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.

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.

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.

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.

Overexpression of S-adenosylhomocysteine hydrolase (SAHH) in esophageal squamous cell carcinoma (ESCC) cell lines: effects on apoptosis, migration and adhesion of cells.

S-adenosylhomocysteine hydrolase (SAHH) is the sole enzyme that catalyses the hydrolysis of S-adenosylhomocysteine (SAH) in methylation reaction. Previous studies have shown that its inhibition or deficiency leads to several human disorders such as severe coagulopathy, hepatopathy and myopathy. However, the effects of SAHH on esophageal squamous cell carcinoma (ESCC) cells have not been explored so far. To determine whether SAHH is involved in carcinogenesis of the esophagus, we investigated the expression of SAHH in ESCC and normal esophageal epithelial cells and found that SAHH was downregulated in ESCC cells compared with normal esophageal epithelial cells (P < 0.05). The overexpressed SAHH in ESCC cells promoted cell apoptosis, inhibited cell migration and adhesion, but did not affect the cell proliferation and cell cycle. Furthermore, an interaction of SAHH with receptor of activated C kinase 1 (RACK1) protein was detected by coimmunoprecipitation and an increased RACK1, which is caused by overexpression of SAHH, was verified by Western blotting. The findings mentioned above demonstrate that SAHH can promote apoptosis, inhibit migration and adhesion of ESCC cells suggesting that it may be involved in carcinogenesis of the esophagus.

CAG Repeat Expansions Increase N1-Methyladenine to Alter TDP-43 Phase Separation: Lights Up Therapeutic Intervention for Neurodegeneration.

N1-methyladenine (m1A), a modification of transcripts, regulates mRNA structure and translation efficiency. In a recent issue of Nature, Sun et al. reported that m1A in CAG repeat RNA contributes to CAG repeat expansion-induced neurodegeneration in Caenorhabditis elegans and Drosophila through enhancing the ability of endogenous TDP-43 to partition into stress granules mediated by m1A. The study is especially important for revealing the pathological function of m1A in RNA and the pathological mechanisms of CAG repeat expansion-related neurodegenerative diseases.

Biomarkers of Parkinson's Disease: From Basic Research to Clinical Practice.

Parkinson's disease (PD) is a common neurodegenerative disease characterized pathologically by dopaminergic neuron loss and the formation of Lewy bodies, which are enriched with aggregated α-synuclein (α-syn). PD currently has no cure, but therapeutic strategies are available to alleviate symptoms. Early diagnosis can greatly improve therapeutic interventions, but the clinical diagnosis of PD remains challenging and depends mainly on clinical features and imaging tests. Efficient and specific biomarkers are crucial for the diagnosis, monitoring, and evaluation of PD. Here, we reviewed the biomarkers of PD in different tissues and biofluids, along with the current clinical biochemical detection methods. We found that the sensitivity and specificity of single biomarkers are limited, and selecting appropriate indicators for combined detection can improve the diagnostic accuracy of PD.

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.

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.

Associations of Multiple Serum Trace Elements with Abnormal Sleep Duration Patterns in Hospitalized Patient with Cirrhosis.

The associations of circulating trace elements with sleep health have attracted increasing attention given their potential link. However, there is scant data on the relationship between serum trace elements and abnormal sleep duration patterns in cirrhosis. We aimed to investigate these associations with the purpose of identifying modifiable risk factors. The blood samples were collected from inpatients with cirrhosis, and serum levels of several trace elements were assessed by inductively coupled plasma mass spectrometry. Self-reported sleep duration was categorized to short- (< 7 h/night), optimal (7-8 h/night), and long-sleep duration (> 8 h/night). The dose-response trends and associations of trace elements levels with sleep duration were determined by restricted cubic splines (RCS) and logistic regression, respectively. Cirrhotic patients with optimal sleep duration experienced the highest levels of serum Zinc (Zn) and the lowest values of copper to zinc ratio (CZr). RCS model corroborated non-linear associations of serum Zn and CZr against sleep duration. Multiple regression analysis showed that both CZr (short vs optimal sleep duration: OR 4.785, P < 0.001; long vs optimal sleep duration: OR 4.150, P = 0.019) and serum Zn levels (short vs optimal sleep duration: OR 0.985, P = 0.040; long vs optimal sleep duration: OR 0.956, P = 0.008) serve as independent risk factors for sleep duration abnormalities. In conclusion, our findings unraveled a close relationship of serum Zn and CZr with sleep duration in cirrhosis. Further trace element-based therapy such as Zn supplementation may be novel approach to reverse this sleep problem.

Dissecting the Contributing Role of Divergent Adipose Tissue to Multidimensional Frailty in Cirrhosis.

Background and Aims: Emerging evidence has demonstrated that abnormal body composition may potentiate the development of frailty, whereas little work focuses on the role of divergent adipose tissue. Therefore, we aimed to determine the potential contribution of adipose tissue distribution to multidimensional frailty in decompensated cirrhosis. Methods: We conducted a retrospective cohort study. Divergent adipose tissues were assessed by computed tomography-derived subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI) and total adipose tissue index (TATI), respectively. Frailty was identified by our validated self-reported Frailty Index. Multiple binary logistic models incorporating different covariates were established to assess the relationship between adipose tissue distribution and frailty. Results: The study cohort comprised 245 cirrhotic patients with 45.3% being male. The median Frailty Index, body mass index (BMI) and model for end-stage liver disease (MELD) score were 0.11, 24.3 kg/m2 and 8.9 points, respectively. In both men and women, patients who were frail exhibited lower levels of SATI in comparison with nonfrail patients. SATI inversely correlated with Frailty Index in the entire cohort (rs=-0.1361, p=0.0332). Furthermore, SATI or TATI was independently associated with frail phenotype in several multiple logistic regression models adjusting for age, BMI, presence of ascites, sodium, Child-Pugh class or MELD score in isolation. Conclusions: In the context of decompensated cirrhosis, low SATI and concomitant TATI were associated with higher risk of being frail. These findings highlight the importance to further apply tissue-specific tools of body composition in place of crude metric like BMI.

Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice.

Hepatocellular death is a sensitive parameter for detecting acute liver injury (ALI) of toxic, viral, metabolic, and autoimmune origin. Ferroptosis has recently been implicated in carbon tetrachloride (CCl4)-induced ALI. However, the underpinning mechanism and mechanistic basis remain elusive. In this study, bicyclol, a proprietary hepatoprotectant in China, and ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) were administered in CCl4-injured mice. A panel of ferroptosis-related markers, including mitochondria morphology, reactive oxygen species production, protein adducts in response to lipid peroxidation, and key modulators of ferroptotic process, was determined in vivo. Erastin-treated L-O2 hepatocytes were transfected with glutathione peroxidase 4 (GPx4) or nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA to delineate the pathway of bicyclol against ferroptosis in vitro. As a result, CCl4 led to iron accumulation, excessive reactive oxygen species production, enhanced lipid peroxidation, and characteristic morphological changes in mitochondria, along with a decrease in GPx4 and xCT protein levels in ALI mice liver, all of which were generally observed in ferroptosis. The use of Fer-1 further corroborated that ferroptosis is responsible for liver damage. Bicyclol exerted its hepatoprotection by preventing the aforesaid ferroptotic process. Furthermore, bicyclol alleviated erastin-induced cellular inviability, destruction, and lipid peroxidation in vitro. Knockdown of GPx4 diminished these protective activities against perturbations associated with ferroptosis in L-O2 hepatocytes. Additionally, Nrf2 silencing drastically reduced GPx4 levels, and further impeded the medicinal effects of bicyclol. In summary, positively regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in CCl4-induced ALI in mice.

Neutrophil-to-lymphocyte ratio is associated with malnutrition risk estimated by the Royal Free Hospital-Nutritional Prioritizing Tool in hospitalized cirrhosis.

BACKGROUND: Liver cirrhosis is characterized by immune dysfunction, contributing to malnutrition. We previously revealed neutrophil-to-lymphocyte ratio (NLR) as an indicator of disordered immune system. Herein we aimed to (1) determine the optimal NLR cutoff that best predicts malnutrition risk and (2) clarify the association between NLR and nutrition status. METHODS: A total of 135 hospitalized patients with cirrhosis were included. Immune dysfunction was evaluated by levels of serum C-reactive protein (CRP), NLR, and other parameters. Malnutrition was screened by a risk score referring to the Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT). Receiver operating characteristic (ROC) curve was implemented to determine the best NLR cutoff that predicts malnutrition risk. Correlation between NLR and indicators of hepatic and physical function (handgrip strength) were also examined. Multivariable logistic regression was used to assess the association between NLR and malnutrition risk. RESULTS: ROC curve revealed that the optimum cutoff to predict malnutrition risk was NLR > 4.2, with a sensitivity of 47.2%, specificity of 81.0%, negative predictive value of 58.0%, and positive predictive value of 74.5%, respectively. Patients with NLR > 4.2 exhibited a higher RFH-NPT score, serum platelet-to-lymphocyte ratio, and CRP. A positive correlation was found between NLR values and Child-Turcotte-Pugh (r = 0.22; P = .010), model for end-stage liver disease (r = 0.36; P < .001), and RFH-NPT scores (r = 0.31; P < .001). NLR was a risk factor for malnutrition independently of alcoholic liver disease and presence of ascites. CONCLUSIONS: Immune dysfunction measured by NLR was associated with malnutrition risk estimated by RFH-NPT in cirrhosis.

Association of myosteatosis with various body composition abnormalities and longer length of hospitalization in patients with decompensated cirrhosis.

Background: Myosteatosis is linked to dismal outcomes in the context of cirrhosis. However, the association of myosteatosis with various body composition abnormalities remains enigmatic. We aimed to clarify the determinants of myosteatosis and its relationship with other body composition profiles and length of hospitalization (LOH). Methods: We retrospectively analyzed the data of 473 consecutive patients with cirrhosis hospitalized for decompensation. Computed tomography-based segmentation of the cross-sectional area at the third lumbar vertebra was used to evaluate body composition abnormalities. The categories of myosteatosis were built according to our previously outcome-based cutoffs for each gender. Results: Totally, 83 patients (17.55%) were stratified as myosteatosis, of whom 85.54% had concomitant high visceral adiposity indicative of increased visceral adipose tissue index (VATI). The prevalence of sarcopenia showed no significant difference between the groups with and without myosteatosis. Multivariate analysis showed that advanced age [odds ratio (OR) = 1.097, p < 0.001], higher visceral to subcutaneous ratio of adipose tissue area (VSR; OR = 1.574, p = 0.032), and higher VATI (OR = 1.026, p < 0.001) are independently associated with myosteatosis. Correlation analyses revealed a positive relationship between intramuscular adipose tissue content (IMAC) and VATI (ρ = 0.48, p < 0.001), subcutaneous adipose tissue index (SATI) (ρ = 0.36, p < 0.001), and age (ρ = 0.36, p < 0.001). None of the skeletal muscle or adipose tissue indicators were significantly related to longer LOH. Conclusion: Higher VSR, higher VATI, and advanced age are associated with myosteatosis among patients with cirrhosis at the decompensation phase. It is tempting to target divergent adipose tissue depots aimed at timely intervention/prevention of myosteatosis.

Sarcopenia and frailty combined increases the risk of mortality in patients with decompensated cirrhosis.

Background: Both sarcopenia and frailty are prevalent in patients with decompensated cirrhosis and associated with negative outcomes. However, few studies investigated the impact of their coexistence on mortality. We aimed to evaluate the role of sarcopenia and frailty on survival in a cohort of hospitalized cirrhotics. Methods: This was an observational cohort study including 221 patients hospitalized for decompensated events. The cutoff for low skeletal muscle index (SMI) at the third lumbar vertebra level on computed tomography built by our previous work (male: SMI <46.96 cm2/m2; female: SMI <32.46 cm2/m2) was used for the diagnosis of sarcopenia. Individuals with a Frailty Index >0.38 were considered frail. The sample was divided into four groups: sarcopenia and frailty (SF); sarcopenia and non-frailty (SN); non-sarcopenia and frailty (NF); and non-sarcopenia and non-frailty (NN). Follow-up for survival lasted 2 years. Results: Sarcopenia and frailty were present in 21.7% and 14.5% of the patients, respectively. The frequency of frailty in the group of sarcopenic patients was significantly higher than in the patients without sarcopenia (27.1% versus 11%, p = 0.009). In the survival analysis, the SF group showed a higher hazard ratio (2.604 in model 1; 4.294 in model 2) for mortality when compared with the NN group. In addition, the concurrence of those two conditions does give rise to incremental risk for mortality when compared with the group with each disturbance separately, namely, the SN/NF group. Conclusion: In conclusion, cirrhotic patients with sarcopenia and frailty combined showed higher mortality risk.

Association between sleep disturbance and multidimensional frailty assessed by Frailty Index in hospitalized cirrhosis.

OBJECTIVES: Both sleep disturbance and frailty are common in patients with cirrhosis, but their correlation remains elusive. We aimed to investigate whether dysregulated sleep [as estimated by Pittsburgh Sleep Quality Index (PSQI)] is independently associated with frailty and their relationship in distinct subgroups. METHODS: In total 105 adult cirrhotic patients were recruited. The frailty phenotype was identified by a self-reported scale (Frailty Index) which demonstrates good validity and moderate performance based on our previous publication. Patients were categorized into frailty and nonfrailty groups according to a cut-point of 0.38 by Frailty Index. Multiple linear regression was performed to determine independent factors associated with frailty. RESULTS: The median PSQI was 6.0 in the entire cohort and sleep disturbance was observed in 61 patients with cirrhosis (58.1%). Poor sleepers had a significantly higher Frailty Index than that in good sleepers (0.11 vs. 0.08; P = 0.025). In univariate analysis, PSQI score was markedly associated with the Frailty Index (ß = 0.012; 95% CI, 0.006-0.018; P < 0.001), and remained significantly associated with frailty phenotype in multivariate adjustment (ß = 0.010; 95% CI, 0.004-0.015; P = 0.001). The escalating PSQI scores were more prominent in frail patients, with female gender or aged 65 years and over. CONCLUSIONS: Poor sleep quality is strongly associated with frailty in patients with cirrhosis. Given that sleep disturbance is modifiable, our data suggest that efficient interventions to mitigate frailty should incorporate strategies by reversing sleep dysfunction in cirrhotics with poor sleep quality.

Relationship between sarcopenia/myosteatosis and frailty in hospitalized patients with cirrhosis: a sex-stratified analysis.

BACKGROUND: Previous studies have shown that sarcopenia appears to be a significant contributor to physical frailty among outpatients with cirrhosis. However, the evidence is scant regarding the relationship between sarcopenia and multi-dimensional frailty among inpatients. We aimed to investigate the potential contribution of sarcopenia to frailty in hospitalized patients with cirrhosis in a sex-dependent manner. METHODS: This cohort enrolled consecutive cirrhotics. Muscle quantity and quality were assessed using the computed tomography-based skeletal muscle index (SMI) and intramuscular adipose tissue content, respectively. Frailty phenotype was clarified by a self-reported Frailty Index. Multiple linear regression determined the association between sarcopenia and frailty phenotype. RESULTS: A total of 202 cirrhotic patients with 48.5% male were included. The median Frailty Index was 0.13, rendering 17.3% subjects as frail. Among the 16 frail men, 68.8% had sarcopenia and 62.5% exhibited myosteatosis. In contrast, among the 19 frail women, 26.3% had sarcopenia and 15.8% exhibited myosteatosis. Frail patients had a significantly lower median SMI (42.80 cm2/m2) compared with those with pre-frailty (48.23 cm2/m2) and with robust status (50.82 cm2/m2) in the male but not the female group. In male patients, multivariate linear regression implicated age (ß = 0.330, p < 0.001), SMI (ß = -0.260, p < 0.001), albumin (ß = -0.245, p = 0.005), and sodium (ß = -0.179, p = 0.037) as independent risk factors for frailty. CONCLUSION: Sarcopenia is associated with multi-dimensional frailty in male patients with cirrhosis. It is tempting to incorporate sex-specific intervention with the purpose of mitigating frailty among inpatients.

A predictive nomogram incorporating gait speed for all-cause mortality in hospitalized cirrhotics.

OBJECTIVES: No tailored model incorporating physical frailty for 2-year mortality in cirrhosis is available for practitioners in general practice. Thus we aimed to develop a model based on laboratory results and physical frailty allowing clinicians for stratifying cirrhotics by using individual estimate. METHODS: One hundred and thirteen cases were assigned to the primary cohort, and all other 76 patients were regarded as the validation cohort. Multivariate Cox regression was performed, and a nomogram including five-meter gait speed (5MGS) were generated. The performance of the proposed model was assessed by C-index, calibration curve, and decision curve analysis (DCA). RESULTS: On multivariate analysis, the Model for End-Stage Liver Disease-Sodium, albumin and 5MGS were independent predictors for 2-year mortality in cirrhosis. A nomogram incorporating all these parameters achieved a C-index of 0.804 (95%CI, 0.731-0.877). The calibration curve implied optimal correspondence between the predicted survival and actual outcomes. Our model is useful in the clinical settings based on DCA. Similar results were observed in the validation cohort with a C-index of 0.796 (95%CI, 0.689-0.899). Moreover, 5MGS, as a surrogate of physical performance, significantly correlated with multiple domains of general frailty according to Frailty Index (our published data), including instrumental activities of daily living, self-reported health, social activity and falls. CONCLUSION: In conclusion, the nomogram incorporating 5MGS may represent an individualized tool for predicting mortality in cirrhosis for primary care physicians.