To explore the correlation between the expression of Tat interacting protein-30 (TIP30) mRNA in serum of patients with hepatitis B virus (HBV) -derived decompensated liver cirrhosis and recompensation as well as short-term prognosis. The clinical data of 109 patients with the HBV-related decompensated cirrhosis who were hospitalized in the First Affiliated Hospital of Xi'an Jiaotong University and the First People's Hospital of Xianyang City from January 2018 to December 2023 were collected and analyzed, retrospectively, including 51 patients who occured recompensation and 58 patients who occured non-recompensation. Serum TIP30 mRNA expression was detected by Real-time polymerase reaction (RT-PCR). An increase in TIP30 mRNA expression after treatment was observed in the recompensation group compared to non-recompensation group (P < 0.001). Our analysis showed that serum TIP30 mRNA expression in the decompensated liver cirrhosis patients was negatively correlated with Child Pugh score, portal vein diameter, spleen length, and the morbidity in ascite, hepatic encephalopathy, hepatorenal syndrome, spontaneous peritonitis, pulmonary infection, and gastrointestinal bleeding (all P < 0.05). Detecting serum expression of TIP30 mRNA can provide a basis for evaluating the recompensation and short-term prognosis of decompensated liver cirrhosis. AS shown in .

Therapeutic effects of berberine on hyperammonemia-associated neuroinflammation in thioacetamide-induced hepatic encephalopathy.

Mechanisms by which neuroinflammation modulates GABAergic neurotransmission in the hippocampus of hyperammonemic rats.

Gut microbiota dysbiosis and the gut–liver–brain axis: Mechanistic insights into hepatic encephalopathy

Background and Purpose: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with liver cirrhosis (LC) that often results in cognitive impairment. Minimal HE (mHE), a subtle form of the condition, significantly affects patients’ quality of life. Advanced imaging techniques, such as quantitative susceptibility mapping (QSM), provide new insights into the brain changes associated with HE. Materials and Methods: The study included 28 patients (17 with mHE and 11 without) with alcohol-induced LC and 25 healthy controls. MR imaging, including QSM, was utilized to assess microstructural tissue changes and iron deposition in the brain. Cognitive function was assessed through a neuropsychological test battery. QSM quantified magnetic susceptibility in deep gray matter, while enlarged perivascular spaces (EPVS) were evaluated using T2-weighted images. Statistical analyses, including non-parametric tests and linear regression, assessed differences in susceptibility and their correlation with cognitive performance and EPVS. Results: Significant differences in cognitive performance and brain susceptibility were observed between patients and controls. Patients exhibited lower susceptibility in the caudate nucleus with the accumbens (CNA); mHE patients, in particular, had a significant reduction in CNA susceptibility. Additionally, EPVS grade correlated positively with cognitive decline, suggesting that EPVS may play an essential role in the pathophysiology of mHE. Conclusions: This study demonstrates that QSM can detect subtle brain changes in LC patients, with decreased susceptibility in the CN (caudate nucleus) linked to cognitive impairment in mHE. The role of EPVS in HE warrants further investigation, as it may affect the efficacy of current diagnostic and therapeutic approaches. These findings highlight the potential of QSM to improve HE assessment.

Beyond its traditional role in calcium and bone metabolism, vitamin D has emerged as a critical regulator of liver health. Its active form, calcitriol [1α,25(OH)2D], signals through the vitamin D receptor (VDR), which is expressed in hepatic stellate cells, Kupffer cells, and cholangiocytes. Through this pathway, vitamin D modulates fibrosis, inflammation, oxidative stress, bile acid homeostasis, and immune responses. This review explores the growing body of evidence linking vitamin D deficiency to chronic liver diseases, including autoimmune hepatitis, primary biliary cholangitis, alcoholic liver disease, viral hepatitis B and C, and metabolic-associated steatotic liver disease. Low vitamin D levels are frequently observed in these conditions and are associated with disease severity, complications (such as spontaneous bacterial peritonitis, sarcopenia, and hepatic encephalopathy), and increased mortality. Mechanistically, vitamin D-VDR signaling inhibits profibrotic TGF-β1/SMAD pathways, downregulates proinflammatory cytokines, enhances regulatory T cell differentiation, and improves insulin sensitivity. Although preclinical studies support its protective effects, clinical trials of vitamin D supplementation have produced mixed results. Overall, vitamin D appears to influence multiple pathways in liver disease pathophysiology, and correcting its deficiency may offer clinical benefits. However, its integration into clinical care will depend on identifying responsive patient subgroups and defining optimal dosing strategies to maximize therapeutic benefit.

Background Traditional cost effectiveness analyses frequently use quality-adjusted life years (QALYs) to quantify health benefits. The Medicare Drug Price Negotiation program, however, cannot use QALYs, but may consider alternative, non-discriminatory metrics. Objective To examine the impact of using alternative quantitative health benefit metrics on the economic value of new medications. The framework was applied to assess the cost-effectiveness of rifaximin for preventing overt hepatic encephalopathy (OHE) recurrence in adults. Methods A cost-effectiveness analysis evaluated the economic value of rifaximin ± lactulose versus standard of care ± lactulose in preventing recurrent OHE in adults over a lifetime horizon from US payer and societal perspectives. Clinical outcomes included time in remission and overt health states, number of liver transplants, and life years (LYs). Health benefit was quantified using QALYs, health years in total (HYT), equal-value of life years gained (evLYG), and generalized risk-adjusted cost-effectiveness (GRACE). Treatment value was measured using incremental cost effectiveness ratio (ICER). A societal perspective scenario added productivity and caregiving impacts to the model. Results Rifaximin patients spent >3 times as long in remission (54.4 vs. 17.3 months), comparable time in the overt health state (1.44 vs. 1.44 months), and had twice as many liver transplants (20 vs. 9), driven by longer survival (8.80 vs. 4.17 LYs), resulting in incremental gains of 3.12 QALYs, 3.26 HYT, 2.78 evLYG, and 3.16 GRA-QALYs. Total costs were higher with rifaximin ($182,369 vs. $38,313, Δ = $144,056), mainly due to drug costs (Δ = $133,330). Including caregiving and productivity reduced the incremental cost to $136,866. From a payer perspective, rifaximin ICERs were $46,215/QALY, $44,198/HYT, $51,847/evLYG, and $45,609/GRA-QALY. After incorporating societal costs, ICERs improved to $43,908/QALY, $41,992/HYT, $49,259/evLYG, and $43,332/GRA-QALY. Conclusion Rifaximin is a cost-effective treatment for preventing OHE recurrence in adults using QALY and non-QALY health benefit measures.

Background and aim Covert hepatic encephalopathy (CHE) is a neurocognitive complication affecting 40.9–50.4% of patients with cirrhosis. It often remains undiagnosed owing to its subclinical nature and the limitations of existing diagnostic tools, which are constrained by subjectivity, variable sensitivity, and limited accessibility. This study aims to develop and validate interpretable machine learning (ML) models for predicting CHE in patients with cirrhosis using multidimensional clinical and lifestyle data. Methods This retrospective study included 503 patients with liver cirrhosis from 16 medical centers in China. CHE was diagnosed using the psychometric hepatic encephalopathy score and EncephalApp Stroop tests. Recursive feature elimination and Pearson’s correlation analysis were used for feature selection. Eight ML models were implemented to predict CHE. Performance was assessed via AUC, sensitivity, specificity, and decision curve analysis. The SHapley Additive exPlanations (SHAP) values are interpreted by the optimal model. Results The light gradient boosting machine (LightGBM) model achieved the highest area under the receiver operating characteristic (ROC) curve (AUC) of 0.810 in the training set and 0.710 in the validation set. Decision curve analysis showed that LightGBM had better diagnostic performance than random forest (RF) and eXtreme gradient boosting (XGBoost). The SHAP analysis identified key predictors of CHE, including lower Mini-Mental State Examination (MMSE) scores, older age, hypoalbuminemia, lack of prior computer usage, and higher blood urea nitrogen levels. Conclusion This study presents a novel ML-based approach for predicting CHE in cirrhotic patients, with LightGBM offering the best balance of performance and interpretability. The identified clinical and demographic predictors could facilitate early CHE detection and personalized management, ultimately improving outcomes for this high-risk population.

Hypogonadism is frequent in AdvCLD and associated with frailty and poor outcomes. This study aimed to evaluate the association between free testosterone (FT) levels and all-cause mortality in male patients with AdvCLD awaiting liver transplantation (LT), and to compare the prognostic value of FT with total testosterone (TT). In this prospective cohort study, 191 male patients with AdvCLD awaiting LT underwent FT and TT evaluation. The primary outcome was all-cause mortality, assessed using a competing-risk model with LT as the competing event. Among the 191 patients, 41 (21.5%) had low FT levels. This group was more likely to have a higher Child-Turcotte-Pugh class and MELD-Na score, as well as higher proportion of individuals with a history of hepatic encephalopathy (HE) compared to those with normal FT levels (p < 0.05). Patients with low FT also exhibited greater frailty (liver frailty index: 4.2 ± 0.8 vs. 3.6 ± 0.9, p < 0.001, respectively). After adjustment for MELD-Na, low FT was significantly associated with increased mortality risk (adjusted subdistribution hazard ratio [aSHR] 1.97; 95% CI: 1.07-3.61). Additionally, patients with low FT had a lower cumulative probability of undergoing LT compared to those with normal FT levels (43.4% vs. 74.3%). In contrast, low TT was not associated with mortality (aSHR: 1.65; 95% CI: 0.90-3.02). Low FT levels are independently associated with higher mortality and lower LT probability in men with AdvCLD and outperform TT as a prognostic marker. These findings support FT as a valuable biomarker to identify high-risk patients and guide future interventional strategies.

Hepatic encephalopathy (HE) is a metabolic encephalopathy caused by liver failure and/or portosystemic shunting. A 68-year-old male developed HE and CT demonstrated cirrhosis and an unusual large portosystemic shunt between the umbilical and femoral vein. He underwent interventional percutaneous embolisation of the shunt, leading to the resolution of HE.

Sleep disturbances and liver diseases have a bidirectional relationship. Unhealthy sleep habits promote liver diseases, such as steatotic liver disease, and impact the prognosis, promoting progression to liver cirrhosis and liver-related mortality. Sleep accounts for 20% of the association between lifestyle and steatotic liver disease, indirectly by promoting obesity and metabolic syndrome and through direct effects in the liver. Conversely, liver diseases can affect sleep. Patients with liver cirrhosis complain of sleep disturbances five times more than the general population, with a profound impact on their quality of life. Common drugs used to treat sleep disorders, such as hypnotics and benzodiazepines, must be used very carefully in patients with cirrhosis due to altered hepatic metabolism and the potential to induce hepatic encephalopathy, making sleep disorders particularly challenging to manage in these patients. This review summarizes the available knowledge on the interplay between sleep and liver diseases.

Bile acids, once considered mere digestive detergents, have emerged as multifaceted signaling molecules with systemic influence extending far beyond the gastrointestinal tract. Recent discoveries reveal their capacity to modulate immune responses, cross the blood–brain barrier, and interact with central nervous system (CNS) cells through their receptors. Neuroinflammation, a key driver of neurodegenerative and neuroimmune disorders, is increasingly linked to bile acid signaling pathways that regulate glial activation, cytokine production, and neuronal survival. This review compiles the current evidence connecting bile acids to CNS inflammation, highlighting mechanistic insights, disease-specific alterations, and the gut–microbiome-bile acid-brain axis. It also explores the therapeutic potential of bile acid derivatives and receptor modulators, as well as their emerging role as biomarkers in conditions such as Alzheimer’s disease, multiple sclerosis, and hepatic encephalopathy. Despite promising advances, critical gaps remain, including the need for bile receptor mapping in human CNS cells, standardized CNS bile acid profiling, and longitudinal metabolomic studies. Bridging these gaps may unlock new strategies for targeting neuroinflammation through bile acid-immune crosstalk.

Structural and functional abnormalities of thalamic subregions in minimal hepatic encephalopathy.

Sirtuin downregulation mediates mitochondrial impairment causing cognitive decline in hepatic encephalopathy.

BackgroundPakistan has a high prevalence of HCV and HBV, causing cirrhosis, leading to hepatic encephalopathy in approximately 30–45% of cirrhotic patients. Overt hepatic encephalopathy (OHE) is a serious type of hepatic encephalopathy that refers to brain dysfunction resulting from acute or chronic liver disease. Patients present flapping tremors and mental alterations leading to a coma, which disrupts daily activities and patient health-related quality of life. OHE can be treated by lactulose, rifaximin, probiotics, and l-ornithine l-aspartate (LOLA). Lactulose (controlled drug for trial) is the main treatment for OHE, even though its effectiveness in clinical trials has remained varied. Rifaximin (interventional drug), probiotics (interventional drug), and LOLA (interventional drug) all showed a significant effect in reducing the grade of hepatic encephalopathy, lowering blood ammonia levels, and enhancing psychomotor function in OHE patients. Our trial aims to determine the most effective treatment combination, as despite the availability of multiple treatment options, the efficacy is still uncertain. Limited studies have compared individual treatments, but no research has been conducted to assess all four treatment groups together, i.e., Group A (lactulose) as the control group, Group B (rifaximin + lactulose), Group C (probiotics + lactulose), and Group D (LOLA + lactulose).MethodsThis trial is a single-center, parallel, multi-arm, randomized, unblinded, lactulose-controlled clinical trial. A total of 252 patients (both male and female aged 18–80 years), 63 in each treatment group, will be recruited in the study from the time of participation in the trial until the end of treatment (days 1–5). Primary outcome is to assess grade reversal of OHE on day 5 of trial participation. The secondary outcome is to determine the length of hospital stay and recovery time (days), monitoring of adverse drug reactions and death by cause in OHE patients.DiscussionThis randomized controlled trial protocol will compare the efficacy of four proposed groups of medications to fill the gap in current knowledge.Trial registrationChinese Clinical Trial Registry ChiCTR2300075925, registered on 19 September 2023; ClinicalTrials.gov NCT07037394, registered on 24 June 2025. Released to the public on 26 June 2025.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13063-025-09173-2.

Polyethylene Glycol in the Treatment of Hepatic Encephalopathy in patients with Liver Cirrhosis

Background/Objectives: Oxidative stress contributes to the pathogenesis of cirrhosis, but its value as a clinical biomarker remains uncertain. Methods: We retrospectively analysed 90 patients with decompensated cirrhosis. Serum malondialdehyde (MDA) and 8-epi-prostaglandin F2α (8-iso-PGF2α) were measured at admission. Biomarker levels were compared between Child–Pugh classes B and C, across hepatic encephalopathy grades, and ascites severity, using Mann–Whitney, Kruskal–Wallis, and Spearman correlation tests. Results: Median MDA did not differ significantly between Child–Pugh classes B and C (2.67 [2.10–3.20] vs. 2.45 [1.98–3.05] μmol/L; p = 0.331), nor across ascites categories (p = 0.453). Similarly, 8-iso-PGF2α values did not vary between Child–Pugh classes (255.8 [220.0–310.0] vs. 250.1 [210.0–295.0] pg/mL; p = 0.784) or ascites groups (p = 0.828). Spearman analysis showed no significant correlations with albumin, INR, bilirubin, creatinine, or age, except for a non-significant trend with bilirubin (ρ = −0.18, p = 0.09). Importantly, MDA levels increased significantly across encephalopathy grades (p = 0.021), suggesting a link between systemic oxidative stress and neuropsychiatric impairment. Conclusions: In this clinical cohort, oxidative stress biomarkers did not provide discriminatory value for staging by Child–Pugh or ascites, but MDA was associated with encephalopathy severity. These findings highlight both the limitations and potential clinical relevance of oxidative stress markers in cirrhosis management.

Hepatic encephalopathy (HE) results from a debilitating complication of liver cirrhosis and acute liver failure, characterized by neuropsychiatric abnormalities ranging broadly from mild cognitive impairment to respiratory failure to coma. The pathogenesis of HE is multifactorial, with gut-derived toxins, particularly ammonia, playing a central role. Recent advances in understanding the gut-liver-brain axis have revealed the importance of gut microbiota and dysbiosis in the development and progression of HE. Fecal microbiota transplantation (FMT), a clinical procedure that is performed to transfer fecal microbiota from a healthy donor to a patient with HE (recipient), has emerged as a promising therapeutic strategy for modulating gut microbiota and ameliorating HE. FMT facilitates the restoration of gut microbiota composition with increased microbial alpha diversity, reestablishment of the balance between beneficial and pathogenic bacteria, reduction in the production of gut-derived toxins, and improvement of intestinal barrier function. It also modulates immune and inflammatory responses, alleviating hepatocyte and biliary injury. FMT has also demonstrated efficacy in improving cognitive function and reducing hospitalizations in HE patients and can maintain a stable donor-like microbiota profile for up to 12 months post-transplantation. FMT is generally well-tolerated, with most adverse events reported to be mild and transient, providing a desirable option for HE treatment. This review provides a comprehensive overview of the current understanding of the role of gut microbiota in the pathogenesis of HE, the mechanisms underlying the therapeutic effects of FMT, and the clinical evidence supporting its use in HE. We will also discuss the limitations, challenges, and future prospects for FMT in the treatment of HE.

Microcystis, a commonly occurring genus of bloom-forming cyanobacteria, can produce numerous secondary metabolites, including microcystins (MCs), which are hepatotoxic and neurotoxic to humans and animals. However, the mechanisms of cyanobacterial neurotoxicity associated with MCs have not yet been clarified. This study reports the first observations of hepatic encephalopathy (HE) after exposure to Microcystis bloom extracts (MEs), which contained MCs. Mechanisms of toxicity were studied in rats exposed to MEs by use of a single intraperitoneal injection of 80μg MC-LR equivalents/kg, body mass. Abnormal serum biochemical markers of hepatic functions and histopathological damage of liver and cerebral cortex were observed. Specifically, Alzheimer type II astrocytes, histological markers of HE, were observed. Motor impairment and significantly increased concentrations of ammonia in serum, increased activities of glutamine synthetase, and concentrations of glutamine in the cerebral cortex were detected, which indicated occurrence of HE. Mechanisms of HE, including ammonia poisoning, oxidative stress and inflammation, were confirmed by real-time quantitative PCR and transcriptomics. Also, transcriptomics revealed that zinc ions dyshomeostasis and ferroptosis are involved in the development of HE. This study presents novel insights into neurotoxic symptoms in human poisonings caused by Microcystis, links neurotoxicity in the brain to the liver, i.e., the liver-brain axis, and provides a new perspective on the multi-organ toxicity of Microcystis and a basis for developing treatments.

Objectives: We hypothesized that specific, region-based magnetic resonance imaging (MRI) patterns and dermatological manifestations are strongly associated with distinct encephalopathy subtypes and can predict clinical outcomes in patients presenting with altered mental status. Methods: This prospective observational study included 100 adult patients who had presented with clinical features of encephalopathy at a tertiary care hospital over a period of 24 months (January 2020 to December 2021). Detailed clinical, laboratory, and dermatological evaluations were conducted. All participants underwent standardized MRI brain scans. Encephalopathy subtypes were classified based on clinical, imaging, and laboratory findings. Statistical analysis assessed the association of imaging and skin findings with clinical outcomes, including mortality. Results: MRI abnormalities were observed in 80% of patients, with region-specific patterns across encephalopathy types. Parieto-occipital hyperintensities predominated in posterior reversible encephalopathy syndrome (PRES), while basal ganglia involvement was prominent in hepatic encephalopathy. Cutaneous manifestations were common in autoimmune (100%) and hepatic (84.6%) encephalopathies, providing diagnostic clues. Overall mortality was 24%, with the highest rates in septic and hemorrhagic encephalopathy (62% each), and no deaths in PRES or metabolic encephalopathies. Dermatological findings and MRI patterns correlated with diagnosis and prognosis, supporting a multimodal assessment approach. Conclusion: MRI-based region-specific patterns and systematic dermatological examination offer a comprehensive and practical approach to diagnosing and prognosticating encephalopathy. This integrated model enhances early identification of reversible conditions and helps guide therapeutic strategies. The findings support incorporating dermatological evaluation into routine encephalopathy assessments and encourage further multicenter validation of this multidisciplinary diagnostic framework.