Spleen volume is associated with overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with portal hypertension.

BACKGROUND: Portal shunt and immune status related to the spleen are related to the occurrence of hepatic encephalopathy (HE). It is unknown whether spleen volume before transjugular intrahepatic portosystemic shunt (TIPS) is related to postoperative HE. AIM: To investigate the relationship between spleen volume and the occurrence of HE. METHODS: This study included 135 patients with liver cirrhosis who underwent TIPS, and liver and spleen volumes were elevated upon computed tomography imaging. The Kaplan-Meier curve was used to compare the difference in the incidence rate of HE among patients with different spleen volumes. Univariate and multivariate Cox regression analyses were performed to identify the factors affecting overt HE (OHE). Restricted cubic spline was used to examine the shapes of the dose-response association between spleen volumes and OHE risk. RESULTS: The results showed that 37 (27.2%) of 135 patients experienced OHE during a 1-year follow-up period. Compared with preoperative spleen volume (901.30 ± 471.90 cm3), there was a significant decrease in spleen volume after TIPS (697.60 ± 281.0 cm3) in OHE patients. As the severity of OHE increased, the spleen volume significantly decreased (P < 0.05). Compared with patients with a spleen volume ≥ 782.4 cm3, those with a spleen volume < 782.4 cm3 had a higher incidence of HE (P < 0.05). Cox regression analysis showed that spleen volume was an independent risk factor for post-TIPS OHE (hazard ratio = 0.494, P < 0.05). Restricted cubic spline model showed that with an increasing spleen volume, OHE risk showed an initial increase and then decrease (P < 0.05). CONCLUSION: Spleen volume is related to the occurrence of OHE after TIPS. Preoperative spleen volume is an independent risk factor for post-TIPS OHE.

Modulation of brain energy metabolism in hepatic encephalopathy: impact of glucose metabolic dysfunction.

Cerebral function is linked to a high level of metabolic activity and relies on glucose as its primary energy source. Glucose aids in the maintenance of physiological brain activities; as a result, a disruption in metabolism has a significant impact on brain function, launching a chain of events that leads to neuronal death. This metabolic insufficiency has been observed in a variety of brain diseases and neuroexcitotoxicity disorders, including hepatic encephalopathy. It is a significant neurological complication that develops in people with liver disease, ranging from asymptomatic abnormalities to coma. Hyperammonemia is the main neurotoxic villain in the development of hepatic encephalopathy and induces a wide range of complications in the brain. The neurotoxic effects of ammonia on brain function are thought to be mediated by impaired glucose metabolism. Accordingly, in this review, we provide an understanding of deranged brain energy metabolism, emphasizing the role of glucose metabolic dysfunction in the pathogenesis of hepatic encephalopathy. We also highlighted the differential metabolic profiles of brain cells and the status of metabolic cooperation between them. The major metabolic pathways that have been explored are glycolysis, glycogen metabolism, lactate metabolism, the pentose phosphate pathway, and the Krebs cycle. Furthermore, the lack of efficacy in current hepatic encephalopathy treatment methods highlights the need to investigate potential therapeutic targets for hepatic encephalopathy, with regulating deficient bioenergetics being a viable alternative in this case. This review also demonstrates the importance of the development of glucose metabolism-focused disease diagnostics and treatments, which are now being pursued for many ailments.

Bibliometrics and knowledge mapping of the pathogenesis of hepatic encephalopathy in patients with liver cirrhosis.

Background: Hepatic encephalopathy is a common and serious complication of decompensated cirrhosis. It can considerably contribute to economic burden and impaired quality of life. However, its pathogenesis remains unclear. Method: In this study, we aimed to visually analyse the research status and development trends in hepatic encephalopathy pathogenesis using bibliometrics and knowledge mapping. Information regarding publications between 1978 and 2022 were obtained from the Web of Science Core Collection. CiteSpace was used to analyse and present data by year, author, institution, country, journal, reference, and keyword. Results: A total of 1578 publications on hepatic encephalopathy pathogenesis in patients with cirrhosis were retrieved from Web of Science Core Collection. A gradual increasing trend in annual publications has occurred. The collaborative network analysis results suggest the United States of America, the University of London, and Bajaj, Jasmohan S as the most influential country, institution, and author, respectively, in this research field. Notably, China appeariiuis to be the most promising country. Research on 'hepatology' garners the most significant papers in the field. Combined with reference co-citation and keyword co-occurrence analyses, we found that ammonia metabolism, gut microbiota, sarcopenia, and trace elements will become future research frontiers that are likely to be explored for a considerable length of time. Conclusion: Future research directions in HE pathogenesis may target modulating the ammonia metabolism, the gut microbiota, sarcopenia, and trace elements.

Hepatic encephalopathy post-TIPS: Current status and prospects in predictive assessment.

Transjugular intrahepatic portosystemic shunt (TIPS) is an essential procedure for the treatment of portal hypertension but can result in hepatic encephalopathy (HE), a serious complication that worsens patient outcomes. Investigating predictors of HE after TIPS is essential to improve prognosis. This review analyzes risk factors and compares predictive models, weighing traditional scores such as Child-Pugh, Model for End-Stage Liver Disease (MELD), and albumin-bilirubin (ALBI) against emerging artificial intelligence (AI) techniques. While traditional scores provide initial insights into HE risk, they have limitations in dealing with clinical complexity. Advances in machine learning (ML), particularly when integrated with imaging and clinical data, offer refined assessments. These innovations suggest the potential for AI to significantly improve the prediction of post-TIPS HE. The study provides clinicians with a comprehensive overview of current prediction methods, while advocating for the integration of AI to increase the accuracy of post-TIPS HE assessments. By harnessing the power of AI, clinicians can better manage the risks associated with TIPS and tailor interventions to individual patient needs. Future research should therefore prioritize the development of advanced AI frameworks that can assimilate diverse data streams to support clinical decision-making. The goal is not only to more accurately predict HE, but also to improve overall patient care and quality of life.

Pediatric Perspectives on Liver Cirrhosis: Unravelling Clinical Patterns and Therapeutic Challenges.

Background: Liver cirrhosis presents significant challenges in the pediatric population due to a complex interplay of etiological factors, clinical manifestations, and limited therapeutic options. The leading contributors to cirrhosis among pediatric patients are chronic cholestasis, metabolic disorders present from birth, and long-term hepatitis. Materials and method: Our narrative review aimed to synthesize literature data on the etiology, clinical picture, diagnostic techniques, optimal management of complications, and timely transplantation. Results: The epidemiology of liver cirrhosis in pediatric patients is evolving. The introduction of a universal vaccination and effective long-term viral suppression in viral hepatitis have significantly decreased complications rates. Liver transplantation programs worldwide have also improved the management of cirrhosis complications. Conclusions: Early diagnosis, comprehensive management strategies, and advancements in treatment modalities are critical for improving outcomes. Understanding these differences is crucial in providing age-appropriate care and support for those affected by cirrhosis.

A Case of Autoimmune Hepatitis Initially Manifesting as Hepatic Encephalopathy.

Autoimmune hepatitis (AIH) is a T-cell-mediated liver disease characterized by elevated transaminases, circulating autoantibodies, hypergammaglobulinemia, and interface hepatitis. A 66-year-old female patient visited our department due to recurrent episodes of altered consciousness, sleep-wake inversion, and asterixis, indicating hepatic encephalopathy (HE). Her liver biopsy results clearly demonstrated interface hepatitis. The patient's severe HE does not parallel her relatively stable liver function and was attributed to a wide retroperitoneal collateral vein shunting blood directly into the inferior vena cava, bypassing the liver, and allowing excess neurotoxins to enter the central nervous system. Due to the unfavorable benefit-risk ratio of embolization and the patient's stable liver function, non-invasive treatments were adopted, and prednisolone was discontinued. The patient experienced no further episodes of HE thereafter. To the best of our knowledge, this is the first AIH case with a spontaneous portosystemic shunt directly shunting blood into the inferior vena cava. A crucial lesson from this case is that when HE cannot be fully explained by liver dysfunction, abdominal CT scans should be carefully inspected for possible anatomical variations. This case also underscores the importance of a multidisciplinary approach in managing AIH in elderly patients, who may benefit more from a tailored treatment regimen rather than strictly following standard treatment guidelines.

Frequency of Hypoglycemia in Cirrhotic Patients Undergoing Endoscopy.

BACKGROUND:  Liver cirrhosis is the replacement of normal liver parenchyma by fibrous tissue and nodularity. Cirrhosis liver has a negative effect on the body's ability to regulate blood glucose levels because the liver cannot release the amount of glucose it would ultimately cirrhotic patients are at risk of hypoglycemia. OBJECTIVE:  To determine the frequency of hypoglycemia in cirrhotic patients just before endoscopy after being nil per mouth (NPO) for 6 hours. METHODOLOGY:  This cross-sectional study was done at the Department of Gastroenterology Lady Reading Hospital, Peshawar from 1st April 2023 to 30th September 2023. Patients aged > 20 years of both genders, having Child-Pugh class C cirrhosis, and undergoing upper gastrointestinal (GI) endoscopy were enrolled in the study while patients with a history of diabetes using oral or parenteral hypoglycemic medications, patients taking steroids, patients with hepatocellular carcinoma and patients with hepatic encephalopathy were excluded. Diagnosis of liver cirrhosis was based on clinical examination, serum albumin level, and prothrombin time followed by characteristic findings on ultrasound. Serum glucose level was determined in the blood sample of the patient from the hospital laboratory.  Results: One hundred and ninety-six patients were enrolled including 130 (67.4%) males and 66 (32.6%) females. Age of the patients ranged from 20 to 60 years. The mean age of the participants was 46.68±10.239 years. Hypoglycemia was found in 48% of patients with liver cirrhosis. A significant association of hypoglycemia was found with disease duration and Child-Pugh class. CONCLUSION:  Hypoglycemia is a frequent finding in patients with liver cirrhosis and needs urgent management to prevent complications. Prolonged illness and patients with Child-Pugh class C cirrhosis are more likely to have hypoglycemia.

Stroop test, Quickstroop, and the 1-min animal naming test for minimal hepatic encephalopathy diagnosis: A multicenter study in Mexico.

INTRODUCTION AND OBJECTIVES: Although the Psychometric Hepatic Encephalopathy Score (PHES) remains the gold standard in diagnosing minimal hepatic encephalopathy (MHE), its complexity limits its application in clinical practice. While more convenient tests, such as the Stroop test, Quickstroop, and the 1-min animal naming test (ANT-1), have emerged, they haven't been validated in our setting. Our objective was to validate these tests in our population. PATIENTS AND METHODS: This multicenter, observational, descriptive, and cross-sectional study was conducted in three hospitals in northeastern Mexico. MHE was defined as a PHES <-4. We included patients with cirrhosis aged >15 years without a history of overt hepatic encephalopathy. Data regarding sex, age, education, Child-Pugh/MELD-Na scores, etiology of cirrhosis, diabetes, hypertension, obesity, ascites, and clinically significant portal hypertension was collected. Fisher's exact test, Mann-Whitney U test, and receiver operating characteristic (ROC) curves were used for statistical analysis. RESULTS: Of the 121 patients included, 35.5 % were diagnosed with MHE. The presence of MHE was significantly associated with education level, years of study, and scores in the Stroop test, Quickstroop, and ANT-1. The AUROC curves were 77.9 %, 74.6 %, and 72.7 % for the Stroop test, Quickstroop, and ANT-1, respectively. The resulting cut-off points were 218.398 (sensitivity: 74 %; specificity: 74 %), 40.535 (sensitivity: 77 %; specificity: 68 %), and <16 animals (sensitivity: 58 %; specificity: 79 %), respectively. CONCLUSIONS: These tests are valid diagnostic tools for detecting MHE in our population. Their simpler use and applicability could increase the early diagnosis of MHE and prompt primary prophylaxis initiation for overt hepatic encephalopathy.

Clinical Implications and Management of Spontaneous Portosystemic Shunts in Liver Cirrhosis.

Portal hypertension from chronic liver disease leads to the formation of collateral blood vessels called spontaneous portosystemic shunts (SPSS). These shunts may form from existing vessels or through neo-angiogenesis. Their location affects clinical outcomes due to varying risks and complications. This review summarizes current knowledge on SPSS, covering their clinical impact and management strategies. Recent data suggest that SPSS increases the risk of variceal bleeding, regardless of shunt size. The size of the shunt is crucial in the rising incidence of hepatic encephalopathy (HE) linked to SPSS. It also increases the risk of portopulmonary hypertension and portal vein thrombosis. Detecting and assessing SPSS rely on computed tomography (CT) and magnetic resonance imaging. CT enables precise measurements and the prediction of cirrhosis progression. Management focuses on liver disease progression and SPSS-related complications, like HE, variceal bleeding, and portopulmonary hypertension. Interventional radiology techniques such as balloon-occluded, plug-assisted, and coil-assisted retrograde transvenous obliteration play a pivotal role. Surgical options are rare but are considered when other methods fail. Liver transplantation (LT) often resolves SPSS. Intraoperative SPSS ligation is still recommended in patients at high risk for developing HE or graft hypoperfusion.

Portosystemic Hepatic Encephalopathy Scores (PHES) differ between Danish and German healthy populations despite their geographical and cultural similarities.

Minimal hepatic encephalopathy (MHE) is common in liver cirrhosis and is identified by psychometric tests. The portosystemic hepatic encephalopathy score (PHES) is the most widely used and serves as an inter-study comparator. PHES has not been standardised for use in the Danish population, where German normal values have been applied until now based on the notion that the populations are comparable. This study aimed to evaluate if German PHES normal values can be applied in the Danish population and establish Danish normal values if needed. 200 Danish and 217 German healthy persons underwent Number Connection Test A and B (NCT), Line Tracing Test (LTT), Digit Symbol Test (DST), and Serial Dotting Test (SDT), and based on performance, PHES was calculated. German and Danish PHES performance declined with age in all subtests but more rapidly in Danes. Both German and Danish norms were impacted by gender and education, but to a different extent in the single tests of the test battery. Accordingly, there was a need for specific Danish normal values, which are presented here. Applying the new Danish normal values instead of the German in patients with cirrhosis yielded a lower percentage of out-of-norm performances (58% vs. 66%) and, hence, a lower prevalence of MHE. Danes and Germans perform differently on PHES, and therefore, normal German values cannot be used in Danish patients. Danish normal values are presented here and yield a lower number of 'out of norm' performances.

Fructooligosaccharides reverses hepatic vascular dysfunction and dysbiosis in rats with liver cirrhosis and portal hypertension.

BACKGROUND: Portal hypertension leads to lethal complications in liver cirrhosis. Oxidative stress induced hepatic vascular dysfunction, which exaggerated vasoconstriction and increases hepatic vascular resistance (HVR). Gut dysbiosis further exacerbates portal hypertension. Fructooligosaccharides are prebiotics with potent antioxidant effect. This study aimed to evaluate the roles of fructooligosaccharides in portal hypertension-related vascular dysregulation and gut microbiome. METHODS: Sprague-Dawley rats received bile duct ligation to induce cirrhosis or sham operation as controls. The rats then randomly received fructooligosaccharides or vehicle for 4 weeks. Experiments were performed on the 29th day after operations. RESULTS: Fructooligosaccharides did not affect portal pressure. Interestingly, fructooligosaccharides significantly attenuated HVR (p = .03). Malondialdehyde, an oxidative stress marker, reduced significantly in the liver in fructooligosaccharides-treated group. In addition, superoxide dismutase and trolox equivalent antioxidant capacity increased in the treatment group. On the other hand, vasodilatation-related protein expressions, GTPCH and phospho-eNOS, enhanced significantly. Fructooligosaccharides had no adverse vasodilatation effects on splanchnic vascular system or porto-systemic collateral systems. Locomotor function was not affected by fructooligosaccharides. Faecal microbiota analysis showed that Negativicutes, Selenomonadales and Lactobacillus salivarius reduced in the fructooligosaccharides-treated group. CONCLUSION: In conclusion, fructooligosaccharides attenuate hepatic vascular dysfunction in cirrhotic rats via at least partly, ameliorate of dysbiosis and oxidative stress.

Elevated serum neurofilament light chain levels are associated with hepatic encephalopathy in patients with cirrhosis.

Increasing evidences implicate vital role of neuronal damage in the development of hepatic encephalopathy (HE). Neurofilament light chain (NfL) is the main frame component of neurons and is closely related to axonal radial growth and neuronal structural stability. We hypothesized that NfL as a biomarker of axonal injury may contribute to early diagnosis of HE. This study recruited 101 patients with liver cirrhosis, 10 healthy individuals, and 7 patients with Parkinson's disease. Minimal hepatic encephalopathy (MHE) was diagnosed using psychometric hepatic encephalopathy score. Serum NfL levels were measured by the electrochemiluminescence immunoassay. Serum NfL levels in cirrhotic patients with MHE were significantly higher than cirrhotic patients without MHE, and increased accordingly with the aggravation of HE. Serum NfL levels were associated with psychometric hepatic encephalopathy score, Child-Pugh score, model for end-stage liver disease score, and days of hospitalization. Additionally, serum NfL was an independent predictor of MHE (odds ratio of 1.020 (95% CI 1.005-1.034); P = 0.007). The discriminative abilities of serum NfL were high for identifying MHE (AUC of 0.8134 (95% CI 0.7130-0.9219); P ˂ 0.001) and OHE (AUC of 0.8852 (95% CI 0.8117-0.9587); P ˂ 0.001). Elevated serum NfL levels correlated with the presence of MHE and associated with the severity of HE, are expected to be a biomarker in patients with cirrhosis. Our study suggested that neuronal damage may play a critical role in the development of HE.

Incidence and risk factors of acute kidney injury in cirrhosis: a systematic review and meta-analysis of 5,202,232 outpatients, inpatients, and ICU-admitted patients.

INTRODUCTION: Acute kidney injury (AKI) is a commonly seen condition in the natural course of cirrhosis. The aim of this study was to evaluate the pooled incidence and risk factors of AKI in different clinical stages and situations in patients with cirrhosis. METHODS: Search was conducted on 13 December 2023 across MEDLINE (PubMed), Embase, and Cochrane databases. Meta-analysis was performed using a generalized linear mixed model. RESULTS: In total, 73 studies with 5,202,232 patients were finally enrolled in the meta-analysis. AKI commonly occurs among hospitalized cirrhotics experiencing any decompensation event (29%) as well as among stable outpatients (28%) throughout a 1-year follow-up period. On admission, patients with infection or sepsis/septic shock had the highest AKI rate (47%), followed by those with hepatic encephalopathy (41%). Furthermore, the severity of liver disease proved to be a substantial driver for AKI development, while patients at intensive care unit had the greatest AKI incidence (61%). CONCLUSIONS: Both hospitalized patients and stable outpatients with cirrhosis exhibited an elevated susceptibility to AKI. Patients at intensive care unit and those with severe liver disease, infection, sepsis/septic shock, hepatic encephalopathy, or acute on chronic liver failure upon admission are at higher risk for AKI. TRIAL REGISTRATION: PROSPERO, registered 09/12/23, CRD42023487736.

The effect of rifaximin and lactulose treatments to chronic hepatic encephalopathy rats: An [18F]PBR146 in-vivo neuroinflammation imaging study.

INTRODUCTION: Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver diseases characterized by neuroinflammation. The efficacies of nonabsorbable rifaximin (RIF) and lactulose (LAC) have been well documented in the treatment of HE. [18F]PBR146 is a translocator protein (TSPO) radiotracer used for in vivo neuroinflammation imaging. This study investigated anti-neuroinflammation effect of RIF or/and LAC in chronic HE rats by [18F]PBR146 micro-PET/CT. METHODS: Bile duct ligation (BDL) operation induced chronic HE models, and this study included Sham+normal saline (NS), BDL+NS, BDL+RIF, BDL+LAC, and BDL+RIF+LAC groups. Behavioral assessment was performed to analyze the motor function, and fecal samples were collected after successfully established the chronic HE model (more than 28 days post-surgery). In addition, fecal samples collection and micro-PET/CT scans were performed sequentially. And we also collected the blood plasma, liver, intestinal, and brain samples after sacrificing the rats for further biochemical and pathological analyses. RESULTS: The RIF- and/or LAC-treated BDL rats showed similar behavioral results with Sham+NS group, while the treatment could not reverse the biliary obstruction resulting in sustained liver injury. The RIF or/and LAC treatments can inhibit IFN-γ and IL-10 productions. The global brain uptake values of [18F]PBR146 in BDL+NS group was significantly higher than other groups (p < .0001). The brain regions analysis showed that the basal ganglia, hippocampus, and cingulate cortex had radiotracer uptake differences among groups (all p < .05), which were consistent with the brain immunohistochemistry results. Sham+NS group was mainly enriched in Christensenella, Coprobacillus, and Pseudoflavonifractor. BDL+NS group was mainly enriched in Barnesiella, Alloprevotella, Enterococcus, and Enterorhabdus. BDL+RIF+LAC group was enriched in Parabacteroides, Bacteroides, Allobaculum, Bifidobacterium, and Parasutterella. CONCLUSIONS: RIF or/and LAC had anti-neuroinflammation in BDL-induced chronic HE rats with gut microbiota alterations. The [18F]PBR146 could be used for monitoring RIF or/and LAC treatment efficacy of chronic HE rats.

Vitamin D deficiency stratifies the risk of covert and overt hepatic encephalopathy in patients with cirrhosis: A retrospective cohort study.

BACKGROUNDS & AIMS: This study aimed to investigate the association between vitamin D deficiency and covert hepatic encephalopathy (CHE), overt hepatic encephalopathy (OHE) occurrence, and mortality in patients with cirrhosis. METHODS: This retrospective study reviewed 679 patients with cirrhosis. Vitamin D deficiency was defined as serum 25-hydorxyvitamin D (25-OHD) levels < 20 ng/mL. The associations between 25-OHD and CHE, OHE occurrence, and mortality were assessed using logistic regression, Fine-Gray competing risk regression, and Cox proportional hazards regression models, respectively. RESULTS: Of 428 eligible patients, 75% had vitamin D deficiency and 23% had CHE. The prevalence of CHE was higher in patients with vitamin D deficiency than in those without vitamin D deficiency (28% vs. 13%, p = 0.002). During the median follow-up period of 2.3 years, 14% of the patients developed OHE and 27% died. Patients with vitamin D deficiency had a higher incidence of OHE (p = 0.002) and mortality (p = 0.006) than those without vitamin D deficiency. After adjustment for potential covariates, multivariate analyses showed that 25-OHE was associated with CHE (odds ratio, 0.95; 95% confidence interval [CI], 0.91-0.99; p = 0.023), OHE occurrence (sub-distribution hazard ratio, 0.92; 95% CI, 0.86-0.98; p = 0.013) and mortality (hazard ratio, 0.96; 95% CI, 0.93-0.99; p = 0.020) in patients with cirrhosis. CONCLUSIONS: Vitamin D deficiency is highly prevalent and is associated with CHE, OHE, and mortality in patients with cirrhosis. Evaluation of vitamin D is essential to predict the outcomes of patients with cirrhosis.

Nutritional management for acute liver failure.

Acute liver failure (ALF) induces increased energy expenditure and disrupts the metabolism of essential nutrients. Hepatic encephalopathy is a complication of ALF with a poor prognosis and mainly involves the metabolic disturbance of amino acids in its pathogenesis. In this review, we discuss the nutritional management for ALF in consideration of the pathophysiology of ALF with respect to the impairment of hepatocyte function. It is known that enteral nutrition is recommended for patients with ALF, while parenteral nutrition is recommended for patients who cannot tolerate enteral nutrition. As ALF leads to a hypermetabolic state, the energy intake is recommended to cover 1.3 times the resting energy expenditure. Because of the high risk of hypoglycemia associated with disturbances in glucose metabolism, substantial glucose intake is recommended. Along with the deterioration of glucose metabolism, protein metabolism is also disrupted. As patients with ALF have increased systemic protein catabolism together with decreased protein synthesis, appropriate amounts of amino acids or protein under monitoring serum ammonia levels are recommended. In conclusion, nutritional management based on the understanding of nutritional pathophysiology is a pivotal therapeutic approach for patients with ALF. The approach should be individualized in the acute phase, the recovery phase, and the pretransplant phase.

Astrocyte-secreted lipocalin-2 elicits bioenergetic failure-induced neuronal death that is causally related to high fatality in a mouse model of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neurological complication arising from acute liver failure with poor prognosis and high mortality; the underlying cellular mechanisms are still wanting. We previously found that neuronal death caused by mitochondrial dysfunction in rostral ventrolateral medulla (RVLM), which leads to baroreflex dysregulation, is related to high fatality in an animal model of HE. Lipocalin-2 (Lcn2) is a secreted glycoprotein mainly released by astrocytes in the brain. We noted the presence of Lcn2 receptor (Lcn2R) in RVLM neurons and a parallel increase of Lcn2 gene in astrocytes purified from RVLM during experimental HE. Therefore, our guiding hypothesis is that Lcn2 secreted by reactive astrocytes in RVLM may underpin high fatality during HE by eliciting bioenergetic failure-induced neuronal death in this neural substrate. In this study, we first established the role of astrocyte-secreted Lcn2 in a liver toxin model of HE induced by azoxymethane (100 µg/g, ip) in C57BL/6 mice, followed by mechanistic studies in primary astrocyte and neuron cultures prepared from postnatal day 1 mouse pups. In animal study, immunoneutralization of Lcn2 reduced apoptotic cell death in RVLM, reversed defunct baroreflex-mediated vasomotor tone and prolonged survival during experimental HE. In our primary cell culture experiments, Lcn2 produced by cultured astrocytes and released into the astrocyte-conditioned medium significantly reduced cell viability of cultured neurons. Recombinant Lcn2 protein reduced cell viability, mitochondrial ATP (mitoATP) production, and pyruvate dehydrogenase (PDH) activity but enhanced the expression of pyruvate dehydrogenase kinase (PDK) 1, PDK3 and phospho-PDHA1 (inactive PDH) through MAPK/ERK pathway in cultured neurons, with all cellular actions reversed by Lcn2R knockdown. Our results suggest that astrocyte-secreted Lcn2 upregulates PDKs through MAPK/ERK pathway, which leads to reduced PDH activity and mitoATP production; the reinforced neuronal death in RVLM is causally related to baroreflex dysregulation that underlies high fatality associated with HE.

Effect of diabetes on mortality and liver transplantation in alcoholic liver cirrhotic patients with acute decompensation.

BACKGROUND: Previous studies have investigated the influence of diabetes on alcoholic liver cirrhosis patients, leaving its impact unclear. Thus, we conducted a study to reveal the association of diabetes and clinical outcomes of such patients. MATERIALS AND METHODS: We prospectively collected data from multicenter pertaining to 965 patients diagnosed with alcoholic liver cirrhosis, all of whom were admitted due to acute decompensation between 2015 and 2019. Risk of major precipitating factors and incidences of death or liver transplantation in patients with and without diabetes was comparatively assessed. Propensity score (PS) matching was performed at a 1:2 ratio for accurate comparisons. RESULTS: The mean age was 53.4 years, and 81.0% of the patients were male. Diabetes was prevalent in 23.6% of the cohort and was positively correlated with hepatic encephalopathy and upper gastrointestinal bleeding, although not statistically significant. During a median follow-up of 903.5 person-years (PYs), 64 patients with and 171 without diabetes died or underwent liver transplantation, with annual incidence of 33.6/100 PYs and 24.0/100 PYs, respectively. In the PS-matched cohort, the incidence of death or liver transplantation was 36.8/100 PYs and 18.6/100 PYs in the diabetes and matched control group, respectively. After adjusting for various factors, coexisting diabetes significantly heightened the risk of death or liver transplantation in the short and long term, in addition to prolonged prothrombin time, low serum albumin, elevated total bilirubin and creatinine, and decreased serum sodium levels. CONCLUSIONS: Diabetes increases the risk of death or liver transplantation in patients with alcoholic liver cirrhosis.

[Liver transplantation in acute and acute-on-chronic liver failure]. / Lebertransplantation bei akutem und akut-auf-chronischem Leberversagen.

Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are diseases with a rapidly progressive course and high mortality. Apart from treating the underlying triggers and intensive care measures, there are very limited therapeutic options for either condition. Liver transplantation is often the only life-saving treatment, but it cannot always be employed due to contraindications and severe disease progression. ACLF is characterized by underlying liver cirrhosis and typical triggers such as bacterial infections, bleeding, or alcohol binges. ALF occurs in previously healthy livers, usually as a result of purely hepatotoxic events. Disease differences are also reflected in the course and regulations of liver transplantation. Newer prognostic parameters and prioritization programs for ACLF can help improve both waiting list mortality and outcomes after transplantation.

Chinese guidelines on the management of ascites in cirrhosis : Chinese Society of Hepatology, Chinese Medical Association.

In 2023, Chinese Society of Hepatology of Chinese Medical Association convened a panel of experts to update the Chinese guidelines on the management of ascites and associated complications in cirrhosis which was launched in 2017 and renamed this guidelines as "Guidelines on the Management of Ascites in Cirrhosis." This comprehensive resource offers essential recommendations for the diagnosis and treatment of cirrhotic ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome.