Search Results (251)

Background/Objectives: SLC13A5 encodes a sodium–citrate cotransporter implicated in early-onset epileptic encephalopathy and metabolic brain dysfunction, yet its developmental regulation and molecular context in the human brain remain incompletely defined. Methods: Leveraging human developmental transcriptomes from the Evo-Devo resource, we delineated tissue trajectories and network context for SLC13A5 across the fetal–postnatal life. Results: In the cerebrum, SLC13A5 expression rises from late fetal stages to peak in the first postnatal year and then declines into adulthood, while cerebellar levels increase across the lifespan; liver shows a fetal decrease followed by sustained postnatal upregulation. A transcriptome-wide scan identified extensive positive and negative associations with SLC13A5, and a signed weighted gene co-expression network analysis (WGCNA) built on biweight midcorrelation placed SLC13A5 in a large module. The module eigengene tracked brain maturation (Spearman rho = 0.802, p = 8.62 × 10⁻⁶) and closely matched SLC13A5 abundance (rho = 0.884, p = 2.73 × 10⁻⁶), with a significant partial association after adjusting for developmental rank (rho = 0.672, p = 6.17 × 10⁻⁴). Functional enrichment converged on oxidative phosphorylation and mitochondria. A force-directed subnetwork of the top intramodular members (|bicor| > 0.6) positioned SLC13A5 adjacent to a densely connected nucleus including CYP46A1, ITM2B, NRGN, GABRD, FBXO2, CHCHD10, CYSTM1, and MFSD4A. Conclusions: Together, these results define a developmentally tuned, mitochondria-centered program that co-varies with SLC13A5 in the human brain across the lifespan. It may provide insights to interrogate age-dependent phenotypes and therapeutic avenues for disorders involving citrate metabolism. Full article

Seipin, a protein encoded by the BSCL2 gene, plays a crucial role in lipid metabolism, and some pathogenic biallelic variants cause lipodystrophy and associated metabolic disorders. This study investigates liver pathology and dysregulation of the FGF21 signalling pathway in two mouse models: Bscl2^−/− (knock-out) and Bscl2^Celia/Celia (knock-in). We evaluated liver histopathology using H&E and Oil red O staining, assessed hepatic triglyceride levels via enzymatic assays, and analyzed gene expression of key FGF21-related components (Fgf21, Ppargc1a, Fgfr1, and Klb) using quantitative real-time PCR. The liver histology was scored using the NAFLD activity score (NAS) system. Both models exhibited hepatic steatosis and inflammatory features. The Bscl2^−/− mice showed more pronounced liver damage, including ballooning degeneration and fibrosis. Gene expression analysis revealed a significant increase in Fgf21 in both models, suggesting an adaptive response to liver injury. Notably, Fgfr1 and Ppargc1a expression was moderately elevated in severe neurologically affected mice showing less hepatic involvement, suggesting a potential adaptive or protective association of these genes with reduced steatosis. Seipin deficiency leads to metabolic-associated steatotic liver disease and dysregulated FGF21 signalling. These findings provide insight into the pathophysiological mechanisms of lipodystrophy and liver disease and suggest that the FGF21 pathway could be a therapeutic target for treating seipin-related metabolic disorders. Full article

Background/Objectives: Sarcopenia and frailty are prevalent and independently prognostic in cirrhosis. Few studies have evaluated both together to ascertain their interaction and phenotypic differences. None have studied their relationship with resting energy expenditure (REE). We simultaneously examined sarcopenia, frailty and REE in a cohort of patients with cirrhosis and portal hypertension—a novel approach. Methods: We retrospectively studied consecutive patients with cirrhosis and portal hypertension, prospectively recruited between 2015 and 2018 to undergo sarcopenia (transversal psoas muscle thickness [TPMT]/height), frailty (Fried Frailty Index [FFI]), and REE assessments via indirect calorimetry. The primary outcome was transplant-free survival (TFS). Results: Ninety-seven patients were recruited with sarcopenia and frailty present in 26% and 40%, respectively. Patients with sarcopenia or frailty alone were phenotypically similar except those with sarcopenia had lower median body mass index (BMI) (23 vs. 28 kg/m², p = 0.032) and were more likely to be hypermetabolic (60% vs. 0%, p = 0.017). Median TFS was lower in patients with sarcopenia (3.6 months) or frailty (4.5 months), compared to those with neither (10.3 months), while patients with both sarcopenia and frailty exhibited the worst TFS (1.8 months, log-rank p = 0.001). Independent predictors of death or liver transplant were sarcopenia, hepatic encephalopathy, and a higher model for end-stage liver disease score. Conclusions: In patients with cirrhosis and portal hypertension, sarcopenia and physical frailty are related but have differences in BMI and REE. The deleterious impact of sarcopenia and frailty on TFS are additive. Sarcopenia remains an independent predictor of TFS after adjusting for frailty. Full article

Objectives: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of cirrhosis within the spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the prognostic impact of diabetes mellitus (DM) in MASH-associated cirrhosis remains unclear. This study aimed to compare clinical outcomes between cirrhotic patients with and without DM. Methods: Patients with MASH-related cirrhosis were stratified into DM (DM-MASH) and non-DM (non-DM MASH) groups. The diagnosis of MASH was based on histological evidence of steatohepatitis with underlying metabolic dysfunction. The non-DM group included both obese individuals and lean/normal-weight individuals with ≥1 metabolic risk factors. Mortality, liver-related events (LREs; ascites, variceal bleeding, encephalopathy, and hepatocellular carcinoma), and sarcopenia were compared using Kaplan–Meier analysis, log-rank tests, and Fisher’s exact test. Risk factors for sarcopenia were assessed using logistic regression. Results: Median survival was significantly shorter in DM-MASH patients compared to non-DM MASH patients (1523 vs. 2618 days; p < 0.05). The incidence of LREs during follow-up was also higher in the DM-MASH group. The prevalence of sarcopenia was significantly greater among DM-MASH patients (36.1% vs. 19.7%; p < 0.05). In multivariate analysis, DM emerged as an independent predictor of sarcopenia in patients with MASH-related cirrhosis. Conclusions: DM is associated with worse outcomes in MASH-driven cirrhosis, including increased sarcopenia and reduced survival. DM may serve as a prognostic marker for identifying high-risk patients with MASH-associated cirrhosis. 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

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

Sarcopenia, the loss of skeletal muscle mass and function, is a common and critical comorbidity in patients with conditions frequently managed by interventional radiologists, such as liver cirrhosis and hepatocellular carcinoma (HCC). Interventional radiologists are well positioned to incorporate opportunistic screening for this condition during routine preprocedural cross-sectional imaging. This review summarizes the current evidence on how sarcopenia influences patient outcomes and informs procedural planning across a spectrum of interventional radiology (IR) procedures. In transarterial embolizations for HCC, sarcopenia is a robust independent predictor of increased mortality, with meta-analyses suggesting it may also predict a lower tumor response rate. Even earlier stages of muscle loss (pre-sarcopenia) are associated with worse survival, and dynamic changes in muscle mass post-treatment can serve as a biomarker for tumor progression. For patients undergoing transjugular intrahepatic portosystemic shunt, pre-procedural sarcopenia and myosteatosis are strong, independent predictors of both mortality and the development of post-procedural hepatic encephalopathy, with the presence of both conferring the highest risk. In the context of pre-surgical portal vein embolization, sarcopenia is consistently associated with impaired volumetric liver growth, although this does not always translate to worse short-term surgical outcomes, as functional liver regeneration may be preserved. Following percutaneous liver tumor ablation, sarcopenia is a powerful predictor of overall mortality, while its role in predicting tumor recurrence remains an area of active investigation. Finally, in non-oncologic interventions for peripheral arterial disease, sarcopenia is highly prevalent and is associated with worse functional status, higher mortality, and a significantly increased risk of major amputation after endovascular therapy. In conclusion, sarcopenia is a powerful and readily available biomarker that provides crucial prognostic information—often independent of standard clinical scores—across a wide spectrum of IR procedures. The consistent evidence supports integrating sarcopenia evaluation into routine practice to enhance risk stratification, improve patient counseling, and guide multidisciplinary treatment planning. Full article

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

Background/Objectives: Oxidative stress is a central mechanism in the pathogenesis of cirrhosis, yet its clinical significance relative to established predictors remains unclear. Methods: We conducted a retrospective cohort study of 90 patients with cirrhosis hospitalized between October 2024 and March 2025. Clinical data, biochemical parameters, systemic inflammatory indices, and oxidative stress markers [malondialdehyde (MDA), 8-epi-prostaglandin F2α (8-epi-PGF2α)] were assessed at admission. Statistical analyses included non-parametric group comparisons, Spearman correlations, logistic regression with interaction terms, ROC analysis with bootstrap confidence intervals, model calibration and discrimination metrics, reclassification indices (NRI, IDI), and decision curve analysis (DCA). Results: Patients with advanced encephalopathy (HE3) had significantly higher MDA levels compared with HE1 (123.4 [107.6–248.4] vs. 131.0 [66.9–301.1] ng/mL; p = 0.021), while 8-epi-PGF2α showed a non-significant but consistent trend. Both oxidative markers correlated with biochemical dysfunction (MDA with INR and albumin; 8-epi-PGF2α with direct bilirubin). ROC analyses demonstrated modest discriminative ability (AUC 0.55–0.60) compared with albumin (AUC 0.74–0.90) and INR (AUC 0.72–0.88). In regression models, albumin remained the strongest independent predictor, whereas oxidative markers did not retain significance. Interaction models suggested that oxidative stress exerted context-dependent effects, particularly in patients with elevated inflammatory indices. Incremental predictive value beyond age and albumin was minimal (ΔAUC ≤ 0.01; NRI + 2–4%). DCA confirmed no added clinical utility. Conclusions: Classical clinical markers, particularly albumin and INR, dominate predictive accuracy in cirrhosis. Oxidative stress markers lack independent predictive power but consistently associate with worsening encephalopathy and liver dysfunction, underscoring their biological relevance and suggesting their role is best understood in conjunction with systemic inflammation. Full article

Malnutrition, sarcopenia, and frailty are highly prevalent in patients with chronic liver disease and are closely associated with poor clinical outcomes. This review highlights the complex interplay between macronutrient metabolism and muscle wasting in liver cirrhosis. We explore the alterations in glucose, lipid, and amino acid metabolism that occur in cirrhosis, including the role of skeletal muscle in compensatory ammonia detoxification. The review also discusses the emerging evidence on sarcopenia as a prognostic marker and therapeutic target, with a focus on the role of branched-chain amino acid (BCAA) supplementation. While several studies have demonstrated the clinical benefits of BCAA in improving muscle mass, hepatic encephalopathy, and quality of life, results remain mixed, emphasizing the need for further well-designed clinical trials. Understanding the muscle–liver–gut axis may offer novel insights into therapeutic strategies for managing sarcopenia in liver disease. Full article

Background: Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of advanced liver disease, driven primarily by ammonia accumulation due to impaired hepatic detoxification and portosystemic shunting. Lactulose is a cornerstone therapy, while rifaximin serves as an effective adjunct for reducing recurrence and hospitalizations. Methods: We conducted a retrospective cohort study at Constanța Emergency County Hospital from January 2022 to March 2025, including 120 adult patients diagnosed with HE. Inclusion criteria were confirmed diagnosis of cirrhosis with clinical and/or biochemical evidence of HE. Patients with other primary neurological disorders or incomplete medical records were excluded. Data on demographics, comorbidities, laboratory results, and medications were collected. Statistical analyses were performed employing descriptive statistics, Friedman’s two-way ANOVA by ranks for medication use, and Cox proportional hazards regression to assess survival associations. Results: The mean age was 61.19 years, with high prevalence of anemia (mean hemoglobin: 9.35 g/dL) and thrombocytopenia (mean: 121.86 × 10³/µL). Inflammatory markers were elevated (mean CRP: 36.95 mg/L; ESR: 55.83 mm/h), and INR averaged 1.86. Lactulose was administered to 63.3% of patients, rifaximin to 52.5%, with diuretics, pantoprazole, and albumin being frequently used. Friedman’s analysis ranked lactulose highest in usage frequency. Cox regression indicated no significant short-term survival difference associated with toxic encephalopathy or rifaximin use. Conclusion: In this cohort, lactulose remained the primary treatment for HE, often complemented by supportive pharmacotherapy. While rifaximin use was limited, the overall medication patterns reflected standard practice priorities in HE management. Full article

Novel coronavirus (SARS-CoV-2) is highly infectious and pathogenic. Novel coronavirus infection can not only cause respiratory diseases but also lead to multiple organ damage through direct or indirect mechanisms, in which the liver is one of the most frequently affected organs. It has been reported that 15–65% of coronavirus disease 2019 (COVID-19) patients experience liver dysfunction, mainly manifested as mild to moderate elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Severe patients may progress to liver failure, develop hepatic encephalopathy, or have poor coagulation function. The mechanisms underlying this type of liver injury are complex. Pathways—including direct viral infection (via ACE2 receptors), immune-mediated responses (e.g., cytokine storm), ischemic/hypoxic liver damage, thrombosis, oxidative stress, neutrophil extracellular trap formation (NETosis), and the gut–liver axis—remain largely speculative and lack robust clinical causal evidence. In contrast, drug-induced liver injury (DILI) has been established as a well-defined causative factor using the Roussel Uclaf Causality Assessment Method (RUCAM). Treatment should simultaneously consider antiviral therapy and liver protection therapy. This article systematically reviewed the mechanism, clinical diagnosis, treatment, and management strategies of COVID-19-related liver injury and discussed the limitations of current research and the future directions, hoping to provide help for the diagnosis and treatment of such patients. Full article

Objectives: Rifaximin is a non-absorbable antibiotic that has an efficacy for hepatic encephalopathy (HE). We previously demonstrated that rifaximin improved liver functional reserve, but this was a single-center study with a limited number of cases, and there were few cases of long-term use. Here, we conducted a multicenter study to evaluate the efficacy of long-term rifaximin administration on the liver functional reserve. Methods: A multicenter retrospective study was conducted on cirrhotic patients who received rifaximin for more than 12 months. We evaluated the efficacy of long-term rifaximin administration on the liver functional reserve. Results: A total of 65 cirrhotic patients were enrolled. Administration of rifaximin for 12 months significantly improved the Child–Pugh score (CPS) and albumin–bilirubin (ALBI) score. Regarding the parameters of the CPS, albumin scores significantly improved in addition to HE scores at 12 months. Univariate and multivariate analysis revealed that high C-reactive protein (CRP) levels (>0.69 mg/dL) at baseline were the predictive factor for improvement in the liver functional reserve. Conclusions: This study suggests that long-term rifaximin administration may improve the liver functional reserve in cirrhotic patients through improvement in albumin levels. CRP levels predict improvement in the liver functional reserve. Full article

Background/Objectives: Hepatic encephalopathy (HE) is a severe neurological complication of acute liver failure (ALF) characterized by the accumulation of neurotoxic metabolites and impaired cerebral function. We aimed to examine the correlation between HE severity and cerebrospinal fluid (CSF) biomarker levels in a rat model of ALF induced by subtotal hepatectomy. Methods: Male Wistar rats underwent 92% hepatectomy and were monitored for neurological impairment via a standardized HE score. At twenty-four hours post surgery, CSF and blood were collected for biochemical analysis. Results: We found a significant positive correlation between neurological severity and CSF levels of glutamine (r = 0.929, p < 0.001) and albumin (r = 0.869, p < 0.001), both with HE grade I scores, highlighting their prominent role as HE biomarkers. Other amino acids, including aspartate (r = 0.790, p < 0.001), glutamate (r = 0.853, p < 0.001), isoleucine (r = 0.834, p < 0.001), leucine (r = 0.813, p < 0.001), lysine (r = 0.861, p < 0.001), methionine (r = 0.889, p < 0.001), phenylalanine (r = 0.916, p < 0.001), ornithine (r = 0.775, p < 0.001), tryptophan (r = 0.814, p < 0.001), and valine (r = 0.721, p < 0.001), also showed significant correlations with HE severity but not with HE grade I scores. Conclusions: These findings underscore the potential of glutamine and albumin in CSF as key biomarkers for assessing neurological severity in ALF patients. Full article