Genipin protects against acute liver injury by abrogating ferroptosis via modification of GPX4 and ALOX15-launched lipid peroxidation in mice.

It is essential to further characterize liver injury aimed at developing novel therapeutic approaches. This study investigated the mechanistic basis of genipin against carbon tetrachloride (CCl4)-triggered acute liver injury concerning ferroptosis, a novel discovered modality of regulated cell death. All experiments were performed using hepatotoxic models upon CCl4 exposure in mice and human hepatocytes in vitro. Immunohistochemistry, immunoblotting, molecular docking, RNA-sequencing and ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) were conducted. CCl4 intoxication was manifested with lipid peroxidation-dictated ferroptotic cell death, together with changes in a cascade of ferroptosis-associated events and several regulatory pathways. Both the administration of genipin and ferrostatin-1 (Fer-1) significantly prevented this hepatotoxicity in response to CCl4 intoxication via upregulating GPX4 and xCT (i.e., critical regulators of ferroptosis). RNA-sequencing unraveled that arachidonic acid metabolism was considerably influenced upon genipin treatment. Accordingly, genipin treatment attenuated arachidonate 15-lipoxygenase (ALOX15)-launched lipid peroxidation in terms of UHPLC-MS/MS analysis and inflammation. In vitro, genipin supplementation rescued erastin-induced hepatocellular inviability and lipid ROS accumulation. The siRNA knockdown of GPX4 partially abrogated the protective effects of genipin on erastin-induced cytotoxicity, whereas the cytotoxicity was less severe in the presence of diminished ALOX15 expression in L-O2 cells. In conclusion, our findings uncovered that genipin treatment protects against CCl4-triggered acute liver injury by abrogating hepatocyte ferroptosis, wherein the pharmacological modification of dysregulated GPX4 and ALOX15-launched lipid peroxidation was responsible for underlying medicinal effects as molecular basis.

Accumulating awareness on the clinical significance and relevance of frailty in cirrhosis: Time to dig deeper into mechanistic basis!

Frailty corresponds to an emerging construct in the hepatology which is originally introduced as a validated geriatric syndrome regarding increased vulnerability to pathophysiological stressors. As for patients with cirrhosis, the presence of frailty is indicative of debilitating conditions that subjects are prone to deleterious acute insults and have difficulties to restore even if the underlying liver function partially returned to normal levels. Since this conceptual development, a variety of tools assessing frailty have been proposed and evaluated in the context of cirrhosis. A recent performance-based metric for frailty, designated as Liver Frailty Index, has broadly been applied in patients with cirrhosis and exhibited acceptable predictive ability in relation to disease progression, mortality and hospitalization. However, those functional tests measuring frailty may be impossible to perform in circumstance that patients are critically ill or undergoing detrimental events. An interesting modality indicates the use of alternative tests to evaluate frailty, which may be more adaptable and of choice for specific subgroups. The interrelation between frailty and various cirrhosis-associated pathological entities is of clinical importance and implication. Noticeably, it is imperative to clarify these complex linkages to highlight novel therapeutic targets or interventional endpoints. The efficient and effective management of frailty is still challenging, but many attempts have been made to overcome barriers of affordability and availability. Some clinical trials on small scale revealed that home-based exercise and individualized nutrition therapy show benefits in patients with cirrhosis, and high adherence to the treatment regimen may direct better efficacy and performance.

The relationship between patient-reported health-related quality of life and malnutrition risk in cirrhosis: an observational cohort study.

Patients with cirrhosis experience worse health-related quality of life (HRQoL), and attempts are warranted further exploration of modifiable factors to improve HRQoL. Data on the impact of malnutrition risk on HRQoL among cirrhosis are limited; thus, we aimed to strengthen understanding by clarifying the relationship between nutritional status and low HRQoL in patients with decompensated cirrhosis. Consecutive inpatients with cirrhosis attending our department within a tertiary hospital were studied. Generic health profiles and malnutrition risk were evaluated by the EuroQol-5D (EQ-5D) and Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT) score, respectively. Multiple linear regression analysis was used to determine association of malnutrition risk with low HRQoL. In this cohort of 364 patients with median age of 64 years and 49·5 % male, 55·5 % of the study population reported impairment pertinent to HRQoL in at least one dimension in terms of the EQ-5D. Moreover, malnutrition risk (RFH-NPT score: ß coefficient = -0·114, P = 0·038) was proved to be independently associated with poor HRQoL in multiple analysis, after adjustment for significant variables like age, BMI and markers of decompensation. Notably, we found that health dimensions representing physical function (i.e. mobility, self-care and usual activities) are substantially affected, while malnourished patients reported less frequencies of complaints in other domain such as anxiety/depression. In conclusion, the risk of malnutrition assessed by the RFH-NPT score is independently associated with low HRQoL. It is operational to improve HRQoL by identifying patients at high malnutrition risk and providing timely nutrition treatment.

Coexistent GLIM-Defined Malnutrition and Sarcopenia Increase the Long-Term Mortality Risk in Hospitalized Patients with Decompensated Cirrhosis.

INTRODUCTION: The synergistic impact of coexistent malnutrition and sarcopenia on morality in hospitalized patients with decompensated cirrhosis remains elusive. This prospective cohort study aimed to delineate the prevalence concerning coexistence of malnutrition and sarcopenia and the prognosticating role on long-term mortality among cirrhosis. METHODS: Adult cirrhotic patients with decompensated episodes between 2019 and 2021 were consecutively enrolled. Malnutrition and sarcopenia were diagnosed according to the Global Leadership Initiative on Malnutrition (GLIM) criteria and the European Working Group on Sarcopenia in Older People (EWGSOP2) algorithm, respectively. The entire cohort was divided into three groups: non-malnutrition and non-sarcopenia (NN), malnutrition or sarcopenia, and coexistent malnutrition and sarcopenia (MS). Log-rank test and multivariate Cox regression model were utilized to evaluate survival status and independent risk factors for mortality, respectively. RESULTS: Our findings indicated that malnutrition manifested in 44.6% of inpatients with decompensated cirrhosis, while sarcopenia presented in 16.4% of the entire cohort, indicative of a prevalence of 14.7% regarding coexistent malnutrition and sarcopenia. The Kaplan-Meier graphic demonstrated a significant difference regarding survival curves among the three groups, referring to the MS group presented with the lowest survival rate (log-rank test: p < 0.001). Moreover, coexistent malnutrition and sarcopenia were associated with nearly 4 times higher mortality risk (model 1: hazard ratio [HR] = 3.31, 95% confidence interval [CI]: 1.20-9.13, p = 0.020; model 2: HR = 4.34, 95% CI: 1.52-12.4, p = 0.006) in comparison with patients without any condition (NN group). CONCLUSIONS: Malnutrition and sarcopenia had superimposed negative impacts on inpatients with decompensated cirrhosis. It is imperative to identify this vulnerable subset to provide prompt therapeutic intervention for better prognosis.

Reduced muscle strength is closely linked to computed tomography-defined myosteatosis among inpatients with cirrhosis.

BACKGROUND: Myosteatosis indicates pathological fat infiltration in muscles and is regarded as a distinct disease from sarcopenia. This muscular condition exhibits a link to muscle fiber disarrangement coinciding with disrupted muscle contractility and weakened mechanical action, mirrored as decreased muscle quality. However, the relationship between handgrip strength (HGS) and computed tomography-defined myosteatosis among cirrhosis is unclear. We aimed to investigate the association between HGS and myosteatosis and determine gender-specific cutoffs regarding HGS to identify myosteatotic subjects. METHODS: We prospectively recruited 221 cirrhotic patients. The presence of myosteatosis was determined according to intramuscular adipose tissue content. The relationship between HGS and myosteatosis was evaluated according to Spearman correlation coefficient, area under the ROC curve, and multivariate logistic regression analysis. Moreover, a model based on the classification and regression tree method was generated. RESULTS: Our results showed that HGS exhibits modestly negative correlation with intramuscular adipose tissue content in the entire cohort (rs = -0.269, P < .001) and across diverse subgroups precluding extremely deteriorating conditions. After controlling for multiple clinical features and biochemical parameters, HGS (odds ratio = 0.921, P = .010) was independently associated with myosteatosis in addition to age and body mass index. On applying the Japan Society of Hepatology-recommended cutoffs, an area under the ROC curve of HGS was 0.627 with a sensitivity of 77.4% and a specificity of 47.9%. The decision tree including body mass index and low HGS correctly classified ~85% of the cases in development and validation sets. CONCLUSIONS: HGS was in close relation to myosteatosis among inpatients with cirrhosis.

The potential role of FNDC5/irisin in various liver diseases: awakening the sleeping beauties.

Fibronectin type III domain-containing protein 5 (FNDC5) is a transmembrane protein and the precursor of irisin, which serves as a systemic exerkine/myokine with multiple origins. Since its discovery in 2012, this hormone-like polypeptide has rapidly evolved to a component significantly involved in a gamut of metabolic dysregulations and various liver diseases. After a decade of extensive investigation on FNDC5/irisin, we are still surrounded by lots of open questions regarding its diagnostic and therapeutic values. In this review, we first concentrated on the structure-function relationship of FNDC5/irisin. Next, we comprehensively summarised the current knowledge and research findings regarding pathogenic roles/therapeutic applications of FNDC5/irisin in the context of non-alcoholic fatty liver disease, fibrosis, liver injury due to multiple detrimental insults, hepatic malignancy and intrahepatic cholestasis of pregnancy. Moreover, the prominent molecules involved in the underlying mechanisms and signalling pathways were highlighted. As a result, emerging evidence reveals FNDC5/irisin may act as a proxy for diagnosing liver disease pathology, a sensitive biomarker for assessing damage severity, a predisposing factor for surveilling illness progression and a treatment option with protective/preventive impact, all of which are highly dependent on disease grading and contextually pathological features.

Therapeutic potential of Saccharomyces boulardii in liver diseases: from passive bystander to protective performer?

Saccharomyces boulardii (S. boulardii) is a probiotic yeast that has been elucidated to be efficacious in fighting various gastrointestinal diseases in preclinical as well as clinical studies. Its general mechanisms of probiotic action in the treatment of gastrointestinal conditions cover multifaceted aspects, including immune regulation, production of antimicrobial substances, pathogen competitive elimination, gut barrier integrity maintenance, intestinal trophic effect and antioxidant potency. In this review, basic knowledge with regard to the gut-liver axis, available probiotics remedies and mechanistic insights of S. boulardii as probiotics will be elucidated. In addition, we summarize the therapeutic potential of S. boulardii in several liver diseases evident from both bench and bedside information, such as acute liver injury/failure, fibrosis, hepatic damages due to metabolic disturbance or infection and obstructive jaundice. Future prospects in relation to medicinal effects of S. boulardii are also exploited and discussed on the basis of novel and attractive therapeutic concept in the latest scientific literature.

The Efficacy of Proton Pump Inhibitor in Cirrhotics with Variceal Bleeding: A Systemic Review and Meta-Analysis.

BACKGROUND AND AIMS: Proton pump inhibitor (PPI) was widely used in cirrhotic patients with variceal bleeding empirically rather than evidence-based practice. We aimed to evaluate the plausible indication of PPI use in variceal bleeding cirrhotic patients and figure out whether it can decrease the re-bleeding rate after endoscopic therapy. Furthermore, we also investigated the association between PPI and bleeding-related mortality in these patients. METHODS: We have searched in PubMed, Medline, Web of Science, Google Scholar, Cochrane and Embase prior to May 2019. Pooled OR and 95% CI were calculated by random-effects model. RESULTS: A total of 11 original articles including 1,818 cirrhotic patients were analyzed. The overall meta-analysis highlighted that PPI use may decrease the re-bleeding rate after endoscopic therapy (OR 0.52, 95% CI 0.35-0.77). The conclusion was irrespective of study methods, endoscopic purpose and hemorrhage sites. However, the conclusion speculated that PPI should be prescribed >1 month. Meanwhile, PPI use may not impact the bleeding-related mortality. CONCLUSIONS: PPI, used for >1 month, can decrease re-bleeding rate after endoscopic therapy in cirrhotic patients for prophylaxis or emergency treatment purpose. No matter how long it takes, PPI use is not associated with bleeding-related mortality.

Scoparone as a therapeutic drug in liver diseases: Pharmacology, pharmacokinetics and molecular mechanisms of action.

Scoparone is an active and efficious ingredient of herbal medicine Artemisia capillaris Thunb, which has been used clinically in traditional Chinese medicine formula (e.g. Yin-Chen-Hao decoction) for the treatment of hepatic dysfunction, cholestasis and jaundice for over thousand years. More recently, scoparone has received increasing attention due to its multiple properties. In this comprehensive review, we provide the first summary of the pharmacological effects and pharmacokinetic characteristics of scoparone, and discuss future research prospects. The results implicated that scoparone possesses a wide spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anti-apoptotic, anti-fibrotic and hypolipidemic properties. Pharmacokinetic studies have addressed that isoscopoletin and scopoletin are major primary metabolites of scoparone. Moreover, hepatic dysfunction might promote bioavailability of scoparone due to limited intrinsic clearance. On the other hand, the bioavailability of multi-component including scoparone in certain TCM formula can also be enhanced by applying this formula at a high dose on account of their interacted effects. In view of good pharmacological actions, scoparone is anticipated to be a potential drug candidate for various liver diseases, such as acute liver injury, fulminant hepatitis, alcohol-induced hepatotoxicity, non-alcoholic fatty liver disease and fibrosis. However, further studies are warranted to clarify its molecular mechanisms and targets, elucidate its toxicity, and identify its interplay with other active ingredients of classical TCM formula in clinical settings.

Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe.

Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.

Prognostic impact of neutrophil-to-lymphocyte ratio in cirrhosis: A propensity score matching analysis with a prespecified cut-point.

BACKGROUND & AIMS: An elevated neutrophil-to-lymphocyte ratio (NLR) has received attention as a prognostic surrogate across chronic liver diseases. However, an exact threshold has not been fully elucidated. METHODS: A total number of 589 patients with cirrhosis (LC) were included. The value of NLR was calculated and its optimal cut-off was initially determined by X-tile program. Independent predictors of 90-day mortality were identified with Cox regression model. The Kaplan-Meier method was used to generate survival curves. To reduce influences of selection bias and possible confounders, a 1:2 propensity score matching (PSM) was performed. RESULTS: The X-tile indicated that the difference in survival was most significant for NLR more than 8.9. Serum NLR > 8.9 was an independent indicator in the entire cohort and PSM subset (HR 4.268, 95% CI 2.211-8.238, P < .001; HR 4.209, 95% CI 1.448-12.238, P = .008 respectively). Subgroup analysis showed that NLR > 8.9 was an independent risk factor of 90-day mortality regardless of age, gender, CTP or MELD score. CONCLUSIONS: The value of NLR more than 8.9 is a feasible cut-off across clinical settings among applicable population. The adding of NLR to other conventional predictive systems has the potential to provide incremental value without extra economic cost.

Endoscopic Ultrasound Imaging for Differential Diagnosis of Pancreatic Neoplasms: A 7-Year Study in a Chinese Population.

BACKGROUND Currently, non-invasive methods for screening pancreatic cancer are lacking. There is little information regarding whether endoscopic ultrasound (EUS) imaging has a discriminatory ability for detecting benign and malignant pancreatic neoplasms. In this study, we retrospectively analyzed the demographic, clinicopathologic, and EUS features and follow-up information. MATERIAL AND METHODS A total of 58 patients with pancreatic neoplasms who underwent endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) over a 7-year period (2009-2016) at our Department of Digestive Diseases were enrolled in our study. RESULTS Of the 58 patients, 38 (65.5%) were diagnosed with malignant pancreatic neoplasms and 20 (34.5%) were benign ones. Of all the EUS findings, size of neoplasm (P=0.037) and regularity of margin (P=0.011) were significantly different between malignant and benign pancreatic neoplasms. However, age, sex, location, echo pattern, and dilation of main pancreatic duct did not show any significant difference (P>0.05). Size combined with regularity to detect malignant pancreatic neoplasms showed the following diagnostic values: sensitivity, 73.68%; specificity, 90%; positive predictive value, 76.60%; negative predictive value 81.82%; and area under the receiver operating characteristic curve, 0.887 (95% CI: 0.777-0.955, P<0.0001). CONCLUSIONS Our results showed the high value of EUS for differentiating malignant pancreatic neoplasms from benign ones. Due to this and its non-invasive nature, EUS should be the first-line method for detection of neoplastic pancreatic lesions.

Health-related quality of life and frailty in liver cirrhosis.

BACKGROUND AND OBJECTIVES: There is limited evidence concerning the predictive value of health-related quality of life (HRQoL) on the presence of frailty in the context of cirrhosis. We aimed to elucidate the relationship between HRQoL and multidimensional frailty and to determine which HRQoL dimension independently impacted frail phenotype in our established cohort. METHODS: This was a prospective observational study by consecutively enrolling 355 patients with cirrhotic with decompensated signs in China. The HRQoL and frail phenotype were evaluated by the EuroQol-5D (EQ-5D) Questionnaire and Frailty Index, respectively. The relationship between EQ-5D utility index, as well as respective EQ-5D dimension, and Frailty Index was analysed according to the multiple linear regression analyses. RESULTS: More than half of the patients (56.3%) reported problems in any dimension of the EQ-5D, suggestive of impaired HRQoL. Moreover, the proportion of patients experiencing some/extreme problems significantly increased across all five dimensions (all p<0.001) in correspondence to transition from the robust to frail phenotype. Multiple linear regression analyses demonstrated that age, ascites and hepatic encephalopathy were positively associated with Frailty Index, while EQ-5D utility index (standardised ß coefficient= -0.442, p<0.001) negatively associated with Frailty Index. Notably, usual activities, self-care and mobility were the most influencing predictors associated with frailty. CONCLUSIONS: Our results support a rapid HRQoL assessment via EQ-5D may assist in predicting multidimensional frailty, and usual activities, self-care and mobility tend to be remediable targets while taking their effect on frail phenotype into consideration among patients with cirrhosis.

Global Leadership Initiative on Malnutrition-defined malnutrition coexisting with visceral adiposity predicted worse long-term all-cause mortality among inpatients with decompensated cirrhosis.

BACKGROUND/OBJECTIVES: Malnutrition coexisting with abdominal adipose tissue accumulation bring a double burden on prognosis. More recently, the Global Leadership Initiative on Malnutrition (GLIM) has reached a novel consensus concerning the diagnostic criteria, that is, a two-step modality combining nutritional risk screening and subsequent phenotypic/etiologic parameters for comprehensive evaluation in hopes of harmonizing the malnutrition diagnosis. We aimed to elucidate their synergistic impact among inpatients with decompensated cirrhosis concerning long-term mortality. SUBJECTS/METHODS: Malnutrition, visceral obesity, and visceral adiposity were defined by the Global Leadership Initiative on Malnutrition (GLIM), visceral fat area (VFA), and visceral to subcutaneous adipose tissue area ratio (VSR) on computed tomography, respectively. Accordingly, the patients were categorized into different groups given their nutritional status and visceral obesity/adiposity. Multivariate Cox regression was performed to identify independent risk factors associated with 1-year all-cause mortality. Kaplan-Meier curves with log-rank tests were compared among distinct groups. RESULTS: Totally, 295 patients were recruited. GLIM, VFA, and VSR identified 131 (44.4%), 158 (53.6%), and 59 (20%) patients with malnutrition, visceral obesity and visceral adiposity, respectively. Malnutrition coexisted with visceral obesity in 55 (MO group) relative to visceral adiposity in 40 patients (MA group). Multivariate Cox analysis showed that MA (hazard ratio: 2.48; 95% confidence interval: 1.06, 5.79; P = 0.036) was independently associated with dire outcome rather than MO. Moreover, patients with cirrhosis in the MA group had the worst survival status when compared with other groups (log-rank test: P < 0.001). CONCLUSIONS: The current study indicated that coexisting GLIM-defined malnutrition and VSR-defined visceral adiposity were in relation to worse long-term mortality among inpatients. It is imperative to delicately manage nutritional status and provide personalized treatment in this vulnerable subgroup for achieving better prognosis.

Association Between Quality of Life Defined by EuroQol Group 5 Dimension and Composite Inferior Outcome Among Inpatients with Cirrhosis.

Purpose: The utility of the EuroQol Group 5 Dimension (EQ-5D) measuring health-related quality of life (HRQoL) has been verified; however, knowledge gaps remain concerning predictive performance in cirrhosis. We aimed to identify the optimal threshold for risk stratification and the pronounced domain in the EQ-5D linked to inferior outcomes. Patients and Methods: The X-tile project was used to obtain a threshold, considering the composite outcome of 1-year all-cause mortality or readmission. A restricted cubic spline (RCS) was performed to test the non-linear relationship between the EQ-5D utility value and the primary outcome. Six multivariate Cox regression models incorporating EQ-5D utility value and each of the five domains were constructed. Setting/Participants: Totally, 420 patients with cirrhosis were recruited. Results: The median utility value of the study population was 0.77 and 59.8% reported impairment in minimal one EQ-5D domain. RCS indicated a linear relationship between the utility value and composite inferior outcome. X-tile pinpointed a utility value of 0.59 stratifying populations into high- and low-risk groups based on the outcome. Inpatients with cirrhosis and deteriorated HRQoL (utility value ≤0.59) were at higher risk of death or readmission (adjusted HR: 2.18, P < 0.001). Furthermore, mobility and usual activities were the most pronounced domains associated with composite inferior outcome. Conclusion: A utility value ≤0.59 can identify cirrhotic inpatients exhibiting compromised HRQoL and mortality/readmission risk. It is tempting to reverse the decreased HRQoL by applying longitudinal measurements and keeping surveillance on utility value, while interventions appear to mainly focus on improving mobility and usual activities.

Relationship between lipid profiles and reduced handgrip strength (dynapenia) in hospitalized patients with cirrhosis.

BACKGROUND: Dynapenia embraces clinical significance and predictive value separated from skeletal muscle loss among cirrhosis. Moreover, alterations in lipid levels may impact muscle function. It has yet to elucidate the relationship between lipid profiles and muscle strength weakness. We sought to explore which lipid metabolism indicator could be useful to identify patients with dynapenia in daily practice. METHODS: A retrospective observational cohort study enrolling 262 cirrhotic patients. Analysis of the receiver operating characteristic (ROC) curve was performed to determine the discriminatory cutoff for dynapenia. Multivariate logistic regression was conducted to assess the association between total cholesterol (TC) and dynapenia. Also, we established a model based on the classification and regression tree method. RESULTS: ROC implicated a cutoff of TC ≤ 3.37 mmol/L to identify dynapenia. Patients with TC ≤ 3.37 mmol/L showed significantly lower handgrip strength (HGS; 20.0 vs. 24.7 kg, P = 0.003), lower hemoglobin, lower platelet, lower white blood cell count, lower sodium and higher prothrombin-international normalized ratio. A positive correlation was found between TC and HGS values ( r = 0.1860, P = 0.003). TC remained a significant association with dynapenia after controlling for variables including age, sex, BMI, and the presence of ascites. The decision tree incorporating TC, BMI, and age had a sensitivity of 71.4%, specificity of 64.9%, and an area under ROC of 0.681. CONCLUSION: TC ≤ 3.37 mmol/L was significantly associated with the presence of dynapenia. Assessing TC may be helpful for identifying dynapenic patients with cirrhosis in the health care or hospital setting.

Handgrip strength is a substitutive metric to the GLIM criteria-defined malnutrition and predicts long-term mortality among hospitalized patients with cirrhosis.

BACKGROUND: Hospitalized patients with cirrhosis are prone to debilitating health conditions and fluid fluctuations, posing barriers to accurately obtain anthropometric measures and physical examinations as surrogates for muscle mass within the Global Leadership Initiative on Malnutrition (GLIM). We hypothesize the handgrip strength (HGS) would serve as a substitutive metric, by comparing the diagnostic consistency and prognostic accuracy with computed tomography-demarcated skeletal muscle index (SMI)-defined malnutrition according to the GLIM criteria. METHODS: Patients with cirrhosis underwent a two-step approach involving nutrition risk screening and those fulfilling GLIM consensus were further diagnosed. The evaluation of muscle mass as one constituent contained in the GLIM criteria was conducted by SMI and HGS, respectively. Consistency test, Kaplan-Meier curve, and multivariate Cox regression were used to assess the performance of GLIM-SMI and GLIM-HGS. RESULTS: Among 184 hospitalized patients with cirrhosis, 63 (34.2%) and 78 (42.4%) were diagnosed with malnutrition following GLIM-SMI and GLIM-HGS criteria, respectively. Considering the GLIM-SMI a gold standard, GLIM-HGS had a sensitivity of 87.3% and a specificity of 81.0%. GLIM-HGS criteria denoted good agreement (κ value = 0.858, P < 0.001) as compared with GLIM-SMI. Both criteria were independently associated with 1-year all-cause mortality, whereas GLIM-SMI showed slightly higher hazard ratios. Moreover, HGS positively correlated with SMI in the population alongside more pronounced correlation among patients at nutrition risk. CONCLUSION: HGS may serve as a substitutive metric of muscle mass contained in the GLIM criteria to diagnose malnutrition and predict long-term mortality among patients with cirrhosis.

Association between serum trace elements and sleep disturbance in patients with decompensated cirrhosis.

Background: Sleep disturbance and trace elements imbalance are common features in patients with decompensated cirrhosis, partially sharing similar mechanistic contributors and linking to adverse outcomes. However, there is a paucity of data concerning their relationship. Objectives: To investigate the association between serum trace elements levels and sleep quality in the context of cirrhosis. Design: Cross-sectional study. Methods: We consecutively enrolled 160 patients with decompensated cirrhosis. The sleep disturbance was determined by the Pittsburgh Sleep Quality Index (PSQI > 5). Serum trace elements [magnesium, calcium, iron, copper (Cu), zinc (Zn), lead, and manganese] was measured by inductively coupled plasma mass spectrometry. Association of examined trace elements levels and sleep disturbance was analyzed by multiple linear (global PSQI scores) and multivariate logistic (dichotomized PSQI categories) regression models, respectively. Results: In total, 91 patients (56.88%) represented PSQI-defined sleep disturbance, characterized by female preponderance, lower body mass index levels, and higher serum Cu levels (all p < 0.05). Looking into its clinical relevance with debilitating conditions, we showed that Cu/Zn ratio (CZr) is significantly higher in cirrhosis with poor sleep quality (1.77 versus 1.48, p = 0.003). Diagnostic performance analysis indicated CZr > 1.62 to exhibit better discrimination relative to respective Cu. Both multiple linear (ß = 0.355, p < 0.001) and multivariate logistic regression (odds ratio = 2.364, p = 0.019) identified higher CZr as an independent risk factor associated with sleep disturbance. Conclusion: Our findings implied an association between higher CZr and the presence of sleep disturbance in patients with decompensated cirrhosis.

Malnutrition according to the Global Leadership Initiative on Malnutrition criteria is associated with in-hospital mortality and prolonged length of stay in patients with cirrhosis.

OBJECTIVES: Malnutrition is prevalent and negatively affects patients with cirrhosis, but a generally accepted consensus pertaining to its diagnosis is lacking. Recently, a framework called the Global Leadership Initiative on Malnutrition (GLIM) has been proposed to diagnose malnutrition, but there is scant evidence regarding its validity. We aimed to investigate associations of malnutrition according to the GLIM criteria, as well as its individual indicator with in-hospital adverse outcomes. METHODS: This was a prospective, observational study of consecutively hospitalized patients with cirrhosis. The malnutrition diagnosis was built on a stepwise GLIM process with initial screening, followed by fulfillment of at least one phenotypic and one etiologic criterion. Patients were followed up for a combined endpoint of in-hospital mortality and prolonged length of stay (LOS). Covariates compromise malnutrition according to the GLIM criteria and its indicators in separation. Logistic regression analyses were implemented to determine predictive validity. RESULTS: A total of 387 cirrhotic patients were assessed. Malnutrition was diagnosed in 28.7% of patients according to the GLIM criteria, and increased the risk of in-hospital mortality and prolonged LOS by 2.166 and 1.767 times, respectively, adjusting for age, sex, biochemical parameters, and clinical scores of disease severity. When analyzing separate criteria, all constituents were independently associated with in-hospital adverse outcomes, adjusting for model for end-stage liver disease sodium score. CONCLUSIONS: Malnutrition according to the GLIM criteria was considerably prevalent among hospitalized patients with cirrhosis, and associated with approximately two times greater probability of in-hospital mortality and prolonged LOS. These diagnostic criteria may be implemented and disseminated during daily practice considering their predictive validity.

Comparison of the GLIM criteria with specific screening tool for diagnosing malnutrition in hospitalized patients with cirrhosis: A descriptive cross-sectional study.

BACKGROUND: The Global Leadership Initiative on Malnutrition (GLIM) has been built to diagnose malnutrition; however, its validity among patients with cirrhosis remains enigmatic. We aimed to investigate the prevalence of malnutrition according to GLIM criteria and compare the differences by using a specific screening tool. METHODS: We conducted a descriptive cross-sectional study analyzing hospitalized patients. The Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT) was chosen as the screening tool. Estimated prevalence was shown with and without the initial screening process. Diverse combinations of phenotypic and etiologic criteria and distinct body mass index (BMI) cutoffs were applied to detect frequency of malnourished patients with cirrhosis. RESULTS: Overall, 363 patients were recruited (median age, 64 years; 51.2% female). The prevalence of malnutrition according to GLIM criteria with and without RFH-NPT screening was 33.3% and 36.4%, respectively. Low BMI and inflammation represented the most prevalent combination resulting in a malnutrition diagnosis (42.4%), followed by low BMI and reduced food intake (39.4%). By contrast, the least prevalence was found when combining reduced muscle mass with inflammation to diagnose malnutrition. Furthermore, the frequency of malnourished and well-nourished participants was not statistically different when using divergent BMI reference values across the study population. CONCLUSIONS: GLIM criteria may serve a specific proxy to diagnose malnutrition, along with RFH-NPT screening. Relevant investigation is required to report on the applied combination of phenotypic/etiologic criteria, taking into consideration the marked impact of different models. More attempts are warranted to delineate the prognostic role of GLIM criteria in the context of cirrhosis.