Vargas, Hugo E

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are among the most prevalent causes of chronic liver disease worldwide, closely linked to the global rise in overweight and obesity, type 2 diabetes, and metabolic syndrome. Until recently, treatment options were limited to lifestyle interventions, with no approved pharmacologic therapies. Resmetirom, a liver-directed, selective thyroid hormone receptor beta (THR-β) agonist, is a promising disease-modifying agent that targets hepatic lipid metabolism, inflammation, and fibrosis. Clinical trials, including the pivotal phase 3 MAESTRO-NASH and MAESTRO-NAFLD-1 trials, have demonstrated significant improvements in liver fat reduction, lipid profiles, histological endpoints, and health-related quality of life, with a favorable safety profile. In March 2024, the FDA granted accelerated approval of resmetirom for adults with MASH and moderate-to-advanced fibrosis, marking a significant milestone in MASLD treatment. This review discusses the mechanistic rationale, preclinical data, and pivotal clinical trial outcomes supporting resmetirom’s role in MASLD/MASH management, while outlining ongoing research needs, including long-term safety, pediatric evaluation, and biomarker development for optimized patient selection.

Background and Aims: Prognosticating outcomes such as hospitalizations in outpatients with cirrhosis is challenging, especially with changing etiologies and demographics. This study aims to determine the impact of multi-omic strategies on outcome prediction. Approach and Results: NACSELD3 enrolls outpatients with cirrhosis with controlled/eradicated etiologies from 10 centers and follows them systematically. At baseline, clinical/demographic and cirrhosis details were recorded and saliva and serum samples were collected for microbiome and metabolome analysis, respectively. Multi-omic bioinformatic studies to determine the interaction of microbiota and metabolites with the clinical prediction of 6-month hospitalizations were performed. Five hundred sixty-five patients (60.2 y, 68% men, 35% alcohol, 33% metabolic dysfunction-associated steatohepatitis, 21%, eradicated HCV with MELD 3.0 12) were enrolled. One hundred sixty-three (29%) required 6-month hospitalizations; most (75%) were liver-related. Those hospitalized had worse cirrhosis severity and comorbidity indices but similar demographics and oral health variables. Salivary microbiome alpha-diversity was lower (1.96±0.48 vs. 2.09±0.45, p =0.018) with greater pathobionts ( Streptococcus , Treponema, Enterococcaceae) and lower commensal genhospitalized/noera ( Veillonella, Prevotella, Haemophilus , Lachnospiraceae spp) at baseline. Serum metabolomics showed significant separation at baseline between hospitalized/non-hospitalized patients using supervised analyses with microbial-origin (phenyllactate, secondary bile acids, indoles), choline moieties, and polyamine/GABA (3-ureidopropionate/spermidine) metabolites being most prominent. Area under the curve using random forest for clinical, microbial, and metabolomic variables was higher than that of these individually. Latent factor analysis showed clinical variables (MELD 3.0, hemoglobin, and albumin) with the greatest impact, followed by salivary microbiota and then serum microbiome for hospitalization prediction. Conclusions: In a multicenter North American outpatient cirrhosis cohort with controlled etiologies, serum metabolomics and salivary microbiome add to clinical variables to prognosticate 6-month hospitalization.

ABSTRACTThe incidence of ischemic cholangiopathy (IC) is expected to remain significant due to rising rates of transplants performed with livers donated after circulatory death (DCD), despite the use of machine perfusion. Absent established pharmacologic interventions against this progressive etiology of allograft dysfunction and failure, we describe the use of fenofibrate—a cheap and widely‐accessible peroxisome proliferator‐activated receptor agonist that downregulates bile acid production—to impede IC progression in 15 DCD liver recipients who were not responding to reactive, standard‐of‐care management. All patients were undergoing serial endoscopic retrograde cholangiopathy (ERC) to maintain biliary patency but demonstrated progressive cholestasis, with serum alkaline phosphatase (ALP) rising 70.3% over the 90 days preceding fenofibrate. Cholestasis improved in all patients after fenofibrate initiation, with a 63.9% reduction in mean ALP at 90 days, maintained at 270 days (p = 0.02) and 360 days (p = 0.06). ALP improvement was associated with reduced ERC frequency during and after fenofibrate treatment, and this improvement was independent of concurrent ERC or ursodeoxycholic acid use during fenofibrate treatment. In patients who stopped treatment, ALP increased. No fenofibrate‐associated adverse events were seen. These preliminary data support the further study of agents that downregulate bile acid production as a means of impeding IC in DCD livers.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). DISCUSSION: 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.

Background. Cardiovascular disease and physical decline are prevalent and associated with morbidity/mortality in liver transplant (LT) patients. Cardiopulmonary exercise testing (CPX) provides comprehensive cardiopulmonary and exercise response assessments. We investigated cardiorespiratory fitness (CRF) and cardiac stress generated during CPX in LT candidates. Methods. LT candidates at 2 centers underwent CPX. Standard-of-care cardiac stress testing (dobutamine stress echocardiography, DSE) results were recorded. Physical function was assessed with liver frailty index and 6-min walk test. CPX/DSE double products were calculated to quantify cardiac stress. To better study the association of CPX-derived metrics with physical function, the cohort was divided into 2 groups based on 6-min walk test median (372 m). Results. Fifty-four participants (62 ± 8 y; 65% men, Model for End-Stage Liver Disease-Na 14 [10–18]) underwent CPX. Peak oxygen consumption was 14.1 mL/kg/min for an anerobic threshold of 10.2 mL/kg/min, with further CRF decline in the lower 6MWT cohort despite lack of liver frailty index-frailty in 90%. DSE was nondiagnostic in 18% versus 4% of CPX (P = 0.058). All CPX were negative for ischemia. A double product of ≥25 000 was observed in 32% of CPX and 11% of DSE (P = 0.020). Respiratory function testing was normal. No patient presented major cardiovascular events at 30 d post-LT. Conclusions. CPX provided efficient and effective combined cardiopulmonary risk and frailty assessments of LT candidates in a 1-stop test. The CRF was found to be very low despite preserved physical function or lack of frailty.

Abstract Background MASLD is a leading reason for liver transplant waitlisting. The relationship between cardiorespiratory fitness (CRF) and liver fibrosis in patients with MASLD remains unclear. This study aims to provide further evidence supporting the relationship between liver fibrosis and CRF. Methods Subjects with MASLD across various fibrosis stages, including those with cirrhosis awaiting liver transplantation from three U.S. transplant centers, underwent cardiopulmonary exercise testing (CPX). We compared participants based on fibrosis stage (F0-F1, F2-F3, and F4) and CPX parameters such as VO2peak, respiratory exchange ratio (RER), ventilatory efficiency (VE/VCO2), double product (DP) and chronotropic incompetence (CI). Multivariable models were then built to evaluate factors associated with these parameters. Results Sixty-one subjects underwent CPX testing across three centers. Subjects with F4 had lower VO2peak (11.8 mL/kg/min) compared to F0-F1 (22.2 mL/kg/min) and F2-F3 (22.9 mL/kg/min), p < 0.001. Subjects with F4 had higher RER (median 1.25) compared to F0-F1 (1.08) and F2-F3 (1.05), p = 0.001. Similarly, F4 subjects exhibited higher VE/VCO2 (median 36.5) compared to F0-F1 (31) and F2-F3 (30), p < 0.001. Additionally, F4 subjects had lower DP values (median 17,696) compared to F0-F1 (25,460) and F2-F3 (25,372), and higher prevalence of CI (90%) compared to F0-F1 (39%) and F2-F3 (25%), both p = < 0.001. Multivariable modeling confirmed advanced fibrosis (F > 3) as an independent predictor of low CRF. Conclusions In MASLD patients, advanced liver fibrosis, particularly cirrhosis, is associated with reduced CRF and poorer hemodynamic performance during CPX. Prioritizing exercise training for those in earlier stages (F3) may prevent fitness decline, which could hinder physical training and liver transplantation candidacy.

Background and Aims: In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial. Approach and Results: Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, with death treated as a competing event. Risk factors considered were age, sex, mean arterial pressure, white blood cell count, albumin, MELD, ascites, HE, and treatment arm. At baseline, no participants had AKI; 33% (n=49) developed AKI during follow-up. AKI incidence was higher in A+Z than in PRED (45% [n=33] versus 22% [n=16], p=0.001). AKI phenotypes were similar between the 2 treatment arms (p=0.361), but peak AKI severity was greater in A+Z than PRED (stage 3 n=21 [63.6%] vs. n=8 [50.0%], p=0.035). At baseline, urine-neutrophil-gelatinase–associated lipocalin levels were similar between participants who developed AKI in both treatment arms (p=0.319). However, day 7 and 14 urine-neutrophil-gelatinase–associated lipocalin levels were significantly elevated in participants treated with A+Z who developed AKI versus participants treated with PRED who developed AKI (p=0.002 and 0.032, respectively). On multivariable competing risk analysis, only A+Z was independently associated with incident AKI (subdistribution hazard ratio 2.35, p=0.005). Conclusions: AKI occurred more frequently and was more severe in participants treated with A+Z. A+Z–treated participants with AKI had higher urine-neutrophil-gelatinase–associated lipocalin, suggesting that A+Z maybe nephrotoxic in patients with severe alcohol-associated hepatitis.