Genome-wide association study of liver-related enzymes suggests putative pleiotropic effects on diverse traits and diseases

Over the last decade, genome-wide association studies (GWAS) have allowed for the dissection of the genetic susceptibility to complex liver diseases.(1) In a recent issue of Nature communications, Chen et al. conducted a meta-analysis of GWAS collected in approximately 390,000 individuals of the UK BioBank and about 160,000 Japanese individuals from the BioBank Japan, to expand the understanding of the genetic determinants of serum levels of liver-related enzymes.(2) They identified 378 independent loci associated with serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). They found several associations of susceptibility loci potentially affecting the level of these enzymes with different traits (pleiotropism), including liver (e.g., steatosis) and non-liver (e.g., ulcerative colitis) diseases. They concluded that these associations were likely not causal, but they provided hypothesis-generating results that can open up avenues of new research.Over the last decade, genome-wide association studies (GWAS) have allowed for the dissection of the genetic susceptibility to complex liver diseases.(1) In a recent issue of Nature communications, Chen et al. conducted a meta-analysis of GWAS collected in approximately 390,000 individuals of the UK BioBank and about 160,000 Japanese individuals from the BioBank Japan, to expand the understanding of the genetic determinants of serum levels of liver-related enzymes.(2) They identified 378 independent loci associated with serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). They found several associations of susceptibility loci potentially affecting the level of these enzymes with different traits (pleiotropism), including liver (e.g., steatosis) and non-liver (e.g., ulcerative colitis) diseases. They concluded that these associations were likely not causal, but they provided hypothesis-generating results that can open up avenues of new research.Fil: Kim, Hyun Seok. Baylor College of Medicine; Estados Unidos. Michael E. Debakey Va Medical Center; Estados Unidos. University of Texas; Estados UnidosFil: Kim, Hyun Seok. Baylor College of Medicine; Estados Unidos. Michael E. Debakey Va Medical Center; Estados Unidos. University of Texas; Estados UnidosFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Hernaez, Ruben. Baylor College of Medicine; Estados Unidos. Michael E. Debakey Va Medical Center; Estados UnidosFil: Hernaez, Ruben. Baylor College of Medicine; Estados Unidos. Michael E. Debakey Va Medical Center; Estados Unido

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

Antitumour necrosis factor-α agents and development of new-onset cirrhosis or non-alcoholic fatty liver disease: a retrospective cohort.

Objective Elevated tumour necrosis factor (TNF)-α has been implicated in the progression of liver fibrosis and pathogenesis of non-alcoholic fatty liver disease (NAFLD). We aim to investigate the impact of anti-TNF-α agents on the development of cirrhosis and NAFLD. Design This retrospective cohort study used a US claims database between 1 January 2010 and 31 December 2016. We identified adult patients with ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis. Anti-TNF-α agents of interest included adalimumab, certolizumab, etanercept, golimumab and infliximab. The primary composite outcome was the development of new-onset cirrhosis, NAFLD or non-alcoholic steatohepatitis (NASH). The secondary outcomes were the development of (1) cirrhosis and (2) NAFLD or NASH. Propensity score for anti-TNF-α agent use was generated by logistic regression. Cox proportional hazard models adjusting for the propensity score were used with regard to time-varying anti-TNF-α agent exposure. Results This study included 226 555 incident patients with immune-related diseases. During the median 1.5 years follow-up, there was an increased hazard with anti-TNF-α agent use in regard to liver outcomes (composite outcome HR: 1.47, 95% CI 1.27 to 1.70; cirrhosis HR 1.47, 95% CI 0.96 to 2.23; NAFLD or NASH HR 1.53, 95% CI 1.32 to 1.77). The composite outcome hazard was increased for each immune-related disease (HR 1.25-1.90). Conclusion In the short term, we did not observe a beneficial effect of anti-TNF-α agent use for development of cirrhosis, NAFLD or NASH in patients with immune-related diseases

Recent advances in the prevention and treatment of decompensated cirrhosis and acute-on-chronic liver failure (ACLF) and the role of biomarkers

The progression of cirrhosis with clinically significant portal hypertension towards decompensated cirrhosis remains clinically challenging and the evolution towards acute-on-chronic liver failure (ACLF), with one or more extrahepatic organ failures, is associated with very high mortality. In the last decade, significant progress has been made in the understanding of the mechanisms leading to decompensation and ACLF. As portal hypertension advances, bacterial translocation across an impaired gut barrier culminates in endotoxaemia, systemic inflammation and cirrhosis-associated immune dysfunction (CAID). Gut-derived systemic inflammation and CAID have become the logical targets for innovative therapies that prevent hepatic decompensation episodes and the progression to ACLF.Furthermore, classification of disease and biomarker discovery to personalise care have advanced in the field. This review discusses progress in biomarker discovery and personalisation of treatment in decompensated cirrhosis and ACLF.</p

Using noninvasive clinical parameters to predict mortality and morbidity after cardiac interventions in patients with cirrhosis: A systematic review

Background: Cardiovascular disease commonly affects advanced liver disease patients. They undergo cardiac interventions to improve cardiac outcomes. Cirrhosis increases complication risk, including bleeding, renal and respiratory failure, and further decompensation, including death, posing a clinical dilemma to proceduralists. Predicting outcomes is crucial in managing patients with cirrhosis. Our aim was to systematically review clinical parameters to assess the mortality and complication risk in patients with cirrhosis undergoing cardiac interventions. Methods: We searched cirrhosis and cardiovascular intervention terminology in PubMed and Excerpta Medica Database (EMBASE) from inception to January 8, 2023. We included studies reporting clinical scores (e.g. Model for End-stage Liver Disease (MELD), Child–Pugh–Turcotte (CPT), cardiovascular interventions, mortality, and morbidity outcomes). We independently abstracted data from eligible studies and performed qualitative summaries. Results: Eight studies met the inclusion criteria. Procedures included tricuspid valve surgery, catheterization-related procedures, aortic valve replacement (AVR), pericardiectomy, and left ventricular assist device (LVAD) placement. MELD primarily predicted mortality (n = 4), followed by CPT (n = 2). Mortality is significantly increased for MELD > 15 after tricuspid valve surgery. Albumin, creatinine, and MELD were significantly associated with increased mortality after transcatheter AVR (TAVR), although specific values lacked stratification. CPT was significantly associated with increased mortality after cardiac catheterization or pericardiectomy. In LVAD placement, increasing MELD increased the unadjusted odds for perioperative mortality. Conclusions: Our systematic review showed that clinical parameters predict mortality and morbidity risk in patients with cirrhosis undergoing cardiac procedures