Beyond the Liver: Neurologic Manifestations of Alcohol Use.

Alcohol use, while commonly associated with liver damage, also has significant neurologic implications, which often mimic hepatic encephalopathy and complicate diagnosis and management. Alcohol mediates its acute central nervous system effects by altering neurotransmitter balance, notably between gamma-aminobutyric acid and glutamate. Its chronic neurotoxicity, compounded by thiamine deficiency, results in chronic neurologic complications. Clinically, alcohol-related neurologic disorders present a spectrum from acute intoxication and withdrawal to chronic conditions like Korsakoff syndrome, dementia, cerebellar degeneration, and peripheral neuropathy. This review underscores differentiating these conditions from hepatic encephalopathy and highlights the importance of history-taking and physical examination in clinical practice.

Alteration of dynamical degree centrality in brain functional network and its association with metabolic disorder in minimal hepatic encephalopathy.

PURPOSE: To investigate dynamical degree centrality (dDC) alteration and its association with metabolic disturbance and cognitive impairment in minimal hepatic encephalopathy (MHE). METHODS: Fifty-eight cirrhotic patients (22 with MHE, 36 without MHE [NHE]) and 25 healthy controls underwent resting-state functional magnetic resonance imaging, 1H-magnetic resonance spectroscopy, and neurocognitive examination based on the Psychometric Hepatic Encephalopathy Score (PHES). We obtained metabolite ratios in the bilateral posterior cingulate cortex and precuneus, including glutamate and glutamine (Glx)/total creatine (tCr), myo-inositol (mI)/tCr, total choline/tCr, and N-acetyl aspartate/tCr. For each voxel, degree centrality was calculated as the sum of its functional connectivity with other voxels in the brain; and sliding-window correlation was used to calculate dDC per voxel. RESULTS: We observed a stepwise increase in Glx/tCr and a decrease in mI/tCr from NHE to MHE. The intergroup dDC differences were observed in the bilateral posterior cingulate cortex and precuneus (region of interest [ROI1]), bilateral superior-medial frontal gyrus and anterior cingulate cortex (ROI2), and left caudate head. The dDC in ROI2 (r = 0.450, P < 0.001) and mI/tCr (r = 0.297, P = 0.024) was correlated with PHES. Significant correlations were found between dDC in ROI1 and Glx/tCr (r = - 0.413, P = 0.001) and mI/tCr (r = 0.554, P < 0.001). The dDC in ROI2, Glx/tCr, and mI/tCr showed potential for distinguishing NHE from MHE (areas under the curve = 0.859, 0.655, and 0.672, respectively). CONCLUSION: Our findings suggested dynamic brain network disorganization in MHE, which was associated with metabolic derangement and neurocognitive impairment.

D-dimer is a prognostic marker for 1-year mortality in patients with chronic liver failure and hepatic encephalopathy.

Background and Aim: Hepatic encephalopathy (HE) is a neuropsychiatric complication of liver failure with poor outcomes. The present study aimed to evaluate the predictive values of D-dimer in patients with HE. Materials and Methods: Patients with chronic liver failure (CLF) and HE were enrolled. Univariate and multivariate logistic analysis was performed to investigate the risk factors for 1-year mortality of HE. Results: During the first year after diagnosis, 39.2% (65/166) of the patients died. D-dimer was significantly higher in non-survivors (Z=2.617, p<0.01). Both D-dimer and international normalized ratio (INR) positively correlated with Child-Pugh and MELD scores, and negatively correlated with sodium (all p<0.01). Moreover, there was a negative relationship between D-dimer and HE grades (r=-0.168, p=0.031), while the relationship between INR and HE grades was not significant (r=0.083, p=0.289). Multivariate analysis showed that age (odds ratio (OR):1.035, 95% CI:1.004-1.067, p=0.03), D-dimer (OR=1.138, 95% CI:1.030-1.258, p=0.01), ALT (OR=1.012, 95% CI:1.001-1.022, p=0.03), and sodium (OR=0.920, 95% CI:0.858-0.986, p=0.02) were independent risk factors for 1-year mortality. Then, a new model Model(Age_DD_ALT_Na) incorporating age, D-dimer, ALT, and sodium was developed. AUROC of Model(Age_DD_ALT_Na) was 0.732, which was significantly higher than MELD and Child-Pugh scores (AUROC: 0.602 and 0.599, p=0.013 and 0.022). Conclusion: D-dimer is a prognostic marker for 1-year mortality in patients with CLF and HE.

Mechanism of Alzheimer Type II Astrocyte Development in Hepatic Encephalopathy.

Type C hepatic encephalopathy (Type C HE) is a major and complex neurological condition that occurs following chronic liver failure. The molecular basis of Type C HE remains elusive. Type C HE is characterized by mental confusion, cognitive and motor disturbances. The presence of Alzheimer type II astrocytes (AT2A) is the key histopathological finding observed in Type C HE. However, nothing is currently known regarding AT2A development and its involvement in cognitive, and motor deficits in Type C HE. We, therefore, examined in rats the mechanisms by which liver failure contributes to the progression of AT2A, and its role in the development of cognitive and motor deficits in thioacetamide (TAA) model of Type C HE. We and others earlier reported increased oxidative/nitrosative stress (ONS), JNK1/2, and cMyc activation in ammonia-treated astrocyte cultures, as well as in brains from chronic liver failure. We now found increased levels of astrocytic glia maturation factor (GMF, a factor strongly implicated in neuroinflammation), as well as various inflammatory factors (IL-1ß, TNF-α, IL-6, MMP-3, COX2, CXCL1, and PGE2), and reduced levels of GFAP and increased levels of aggregated nuclear protein Lamin A/C in rat brain cortex post-chronic liver failure. We also found increased levels of GMF and inflammatory factors (MMP-3, COX2, CXCL1, and PGE2) in astrocytes post-ammonia treatment in vitro. Additionally, pharmacological inhibition of upstream signaling of GMF (ONS, JNK1/2, and cMyc) or GMF inhibitors W-7 and trifluoperazine significantly reduced the levels of inflammatory factors, the number of AT2A cells, as well as the cognitive and motor deficits in TAA-treated rats. Increased levels of GMF were also identified in human post-mortem brain sections. These findings strongly suggest that increased levels of astrocytic GMF due to elevated levels of ONS, JNK1/2, and cMyc and the subsequent inflammation contribute to the development of AT2A and the consequent cognitive, and motor deficits in chronic liver failure.

Splenic spread and hepatic encephalopathy in metastatic malignant melanoma.

An older adult patient was admitted with epigastric pain and vomiting and found to have an abdominal mass, increased cholestatic liver enzymes and markedly elevated serum lactate dehydrogenase (LDH). Imaging revealed extensive liver metastases of unknown primary but also an unusual splenic metastasis diagnosed by liver biopsy as malignant melanoma. The patient became lethargic and developed mental status changes associated with asterixis, abnormal EEG, and increased serum ammonia levels. All reversed with high-dose lactulose and had no alternative explanation other than an unusual hepatic encephalopathy secondary to portosystemic shunts bypassing the extensively metastatic liver.

Meta-analysis of probiotics efficacy in the treatment of minimum hepatic encephalopathy.

OBJECTIVE: This study aims to systematically evaluate the efficacy of probiotics in treating minimum hepatic encephalopathy (MHE). METHODS: A systematic search was conducted across three major databases: PubMed, China National Knowledge Infrastructure and Wanfang. The search period spanned from the inception of each database to 9 March 2023. The objective was to identify all randomised controlled trials (RCTs) examining the efficacy of probiotic preparations in treating MHE. The search terms included 'probiotics' along with other clinically relevant terms to comprehensively capture all pertinent studies. RESULTS: A total of 18 RCTs were included. The meta-analysis showed that probiotic treatment outperformed control groups in reducing blood ammonia levels (standard mean difference [MD] = -2.68, 95% confidence interval [CI]: -3.90 to -1.46, p < .0001), improving the remission rate of MHE (risk ratio [RR] = 2.79, 95% CI: 1.23-6.35, p = .01) and lowering alanine aminotransferase levels (MD = -11.10, 95% CI: -16.17 to -6.03, p < .0001). It also significantly reduced the Model for End-Stage Liver Disease scores (MD = -2.55, 95% CI: -3.56 to -1.54, p < .00001) and the incidence of MHE (RR = .18, 95% CI: .09-.34, p < .00001). CONCLUSION: Our study demonstrates that probiotics effectively improve blood ammonia levels, liver function and cognitive function in patients with MHE. They significantly enhance the remission rate of MHE and effectively reduce its incidence, providing solid new evidence for treating MHE with probiotics.

NMDA Receptors and Indices of Energy Metabolism in Erythrocytes: Missing Link to the Assessment of Efficiency of Oxygen Transport in Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that develops in patients with severe liver dysfunction and/or portocaval shunting. Despite more than a century of research into the relationship between liver damage and development of encephalopathy, pathogenetic mechanisms of hepatic encephalopathy have not yet been fully elucidated. It is generally recognized, however, that the main trigger of neurologic complications in hepatic encephalopathy is the neurotoxin ammonia/ammonium, concentration of which in the blood increases to toxic levels (hyperammonemia), when detoxification function of the liver is impaired. Freely penetrating into brain cells and affecting NMDA-receptor-mediated signaling, ammonia triggers a pathological cascade leading to the sharp inhibition of aerobic glucose metabolism, oxidative stress, brain hypoperfusion, nerve cell damage, and formation of neurological deficits. Brain hypoperfusion, in turn, could be due to the impaired oxygen transport function of erythrocytes, because of the disturbed energy metabolism that occurs in the membranes and inside erythrocytes and controls affinity of hemoglobin for oxygen, which determines the degree of oxygenation of blood and tissues. In our recent study, this causal relationship was confirmed and novel ammonium-induced pro-oxidant effect mediated by excessive activation of NMDA receptors leading to impaired oxygen transport function of erythrocytes was revealed. For a more complete evaluation of "erythrocytic" factors that diminish brain oxygenation and lead to encephalopathy, in this study, activity of the enzymes and concentration of metabolites of glycolysis and Rapoport-Lubering shunt, as well as morphological characteristics of erythrocytes from the rats with acute hyperammoniemia were determined. To elucidate the role of NMDA receptors in the above processes, MK-801, a non-competitive receptor antagonist, was used. Based on the obtained results it can be concluded that it is necessary to consider ammonium-induced morphofunctional disorders of erythrocytes and hemoglobinemia which can occur as a result of alterations in highly integrated networks of metabolic pathways may act as an additional systemic "erythrocytic" pathogenetic factor to prevent the onset and progression of cerebral hypoperfusion in hepatic encephalopathy accompanied by hyperammonemia.

Absence of TNFR1 promotes a protective response in the early phase of hepatic encephalopathy induced by thioacetamide in mice.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome with a wide spectrum of cognitive deficits, motor impairment, and psychiatric disturbances resulting from liver damage. The cytokine TNF has been considered the main cytokine in the development and progression of HE, with a pivotal role in the initiation and amplification of the inflammatory cascade. The aim of the present study was to evaluate the involvement of TNF type 1 receptor (TNFR1) in locomotor deficits and in the levels of TNF, IFN-γ, IL-6, IL-10, IL-12p70, CCL2, CX3CL1 and BDNF from the frontal cortex and hippocampus of TNFR1 knockout mice (TNFR1-/-) mice with HE induced by thioacetamide. Wild-type (WT) animals with HE developed locomotor deficit. The absence of TNFR1 absence of TNFR1 in HE animals attenuated the locomotor activity impairment in parallel with a balanced neuroinflammatory environment 24 h after the administration of thioacetamide. Taken together, the data suggests that the absence of TNFR1 promoted a protective response in the early phase of hepatic encephalopathy induced by thioacetamide in mice.

The effects of Qingchang Ligan formula on hepatic encephalopathy in mouse model: results from gut microbiome-metabolomics analysis.

Background: Hepatic encephalopathy (HE) is a neurological disorder resulting from advanced liver injury. HE has a high mortality rate and poor prognosis. The pathogenesis of HE is still unclear, which has led to the lack of a satisfactory specific treatment method. There is increasing evidence that the intestinal flora affects the communication between the gut and the brain in the pathogenesis of HE. Adjusting the intestinal flora has had a beneficial effect on HE in recent studies, and the Qingchang Ligan formula (QCLG) has been shown in previous studies to regulate intestinal flora and metabolites. In this study, we established a thioacetamide-induced HE mouse model to evaluate the protective effect of QCLG on HE and explore its potential mechanism, which also demonstrated that intestinal flora dysbiosis is involved in the pathogenesis of HE. Methods: Mice were intraperitoneally injected with thioacetamide (TAA, 150 mg/kg) to induce HE. Additionally, they were orally administered Qingchang Ligan Formula (QCLG) at a dose of 6.725 g/kg·d for seven days, while control mice received an equal volume of saline via gavage. Subsequently, samples were subjected to 16S ribosomal ribonucleic acid (rRNA) gene sequencing, high-performance liquid chromatography-mass spectrometry (LC-MS), and RNA-sequencing (RNA-seq) analysis. Result: QCLG improved weight loss, cognitive impairment, neurological function scores, blood ammonia, and brain gene expression of interleukin-6 (TNF-α), Interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) induced by HE. Moreover, QCLG increased the levels of liver function indicators, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum TNF-α, IL-1ß, and IL-6. 16S RNA sequencing revealed increased Oscillibacter, Colidextribacter, and Helicobacter in TAA-induced mouse fecal samples. Also, the abundance of Bifidobacterium decreases TAA-induced mouse fecal samples. In contrast, QCLG treatment significantly restored the gut microbial community. Metabolomics indicated significant differences in some metabolites among the normal control, treatment, and model groups, including 5-methoxytryptophan, Daidzein, Stercobilin, and Plumieride (PLU). Conclusion: QCLG can alleviate neuroinflammation and prevent HE caused by liver injury by regulating intestinal flora in mouse models.

Regulation of autophagy by ST3GAL2-mediated α2-3 sialylated glycosphingolipids in hepatic encephalopathy.

In neurological diseases, the regulation of autophagy plays a crucial role in their pathology, particularly the relationship between autophagy and hepatic encephalopathy (HE) which merits detailed investigation. Glycosphingolipids are abundant and broadly functional in the nervous system and are closely associated with autophagy. However, the specific link and mechanisms between glycosphingolipids and autophagy in HE remain unclear. This study aims to explore the impact of glycosphingolipid changes on the autophagy in HE and its potential mechanisms. Utilizing lectin microarrays, we observed elevated expression levels of α2-3 sialylated glycosphingolipid in the brain tissue of HBV transgenic mice and ammonia-induced astrocyte models, suggesting that the increase in α2-3 sialylated glycosphingolipid is related to HE. Further research revealed that the increased expression of α2-3 sialylated glycosphingolipid, mediated by ST3GAL2, affects autophagy by regulating the autophagy initiation complex Vps34-Beclin-1. In summary, our research not only comprehensively reveals the changes in brain glycosphingolipid during HBV-related HE but also elucidates the interactions and regulatory mechanisms between α2-3 sialylated glycosphingolipid and autophagy. This study provides a new perspective on understanding the pathogenesis of HE and offers novel theories and targets for future research and treatment strategies.

Proton Pump Inhibitors in Patients with Cirrhosis: Pharmacokinetics, Benefits and Drawbacks.

PURPOSE OF REVIEW: This review explores the pharmacokinetics, benefits, and risks of proton pump inhibitors (PPIs) in cirrhotic patients, focusing on the appropriateness of their use and potential adverse effects. RECENT FINDINGS: Recent studies highlight significant pharmacokinetic alterations in PPIs among cirrhotic patients, with marked increases in lansoprazole and pantoprazole exposure and relatively stable levels of esomeprazole. While effective for managing acid-related disorders and post-band ulcer rebleeding, evidence supporting PPI use for portal hypertension-related bleeding is lacking. Emerging research suggests potential adverse effects such as hepatic decompensation, spontaneous bacterial peritonitis, hepatic encephalopathy, and increased mortality, possibly linked to dysbiosis and bacterial translocation. PPI use in cirrhotic patients alters pharmacokinetics significantly, with esomeprazole potentially safer in advanced cirrhosis. The review advises caution in routine PPI use beyond acid-related conditions due to limited evidence and substantial risks. It underscores the need for careful risk-benefit assessments and exploration of alternative therapies. Future research should aim to identify safer management strategies for portal hypertension complications and to develop evidence-based guidelines for PPI use in patients with cirrhosis.

Infection, inflammation and hepatic encephalopathy from a clinical perspective.

Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.

Unveiling the protective potential of mirabegron against thioacetamide-induced hepatic encephalopathy in rats: Insights into cAMP/PPAR-γ/p-ERK1/2/p S536 NF-κB p 65 and p-CREB/BDNF/TrkB in parallel with oxidative and apoptotic trajectories.

Hepatic encephalopathy (HE) is one of the most prevalent and severe hepatic and brain disorders in which escalation of the oxidative, inflammatory and apoptotic trajectories pathologically connects acute liver injury with neurological impairment. Mirabegron (Mira) is a beta3 adrenergic receptor agonist with proven antioxidant and anti-inflammatory activities. The current research pointed to exploring Mira's hepato-and neuroprotective impacts against thioacetamide (TAA)-induced HE in rats. Rats were distributed into three experimental groups: the normal control group, the TAA group, received TAA (200 mg/kg/day for three consecutive days) and the Mira-treated group received Mira (10 mg/kg/day; oral gavage) for 15 consecutive days and intoxicated with TAA from the 13th to the 15th day of the experimental period. Mira counteracted hyperammonemia, enhanced rats' locomotor capability and motor coordination. It attenuated hepatic/neurological injuries by its antioxidant, anti-apoptotic as well as anti-inflammatory potentials. Mira predominantly targeted cyclic adenosine monophosphate (cAMP)/phosphorylated extracellular signal-regulated kinase (p-Erk1/2)/peroxisome proliferator-activated receptor gamma (PPARγ) dependent pathways via downregulation of p S536-nuclear factor kappa B p65 (p S536 NF-κB p 65)/tumor necrosis alpha (TNF-α) axis. Meanwhile, it attenuated nuclear factor erythroid 2-related factor (Nrf2) depletion in parallel with restoring of the neuroprotective defensive pathway by upregulation of cerebral cAMP/PPAR-γ/p-ERK1/2 and p-CREB/BDNF/TrkB besides reduction of GFAP immunoreactivity. Mira showed anti-apoptotic activity through inhibition of Bax immunoreactivity and elevation of Bcl2. To summarize, Mira exhibited a hepato-and neuroprotective effect against TAA-induced HE in rats via shielding antioxidant defense and mitigation of the pathological inflammatory and apoptotic axis besides upregulation of neuroprotective signaling pathways.

A DNA Polymerase Subunit Gamma (POLG) Mutation Imposing a Difficult Differential Diagnosis of Hepatic Encephalopathy in a Newborn: A Case Report.

Hepatic encephalopathy (HE) is a condition connected with neuropsychiatric alteration during hepatic failure. The differential diagnosis of HE is challenging due to overlapping symptoms with other conditions. Polymerase subunit gamma (POLG) is a mitochondrial gene, and an infant POLG mutation can manifest with severe and progressive hepatic failure and encephalopathy, imposing a difficult differential diagnosis due to similarities to other conditions. The lack of curative treatment leads to a poor prognosis.  An 11-month-old boy was admitted to the intensive care unit (ICU) due to altered consciousness and increasing edema due to acute hepatic failure of unknown etiology. After extensive multidisciplinary discussions and a lack of response to treatment for more than three weeks, a mitochondrial disease was suspected, and a genetic test was taken. The patient's condition continued to deteriorate. The patient died on the 25th day of hospitalization in the ICU. After death, a genetic test confirmed a rare POLG mutation NM_002693.3(POLG):c.3104+2T>A (Variation ID: 422378 Accession: VCV000422378.8).  We suggest that a screen test for POLG mutations be considered early in the diagnostic process and that clinicians consider mitochondrial genetic mutations, such as POLG mutations, more often. This article is the first to describe a patient with this specific mutation.

Prognostic Value of High-Density Lipoprotein Cholesterol in Patients with Overt Hepatic Encephalopathy.

Overt hepatic encephalopathy (OHE), a serious complication of liver cirrhosis, is associated with alterations in lipid and lipoprotein metabolism. We evaluated the correlation between high-density lipoprotein cholesterol (HDL-C) levels and transplant-free (TF) mortality in patients with OHE. Patients with OHE admitted to Beijing Ditan Hospital between January 2010 and August 2016 (n = 821) and between September 2016 and December 2020 (n = 480) were included in the training and validation sets, respectively. Independent predictors were explored by a multivariate Cox regression analysis, and the area under the receiver operating characteristic curve (AUC) was used to assess the prognostic value of these factors. The prognostic value of HDL-C was good (AUC at 1 year: 0.745) and was equivalent to that of the Model for End-Stage Liver Disease (MELD) score (AUC at 1 year: 0.788). The optimal threshold values for HDL-C and MELD were 0.5 mmol/L and 17, respectively. The 1-year TF mortality rates in the low-risk (HDL-C ≥ 0.5 mmol/L and MELD < 17) and high-risk (HDL-C < 0.5 mmol/L and MELD ≥ 17) groups were 7.5% and 51.5% in the training set and 10.1% and 48.2% in the validation set, respectively. HDL-C level < 0.5 mmol/L and MELD score > 17 can facilitate the identification of high-risk patients and provide a basis for timely treatment.

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.

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.

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.

The causal effect of gut microbiota on hepatic encephalopathy: a mendelian randomization analysis.

BACKGROUND: There is growing evidence for a relationship between gut microbiota and hepatic encephalopathy (HE). However, the causal nature of the relationship between gut microbiota and HE has not been thoroughly investigated. METHOD: This study utilized the large-scale genome-wide association studies (GWAS) summary statistics to evaluate the causal association between gut microbiota and HE risk. Specifically, two-sample Mendelian randomization (MR) approach was used to identify the causal microbial taxa for HE. The inverse variance weighted (IVW) method was used as the primary MR analysis. Sensitive analyses were performed to validate the robustness of the results. RESULTS: The IVW method revealed that the genus Bifidobacterium (OR = 0.363, 95% CI: 0.139-0.943, P = 0.037), the family Bifidobacteriaceae (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039), and the order Bifidobacteriales (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039) were negatively associated with HE. However, no causal relationship was observed among them after the Bonferroni correction test. Neither heterogeneity nor horizontal pleiotropy was found in the sensitivity analysis. CONCLUSION: Our MR study demonstrated a potential causal association between Bifidobacterium, Bifidobacteriaceae, and Bifidobacteriales and HE. This finding may provide new therapeutic targets for patients at risk of HE in the future.

Impact of fecal microbiota transplantation in severe alcoholic hepatitis: A systematic review and meta-analysis.

Background and Aim: Severe alcoholic hepatitis (SAH) is a serious condition with few treatments. By modifying the gut-liver axis, fecal microbiota transplantation (FMT) was proposed as a treatment for SAH. The purpose of this meta-analysis was to evaluate the efficacy of FMT versus the standard of care (SOC) in improving SAH patient survival rates. Methods: A thorough search of electronic databases was conducted till September 2023. The survival rates of SAH patients undergoing FMT versus SOC were compared. Using Review Manager 5.4, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: The meta-analysis consisted of six studies with a total of 371 patients with SAH. Patients who received FMT had significantly higher survival rates at 1 and 3 months compared to those who received SOC, with pooled OR of 2.91 (95% CI: 1.56-5.42, P = 0.0008) and 3.07 (95% CI: 1.81-5.20, P < 0.0001), respectively. However, the survival advantage disappeared after 6 months (OR: 2.96, 95% CI: 0.99-8.85, P = 0.05) and 1 year of follow-up (OR: 1.81, 95% CI: 0.44-7.46, P = 0.41). Conclusion: This meta-analysis highlights the potential of FMT to significantly improve short-term survival rates in SAH patients. However, the survival benefit did not last 6-12 months. These findings call for additional research into the effectiveness of FMT over the long term, along with strategies for extending the survival benefit.