Minimal hepatic encephalopathy (MHE) appearance is associated with a pro-inflammatory shift in peripheral inflammation. Treatment of MHE patients with rifaximin reverses this shift in and improves MHE. How peripheral alterations are transmitted to brain to induce MHE remains unclear. In rats with MHE, plasma extracellular vesicles (EV) induce cognitive impairment. We hypothesized that in cirrhotic patients, the shift in peripheral inflammation is associated with alterations in plasma EV which contribute to induce MHE in cirrhotic patients. We also hypothesized that rifaximin treatment reverses MHE by reversing changes in EV. The aims were: 1) assess if injecting rats with plasma EV from MHE patients (MHE-EV) induce cognitive impairment, 2) identify the underlying mechanisms, 3) assess if treating MHE patients with rifaximin reverses the pathological effects of their EV and, 4) if this is associated with reversal of changes in EV protein cargo. We isolated plasma EV from cirrhotic patients without and with MHE, treated or not with rifaximin, and controls and injected them to rats. We analysed cognitive function, neuroinflammation and glutamate receptors membrane expression in hippocampus. MHE-EV, but not EV from patients without MHE show increased TNFα content and trigger a strong cognitive impairment in rats. This is mediated by altered membrane expression of AMPA and NMDA glutamate receptors in hippocampus, due to increased neuroinflammation, with glial activation and enhanced activation of the TNFα-TNFR1-S1PR2-IL-1β-IL-1R pathway. The EV from MHE patients treated with rifaximin did not show increased TNFα levels and did not induce the above pathological effects. Rifaximin treatment reverses the changes in the cargo of the EV from plasma of MHE patients, including the increase in TNFα and eliminates the pathological effects of the EV. The data show that in cirrhotic patients the presence of MHE is associated with changes in their blood EV which transmit pathological effects to the brain, inducing neuroinflammation and altered glutamatergic neurotransmission in hippocampus which leads to cognitive impairment. Rifaximin treatment reduces TNFα and other altered proteins in the EV and reverses their pathological effects. EV could be a therapeutic target to improve MHE by modifying EV content or blocking the TNFα effects.

BACKGROUND & AIMS:Cirrhosis is increasingly recognized as a condition affecting neuroendocrine regulation, emotional functioning, and cognitive performance. Altered cortisol physiology has been documented in cirrhosis, yet its cognitive and emotional consequences remain insufficiently understood. This study examined whether cortisol reactivity predicts verbal fluency (VF) performance and whether difficulties in emotion regulation mediate this association, comparing cirrhotic patients with healthy controls. METHODS:Twenty-eight cirrhotic patients (mean age = 63.4 years, SE = 1.4) and thirty-three controls (mean age = 68.1 years, SE = 1.0) completed phonemic (PVF) and semantic (SVF) verbal fluency tasks, the Difficulties in Emotion Regulation Scale (DERS), and provided salivary samples to measure cortisol before and after a standardized neuropsychological evaluation. Cortisol reactivity was computed as post minus baseline change. Moderated mediation models tested whether emotion regulation mediated the cortisol reactivity-VF relationship and whether these pathways differed across groups. RESULTS:Baseline cortisol levels did not differ significantly between groups, but the cirrhotic patients showed significantly higher post-assessment cortisol concentrations than controls. Patients also displayed lower VF performance and greater emotion regulation difficulties. For PVF, higher cortisol reactivity predicted poorer performance in cirrhotic patients indirectly through higher emotion dysregulation, whereas no such effects emerged in controls. For SVF, no significant direct or indirect effects were observed. CONCLUSIONS:These results suggest that altered cortisol regulation and emotion regulation difficulties may contribute to poorer PVF performance associated with cirrhosis. The findings further highlight emotion regulation as a potentially relevant mechanism linking stress-related physiological responses and cognitive vulnerability in chronic liver disease.

BACKGROUND & AIMS:Resmetirom is the first Food and Drug Administration-approved drug for metabolic dysfunction-associated liver disease (MASLD) in F2 and F3 patients with steatohepatitis. Noninvasive criteria have been proposed for initiating treatment; however, these have not been validated in clinical practice. We validated the proposed criteria and established new guidelines for initiating resmetirom treatment in clinical practice. METHODS:This was a cross-sectional study of 1281 MASLD patients from the HEPAmet registry with biopsy, comorbidity assessment, analytical profile, and elastography. Identification of MASLD with F2 and F3 was the main endpoint. A comprehensive review of international guidelines and expert consensus up to November 2024, focusing on therapeutic indications, was conducted. RESULTS:A total of 38% (n = 486 of 1281) of patients were diagnosed with MASLD F2 and F3 based on biopsy. However, only 39% and 56% of them met treatment eligibility criteria according to the Expert Panel Criteria and the American Association for the Study of Liver Diseases Practice Guidance, respectively. They included 45% of patients with early-stage fibrosis. False positive and false negative rates ranged from 23% to 41% and 44% to 60%, respectively, with area under the receiver-operating characteristic curve values below 0.60.These findings were validated in an external cohort. A two-step strategy, first selecting patients with Fibrosis-4 (FIB-4) ≥1.30, or with diabetes and overweight if FIB-4 <1.30, followed by a liver stiffness between 8 and 25 kPa, demonstrated higher positive (55%) and negative predictive values (77%) and higher area under the receiver-operating characteristic curve (0.67).This approach successfully identified 74% of the target population. CONCLUSIONS:The diagnostic performance and reliability of the proposed noninvasive criteria for initiating resmetirom treatment were suboptimal. About the half of patients with indication would not receive treatment under these criteria. A new strategy, using FIB-4, the presence of diabetes and overweight, and liver stiffness improved the identification of MASLD patients with F2 and F3.

INTRODUCTION:Patients with liver cirrhosis who are candidates for liver transplantation must be evaluated both clinically and socially in order to obtain the optimal outcomes and avoid futile therapeutic measures. For the evaluation of the social aspects in these patients, no validated scale in Spanish is available. The SIPAT (Stanford Integrated Psychosocial Assessment for Transplantation) scale is an instrument that measures the social, family and psychological aspects in candidates for solid organ transplantation. The objective of this study is to adapt and validate an abbreviated version of the SIPAT scale in Spanish for patients with liver cirrhosis. MATERIAL AND METHODS:Prospective observational study carried out in the Hepatology Unit of the La Fe Unversity Hospital in Valencia, by questionnaire validation methodology. To analyze the reliability of the questionnaire, the internal consistency of all variables was calculated, for variability an exploratory factor analysis, and for stability the test-retest test was carried out. RESULTS:96 patients who were admitted for decompensated cirrhosis to the Hepatology Unit of the La Fe Hospital in Valencia between November 1, 2017 and January 31, 2017 were selected. 84% were men, the mean age was 60.01 (SD 10.12) years. In 73.2% of those admitted, the etiology of cirrhosis was alcoholic. 14.4% had a Child's stage A, 57.7% B and 27.8% C. The internal consistency of all variables reached a Cronbach's Alpha of 0.766. In the exploratory factor analysis, 6 dimensions of the questionnaire were identified that explain 84.27% of the total variability. To see the stability of the instrument, the measurement was repeated at 2 and 6 months of follow-up, obtaining in the test-retest a kappa agreement of 0.612 and 0.565 respectively. CONCLUSION:The SIPAT-11 questionnaire has good psychometric characteristics in cirrhotic patients who are candidates for liver transplantation. It is easy to complete and can be administered by professionals who are not specialists in the area of Mental Health.

Minimal hepatic encephalopathy (MHE) affects attention, visuo-motor coordination, and visual perception, with mixed evidence on its impact on memory. Brain-derived neurotrophic factor (BDNF) is associated with memory dysfunction, and plays a crucial role in modulating neuroplasticity. This study investigates the mediating role of BDNF in the relationship between pro-inflammatory cytokines (IL-6, IL-15, IL-18), and declarative memory performance, and the moderating effects of sex. Sixty-eight cirrhotic patients and 22 healthy volunteers performed the Psychometric Hepatic Encephalopathy Score for MHE diagnosis and logical memory subtest (Wechsler Memory Scale-III). Moderated mediation analysis using bias-corrected bootstrapping and multiple regression was performed. Results showed that increased levels of IL-18 and IL-15 were significantly associated with lower BDNF levels (p = 0.03 and p = 0.02 respectively). However, no direct effect was observed between IL-18 and IL-15 and memory. The conditional effects of BDNF on memory were significant only for women with and without MHE, and lower BDNF levels were associated with lower memory performance (without MHE: p = 0.002; MHE: p = 0.001). Moreover, BDNF mediated indirectly the relationship between pro-inflammatory cytokines and memory. IL-18 and IL-15 impacted memory through reduced BDNF levels only in women with and without MHE, whereas IL-6 showed no significant effect on BDNF or memory across groups. These findings underscore the important role of BDNF in memory in cirrhotic patients, especially women with MHE, by mediating the IL-18 and IL-15 effects. The study highlights the role of IL-18 and IL-15 cytokines in neuroplasticity-related memory decline, positioning BDNF as a key biomarker for inflammation-associated cognitive impairment in this population.

Background and Aims Minimal hepatic encephalopathy (MHE) affects 30%-40% of cirrhotic patients, showing cognitive and motor impairment, and affecting quality of life. MHE represents the earliest stage of hepatic encephalopathy, a condition with severe consequences. Assessing MHE from different perspectives, such as sex differences, can enhance early diagnosis and treatment, potentially preventing its progression to hepatic encephalopathy. We aimed to investigate the influence of sex on MHE and to develop a more precise diagnostic method based on clinical and biochemical parameters, taking sex differences into account.Methods A cross-sectional study was conducted in 612 cirrhotic patients and 167 controls (82/85 females/males). Patients were classified as without MHE (101/343 females/males) or with MHE (48/120 females/males) by Psychometric Hepatic Encephalopathy Score. Clinical and biochemical data were collected, along with cognitive and motor assessments, and blood samples to measure ammonia levels and inflammatory and oxidative stress parameters.Results While cognitive and motor impairment associated with MHE was similar in both sexes, inflammatory, biochemical, and oxidative stress parameters differed between females and males with MHE. MHE males showed higher levels of inflammation, oxidative stress, and biochemical markers of liver disease severity than MHE females. Based on clinical and biochemical data, a multivariate model was developed for each sex, capable of effectively predicting the risk of having MHE with sensitivities of 79.2%-75% and specificities of 81.2%-75.9% for females and males, respectively.Conclusion Sex is an important factor in the onset and progression of MHE and should be considered in diagnosis and treatment.

BACKGROUND AND AIMS: A noteworthy proportion of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) have an indeterminate vibration-controlled transient elastography (VCTE). Among these patients, we aimed to identify candidates for MASLD treatment by diagnosing significant fibrosis. METHODS: This was a real-world prospective study including a large dataset of MASLD patients with paired VCTE and liver biopsy from 6 centers. A total of 1196 patients were recruited and divided in training (3 centers, Spain), internal validation (2 centers, Spain), and external validation (1 center, United States) cohorts. In patients with indeterminate liver stiffness measurement (LSM) (8-12 kPa), a diagnostic algorithm was developed to identify significant fibrosis, defined as histological stage >= F2. Statistical analysis was performed using Gaussian mixture model (GMM) and k-means unsupervised clusterization. RESULTS: From the eligible population, 33%, 29%, and 31% had indeterminate VCTE in the training, internal and external validation samples, respectively. The controlled attenuation parameter allowed the differentiation of GMM clusters with a cutoff of 280 dB/m (area under the curve, 0.89; 95% confidence interval, 0.86-0.97). Within patients with <280 dB/m, a LSM between 8.0-9.0 kPa showed a 93% sensitivity and a 91% negative predictive value to exclude significant fibrosis. Among patients with >= 280 dB/m, a LSM between 10.3 and 12.0 kPa diagnosed significant fibrosis with a 91% specificity. Applying this algorithm to the validation cohorts, 36% of the indeterminate VCTE were reallocated. The reallocated high-risk group showed a prevalence of 86% significant fibrosis, opening the therapeutic window for MASLD patients. CONCLUSIONS: To identify candidates for MASLD treatment among indeterminate VCTE, an algorithm-based on the sequential combination of LSM and controlled attenuation parameter thresholds can optimize the diagnosis of moderate-to-advanced fibrosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a major contributor to systemic metabolic dysfunction and is increasingly recognized as a risk enhancer for both cardiovascular disease (CVD) and chronic kidney disease (CKD). This review explores the complex interconnections between MASLD, CVD, and CKD, with emphasis on shared pathophysiological mechanisms and the clinical implications for risk assessment and management. We describe the crosstalk among the liver, heart, and kidneys, focusing on insulin resistance, chronic inflammation, and progressive fibrosis as key mediators. The severity of liver fibrosis in MASLD is independently associated with both cardiovascular and renal outcomes. Conventional cardiovascular risk scores may underestimate risk in MASLD-CKD populations, highlighting the need for integrated approaches that include hepatic, renal, and metabolic profiling. We also review current non-invasive diagnostic tools, including fibrosis scores and cardiovascular biomarkers, as well as emerging genetic and epigenetic markers that may enhance risk stratification. The therapeutic landscape is evolving, with promising results from lifestyle interventions and pharmacological agents such as GLP-1 receptor agonists, SGLT2 inhibitors, and novel antifibrotic compounds. We also propose a practical algorithm for the screening and risk stratification of MASLD in CKD patients, incorporating non-invasive fibrosis assessment and cardiometabolic risk evaluation. This stepwise approach supports early detection and personalized management, particularly in patients with CKD or type 2 diabetes. In conclusion, MASLD significantly amplifies cardiovascular and renal risk. Early, multidisciplinary intervention is essential to improve long-term outcomes in this high-risk population.

IntroductionAlthough it is well established that liver disease is associated with alterations in the gut microbiome (GM), the mechanisms linking these microbial changes to the progression of liver disease—and more critically, to its related cognitive impairment—remain poorly understood. Therefore, to define biomarkers for the early and advanced phases of these conditions, it is necessary to gain insight into changes in the GM throughout the evolution of the disease, particularly regarding the early onset of cognitive decline.MethodsThe GM taxonomy and function profiles were defined, data were collected for dietary intake, fecal short-chain fatty acids (SCFA), cognitive status, quality of life and biochemical and immunological blood parameters of patients belonging to different stages of liver disease (MASLD and cirrhosis) and cognitive function.ResultsThis study showed: 1) the fibrosis stage severity (F1 to F4) in liver disease was associated with reduced GM diversity independently of cognitive status and with a decline in beneficial autochthonous bacteria; 2) Streptococcus mutans and Allisonella histaminiformans could serve as potential biomarkers for NAFLD-associated mild cognitive impairment; 3) bacterial metabolic functions involved in sugar degradation and the breakdown of tryptophan and glutamate were downregulated and linked to CXCL13 plasma levels and neuroinflammation; 4) correlations between SCFA concentrations disappeared with liver disease and cognitive impairment.ConclusionIn this context, maintaining a balanced production of fecal SCFA is more important than individual concentrations. The downregulation of specific microbial metabolic pathways, along with the presence of certain bacterial species, holds promise as early-stage biomarkers and highlights the potential of microbiome-targeted strategies for monitoring and managing liver-related cognitive impairment.

Minimal hepatic encephalopathy (MHE) is common in cirrhosis, leading to cognitive impairment and eye-hand coordination (EHC) alterations. Hyperammonemia plays a key role in MHE, contributing to motor and cognitive deficits. Elevated blood ammonia levels and impaired EHC correlate with neuropsychiatric dysfunction, yet their direct impact on health-related quality of life (HRQoL) is complex. This study examines the associations between blood ammonia, EHC, and HRQoL, and the moderating influence of sex on these associations. Eighty-seven cirrhotic patients (67 male) and 23 healthy volunteers (11 male), aged 44–80 years, performed the Psychometric Hepatic Encephalopathy Score (PHES) for MHE diagnosis, the Vienna Test System, bimanual and visuomotor tests, and completed the SF-36 questionnaire to measure HRQoL. Blood samples were taken to test ammonia levels. Results indicated a significant association between elevated blood ammonia and impaired EHC among cirrhotic patients. However, increased blood ammonia and EHC did not directly predict HRQoL. Moderated moderation analysis revealed that women with MHE showed greater sensitivity to hyperammonemia and EHC deficits in tasks requiring fine motor control and stability skills (aiming, tapping, and bimanual coordination), which were linked to lower HRQoL in both physical and mental domains. In women without MHE, alterations in linear tracking were linked to worse HRQoL. These effects were not observed in men. The findings underscore the sex-specific impacts of MHE, with women disproportionately affected by ammonia-related motor impairments and their subsequent influence on HRQoL. These results could contribute to developing targeted strategies to improve outcomes in this vulnerable population.