Karachaliou, Georgia Sofia

Background: Statins have been associated with a reduced risk of primary liver cancer (PLC), primarily hepatocellular carcinoma (HCC). However, the optimal use for effective protection and whether benefits vary by patient characteristics remain unclear. We evaluated the association between statin use and PLC risk in metabolic-dysfunction-associated steatotic liver disease (MASLD), considering cumulative exposure and potential effect modifiers. Methods: We conducted a retrospective cohort study using the Veteran Affairs electronic health records. Patients with chronically elevated liver enzymes and metabolic dysfunction, without other chronic liver diseases, were identified between 2007 and 2009 and followed through 2019 for incident PLC. Statin exposure was assessed at baseline and during the follow-up, with dose standardization by LDL-lowering potency (simvastatin-equivalent units). Time to PLC was analyzed using Cox models adjusted for covariates, considering potential interactions. Results: Among 329,577 patients (92% male; median age 62 years), 0.82% developed PLC (median follow-up of 9.7 years). Baseline statin use showed a significantly lower PLC risk (adjusted hazard ratio 0.64; 95% CI, 0.57–0.71; p < 0.0001). No significant interaction was observed with age, sex, metabolic syndrome, or cirrhosis. Higher cumulative statin exposure demonstrated a dose-dependent risk reduction, remaining significant at simvastatin-equivalent doses > 15,561 mg annually after accounting for incident cirrhosis. Atorvastatin/rosuvastatin use provided comparable protection, despite different lipophilicity, and demonstrated stronger effects than others. Conclusions: In MASLD, statin therapy was associated with a dose-dependent PLC risk reduction. High-intensity therapy (simvastatin-equivalent > 40 mg daily) conferred substantial protection regardless of age, sex, insulin resistance, or cirrhosis, supporting a potential statin-based PLC chemoprevention in MASLD.

Background and Aims: Older age increases susceptibility to metabolic dysfunction–associated steatotic liver disease (MASLD), but whether it impacts response to therapies, and how the therapies impact regulators of biological aging, are poorly understood. Statins inhibit the mevalonate pathway to block cholesterol biosynthesis and are widely used in MASLD patients to reduce cardiovascular disease. Whether statins prevent progression to cirrhosis is under investigation. However, the molecular effects of statins in human liver, particularly in the context of aging, remain poorly defined. Approach and Results: We analyzed liver transcriptomes and matched clinical data from 368 adults enrolled in the Duke MASLD Biorepository with a focus on age-dependent responses and the interplay between senescence and ferroptosis, a regulated death process that is constrained by the mevalonate pathway. Serum ALT, AST, and LDL cholesterol levels were lower in statin users of both sexes, particularly among older individuals. Transcriptome analyses revealed that statin use is strongly associated with suppression of senescence-related pathways. Statin use is also associated with increased activation of pathways linked to ferroptosis. Both responses persisted after propensity score matching to control for clinical confounders and were validated in an independent obese cohort. Conclusions: Age-dependent transcriptional remodeling in the liver differs in statin users and non-users. Pathways involved in senescence are suppressed while those that promote ferroptosis are induced in statin users. These results suggest that statins may suppress biological aging in MASLD by acting as senolytics and highlight the complex, context-specific roles of senescence in liver adaptation and remodeling.

ABSTRACT Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with heart failure (HF), independent of shared risk factors. Our aim was to describe the incidence of HF in patients with biopsy-proven MASLD. Methods and results We followed patients with biopsy-proven MASLD from the prospective Duke NAFLD Biorepository and Clinical Database from liver biopsy (2007–2013) until death or 5 January 2023. Clinical and echocardiographic data were abstracted via manual chart review. Incident HF was defined as one of the following: (1) hospitalization for HF, (2) medical record diagnosis of HF, (3) ≥1 sign/symptom of HF and elevated natriuretic peptide, or (4) diastolic dysfunction on transthoracic echocardiography with ≥1 sign/symptom of HF. Univariable and multivariable logistic regression models were evaluated. Overall, 570 patients with biopsy-proven MASLD were included. The mean age was 49.5 years, 42.5% were male and 87.0% were non-Hispanic White. Ten patients (1.8%) had baseline HF, leaving 560 patients to assess for incident HF. Over a median follow up of 4009 days (11.0 years) (interquartile range 2270–4672 days), 100 (17.9%) patients developed incident HF while 268 (47.9%) met criteria for HF suspicion. In a multivariable model, increasing age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02–1.08, p &lt; 0.001) and female sex (OR 1.85, 95% CI 1.12–3.04, p = 0.02) were associated with incident HF. Conclusions We found a high incidence of HF in patients with biopsy-proven MASLD. Despite nearly half of patients having suspected HF, very few carried a chart diagnosis. Screening for HF in high-risk patients and establishment of formal care pathways to address early HF may reduce morbidity and mortality.

Background: NAFLD is highly prevalent with limited treatment options. Bile acids (BAs) increase in the systemic circulation and liver during NAFLD progression. Changes in plasma membrane localization and zonal distribution of BA transporters can influence transport function and BA homeostasis. However, a thorough characterization of how NAFLD influences these factors is currently lacking. This study aimed to evaluate the impact of NAFLD and the accompanying histologic features on the functional capacity of key hepatocyte BA transporters across zonal regions in human liver biopsies. Methods: A novel machine learning image classification approach was used to quantify relative zonal abundance and plasma membrane localization of BA transporters (bile salt export pump [BSEP], sodium-taurocholate cotransporting polypeptide, organic anion transporting polypeptide [OATP] 1B1 and OATP1B3) in non-diseased (n = 10), NAFL (n = 9), and NASH (n = 11) liver biopsies. Based on these data, membrane-localized zonal abundance (MZA) measures were developed to estimate transporter functional capacity. Results: NAFLD diagnosis and histologic scoring were associated with changes in transporter membrane localization and zonation. Increased periportal BSEP MZA (mean proportional difference compared to non-diseased liver of 0.090) and decreased pericentral BSEP MZA (−0.065) were observed with NASH and also in biopsies with higher histologic scores. Compared to Non-diseased Liver, periportal OATP1B3 MZA was increased in NAFL (0.041) and NASH (0.047). Grade 2 steatosis (mean proportional difference of 0.043 when compared to grade 0) and grade 1 lobular inflammation (0.043) were associated with increased periportal OATP1B3 MZA . Conclusions: These findings provide novel mechanistic insight into specific transporter alterations that impact BA homeostasis in NAFLD. Changes in BSEP MZA likely contribute to altered BA disposition and pericentral microcholestasis previously reported in some patients with NAFLD. BSEP MZA assessment could inform future development and optimization of NASH-related pharmacotherapies.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is associated with heart failure with preserved ejection fraction (HFpEF), independent of shared risk factors. The aim of this study was to determine the prevalence, clinical, and echocardiographic (TTE) features of HFpEF in patients with biopsy-proven NAFLD. Methods: We performed a retrospective single-center cohort study of patients with biopsy-proven NAFLD in the Duke NAFLD Biorepository and Clinical Database. Study entry was at the time of liver biopsy and patients were followed until death or 5/1/2023. Clinical and echocardiographic data were abstracted via manual chart review. HFpEF was defined as: at least one TTE characteristic (left atrial volume index ≥ 29 ml/m 2 , septal wall thickness ≥ 1 cm, or evidence of diastolic dysfunction) and signs or symptoms of heart failure (diagnosis of heart failure on problem list, hospitalization for heart failure, elevated NT pro-BNP level, jugular venous distention, use of loop diuretics, pulmonary or peripheral edema, fatigue, or exertional symptoms). Descriptive statistics were evaluated. Results: A total of 742 patients were included in the study. The mean age of the cohort was 50 +/- 12 years, and 83% were White. 95 (13%) had TTE both prior to study entry and during follow up, while 279 patients (38%) had TTE only during follow up. A total of 185 patients met criteria for HFpEF during follow up. After removing patients with TTE evidence of HFpEF prior to study entry, there were 132 cases of incident HFpEF over a mean follow up of 9.1 years, representing 47% of those with TTE after liver biopsy, and 18% of the overall cohort. Considering only TTE criteria, 142 patients had incident HFpEF. During follow up, 12 patients were hospitalized for heart failure. Conclusions: HFpEF is common in patients with NAFLD and a small percentage of patients do not have a chart diagnosis despite meeting echocardiographic criteria, suggesting that HFpEF may be under-recognized. Screening for HFpEF and/or formal care pathways to address early heart failure will be important to prevent morbidity and mortality in this population.