Search Results (38)

Background: Hepatocellular carcinoma (HCC) is a major global health burden and a leading cause of cancer-related deaths. While aspirin has shown potential chemopreventive effects in chronic liver disease, its impact on clinical outcomes among patients hospitalized with HCC remains under-investigated. Methods: Using the National Inpatient Sample (NIS) from 2016 to 2022, we conducted a retrospective cohort study to evaluate the association between aspirin use and clinical outcomes in adult HCC hospitalizations. Patients were stratified based on documented aspirin use, and propensity score matching with inverse probability of treatment weighting (IPTW) was applied to minimize confounding. The primary outcome was in-hospital mortality; secondary outcomes included morbidity-related complications, hospital length of stay, and total charges. Results: Among 337,730 hospitalizations with HCC, 8.37% involved aspirin use. Aspirin users demonstrated significantly lower in-hospital mortality (5.2% vs. 10.09%), with an adjusted odds ratio (OR) of 0.58 (95% CI: 0.50–0.68; p < 0.001). Aspirin use was also associated with shorter hospital stays (5.42 vs. 6.39 days), lower total charges ($80,310 vs. $95,098), and reduced incidence of complications, including acute liver failure, hepatic encephalopathy, ascites, spontaneous bacterial peritonitis, sepsis, ICU admission, and acute kidney injury. Importantly, no statistically significant increase in gastrointestinal or variceal bleeding was observed among aspirin users. Conclusions: These findings suggest that aspirin use may reduce mortality, morbidity, and healthcare burden in patients hospitalized with HCC. Full article

Background: Locally acting gastrointestinal (GI) drugs present challenges for generic drug development because traditional bioequivalence measures, which rely on systemic drug levels, do not reflect local efficacy. This review examines regulatory guidelines for establishing therapeutic equivalence for such drugs, using rifaximin—a minimally absorbed, gut-localized antibiotic—as a case study. Methods: We reviewed bioequivalence guidelines from the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA), along with the literature on rifaximin’s biopharmaceutical and clinical properties, to identify strategies and challenges for establishing equivalence for locally acting GI drugs. Results: Rifaximin exemplifies the limitations of standard bioequivalence methods: as a Biopharmaceutics Classification System (BCS) class IV drug with minimal absorption and low solubility, in vitro dissolution may not predict local drug availability. Clinical endpoint trials (e.g., traveler’s diarrhea, hepatic encephalopathy, IBS-D) are resource-intensive and insensitive to formulation differences. Pharmacokinetic (PK) studies in healthy volunteers show low, variable plasma levels, which may inaccurately discriminate between formulations. The EMA requires evidence of non-saturable absorption to accept PK data, a difficult-to-establish but potentially irrelevant criterion. Differences between FDA and EMA approaches highlight a lack of harmonization, complicating global generic development. Conclusions: A tailored, multifaceted approach is needed to demonstrate bioequivalence for GI-localized drugs like rifaximin. This case underscores the need for more sensitive surrogate methods (e.g. advanced in vitro or pharmacodynamic models) and flexible regulatory criteria. Harmonization across international guidelines and innovative bioequivalence study designs are key to facilitating the approval of safe and effective generic alternatives in this drug class. Full article

Background/Objectives: Minimal hepatic encephalopathy (MHE) is a clinical condition characterized by neurological impairments, including brain inflammation, arising from the accumulation of toxic metabolites associated with liver dysfunction and leaky gut. This study investigated the pharmacological activity of a new phytocomplex extracted from red orange by-products (AL0042) using hydrodynamic cavitation and consisting of a mixture of pectin, polyphenols, and essential oils. Methods: Preliminary in vitro studies evaluated the impact on the epithelial integrity (TEER) of enterocytes challenged by a pro-inflammatory cocktail. The effect of AL0042 was then evaluated in a model of thioacetamide (TAA)-treated mice that mimics MHE. A group of 8–10-week-old male C57BL/6 mice was intraperitoneally injected with TAA to establish the MHE model. The intervention group received TAA along with AL0042 (20 mg/kg, administered orally once daily for 7 days). At the end of the treatment, the rotarod test was conducted to evaluate motor ability, along with the evaluation of blood biochemical, liver, and brain parameters. Results: In vitro, AL0042 (250 μg/mL) partially recovered the TEER values, although anti-inflammatory mechanisms played a negligible role. In vivo, compared with the control group, the test group showed significant behavioral differences, together with alterations in plasma ammonia, serum TNF-α, ALT, AST, corticosterone levels, and SOD activity. Moreover, histological data confirmed the anti-inflammatory effect at liver and brain level. Conclusions: AL0042 treatment revealed a significant therapeutic effect on the TAA-induced MHE mouse model, curbing oxidative stress and peripheral and central inflammation, thus suggesting that its pharmacological activity deserves to be further investigated in clinical studies. Full article

Purpose: Porto-systemic shunting (PSS) in patients with Abernethy malformation (AM) or obstruction of the portal vein (OVP) is often associated with normal liver parenchyma and hepatic function. This association provides an interesting natural model for studying the brain functional connectivity changes secondary to PSS but independently from hepatic (dys)function. Because PSS can be eliminated with appropriate interventions, these particular conditions offer a unique physio-pathological model where the same patient can be studied in both “active PSS” and “absent PSS” conditions (pre- and post-cure analyses). Methods: Four children (<18 years) who were evaluated for Abernethy malformation (n = 2) or portal cavernoma (n = 2) and underwent corrective surgery (living-donor liver transplantation for AM, or Meso-Rex bypass for OPV, respectively) were included in the study. Brain magnetic resonance imaging and resting-state functional magnetic resonance imaging (rest-fMRI) were acquired in all patients before and after the corrective surgery. A functional connectome analysis was performed before (“active PSS” condition) and after (“absent PSS”—physiological condition) the cure of PSS. Results: As a result of the cancelation of PSS, rest-fMRI connectomics revealed a statistically significant (p < 0.05 family-wise error) improvement in global brain functional connectivity in both groups following each surgical procedure. Conclusions: In this clinical model of isolated PSS (with absence of hepatic dysfunction), brain functional connectivity was altered even in young patients and in the absence of hyperammonemia; moreover, specific interventions to cancel out PSS consequently significantly improved brain functional connectivity. Full article

Background and Objectives: Patients with cirrhosis who seem normal during physical examinations may still have abnormalities in their electroencephalogram (EEG) or show pathological results in neuropsychological tests. This study aimed to investigate the progression of minimal hepatic encephalopathy, its effects on quality of life, its prognostic value, and its significance for daily functioning. Materials and Methods: This study involved 50 patients with confirmed cirrhosis (28 Child A, 12 Child B, 10 Child C) who were assessed for psychological symptoms and underwent several tests: the Minimal Mental State Examination (MMSE), the Letter Cancellation Test, the Digit Symbol Coding Test, and EEG. Results: showed that 40% of patients exhibited neuropsychiatric symptoms, with somatization being the most common at 96%. The MMSE revealed cognitive impairment in 48% of patients. In the Letter Cancellation Test (LCT) (total error), 80% of patients had organic disorders, and 24% showed affections with (LCT) (completion time). The Digit Symbol Coding Test results showed affection in 28% of patients. Significant EEG changes were observed in patients with Child C cirrhosis. Patients with portal hypertension (including varices and variceal bleeding), liver cell failure symptoms (such as ascites, lower limb edema, and bleeding tendency), as well as those who smoke, or obese, or have hyperlipidemia, all displayed notable EEG and psychological test abnormalities, making them more likely to develop hepatic encephalopathy. Conclusions: psychological testing and EEG changes are effective in detecting minimal hepatic encephalopathy, with a higher incidence in Child C patients compared to those in Child A and B. Full article

Background: Minimal hepatic encephalopathy (MHE) is the mildest form of hepatic encephalopathy. One of the neuropsychological tests that detects MHE is the Stroop test (via EncephalApp). The aim was to evaluate the Stroop test for the screening and diagnosis of MHE. Methods: This prospective case–control study was performed at the Clinic for Gastroenterology and Hepatology, University Clinical Center of Serbia, and included patients with cirrhosis and MHE and healthy controls. In all patients, the presence of MHE was confirmed using the animal naming test. The Stroop test was performed on each participant, and the results were compared between the two groups. The test has two components, the “OFF” and “ON” states. Results: A total of 111 participants were included. The median OFF time did not differ between the two groups, 106.3 and 91.4, p > 0.05. However, in patients with MHE, the median values of ON time and total time were significantly higher, with 122.3 vs. 105.3 and 228.0 vs. 195.6, respectively, p < 0.05. Statistical significance between patients and controls in examined parameters was detected in younger participants and the group with higher educational levels. Conclusions: The Stroop test displayed limited sensitivity in Serbian patients. Age and education affect time measurements and test performance. Full article

Hepatic encephalopathy (HE) is a common complication of advanced liver disease and acute liver failure. It is a condition that features several neuropsychiatric symptoms that affect mortality, morbidity and the quality of patients’ and caregivers’ lives. An HE diagnosis is generally an exclusion diagnosis. Once the patient is admitted to the hospital, clinical examination, blood tests and eventually neuroimaging should be performed with the aim of ruling out other causes of acute brain dysfunction. Moreover, HE is recognized using various precipitants that can potentially promote its onset, alone or in combination, and must be identified. Once the diagnostic process is complete, a correct treatment should be started. The anti-HE treatment is based on a combination of the correction of precipitants; non-absorbable antibiotics, such as rifaximin; and non-absorbable disaccharides. Once the patient is discharged from the hospital, specific anti-HE therapy should be maintained in order to prevent other HE episodes. Full article

In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic encephalopathy. The underlying mechanisms are not yet completely clarified. It is well known that portal hypertension causes mesenteric congestion which produces reactive oxygen species (ROS). ROS has been associated with intestinal mucosal injury, increased intestinal permeability, enhanced gut bacterial overgrowth, and translocation; all these changes result in increased endotoxin and inflammation. Portal hypertension also results in the development of collateral circulation and reduces liver mass resulting in an overall increase in endotoxin/bacteria bypassing detoxication and immune clearance in the liver. Endotoxemia can in turn aggravate oxidative stress and inflammation, leading to a cycle of gut barrier dysfunction → endotoxemia → organ injury. The phenotype of cardiovascular abnormalities includes hyperdynamic circulation and cirrhotic cardiomyopathy. Oxidative stress is often accompanied by inflammation; thus, blocking oxidative stress can minimize the systemic inflammatory response and alleviate the severity of cardiovascular diseases. The present review aims to elucidate the role of oxidative stress in cirrhosis-associated cardiovascular abnormalities and discusses possible therapeutic effects of antioxidants on cardiovascular complications of cirrhosis including hyperdynamic circulation, cirrhotic cardiomyopathy, and hepatorenal syndrome. Full article

It is a matter of current interest which rifaximin-α regimens in patients with liver cirrhosis and minimal hepatic encephalopathy are the most efficient. Study objective: to evaluate the effect of various rifaximin-α regimens for 12 months on clinical and laboratory parameters and quality of life in patients with liver cirrhosis and minimal hepatic encephalopathy. Methods. It was a multicenter, prospective, open-label, observational study that included 288 patients with liver cirrhosis and minimal hepatic encephalopathy of both sexes over the age of 18 years, who were prescribed a 12-month course of treatment with rifaximin-α in accordance with the product label. Statistical analysis was performed in the population of patients who completed all visits according to the protocol (n = 258). Retrospectively, the patients were divided into two subgroups: subgroup 1 (continuous course)—patients who received the study drug for a year and the number of days of administration was 360 days (n = 41); subgroup 2 (cyclic course)—patients who received the study drug during the year for less than 360 days (n = 217). At each of the 4 visits, the quality of life was assessed using the CLDQ questionnaire, the time to perform the number connection test, the severity of symptoms associated with hepatic encephalopathy, and laboratory parameters. Results. During the 12-month observation period, an increase in the total score on the CLDQ quality of life questionnaire in patients with chronic liver diseases was revealed, which indicates an improvement in the quality of life of patients receiving rifaximin-α therapy. When patients were divided into subgroups depending on the duration of therapy, some benefits of continuous rifaximin-α therapy were noted in the more pronounced dynamics of decrease in the time to perform the number connection test, and in decreased severity of the following symptoms associated with hepatic encephalopathy: impaired concentration and memory, cognitive impairment, and decreased performance. Laboratory findings showed positive dynamics in both subgroups. Conclusion. A continuous rifaximin-α regimen in patients with liver cirrhosis and minimal hepatic encephalopathy for 12 months was superior to cyclic use with a more pronounced effect on the quality of life of patients and on the symptoms associated with hepatic encephalopathy. Full article

Neurofilament light chain protein (NfL) levels reflect neuronal damage in several neurological diseases and have been proposed as a possible biomarker. Plasma extracellular vesicles (EVs) could play an important role as mediators of the inflammatory changes associated with inducing minimal hepatic encephalopathy (MHE) in cirrhotic patients. This study investigated the association of NfL levels in plasma and EVs with the presence of MHE in cirrhotic patients, and with responses to rifaximin treatment. The NfL levels in plasma and EVs were assessed in 71 patients with liver cirrhosis (40 with MHE and 31 without MHE) and 26 controls. A total of 31 patients with MHE received rifaximin treatment. We examined changes in NfL levels in plasma and EVs before and after 6 months of rifaximin treatment. The NfL measures were correlated with cognitive alterations and plasma inflammatory cytokines. MHE patients showed increased plasma levels of NfL, which were reverted after rifaximin treatment in patients who responded to treatment. The NfL content in EVs also showed a reversal pattern in MHE patients treated with rifaximin. In multivariable analyses, NfL levels were independently associated with the presence of MHE. We also showed that patients with high levels of both ammonia and fractalkine had significantly higher NfL levels than patients with low levels of least one of these parameters. Rifaximin treatment in MHE patients showed promising results in improving axonal damage, suggesting that rifaximin may have therapeutic benefits against disease progression in MHE. Full article

This article presents an automatic gaze-tracker system to assist in the detection of minimal hepatic encephalopathy by analyzing eye movements with machine learning tools. To record eye movements, we used video-oculography technology and developed automatic feature-extraction software as well as a machine learning algorithm to assist clinicians in the diagnosis. In order to validate the procedure, we selected a sample ($n=47$) of cirrhotic patients. Approximately half of them were diagnosed with minimal hepatic encephalopathy (MHE), a common neurological impairment in patients with liver disease. By using the actual gold standard, the Psychometric Hepatic Encephalopathy Score battery, PHES, patients were classified into two groups: cirrhotic patients with MHE and those without MHE. Eye movement tests were carried out on all participants. Using classical statistical concepts, we analyzed the significance of 150 eye movement features, and the most relevant (p-values ≤ 0.05) were selected for training machine learning algorithms. To summarize, while the PHES battery is a time-consuming exploration (between 25–40 min per patient), requiring expert training and not amenable to longitudinal analysis, the automatic video oculography is a simple test that takes between 7 and 10 min per patient and has a sensitivity and a specificity of 93%. Full article

(1) Background: Minimal hepatic encephalopathy (MHE) is an important complication of decompensated cirrhosis. Previous studies have demonstrated spontaneous brain activity alterations in cirrhotic patients with MHE. However, the reported results are inconsistent, which has limited our understanding of the potential neural mechanisms. Thus, we conducted a quantitative meta-analysis of resting-state functional imaging studies to identify the regional activity alterations consistently involved in MHE. (2) Methods: We searched six databases to include resting-state functional imaging studies and compared spontaneous brain activity patterns between MHE patients and healthy controls (HCs), and between cirrhotic patients without minimal hepatic encephalopathy (NMHE) and HCs. Then, a separate whole-brain voxel-wise meta-analysis between MHE or NMHE patients and HCs was conducted using seed-based d mapping with permutation of subject images. We further conducted the conjunction analysis to assess the distinct regional activity alterations between MHE and NMHE patients as compared to HCs. (3) Results: Thirteen studies with twenty datasets were included in this meta-analysis. Compared with HCs, MHE patients showed decreased spontaneous brain activity in the left superior frontal gyrus, left median cingulate/paracingulate gyri, and right precuneus. Compared with NMHE patients, MHE patients indicated decreased spontaneous brain activity in the left superior frontal gyrus, left median cingulate/paracingulate gyri, and right precuneus. (4) Conclusions: MHE is associated with spontaneous brain activity alterations involving the left superior frontal gyrus and median cingulate/paracingulate gyri, which may implicate primarily in spatial working memory and emotional disorders. These findings may contribute to a better understanding of the potential neural mechanisms, and guide further research. Full article

Hepatic encephalopathy (HE) is a common complication in patients with advanced liver disease. It is a brain dysfunction characterized by neurological and psychiatric symptoms that significantly affects quality of life, morbidity and mortality of patients. HE has various precipitants that can potentially promote its onset, alone or in combination. Among the historically well-known precipitants, such as infections, gastrointestinal bleeding, dehydration, electrolyte disorders and constipation, recent studies have highlighted the role of malnutrition and portosystemic shunts as new precipitating factors of HE. The identification, management and correction of these factors are fundamental for effective HE treatment, in addition to pharmacological therapy with non-absorbable disaccharides and/or antibiotics. Full article

Hepatic encephalopathy (HE) is one of the main complications of liver cirrhosis (LC) and is classified into minimal hepatic encephalopathy (MHE) and overt hepatic encephalopathy (overt HE). S100B is expressed mainly in astrocytes and other glial cells, and S100B has been reported to be associated with various neurological disorders. The present study aimed to investigate the diagnostic ability of serum S100B to discriminate the grade of HE and the parameters correlated with serum S100B levels. Additionally, we investigated whether serum S100B levels can be used to predict 1-year mortality in cirrhotic patients. In total, 95 cirrhotic patients were consecutively enrolled and divided into the following three groups: (i) without any types of HEs; (ii) with MHE; and (iii) with overt HE. The diagnosis of MHE was made by the Mini-Mental State Examination (MMSE) and Psychometric Hepatic Encephalopathy Score (PHES). Among the three groups, there were no significant differences in serum S100B levels regardless of HE severity. The clinical parameters correlated with serum S100B levels were age, serum bilirubin, and creatinine levels. The Model for End-Stage Liver Disease (MELD) score showed a significant positive correlation with serum S100B levels. The relationship between serum S100B levels and MELD score was maintained in 48 patients without any type of HE. Additionally, hyperammonemia, low cholesterol levels, and the combination of serum S100B levels ≥ 35 pg/mL with MELD score ≥ 13 were factors for predicting 1- year mortality. In conclusion, serum S100B level was not useful for differentiating the severity of HE. However, we found that serum S100B levels can be affected by age, serum bilirubin, and creatinine in cirrhotic patients and are associated with MELD scores. Additionally, serum S100B levels showed the possibility of predicting 1-year mortality in cirrhotic patients. These findings suggest that serum S100B levels may reflect liver dysfunction and prognosis in liver disease. Full article

The psychometric hepatic encephalopathy score (PHES) is the gold standard for diagnosing minimal hepatic encephalopathy (MHE). Screening for MHE is frequently overlooked in clinical practice due to time constraints. Furthermore, the simplified animal naming test (S-ANT1) is a new simple tool for evaluating MHE in cirrhotic patients. The purpose of this study was to standardize the PHES in a healthy Thai population, assess the prevalence of MHE, and validate the S-ANT1 in detecting MHE in patients with cirrhosis. The study included 194 healthy controls and 203 cirrhotic patients without overt HE. Psychometric tests and the S-ANT1 were administered to all participants. Multiple linear regression was used to analyze factors related to PHES results, and formulas were developed to predict the results for each PHES subtest. In healthy controls, age and education were predictors of all five subtests. The PHES of the control group was −0.26 ± 2.28 points, and the threshold for detecting MHE was set at ≤ −5 points. The cirrhotic group had PHES values of −2.6 ± 3.1 points. Moreover, MHE was found to be present in 26.6% of cirrhotic patients. S-ANT1 had a moderate positive correlation with PHES (r = 0.44, p < 0.001). S-ANT1 < 22 named animals detected MHE with a sensitivity of 71.2%, specificity of 65%, and area under the receiver operating curve of 0.68 (p < 0.001). In conclusion, Thai PHES normative data have been developed to detect MHE in cirrhotic patients who do not have overt HE. The optimal cutoff for detecting MHE in Thai cirrhotic patients was PHES ≤ −5 points and S-ANT1 < 22 named. Full article