Physical activity decreases in patients on the liver transplant waiting list and influences postoperative outcome-a prospective cohort study.

Background: Physical deconditioning affects patients suffering from end-stage liver disease (ESLD). Liver transplantation (LT) is the only curative option for ESLD. Growing evidence suggests that pre-habilitation is beneficial in reducing post-surgical morbidity and mortality. We investigated physical activity (PA) in patients awaiting LT in a country with long waiting times. Methods: Prospective, single center, longitudinal study in Bern, Switzerland between June 2019 and February 2020 (halted due to SARS-CoV-2 pandemic), with follow-up data up to six months post-transplant. Patients were instructed to use a wrist tracker (FitBit) to monitor PA, which was assessed using mixed-effects generalized linear models. The study was approved by the local ethics committee (BASEC ID 2019-00606). Results: Thirty-five patients were included [71% male, median 59 years, body mass index (BMI) 28 kg/m2, lab Model End-Stage Liver Disease (MELD) 11], 17 (49%) pre-frail and 5 (14%) frail according to the Liver Frailty Index (LFI). Twenty-eight patients underwent transplantation with 0 ninety-day mortality and 15 (53.6%) composite adverse clinical outcome. Median daily steps were 4,661 [interquartile range (IQR), 1,685-8,609] and weekly moderate PA (MPA) was 41 min (IQR, 0-127 min). Longitudinal analysis showed that female patients and patients on nutritional support had an increase in MPA between weeks 20 and 40. A significant decrease was seen in MPA after week 40, whilst no significant association was seen with age, Child-Pugh Score, LFI or quality of life at time of inclusion. MPA was significantly associated with the occurrence of the composite clinical endpoint after week 30 of waiting time (odds ratio 0.882, P=0.026). World Health Organization (WHO)-recommended MPA was significantly associated with less adverse composite clinical outcomes (P<0.001). Conclusions: In patients listed for LT, MPA decreased over time, showing a significant association with adverse outcome, specifically after week 30 on the waiting list. Our data support the implementation of routine pre-habilitation in patients awaiting LT.

First-in-human diagnostic study of hepatic steatosis with computed ultrasound tomography in echo mode.

BACKGROUND: Non-alcoholic fatty liver disease is rapidly emerging as the leading global cause of chronic liver disease. Efficient disease management requires low-cost, non-invasive techniques for diagnosing hepatic steatosis accurately. Here, we propose quantifying liver speed of sound (SoS) with computed ultrasound tomography in echo mode (CUTE), a recently developed ultrasound imaging modality adapted to clinical pulse-echo systems. CUTE reconstructs the spatial distribution of SoS by measuring local echo phase shifts when probing tissue at varying steering angles in transmission and reception. METHODS: In this first-in-human phase II diagnostic study, we evaluated the liver of 22 healthy volunteers and 22 steatotic patients. We used conventional B-mode ultrasound images and controlled attenuation parameter (CAP) to diagnose the presence (CAP≥ 280 dB/m) or absence (CAP < 248 dB/m) of steatosis in the liver. A fully integrated convex-probe CUTE implementation was developed on the ultrasound system to estimate liver SoS. We investigated its diagnostic value via the receiver operating characteristic (ROC) analysis and correlation to CAP measurements. RESULTS: We show that liver CUTE-SoS estimates correlate strongly (r = -0.84, p = 8.27 × 10-13) with CAP values and have 90.9% (95% confidence interval: 84-100%) sensitivity and 95.5% (81-100%) specificity for differentiating between normal and steatotic livers (area under the ROC curve: 0.93-1.0). CONCLUSIONS: Our results demonstrate that liver CUTE-SoS is a promising quantitative biomarker for diagnosing liver steatosis. This is a necessary first step towards establishing CUTE as a new quantitative add-on to diagnostic ultrasound that can potentially be as versatile as conventional ultrasound imaging.

Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in the liver, is rapidly becoming the most common cause of chronic liver disease worldwide. Therefore, there is an urgent need to develop accurate diagnostic techniques that are inexpensive, non-invasive, and broadly available. Ultrasound imaging systems, which use sound waves to produce images of internal body structures, possess these qualities but cannot currently diagnose NAFLD accurately. Here, we propose to use a recently developed technique called computed ultrasound tomography in echo mode (CUTE). It measures the speed at which ultrasound waves propagate in tissues, a property that substantially varies with the fat content. We show that CUTE measurements allow us to accurately distinguish the livers of healthy people from those of individuals diagnosed with NAFLD. This promising finding encourages the integration of CUTE into standard ultrasound systems.

Evolution of humoral immune response to SARS-CoV-2 mRNA vaccine in liver transplant recipients - a longitudinal study.

BACKGROUND AND AIM: Liver transplant recipients show suboptimal vaccine-elicited immune responses to severe acute respiratory coronavirus 2 (SARS-CoV-2) vaccination. This study aimed to assess real-world data on SARS-CoV-2 antibodies after the second and third SARS-CoV-2 vaccination in liver transplant recipients in Switzerland. METHODS: We enrolled liver transplant recipients who attended regular follow-up visits between 01/07/2021 and 30/04/2022 at the outpatient clinic of the Department of Visceral Surgery and Medicine at Bern University Hospital, Switzerland. Following the Swiss Federal Office of Public Health recommendations, we measured SARS-CoV-2 anti-spike IgG antibodies in 117 liver transplant recipients ≥4 weeks after the second SARS-CoV-2 mRNA vaccination from 07/2021-04/2022. In case of antibody levels of <100 AU/ml, patients received a third vaccination and antibodies were re-measured. Patients with antibody levels of >100 AU/ml were defined as "responders", those with 12-100 AU/ml as "partial responders" and those with <12 AU/ml as "non-responders". RESULTS: After two vaccinations, 36/117 (31%) were responders, 42/117 (36%) were partial responders and 39/117 (33%) were non-responders. The humoral immune response improved significantly after the third vaccination, resulting in 31/55 (56%) responders among the previous partial or non-responders. A total of 26 patients developed COVID-19, of whom two had a moderate or severe course (both non-responders after three doses). DISCUSSION: One third of liver transplant recipients showed an optimal response following two vaccinations; a third dose achieved a complete antibody response in more than half of partial and non-responders. We observed only one severe course of COVID-19 and no deaths from COVID-19 in the vaccinated liver transplant recipients.

Ultrasonography as a diagnostic tool for sarcopenia in patients with cirrhosis: Examining the pros and cons.

Sarcopenia has emerged as a significant prognostic factor in liver disease, posing a significant risk to patients in terms of morbidity and mortality. However, the evaluation of skeletal muscle mass and quality remains challenging, as cross-sectional imaging is not a suitable screening tool. In order to better include this crucial variable in the routine risk stratification of patients with chronic liver disease, there is an urgent need for simple and reliable non-invasive diagnostic tools for sarcopenia. Therefore, the use of ultrasound techniques has garnered attention as a promising alternative for detecting sarcopenia and muscle abnormalities. This narrative review aims to provide an overview of the current literature on the use of ultrasound as a diagnostic tool for sarcopenia, with particular focus on patients with cirrhosis, emphasizing its potential limitations and future prospects.

Addressing the Burden and Management Strategies for Disparities and Inequities Among Liver Transplant Professionals: The ILTS Experience.

Medical professional environments are becoming increasingly multicultural, international, and diverse in terms of its specialists. Many transplant professionals face challenges related to gender, sexual orientation or racial background in their work environment or experience inequities involving access to leadership positions, professional promotion, and compensation. These circumstances not infrequently become a major source of work-related stress and burnout for these disadvantaged, under-represented transplant professionals. In this review, we aim to 1) discuss the current perceptions regarding disparities among liver transplant providers 2) outline the burden and impact of disparities and inequities in the liver transplant workforce 3) propose potential solutions and role of professional societies to mitigate inequities and maximize inclusion within the transplant community.

Influence of sex in alcohol-related liver disease: Pre-clinical and clinical settings.

Alcohol-related liver disease (ArLD) is a major cause of chronic liver disease globally. Traditionally, ArLD was mostly a concern in men rather than in women; however, such a sex gap is rapidly narrowing due to increasing chronic alcohol consumption among women. Female sex is more vulnerable to the harmful effects of alcohol with a higher risk of progression to cirrhosis and development of associated complications. The relative risk of cirrhosis and liver-related mortality is significantly higher in women than in men. Our review endeavors to summarize the current knowledge on sex differences in alcohol metabolism, pathogenesis of ArLD, disease progression, indication for liver transplant and pharmacological treatments of ArLD, and provide evidence in support of a sex-specific management of these patients.

2D shear wave elastography of the rectus femoris muscle in patients with cirrhosis: Feasibility and clinical findings. A pilot study.

BACKGROUND AND AIMS: Frailty is frequent in cirrhosis and associated with skeletal muscle abnormalities and worse prognosis. 2D shear-wave elastography (2D-SWE) could mirror biomechanical properties of skeletal muscle reflecting muscle quality. However, there is no data on 2D-SWE on skeletal muscle stiffness assessment in cirrhosis and on frailty. METHODS: Outpatients with cirrhosis were prospectively included in a single center. Skeletal muscle stiffness was studied at the rectus femoris by 2D-SWE. Ileo-psoas area and index (area/height2), and antero-posterior diameter of rectus femoris (RF) was measured on ultrasound. RESULTS: We included 44 patients (24 male, age 59 [IQR 49-66]) with a median liver frailty index (LFI) of 3.7 (IQR 3.2-4.0). Measurement of RF muscle stiffness (RFMS) was feasible in all with high inter-measurement reproducibility. RFMS did not correlate with LFI, liver function and skeletal muscle diameters. Ileo-psoas index was lower in frail patients (1.7 vs 1.0 cm2/m2, p = 0.024). RF antero-posterior diameter inversely correlated with LFI (r -0.578: p<0.001). CONCLUSION: RFMS by 2D-SWE is feasible and reproducible in cirrhosis and is independent of liver function and LFI, and warrants further studies in this setting. RF antero-posterior diameter could be reported as an objective parameter mirroring sarcopenia and frailty.

The impact of perceived donor liver quality on post-transplant outcome.

BACKGROUND: We analysed the impact of perceived liver donor quality on transplant recipient outcomes. METHODS: this prospective cohort study included all deceased liver donors during 2008-2018 in the Swiss Transplant Cohort Study. Perceived low-quality liver donors were defined when refused for ≥5 top listed recipients or for all recipients in at least one centre before being transplanted. The effect of liver donor quality on relisting or recipient death at 1 week and 1 year after transplantation was analysed using Kaplan-Meier and Cox proportional hazard models. A 1:3 matching was also performed using a recipient score. RESULTS: Of 973 liver donors, 187 (19.2%) had perceived poor-quality. Males, obesity, donation after circulatory death and alanine aminotransferase values were significantly associated with perceived poor-quality, with no significant effect of the perceived quality on re-listing or death within the first week and first year post-transplant [(aHR) = 1.45, 95% CI: (0.6, 3.5), P = 0.41 and aHR = 1.52 (95% CI 0.98-2.35), P = 0.06], adjusting by recipient age and gender, obesity, diabetes, prior liver transplantation and model for end-stage liver disease (MELD) score. At 1 year, prior liver transplantation and higher MELD score associated with higher risk of re-listing or death. CONCLUSION: Comparable post-transplant outcomes with different perceived quality liver donors stresses the need to improve donor selection in liver transplantation.

Vascular liver diseases: A sex-oriented analysis of the literature.

Vascular liver diseases are an heterogenous group of diseases that collectively represent an important health issue in the field of liver diseases. This narrative review was elaborated by the Special Interest Group (SIG) "Gender in Hepatology" of the Italian Association for the Study of the Liver (AISF). We aimed to review the current knowledge regarding the potential role of biological sex in patients with vascular liver diseases such as splanchnic vein thrombosis, hepatic vein thrombosis, porto-sinusoidal vascular disorder, and hereditary hemorrhagic telangiectasia. As vascular liver diseases commonly affect young individuals, including women in childbearing age, we also included a specific section on the management of pregnancy in these challenging patients.

Liver Transplantation for Porto-sinusoidal Vascular Liver Disorder: Long-term Outcome.

BACKGROUND: Porto-sinusoidal vascular liver disorder (PSVD) is a rare disease that occasionally requires liver transplantation (LT), despite usually presenting preserved liver function. There remains a paucity of data pertaining to LT in PSVD. The aim was to identify features associated with post-LT outcomes in PSVD. METHODS: Retrospective multicentre study of 79 patients who received LT for PSVD. RESULTS: Median post-LT follow-up was 37 (range 1-261) mo. Refractory ascites 24 (30%), hepatic encephalopathy 16 (20%), and hepatopulmonary syndrome 13 (16.3%) were the most frequent indications for LT. Hepatocellular carcinoma was the indication in only 2 patients. Twenty-four patients died, 7 due to liver and 17 to non-liver related causes. Post-LT survival was 82.2%, 80.7%, and 68.6% at 1, 2, and 5 y, respectively. Post-LT survival was significantly better in patients without (n = 58) than in those with a persistent severe PSVD-associated condition (n = 21). Pre-LT hyperbilirubinemia levels and creatinine >100 µmol/L were also independently associated with poor survival. Six patients (7.6%) required a second LT. Recurrence of PSVD was confirmed by liver biopsy in only 1 patient and in 3 further patients it was likely. CONCLUSIONS: LT in PSVD is associated with an acceptable outcome in the absence of associated severe conditions. However, persistence of a severe associated condition, pre-LT high bilirubin levels, or creatinine >100 µmol/L impact outcome, and these are features that should be considered when evaluating PSVD patients for LT. PSVD recurrence is possible after LT and needs to be explored, at least, in cases of posttransplant portal hypertension.

Gender and Racial Disparity Among Liver Transplantation Professionals: Report of a Global Survey.

Equality, diversity, and inclusion (EDI) are fundamental principles. Little is known about the pattern of practice and perceptions of EDI among liver transplant (LT) providers. International Liver Transplant Society (ILTS) EDI Committee survey around topics related to discrimination, mentorship, and gender. Answers were collected and analyzed anonymously. Worldwide female leadership was also queried via publicly available data. The survey was e-mailed to 1312 ILTS members, 199 responses (40.7% female) were collected from 38 countries (15.2% response rate). Almost half were surgeons (45.7%), 27.6% hepatologists and 26.6% anesthetists. Among 856 LT programs worldwide, 8.2% of leadership positions were held by females, and 22% of division chiefs were female across all specialties. Sixty-eight of respondents (34.7%) reported some form of discrimination during training or at their current position, presumably related to gender/sexual orientation (20.6%), race/country of origin (25.2%) and others (7.1%). Less than half (43.7%) received mentorship when discrimination occurred. An association between female responses and discrimination, differences in compensation, and job promotion was observed. This survey reveals alarmingly high rate of experience with racial and gender disparity, lack of mentorship, and very low rates of female leadership in the LT field and calls to action to equity and inclusion.

Use of statins after liver transplantation is associated with improved survival: results of a nationwide study.

BACKGROUND: There is limited information on the effects of statins on the outcomes of liver transplantation (LT), regarding either their use by LT recipients or donors. AIM: To analyse the association between statin exposure and recipient and graft survival. METHODS: We included adult LT recipients with deceased donors in a nationwide prospective database study. Using a multistate modelling approach, we examined the effect of statins on the transition hazard between LT, biliary and vascular complications and death, allowing for recurring events. The observation time was 3 years. RESULTS: We included 998 (696 male, 70%, mean age 54.46 ± 11.14 years) LT recipients. 14% of donors and 19% of recipients were exposed to statins during the study period. During follow-up, 141 patients died; there were 40 re-LT and 363 complications, with 66 patients having two or more complications. Treatment with statins in the recipient was modelled as a concurrent covariate and associated with lower mortality after LT (HR = 0.35; 95% CI 0.12-0.98; p = 0.047), as well as a significant reduction of re-LT (p = 0.004). However, it was not associated with lower incidence of complications (HR = 1.25; 95% CI = 0.85-1.83; p = 0.266). Moreover, in patients developing complications, statin use was significantly associated with decreased mortality (HR = 0.10; 95% CI = 0.01-0.81; p = 0.030), and reduced recurrence of complications (HR = 0.43; 95% CI = 0.20-0.93; p = 0.032). CONCLUSIONS: Statin use by LT recipients may confer a survival advantage. Statin administration should be encouraged in LT recipients when clinically indicated.

COVID-19 and liver disease.

Knowledge on SARS-CoV-2 infection and its resultant COVID-19 in liver diseases has rapidly increased during the pandemic. Hereby, we review COVID-19 liver manifestations and pathophysiological aspects related to SARS-CoV-2 infection in patients without liver disease as well as the impact of COVID-19 in patients with chronic liver disease (CLD), particularly cirrhosis and liver transplantation (LT). SARS-CoV-2 infection has been associated with overt proinflammatory cytokine profile, which probably contributes substantially to the observed early and late liver abnormalities. CLD, particularly decompensated cirrhosis, should be regarded as a risk factor for severe COVID-19 and death. LT was impacted during the pandemic, mainly due to concerns regarding donation and infection in recipients. However, LT did not represent a risk factor per se of worse outcome. Even though scarce, data regarding COVID-19 specific therapy in special populations such as LT recipients seem promising. COVID-19 vaccine-induced immunity seems impaired in CLD and LT recipients, advocating for a revised schedule of vaccine administration in this population.

Humoral response to SARS-CoV-2 infection among liver transplant recipients.

OBJECTIVE: Immunosuppressive agents are known to interfere with T and/or B lymphocytes, which are required to mount an adequate serologic response. Therefore, we aim to investigate the antibody response to SARS-CoV-2 in liver transplant (LT) recipients after COVID-19. DESIGN: Prospective multicentre case-control study, analysing antibodies against the nucleocapsid protein, spike (S) protein of SARS-CoV-2 and their neutralising activity in LT recipients with confirmed SARS-CoV-2 infection (COVID-19-LT) compared with immunocompetent patients (COVID-19-immunocompetent) and LT recipients without COVID-19 symptoms (non-COVID-19-LT). RESULTS: Overall, 35 LT recipients were included in the COVID-19-LT cohort. 35 and 70 subjects fulfilling the matching criteria were assigned to the COVID-19-immunocompetent and non-COVID-19-LT cohorts, respectively. We showed that LT recipients, despite immunosuppression and less symptoms, mounted a detectable antinucleocapsid antibody titre in 80% of the cases, although significantly lower compared with the COVID-19-immunocompetent cohort (3.73 vs 7.36 index level, p<0.001). When analysing anti-S antibody response, no difference in positivity rate was found between the COVID-19-LT and COVID-19-immunocompetent cohorts (97.1% vs 100%, p=0.314). Functional antibody testing showed neutralising activity in 82.9% of LT recipients (vs 100% in COVID-19-immunocompetent cohort, p=0.024). CONCLUSIONS: Our findings suggest that the humoral response of LT recipients is only slightly lower than expected, compared with COVID-19 immunocompetent controls. Testing for anti-S antibodies alone can lead to an overestimation of the neutralising ability in LT recipients. Altogether, routine antibody testing against separate SARS-CoV-2 antigens and functional testing show that the far majority of LT patients are capable of mounting an adequate antibody response with neutralising ability.

The MELD upgrade exception: a successful strategy to optimize access to liver transplantation for patients with high waiting list mortality.

BACKGROUND: MELD exceptions are designed to equipoise liver transplant waiting list survival. We aimed to analyze the impact of the MELD Upgrade rule and all other MELD exceptions on the liver transplant waiting list outcomes during 2012-2017 in Switzerland. METHODS: We conducted a nationwide cohort study including all adult patients registered on the Swiss liver transplant waiting list between 2012 and 2017. Waiting list mortality and access to transplantation were analyzed, considering MELD exceptions as time-dependent covariates. RESULTS: 730 patients were included. Patients with MELD Upgrade exceptions had a higher risk of dying while on the waiting list (OR 2.13; CI 95% 1.30-3.47) and also an increased likelihood of receiving a liver transplantation, when compared to patients without MELD exceptions. Patients with any type of MELD exceptions were more likely to be transplanted when compared to patients without MELD exceptions. The proportion of patients with MELD exceptions increased from 2012 to 2017 (44% vs 88%). Allocation MELD at the time of transplantation showed an annual increase (23 ± 8 points vs 32 ± 5 points, p < 0.001). CONCLUSION: Only patients with MELD Upgrade exceptions had the expected combination of higher waiting list mortality and quicker access to liver transplantation.

Sarcopenia in chronic advanced liver diseases: A sex-oriented analysis of the literature.

Sarcopenia, defined as progressive and generalized loss of muscle mass and strength, is common in chronic liver disease. It significantly impacts the quality of life and increases the risk of liver-related complications and mortality in cirrhotic patients. Moreover, recent studies showed a negative impact of sarcopenia on patients awaiting liver transplantation (LT), on post-LT outcomes, and on response to hepatocellular carcinoma therapies. Data about the influence of sex on the incidence, prevalence, diagnosis and treatment of sarcopenia in chronic liver diseases are poor and conflicting. The aims of this review of the literature are to define sex differences in sarcopenic cirrhotic patients and to highlight the necessity of a sex stratified analysis in future studies. This analysis of the literature showed that most of the studies are retrospective, with a higher prevalence of sarcopenia in males, probably due to anatomical differences between the sexes. Moreover, diagnostic criteria for sarcopenia are different between studies, as there is not a defined cut-off and, as a consequence, no comparable results. In conclusion, sex seems to have an impact on sarcopenia, and future studies must accurately investigate its role in identifying and treating high-risk patients, reducing the negative impact of sarcopenia on the survival and quality of life of cirrhotic patients.

A prospective longitudinal assessment of de novo metabolic syndrome after liver transplantation.

BACKGROUND: De novo metabolic syndrome (MS) is a frequent complication after liver transplantation (LT). The aim of this prospective study is to identify potential risk factors longitudinally associated to post-LT de novo MS. Patients without pre-LT MS who underwent LT between April 2013 and October 2017 were prospectively included. Metabolic variables were collected at LT and at 6, 12, and 24 months post-LT. RESULTS: Sixty-three patients fulfilled the inclusion criteria (76% male, mean age 53.6±9.5 years). The prevalence of de novo MS was 46%, 43%, and 49% at 6, 12, and 24 months after LT, respectively. Among other MS components, the prevalence of type 2 diabetes, hypertension and hypertriglyceridemia significantly increased after LT. Considering the baseline characteristics at the adjusted analysis, alcoholic liver disease (OR 4.17, 95%CI 1.20-14.51; p = .03) and hypertension pre-LT (OR 11.3, 95% CI 1.49-85.46; p = .02) were confirmed as independent risk factors of post-LT de novo MS. In the time-varying analysis, only eGFR (OR .97, 95% CI .97-.98; p < .0001) was found associated with post-LT de novo MS. CONCLUSIONS: De novo MS frequently occurs shortly after LT, affecting nearly half of patients at 24 months post-LT. Lifestyle modifications should be recommended starting early post-LT, particularly for patients with established risk factors.

COVID-19 in Liver Transplant Recipients: A Systematic Review.

Liver transplant (LT) recipients are considered a vulnerable population amidst the COVID-19 pandemic. To date, available data have been heterogeneous and scarce. Therefore, we conducted a systematic literature review identifying English-language articles published in PubMed between November 2019 and 30 May 2021. We aimed to explore three areas: (1) outcome and clinical course; (2) immunological response after COVID-19 in LT recipients; and (3) vaccination response. After systematic selection, 35, 4, and 5 articles, respectively, were considered suitable for each area of analysis. Despite the heterogeneity of the reports included in this study, we found that gastrointestinal symptoms were common in LT recipients. The outcome of the LT population was not per se worse compared to the general population, although careful management of immunosuppressive therapy is required. While a complete therapy discontinuation is not encouraged, caution needs to be taken with use of mycophenolate mofetil (MMF), favoring tacrolimus (TAC) use. Although data conflicted about acquired immunity after SARS-CoV-2 infection, vaccine immunogenicity appeared to be low, suggesting that the level of surveillance should be kept high in this population.