weeks post-LT.

The protocol was approved by the South Central-Hampshire A National Research Ethics Committee. Recruitment into the EXALT trial started in May 2022 and is due to end in June 2024, with 217/266 patients randomised to date. The intervention follow-up is due to finish in May 2026. The findings of this trial will be disseminated through peer-reviewed publications, conferences and social media.

ISRCTN13476586.

Liver transplantation (LT) remains one of the most effective treatments for hepatocellular carcinoma (HCC) and significantly enhances patient survival. However, the application of LT for HCC faces challenges owing to advancements in cancer-specific treatment modalities and the increased burden of patients' comorbidities. This narrative review explores current controversies and advancements in LT for HCC. Key areas of focus include the management of comorbidities and patient education by advanced practice nurses, impacts of frailty on waitlists and post-LT outcomes, selection criteria for LT in the era of new downstaging tools, role of radiology in patient selection, and implications of potential immunotherapy use both before and after LT. Additionally, the importance of immunosuppression management with strategies aimed at minimizing rejection while considering the risk of HCC recurrence and the role of surveillance for HCC recurrence is highlighted. This review also underscores the importance of a multidisciplinary approach for optimizing outcomes in patients with HCC undergoing LT.

Frailty and sarcopenia are well-recognized factors related to worse outcomes in patients with cirrhosis, including liver transplant (LT) candidates. Implications of pre-LT functional and muscle deterioration also affect post-LT outcomes. Patients with cirrhosis and acute-on-chronic liver failure (ACLF) have a lower survival rate, both before and after LT. There is a need to better identify those patients with ACLF who would benefit from LT. This review aims to present the available data about frailty and sarcopenia in patients with ACLF in the LT setting. An exhaustive review of the published literature was conducted. Data regarding frailty and sarcopenia in LT candidates with ACLF are scarce and heterogeneous. Studies evaluating frailty and sarcopenia in critically ill patients outside the liver literature are also presented in this review to enrich the knowledge of this field in expansion. Frailty and sarcopenia seem to contribute to worse outcomes in LT candidates with ACLF, both before and after LT. Sarcopenia evaluation may be the most prudent approach for those very sick patients. Skeletal muscle index assessed by computed tomography is recommended to evaluate sarcopenia. The role of muscle ultrasound and bioelectrical impedance analysis is to be determined. Frailty and sarcopenia are crucial factors to consider on a case-by-case basis in LT candidates with ACLF to improve patient outcomes.

Liver transplantation (LT) represents a curative avenue for individuals with advanced chronic liver disease. Given the inherent illness severity of LT candidates, identifying patients at greater risk for adverse outcomes before and after transplantation is paramount. Approximately 50% of cirrhotic patients are frail and have considerable functional impairment. Various measures have been used to assess frailty, including performance-based tests and functional status evaluations. Frailty carries significant prognostic implications and predicts both mortality and pre- and post-LT complications. Contributing factors to frailty in this population include sarcopenia, malnutrition, inflammation, and psychosocial factors. Recognizing the prevalence of frailty among LT candidates, exercise interventions have been developed to improve physical frailty and offer potential to improve patient outcomes. While many interventions have demonstrated efficacy without notable adverse events, the absence of a universally accepted standard for exercise prescription underscores the variability in intervention elements and patient adherence. Given the safety profile of exercise interventions, there remains a critical need for standardized protocols and guidelines to optimize exercise regimens for LT candidates. This review delves into the landscape of frailty among LT candidates, elucidating its etiological underpinnings, impact on outcomes, utilization of exercise interventions, and the efficacy of exercise programs in reducing the burden frailty in those awaiting LT.

Sarcopenia and frailty are common complications in patients with cirrhosis evaluated for liver transplantation (LT). Although the negative impact of sarcopenia on patient's outcome has been well studied, the prognostic role of frailty is not as clear. We assessed the prevalence of sarcopenia and frailty and the clinical impact of frailty in a prospective cohort of cirrhosis patients with and without hepatocellular carcinoma (HCC) listed for LT. Patients with cirrhosis were prospectively recruited at the time of admission into the waiting list. Clinical and lab values were collected. Physical frailty was assessed by liver frailty index (LFI) and patients were categorized into robust (< 3.2); pre-frail (between 3.2 and 4.5), and frail (> 4.5). Skeletal muscle mass was evaluated via skeletal muscle index (SMI) obtained from last CT scan before LT; sarcopenia was defined by SMI < 50 cm2/m2 in males and < 39 cm2/m2 in females. 105 patients were included, of which 42 (40%) had hepatocellular carcinoma (HCC). In patients without HCC (63.5% males, median age 61 years), 36.5% were frail, 50.8% were pre-frail and 12.7% were robust. Frail patients were older than non-frail patients (63 vs. 56; p = 0.008) and had more severe liver disease (Child C: 65% vs. 37.5%; p = 0.02). Prevalence of sarcopenia in patients without HCC was 63%, with similar value of median SMI between frail and not frail patients (p = 0.454). Patients with HCC (78.6% males, 65 years old) were 21.4% frail, 61.9% pre-frail, and 16.7% robust. Frail patients had more severe liver disease (Child C: 77% vs. 18.2%; p = 0.004), whereas age was comparable to non-frail patients; among patients without HCC, during a median follow-up of 263 days, 17% died (of which 72% were frail) and 10 patients were delisted due to clinical improvement (none of whom were frail). Among those with HCC, during a median follow-up of 289 days, 4 (9%) patients died of which 50% were frail. Frailty and sarcopenia are common complications in patients with cirrhosis awaiting LT. Frailty appears to be associated with an increased risk of mortality during wait-list time especially in those with decompensated cirrhosis. At univariate analysis Meld score, Child score and presence of frailty were found to be associated with shorter survival, however, at multivariate analysis presence of frailty and Child C vs. A/B were the only independent predictor of death. Larger cohorts are required to confirm these results.