Lizaola-Mayo, Blanca C

Background: Given aspirin’s biologic plausibility for antifibrotic and antineoplastic effects, we conducted a systematic review and meta-analysis to examine the association between aspirin use and major liver-related outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD). To our knowledge, this is the first systematic review and meta-analysis restricted exclusively to patients with biopsy- or registry-confirmed MASLD. Methods: A comprehensive search of Ovid MEDLINE, Ovid EMBASE, Scopus, and Web of Science was performed in October 2025. Studies enrolling adults with a confirmed MASLD diagnosis were included; those with viral hepatitis or alcohol-related liver disease were excluded. Outcomes assessed included hepatocellular carcinoma (HCC), fibrosis progression, cirrhosis, all-cause and liver-related mortality, gastrointestinal (GI) bleeding, hemorrhagic stroke, and liver disease progression. Hazard ratios (HRs) with 95% CIs were pooled using random-effects models. Heterogeneity was assessed using I2 statistics. Results: Seven studies met the eligibility criteria, with approximately 720,000 individuals included. Pooled analysis showed that aspirin use was associated with a significantly lower HCC risk (HR 0.59; 95% CI 0.43–0.81; I2 = 83%). No statistically significant association was found between aspirin use and cirrhosis incidence (HR 0.55; 95% CI 0.13–2.37; I2 = 83.4%) or GI bleeding (HR 1.11; 95% CI 0.74–1.66; I2 = 98.9%). Among the two studies that explored all-cause mortality, aspirin was associated with a modest but statistically significant reduction in all-cause mortality (HR 0.86; 95% CI 0.78–0.95; I2 = 0%). Conclusions: Aspirin use is associated with a reduced risk of HCC and all-cause mortality in MASLD without significantly increasing GI bleeding or hemorrhagic strokes. These associations may reflect aspirin’s anti-inflammatory properties in liver disease. Further RCTs are needed to verify the causal role of aspirin in MASLD management.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease marked by cholestasis and progressive fibrosis. While ursodeoxycholic acid (UDCA) remains the first-line therapy, approximately 30–40% of patients have an inadequate biochemical response, increasing the risk of disease progression. Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, was the first second-line agent approved by the only Food and Drug Administration (FDA) and has demonstrated moderate biochemical efficacy but limited tolerability due to dose-dependent pruritus and safety concerns in cirrhosis. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, showed substantial alkaline phosphatase (ALP) reductions when added to UDCA, although its long-term benefit remains unconfirmed in large-scale trials and its use remains off-label in the United States, unlike FDA-approved agents. Seladelpar, a selective peroxisome proliferator-activated receptor delta (PPAR-δ) agonist, and elafibranor, a dual PPAR-α/δ agonist, have both recently received FDA accelerated approval after demonstrating significant improvements in ALP, biochemical response rates, and pruritus relief in phase 3 trials. This review summarizes these second-line therapies’ mechanisms, efficacy, safety, and limitations emphasizing the need for individualized treatment decisions and ongoing research into long-term clinical outcomes.

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.

Objective: To develop and validate a risk score for predicting post-transplant recurrence in perihilar cholangiocarcinoma (pCCA) patients. Background: pCCA is an aggressive malignancy with a poor prognosis. Although neoadjuvant chemoradiation (CRT) followed by liver transplantation (LT) offers a potential cure for patients with unresectable, early-stage de novo or primary sclerosing cholangitis (PSC)-associated pCCA, post-transplant recurrence negatively impacts survival. Currently, no risk stratification tools exist. Methods: This retrospective study included consecutive patients with unresectable de novo or PSC-associated pCCA who underwent neoadjuvant CRT followed by LT at Mayo Clinic (1993–2024). Predictors of post-transplant recurrence were identified using multivariable Cox regression with LASSO variable selection. The Perihilar Cholangiocarcinoma Risk Estimation of Tumor Recurrence after Transplant (PRETREAT) risk score was created by assigning points from model coefficients. Score performance was evaluated by discrimination (c-statistic), internally validated with 10-fold cross-validation, and externally validated in a separate cohort. Survival outcomes were compared across 3 PRETREAT risk groups and between 2 time periods. Results: This study included 399 patients (development: 301; validation: 98). The 5-year cumulative incidence of post-transplant recurrence was 29.7% in the development cohort and 27.6% in the validation cohort. Multivariable analysis identified 4 independent predictors: macroscopic residual tumor on explant [hazard ratio (HR): 12.4], vascular encasement (HR: 2.18), lymphovascular invasion (HR: 2.04), and radial tumor diameter (HR: 1.02/mm). The PRETREAT score (0–22), based on these factors, demonstrated excellent performance in both internal and external validation (C-index 0.83 and 0.85, respectively). Patients were stratified into low-risk (0–7), moderate-risk (8–15), and high-risk (16–22) groups. The 5-year recurrence-free survival rates significantly differed across low-risk, moderate-risk, and high-risk groups (89.0%, 38.3%, and 15.4%, respectively; P<0.001). Over the last decade, overall survival improved significantly only in moderate-risk patients (70.4% vs 46.9%, P=0.024), without significant improvement in recurrence-free survival. Conclusions: The PRETREAT score provides a valuable tool for guiding post-transplant management of pCCA, enabling risk-stratified surveillance, and laying the foundation for future clinical trials.

Importance Normothermic machine perfusion (NMP) has been shown to reduce peritransplant complications. Despite increasing NMP use in liver transplant (LT), there is a scarcity of real-world clinical experience data. Objective To compare LT outcomes between donation after brain death (DBD) and donation after circulatory death (DCD) allografts preserved with NMP or static cold storage (SCS). Design, Setting, and Participants This single-center, retrospective observational cohort study included all consecutive adult LTs performed between January 2019 and December 2023 at the Mayo Clinic in Arizona. Data analysis was performed between February 2024 and June 2024. Outcomes of DBD-SCS, DBD-NMP, DCD-SCS, and DCD-NMP transplants were compared. Exposure DBD and DCD livers preserved on NMP or SCS. Main Outcomes and Measures The primary outcomes were early allograft dysfunction (EAD), intraoperative transfusion, and post-LT hospital resource use, including length of stay (LOS) and readmissions. Secondary outcomes included acute kidney injury (AKI) and 1-year graft and patient survival. Results A total of 1086 LTs were included in the following 4 groups: DBD-SCS (n = 480), DBD-NMP (n = 63), DCD-SCS (n = 264), and DCD-NMP (n = 279). Among LT recipients, median (IQR) age was 60.0 years (52.0-66.0); 399 LT recipients (36.7%) were female. DCD-NMP had the lowest EAD rate (17.5%), followed by DCD-SCS (50.0%), DBD-NMP (36.8%), and DBD-SCS (27.3%) ( P &amp;lt; .001). DCD-NMP had the lowest intraoperative transfusion requirement compared to all other groups. Hospital and intensive care unit (ICU) LOS were shortest in DCD-NMP (median [IQR] hospital LOS, 5.0 days [4.0-7.0]; P = .01; median [IQR] ICU LOS, 1.5 days [1.2-3.1]; P = .01). One-year cumulative readmission probability was 86% lower for DCD-NMP vs DCD-SCS (95% CI, 0.09-0.22; P &amp;lt; .001) and 53% lower for DBD-NMP vs DBD-SCS (95% CI, 0.26-0.87; P &amp;lt; .001). AKI events were lower in DCD-NMP (31.1%) vs DCD-SCS (47.4%) ( P = .001). Compared to SCS, the NMP group had a 78% overall reduction in graft failure (hazard ratio [HR], 0.22; 95% CI, 0.10-0.49; P &amp;lt; .001). For those receiving DCD allografts, the risk reduction was even more pronounced, with an 87% decrease in graft failure (HR, 0.13; 95% CI, 0.05-0.33; P &amp;lt; .001). NMP was significantly protective from patient mortality vs SCS (HR, 0.31; 95% CI, 0.12-0.80; P = .02). Conclusions and Relevance In this observational high-volume cohort study, NMP significantly improved LT clinical outcomes and reduced hospital resource use, especially in DCD allografts. NMP may enhance access to LT by addressing the challenges historically linked with DCD liver use.

BACKGROUND: During orthotopic liver transplantation, allograft reperfusion is a dynamic point in the operation and often requires vasoactive medications and blood transfusions. Normothermic machine perfusion (NMP) of liver allografts has emerged to increase the number of transplantable organs and may have utility during donation after circulatory death (DCD) liver transplantation in reducing transfusion burden and vasoactive medication requirements. METHODS: This is a single-center retrospective study involving 226 DCD liver transplant recipients who received an allograft transported with NMP (DCD-NMP group) or with static cold storage (DCD-SCS group). Veno-venous bypass was not used in any patients. Infusion doses of norepinephrine, epinephrine, and vasopressin as well as bolus doses of vasoactive medications during reperfusion were recorded. Blood component therapy was recorded according to phase of liver transplantation and during the first 24 hours postprocedure. RESULTS: A total of 103 recipients in the DCD-NMP group and 123 patients in the DCD-SCS group were included. Post-reperfusion syndrome (PRS) incidence was reduced in the DCD-NMP group compared to the DCD-SCS group (10.7% [95% confidence interval, CI, 5.5%–18.3%] vs 42.3% [95% CI, 33.4%–51.5%]; P < .001). During the reperfusion period, patients in the DCD-SCS group required increased bolus doses of epinephrine and vasopressin compared to the DCD-NMP group (24.6 vs 7.5 µg; P < .001) and (5.4 vs 2.4 units; P < .001), respectively. The DCD-SCS group received a higher infusion dose of epinephrine during anhepatic phase, at reperfusion, and up to 90 minutes after reperfusion. In the postreperfusion period, there were significant increases in the transfusion of red blood cells (RBCs; 5.3 vs 3.7 units; P = .006), fresh frozen plasma (FFP; 3.4 vs 1.9 units; P < .001), cryoprecipitate (2.7 vs 1.8 pooled units; P = .015) and platelets (0.9 vs 0.4 units; P = .008) in the DCD-SCS group compared to the DCD-NMP group. During the first 24 hours postprocedure, transfusion of RBCs, FFP, and cryoprecipitate in the DCD-SCS group was increased compared to the DCD-NMP group ([2.6 vs 1.7 units; P = .028], [1.6 vs 0.8 units; P < .001], [1.5 vs 0.9 pooled units; P = .031]) respectively. Administration of tranexamic acid was more frequent in the DCD-SCS group during the post-reperfusion period compared to the DCD-NMP group (13% [95% CI, 5.7%–17.4%] vs 3.9% [95% CI, 1.1%–9.6% 95%]; P = .018). CONCLUSIONS: In DCD liver transplantation, use of NMP was associated with reduced incidence of PRS and decreased vasopressor and inotrope requirements at the time of allograft reperfusion compared to using SCS. Additionally, NMP was associated with reduced transfusion of all blood product components as well as antifibrinolytic agent administration in the post-reperfusion period. Reduced transfusion burden in the DCD-NMP group also occurred during the first 24 hours posttransplant.

The rise in liver disease incidence and prevalence has led to increasing morbidity and mortality worldwide. Persistent hepatic inflammation drives disease progression by increasing fibrosis, advancing to cirrhosis, and potentially developing into hepatocellular carcinoma (HCC). Addressing these complications is essential to reduce liver-related mortality. Recent studies suggest that non-steroidal anti-inflammatory drugs, particularly aspirin, may play a beneficial role in managing liver disease. Aspirin’s anti-inflammatory and chemoprotective effects contribute to slowing disease progression and reducing the risks associated with chronic liver disease (CLD). This review highlights the current literature on the effects of aspirin in CLD, with a focus on patients with metabolic-associated steatotic liver disease (MASLD) and hepatitis B and C. We will examine aspirin’s potential ability to mitigate fibrosis, reduce the incidence of HCC, and lower liver-related mortality. Additionally, we will discuss its potential side effects and safety considerations, particularly in the context of liver disease, where there is an increased risk of bleeding.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a liver disorder characterized by steatosis with underlying metabolic risk factors. The prevalence of MASLD continues to rise, leading to increased patient risk of various complications. Recent research has been focused on new therapeutic strategies to reduce the incidence of MASLD and provide effective treatment plans to prevent further irreversible liver damage. The treatment approach is multifactorial, with a primary focus on weight loss and management of underlying comorbidities through lifestyle modifications, pharmacotherapy, or surgical options. Ongoing research is exploring new pharmacological therapies that could enhance the treatment of MASLD.

Hepatocellular Carcinoma (HCC) is the most common liver malignancy and third leading cause of cancer death worldwide. For early- and intermediate-stage disease, liver-directed therapies for locoregional control, or down-staging prior to definitive surgical therapy with hepatic resection or liver transplantation, have been studied broadly, and are the mainstays of current treatment guidelines. As HCC incidence has continued to grow, and with more patients presenting with advanced disease, our current treatment modalities do not suffice, and better therapies are needed to improve disease-specific and overall survival. Until recently, sorafenib was the only systemic therapy utilized, and was associated with dismal results. The advent of immuno-oncology has been of significant interest, and has changed the paradigm of therapy for HCC. Lately, combination regimens including atezolizumab plus bevacizumab; durvalumab plus tremelimumab; and pembrolizumab plus Lenvatinib have shown impressive responses of between 25–35%; this is much higher than responses observed with single agents. Complete responses with checkpoint inhibitor therapy have been observed in advanced-stage HCC patients. These dramatic results have naturally led to several questions. Can or should checkpoint inhibitors, or other immunotherapy combinations, be used routinely before resection or transplant? Is there a synergistic effect of immunotherapy with locoregional therapy, and will pre-treatment increase disease-free survival after surgical intervention? Is it immunologically safe to use these therapies prior to transplantation? Much is still to be learned in terms of the dosing, timing, and overall utility of the use of immune checkpoint inhibitors for pre-transplant care and down-staging. More studies will be needed to understand the management of adverse events while maximizing the therapeutic window of these agents. In this review, we look at the current data on therapy with immune checkpoint inhibitors in advanced HCC, with a focus on pre-transplant treatment prior to liver transplant.