Search Results (43)

Background/Objectives: Hepatic encephalopathy (HE) significantly impairs quality of life (QoL) in patients with cirrhosis. While rifaximin is established in HE treatment and prevention, its specific impact on QoL remains less clearly defined. This systematic review aims to evaluate the effects of rifaximin on QoL in patients with HE. Methods: A comprehensive literature search was conducted in MEDLINE/PubMed, Embase, and CENTRAL through November 2025. Clinical studies evaluating rifaximin’s impact on QoL in patients with cirrhosis and minimal/covert or recurrent overt HE were included. Study selection followed PRISMA guidelines. Data extraction focused on study design, population, treatment, and QoL outcomes. Results: Out of 4343 records screened, 10 studies met the inclusion criteria. Several studies evaluated rifaximin in comparison with placebo and focused on patients with minimal or covert HE. Rifaximin was generally associated with improvements in overall and domain-specific QoL scores compared with placebo. These benefits were observed across different dosages and treatment durations. In comparative studies, rifaximin showed QoL outcomes comparable to those of lactulose, L-ornithine L-aspartate, and combination regimens. Conclusions: Rifaximin may be associated with improvements in QoL in patients with cirrhosis and HE, with benefits observed across multiple domains and outcomes broadly comparable to alternative therapies. However, given the limitations of available evidence and the heterogeneity in study designs, HE phenotypes, QoL instruments, and outcome reporting, these findings should be interpreted with caution. Further high-quality comparative trials, particularly in patients with recurrent overt HE and in prophylactic settings, are needed to confirm these findings. Full article

Overt hepatic encephalopathy (OHE) is a defining decompensation event in liver cirrhosis, associated with substantial morbidity, mortality, and high readmission rates. For the bedside clinician, managing OHE presents a complex diagnostic and investigative challenge that extends well beyond the simple administration of laxatives. This review synthesizes core recommendations from the 2022 EASL and the recent 2026 ACG guidelines to provide a structured, evidence-based framework for acute inpatient management. We emphasize that OHE diagnosis remains a clinical endeavor, where serum ammonia is valuable primarily for its high negative predictive value rather than as a confirmatory biomarker. Successful resolution hinges on a proactive ‘detective approach’ to identify and correct precipitating factors—such as infections, gastrointestinal bleeding, and iatrogenic dehydration—which drive clinical deterioration. Furthermore, we highlight the critical role of the ‘four pillars’ of management, including structured discharge planning, caregiver education, and nutritional support to ensure effective secondary prophylaxis. By bridging the gap between the latest international clinical consensus and bedside practice, this review provides essential strategies to optimize OHE management, minimize recurrence, and ultimately reduce the healthcare burden of this pleomorphic syndrome. Full article

Background and Objectives: Hepatic encephalopathy (HE) management becomes particularly challenging in older patients. This study aimed to evaluate the physician-reported diagnostic approaches, therapeutic strategies, and specific challenges in managing HE in older cirrhotic patients across Italy. Methods: A nationwide survey was conducted under the aegis of the Italian Association for the Study of the Liver (AISF). Forty-three hepatology centres participated. Data were analyzed using descriptive statistics. Results: Participating centers followed over 6000 older patients with cirrhosis, nearly one-third of whom experienced overt HE and/or minimal HE episodes in the previous year. Physicians reported that infections were the most frequently reported precipitating factor, followed by constipation and electrolyte disturbances for OHE. Half of patients with HE (50%; IQR 30.0–50.0%) experienced recurrent episodes, while 22% (IQR 10.0–30.0%) were reported to have persistent HE. In this setting, the diagnosis of HE was often complicated by cognitive decline. Treatment primarily consisted of a combination of lactulose and rifaximin, but adherence was often limited. Caregiver support emerged as a critical element in patient management. The management of comorbidities such as diabetes and chronic kidney disease was a major challenge, and nutritional screening was not routinely implemented across centres. Conclusions: This study highlights the need for better multidisciplinary management, improved caregiver support, and more consistent approaches to the diagnosis and treatment of HE in the elderly. The survey also explored how centres approach the differential diagnosis between HE and age-related cognitive disorders, the practical role of caregivers in outpatient management, and the impact of comorbidities, polypharmacy, and nutritional issues on everyday care. Marked heterogeneity emerged in psychometric assessment, multidisciplinary collaboration, and nutritional screening, indicating that several relevant aspects of care remain insufficiently standardized. Overall, the findings suggest that older patients with HE should be regarded as a distinct high-risk subgroup requiring tailored diagnostic pathways and integrated management models. Full article

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. Full article

Background and Objectives: Neuroinflammation plays a significant role in liver and neurological disorders via its disruption of neurotransmission, which alters cerebral function, resulting in cognitive and motor impairment, fatigue, anxiety, and depression. A key interaction exists between GABAergic neurotransmission and neuroinflammation, whereby excessive GABA_A receptor activation exacerbates cognitive and behavioural impairment. Golexanolone, a novel GABA_A-receptor-modulating steroid antagonist (GAMSA), primarily attenuates GABAergic potentiation via GABA_A-positive steroid allosteric receptor modulators such as allopregnanolone. This review aims to summarize new evidence showing that golexanolone improves peripheral inflammation, neuroinflammation, and neurological alterations in animal models of different neurological pathologies. We provide an overview of the first clinical trial using this novel compound. Results: In rat models of hyperammonemia and minimal hepatic encephalopathy (MHE), peripheral inflammation induces microglia and astrocyte activation and neuroinflammation, altering GABAergic neurotransmission and resulting in cognitive and motor impairment. Golexanolone’s unique dual action reduces peripheral inflammation and glial activation, thus normalizing neurotransmission and cognitive and motor function. Furthermore, a phase II study in cirrhotic patients with MHE shows that golexanolone is well tolerated and improves cognition. Similarly, in a model of primary biliary cholangitis (PBC) involving bile-duct ligation, peripheral inflammation, neuroinflammation, and altered neurotransmission—associated with fatigue, impaired memory, and locomotor gait and motor incoordination—were reversed by the dual action of golexanolone. In the Parkinson’s disease (PD) rat model induced by neurotoxin 6-OHDA, rats exhibited fatigue, anhedonia, impaired memory, and locomotor gait and motor incoordination, which were associated with microglia and astrocyte activation in the substantia nigra and striatum, in addition to tyrosine hydroxylase (TH) loss. Golexanolone reduces microglia and astrocyte activation, partially reduces TH loss, and improves fatigue, anhedonia, memory, locomotor gait, and motor incoordination. Golexanolone also normalizes elevated levels of α-synuclein. Conclusions: These findings suggest that golexanolone has beneficial therapeutic effects for treating fatigue, depression, motor, and cognitive impairment across diverse neuroinflammatory conditions, including synucleinopathies. Full article

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