Moderate Liver Research Articles

Metabolomics analysis of urine from patients with alcohol-associated liver disease reveals dysregulated caffeine metabolism.

Excess alcohol intake causes millions of deaths annually worldwide. Asymptomatic early-stage, alcohol-associated liver disease (ALD) is easily overlooked, and ALD is usually only diagnosed in more advanced stages. We explored the possibility of using polar urine metabolites as biomarkers of ALD for early-stage diagnosis and functional assessment of disease severity by quantifying the abundance of polar metabolites in the urine samples of healthy controls (n = 18), patients with mild or moderate liver injury (n = 21), and patients with severe alcohol-associated hepatitis (n = 25). The polar metabolites in human urine were first analyzed by untargeted metabolomics, showing that 209 urine metabolites are significantly changed in patients, and 17 of these are highly correlated with patients' model for end-stage liver disease (MELD) score. Pathway enrichment analysis reveals that the caffeine metabolic pathway is the most affected in ALD. We then developed a targeted metabolomics method and measured the concentration of caffeine and its metabolites in urine using internal and external standard calibration, respectively. The described method can quantify caffeine and its 14 metabolites in 35 min. The results of targeted metabolomics analysis agree with the results of untargeted metabolomics, showing that 13 caffeine metabolites are significantly decreased in patients. In particular, the concentrations of 1-methylxanthine, paraxanthine, and 5-acetylamino-6-amino-3-methyluracil are markedly decreased with increased disease severity. We suggest that these three metabolites could serve as functional biomarkers for differentiating early-stage ALD from more advanced liver injury.NEW & NOTEWORTHY Our study using both untargeted and targeted metabolomics reveals the caffeine metabolic pathway is dysregulated in ALD. Three caffeine metabolites, 1-methylxanthine, paraxanthine, and 5-acetylamino-6-amino-3-methyluracil, can differentiate the severity of early-stage ALD.

Impact of liver dysfunction on outcomes in children with Alagille syndrome undergoing congenital heart surgery.

Children with Alagille syndrome often have complex forms of congenital heart defects with the majority having peripheral pulmonary artery stenosis (PPAS) and pulmonary valve atresia (PA) or stenosis (PS). Children with Alagille syndrome also have variable amounts of liver dysfunction. The purpose of this study was to evaluate the impact of liver dysfunction on outcomes in children with Alagille syndrome undergoing congenital heart surgery. This was a retrospective review of 69 patients with Alagille syndrome who underwent congenital heart surgery at our institution. The underlying diagnoses included PPAS (n=29), tetralogy of Fallot with PPAS (n=14), tetralogy with PA (n=3), PA with ventricular septal defect and major aortopulmonary collateral arteries (n=21), and one each with D-transposition and supravalvar aortic stenosis. The median age at surgery was 16 months (range 0-228 months). Procedures performed included PPAS repair (n=43), tetralogy with PA repair (n=3), unifocalization procedures (n=21), and other (n=2). Forty-two (61%) patients had mild or no liver dysfunction, while 26 (38%) had moderate or severe liver dysfunction. Median cardiopulmonary bypass time was 345 minutes (341with liver dysfunction, 345 without liver dysfunction). There were a total of 8 operative (12%) deaths and 3 late (4%) deaths. Six operative and two late deaths occurred in patients with liver dysfunction (combined 30.7%) versus two operative and one late death (combined 7.1%) for patients without liver dysfunction (p < 0.05). These results suggest that liver dysfunction has a profound impact on survival in children with Alagille syndrome undergoing congenital heart surgery.

A high relapse risk of chronic drug-induced liver injury is correlated with a greater severity of liver fibrosis

To construct a risk prediction model for relapse of chronic drug-induced liver injury (DILI) and explore the correlation between DILI relapse risk and liver fibrosis. We retrospectively collected the clinical data of 1138 patients with chronic DILI hospitalized from January, 2017 to January, 2022, including 154 patients with and 984 without DILI relapse. Based on the results of univariable and multivariable logistic regression analyses, a risk prediction model for DILI relapse was constructed, evaluated for its discrimination and calibration using AUC value and Hosmer-Lemeshow test, and verified with a 200 times 5, 10 and 20 folds cross validation method. Spearman correlation analysis was used to evaluate the correlation between the new model and liver fibrosis, and its diagnostic efficiency for liver fibrosis was assessed by comparison with APRI and FIB-4 using ROC curve. The proportions of patients with S0, S1, S2, S3 and S4 liver fibrosis were 1.9%, 13.1%, 42.2%, 27.9% and 14.9% in the relapse group, respectively, as compared with 8.9%, 43.5%, 26.1%, 17.1% and 4.4% in the non-relapse group, respectively, showing severer liver fibrosis in patients with than those without DILI relapse. Multivariable logistic regression analysis identified LSM≥13.7 kPa (OR=4.35, 95%CI: 2.61-7.25, P < 0.001), CHE < 2500 U/L (OR=5.17, 95%CI: 2.13-12.53, P < 0.001), CHE of 2500-5000 U/L (OR=4.07, 95%CI: 2.75-6.01, P < 0.001), and AST > 2×ULN (OR=2.29, 95%CI: 1.38-3.80, P=0.001) as risk factors for relapse of chronic DILI. The ACLS model constructed based on these non-invasive indicators had an AUC value of 0.803 (95%CI: 0.78-0.83). The results of Hosmer-Lemeshow goodness of fit test (χ2=7.73, P=0.46) and the cross validation tests (average AUC of 0.803) all showed a good stability of the model. Spearman correlation analysis showed that ACLS score was positively correlated with the severity of liver fibrosis (rho=0.530, P < 0.001). At the optimal cut-off value of 3 points for diagnosing moderate liver fibrosis, the ACLS model had an AUC value of 0.78 (with specificity of 72.7% and sensitivity of 73.3%), demonstrating a better efficacy than that of APRI and FIB-4 (P < 0.001). At the cut-off value of 6 for severe liver fibrosis, the diagnostic efficacy of the model (AUC=0.83; specificity 75.7%, sensitivity 72.7%) was still better than that of APRI (P < 0.001) but comparable with that of FIB-4 (P=0.38). The patients at high risks of chronic DILI relapse have severer liver fibrosis and should be followed up regularly for timely aggressive treatment.

The Synergic Effect of a Nutraceutical Supplementation Associated to a Mediterranean Hypocaloric Diet in a Population of Overweight/Obese Adults with NAFLD.

Overweight/obesity is often associated with a non-alcoholic fatty liver disease (NAFLD). The study aim was to investigate the effects of a nutraceutical supplementation associated to a Mediterranean-hypocaloric-diet (MHD) on ultrasound-liver-steatosis (ULS) grade improvement in overweight/obese patients with NAFLD. A total of 68 subjects (BMI ≥ 25 kg/m2) with NAFLD were recruited, randomized into 2 groups and treated for 3 months: the Nutraceutical group was treated with MHD plus nutraceutical supplementation (Vitamin E, L-glutathione, silymarin and hepato-active compounds); the Control-group only with a MHD. Anthropometric measurements, body composition, biochemical parameters and Hepatic steatosis index (HSI) were evaluated at baseline and after 3 months; patients with HSI &gt;36 underwent a liver ultrasound to determine liver steatosis grade (3 severe, 2 moderate, 1 mild). In all patients, a significant improvement in nutritional and biochemical parameters was observed after treatment. After treatment, the nutraceutical group showed a significant improvement in hepatic steatosis, either according to ULS-grade (11.1% and 5.6% of patients with mild and moderate liver steatosis, respectively, showed a complete NAFLD regression; 33.3% and 22.2% of patients with moderate and severe liver steatosis, respectively showed a regression to mild liver steatosis), or according to HSI (49.3 ± 10.1 vs. 43.3 ± 9.0, p = 0.01), suggesting that a healthy diet is still the best choice, although the use of specific supplements can enhance the efficacy of dietary intervention in overweight/obese patients with NAFLD.

Gamma-glutamyltransferase predicts macrovesicular liver graft steatosis – an analysis of discarded liver allografts in Finland

Objective Liver-transplantation activity is limited by the shortage of grafts. Donor-liver macrovesicular steatosis predisposes to ischemia-reperfusion injury and is associated with reduced graft survival. The increasing prevalence of fatty-liver disease underlines the importance of identifying macrovesicular steatosis in potential donor livers. We analyzed liver grafts discarded for transplantation, and particularly the role of gamma-glutamyltransferase (GGT) in predicting graft steatosis. Methods One-hundred sixty rejected cadaveric-donor liver grafts were studied. Donor selection was based on clinical data, and macroscopic graft inspection. Discarded grafts were biopsied at procurement of non-liver organs. Results The most common reasons for discarding the graft were abnormal liver tests, ultrasound-verified steatosis and history of harmful alcohol use. GGT correlated moderately with macrovesicular steatosis (r = 0.52, p < 0.001), but poorly with microvesicular steatosis (r = 0.36, p < 0.001). Increased correlation between GGT and macrovesicular steatosis was observed among alcohol abusers (r = 0.67, p < 0.001). Area under the curve (AUC) of GGT for predicting >30% macrovesicular steatosis was 0.79 (95% CI 0.71–0.88), and for >60% steatosis, 0.79 (95% CI 0.68–0.90). The optimal GGT-cut off for detecting >30% and >60% macrovesicular steatosis were, respectively, 66 U/L (sensitivity 76% and specificity 68%) and 142 U/L (sensitivity 66% and specificity 83%). Among alcohol users, a GGT value >90 U/L showed 100% sensitivity for >60% macrovesicular steatosis. AUC for GGT in predicting fibrosis Stages 2–4 was 0.82 (95% CI 0.71–0.92, p < 0.001, optimal cut off 68, sensitivity 92%, specificity 61%). Conclusions Abnormal liver values, steatosis and harmful alcohol use were the main reasons for discarding liver-graft offers in Finland. GGT proved useful in predicting moderate and severe liver graft macrovesicular steatosis.

Genotype and phenotype analysis and transplantation strategy in children with kidney failure caused by NPHP

BackgroundNephronophthisis-related ciliopathies (NPHP-RC) have strong genotype and phenotype heterogeneity, and the transplantation strategy of Boichis syndrome is still controversial. Our purpose was to examine associations of genotype and phenotype in children with NPHP-RC and analyze the transplantation strategies of different phenotypes.MethodsThe records of children with NPHP treated at our center from 01/2018 to 03/2021 were retrospectively reviewed. Inclusion criteria were a diagnosis of NPHP, received kidney transplantation, and received whole exome sequencing (WES) or nephropathy gene panel testing.ResultsTwenty-nine children with NPHP were included. Nine children (31%) had NPHP1 mutations, and all presented with isolated nephropathy. Eighteen of 20 patients with non-NPHP1 mutations had compound heterozygous mutations, and 70% had extrarenal phenotype. Age at disease presentation (11.2 ± 1.94 years) and the development of kidney failure (12.4 ± 2.70 years) were later in children with NPHP1 mutations than those with non-NPHP1 mutations (5.2 ± 2.83 years and 5.7 ± 2.92 years, respectively). Four of six children with NPHP3 mutations were diagnosed with Boichis syndrome due to liver fibrosis. Isolated kidney transplantation resulted in good outcomes for patients with mild or moderate liver fibrosis without portal hypertension, while cholestasis was common postoperatively and could be resolved with ursodeoxycholic acid.ConclusionsNPHP1 mutations are the most common in children with NPHP, and the phenotype of NPHP1 mutation is significantly different from that of non-NPHP1 mutation. For NPHP patients with mild to moderate liver fibrosis without portal hypertension, timely treatment of cholestasis could prevent the rapid progression of liver function damage after isolated kidney transplantation.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Clinical study on the efficacy of hepatitis B vaccination in hepatitis C virus related chronic liver diseases in Egypt

BackgroundChronic hepatitis B (HBV) and C virus (HCV) infections represent significant public health issues internationally. HBV vaccination has high sero-conversion rates in patients with mild to moderate chronic liver disease but has reduced efficacy in advanced stages. Aimto evaluate the efficacy of hepatitis B vaccination in HCV-related chronic liver disease and identify possible factors that may contribute to hypo-responsiveness in those patients. MethodsOur study was a retrospective observational clinical study carried out at the tropical medicine department. It was conducted on 500 individuals (400 chronic HCV patients and 100 healthy controls). Individuals were divided into 5 groups: A (control group), B (cirrhotic patient not receiving treatment), C (chronic hepatitis patients receiving treatment), D (cirrhotic patients receiving treatment), and E (HCC patients receiving treatment). All individuals were subjected for comprehensive history taking, clinical examination, laboratory investigations, and assessment of anti-HBs titer. ResultsThere is an inverse relationship between the level of anti-HBs Abs and the duration of vaccine. Diabetes and presence of cirrhosis have statistically significant relationship with serum anti-HBs Abs titer (P = 0.007). Oral DAAs therapy is associated with reduced response to HBV vaccine (only 31.75% of the patients were protected). ConclusionHCV infection and its complications significantly impair HBV vaccine response. Levels of anti-HBs Abs decline progressively with increasing duration from the last dose in immunization schedule of HBV vaccine. Diabetes and presence of cirrhosis being the main risk factors for vaccine hypo-responsiveness, also oral DAAs therapy is associated with reduced response to HBV vaccine.

Relation of Liver Siderosis to Liver Fibrosis in Hemodialysis Patients With Severe Hyperferritinemia Secondary to High Doses of Intravenous Iron Supplementation

ObjectiveAggressive iron substitution in hemodialysis (HD) patients leads to iron overload. The association between liver siderosis and fibrosis is still debatable. We studied the association of liver siderosis with liver fibrosis in HD patients. Furthermore, we studied the performance of liver stiffness measurements (LSMs) in identifying advanced liver fibrosis. We investigated the performance of biochemical indicators of iron status in identifying advanced liver fibrosis. MethodsFifty-five HD patients (average HD duration 6 ± 2 years) with hyperferritinemia secondary to intravenous iron supplementation (weakly iron dose 252.7 ± 63 mg; median blood transfusions 3 [2-5]) were recruited. The liver fibrosis grade was determined with Fibroscan, aminotransferase-to-platelet ratio index (APRI), and Fib-4 index. Liver iron concentration (LIC) was estimated with magnetic resonance imaging (MRI). Iron parameters and liver function biochemical indicators were also assessed. ResultsThe median serum ferritin and transferrin saturation (TSAT) were 3531 μg/L and 77%, respectively. 34.5%, 20%, and 45.5% of the patients showed mild, moderate, or severe liver siderosis, respectively. All patients with severe liver siderosis showed advanced liver fibrosis. Patients with severe liver siderosis and advanced liver stiffness showed higher serum iron, TSAT, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum bilirubin, APRI, and Fib-4 index scores than those with mild liver siderosis. Serum iron and TSAT showed good utility in identifying advanced liver fibrosis determined with Fibroscan, APRI, and Fib-4 index. Liver stiffness exhibited good utility in identifying advanced liver fibrosis diagnosed with APRI and Fib-4 index. ConclusionsHigh weekly intravenous iron dose associated with severe hyperferritinemia, high serum iron, and TSAT might lead to severe liver siderosis and concomitant liver fibrosis in HD patients. Serum iron, TSAT, Fibroscan, Fib-4, and APRI scores might offer noninvasive tools for identifying advanced liver fibrosis in those patients.

Systematic Review and Meta-Analysis of the Usefulness of Epicardial Fat Thickness as a Non-Invasive Marker of the Presence and Severity of Nonalcoholic Fatty Liver Disease.

We performed a systematic review and meta-analysis to assess the association between epicardial fat thickness (EFT) and nonalcoholic fatty liver disease (NAFLD). This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) and was based on a registered protocol (CRD 4201809 5493). We searched Medline and Embase until December 2021 for studies reporting on the association between EFT and NAFLD. Qualitative reviews, meta-analyses and meta-regressions were performed to explore this association. Effect sizes are reported as standardized mean differences. We included 12 studies, comprising 3610 individuals. EFT was evaluated with trans-thoracic echocardiography in nine studies, two studies using cardiac computed tomography and one study using magnetic resonance imaging (MRI). The presence of NAFLD was evaluated using transabdominal liver ultrasound in nine studies. Other studies used histology, magnetic resonance spectroscopy and MRI-derived proton density fat fraction. Liver biopsy was performed to assess the severity of NAFLD in four studies. The random-effects meta-analysis indicated that, as compared to control patients with lean livers, patients with NAFLD displayed significantly higher EFT (standardized mean difference 0.61, 95% confidence interval: 0.47–0.75, p < 0.0001, I2 = 72%). EFT was further significantly higher in patients with severe liver steatosis versus patients with mild–moderate liver steatosis (standardized mean difference 1.21 95% confidence interval: 0.26–2.16, p < 0.001, I2 S = 96%). Through the meta-regression analysis, we found that patients with increasingly higher blood levels of aspartate aminotransferase displayed an increasingly higher depth of association. The current meta-analysis suggests that EFT may represent a useful surrogate for assessing the presence and severity of NAFLD in a non-invasive manner.

Minimal Development of Liver Fibrosis in Adult Tolerant Liver Transplant Recipients Late After Immunosuppressive Drug Weaning and Transplantation

Operationally tolerant liver transplant (LTx)-recipients can be weaned off immunosuppressive (IS) drugs without development of graft rejection. However, it is feared that liver fibrosis might develop after complete IS weaning. The purpose of this small single-center study was to assess liver fibrosis in adult tolerant LTx recipients long after LTx and IS weaning. Liver fibrosis was assessed in adult tolerant LTx-recipients (n=9) using noninvasive transient elastography and measurements of multiple pro- and antifibrotic serum markers associated with liver fibrosis. The data was collected for 2 subsequent years; 8 and 9 years after IS weaning and 19 and 20 years after transplantation. Healthy individuals (n=9) matched for age and sex were included as a reference for fibrosis-related serum markers. This study was conducted in accordance with the Declaration of Helsinki and approved by the medical ethics committee of our institution. Transient elastography indicated that 7 of 9 tolerant LTx recipients had no or minimal liver fibrosis (F0-F1), whereas 2 recipients had moderate or severe liver fibrosis (F2-F3). Most fibrosis-related serum markers in tolerant LTx recipients were within or close to the range obtained for healthy individuals. The results from this small, single-center study indicated that most adult tolerant LTx recipients have no or minimal liver graft fibrosis long after transplantation and IS weaning, and their fibrosis-related serum marker profile indicates an absence of a profibrotic status.

Structure-based discovery of 1-(3-fluoro-5-(5-(3-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)-3-(pyrimidin-5-yl)urea as a potent and selective nanomolar type-II PLK4 inhibitor

Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase involved in regulating cell mitosis and centriole duplication, and has emerged as a therapeutic target for treating multiple cancers. At first, the design and in vitro validation of PLK4 inhibitors (12a-12e, 17a-17f, 22a-22e) bearing 1H-pyrazolo[3,4-b]pyridine scaffold was described and lead compound 22a (IC50 = 0.106 μM) was identified. Then, selectivity- and activity-guided development of a series of potent and selective type-II PLK4 inhibitors using a homology model approach was carried out. Further structure-based optimization resulted in a potent type-II PLK4 inhibitor 29u (IC50 = 0.026 μM), which exhibited outstanding selectivity in a panel of 47 kinases at a single concentration of 1.0 μM. Furthermore, compound 29u significantly inhibited the proliferation of breast cancer cell line MCF-7 with an IC50 value of 1.52 μM, while it exhibited no inhibitory effect on normal cell lines (L02 and HUVECs). Meanwhile, the clone formation, senescence and migration abilities of compound 29u were evaluated using MCF-7 cells. The detailed biological evaluation revealed that compound 29u could arrest cell division in S/G2 phase by inhibiting PLK4, and then affect the expression of downstream signalling pathway proteins regulated by PLK4. Moreover, the in vitro preliminary evaluation of the drug-like properties of compound 29u exhibited outstanding plasma stability, moderate liver microsomal stability, and low risk of drug-drug interactions (DDIs). The current discovery will support the further development of compound 29u as a lead compound for PLK4-targeted anticancer drug discovery and as a useful chemical probe for the further biological research of PLK4.

Effectiveness of Hemopatch® versus Surgicel® Original to control mild and moderate liver bleeding

BackgroundAdjunct hemostats can be of use in certain surgical settings. We compared the effectiveness of two hemostats, Hemopatch® and Surgicel® Original in controlling bleeding from liver lesions in an experimental model.MethodsControl of grades 1 (mild) and 2 (moderate) bleeding (according to the Validated Intraoperative Bleeding [VIBe] SCALE) was assessed for 10 min after Hemopatch® (n = 198) or Surgicel® Original (n = 199) application on 397 liver surface lesions. The primary endpoint was hemostatic success (reaching VIBe SCALE grade 0 at 10 min). The secondary endpoint was time to hemostasis (time to reach and maintain grade 0). A generalized linear mixed model and an accelerated failure time model were used to assess the primary and secondary endpoints, respectively.ResultsThe overall hemostatic success rate of Hemopatch® was statistically significantly superior to that of Surgicel® Original (83.8% versus 73.4%; p = 0.0036; odds ratio [OR] 2.38, 95% confidence interval [CI] 1.33–4.27) and time to hemostasis was reduced by 15.9% (p = 0.0032; 95% CI 0.749–0.944). Grade 2 bleeds treated with Hemopatch® had statistically significantly higher hemostatic success (71.7% versus 48.5%; p = 0.0007; OR 2.97, 95% CI 1.58–5.58) and shorter time to hemostasis (49.6% reduction, p = 3.6 × 10–8); differences for grade 1 bleeds (hemostatic success rate or time to hemostasis) were not statistically significant.ConclusionsHemopatch® provided better control of VIBe SCALE bleeding compared to Surgicel® Original for Grade 2 bleeds in this porcine model, highlighting the importance of choosing a suitable hemostat to optimize control of bleeding during surgery.

Hepatoprotective drugs for prevention of liver injury resulting from anti-tuberculosis treatment: A meta-analysis of cohort studies

BackgroundThe incidence of liver injury caused by anti-tuberculous (TB) drugs is very high. However, owing to a lack of sufficient evidence, preventive use of hepatoprotective drugs is not yet recommended. Therefore, we aimed to assess the protective effect of hepatoprotective drugs for anti-TB drug-induced liver injury. MethodsWe conducted a literature search in China Biology Medicine disc, China National Knowledge Infrastructure, WanFang, Chinese Scientific and Technological Journal, PubMed, Cochrane Library, Web of Science, and Embase. We performed meta-analysis using R 4.0 and Review Manager 5.3 software. ResultsA total of 18 studies involving 3589 patients from 2 groups were included. Use of hepatoprotective drugs contributed to a lower incidence of liver injury as compared with conventional anti-TB treatment alone (relative risk [RR] = 0.39, 95% confidence interval [CI]: 0.28–0.53, p < 0.001). In subgroup analysis, significant protective effects were noted for mild liver injury (RR = 0.30, 95% CI 0.15–0.58), moderate (or severe) liver injury (RR = 0.35, 95% CI 0.19–0.65), and liver injury within 2–4 weeks (RR = 0.37, 95% CI 0.19–0.71). We also found a statistically significant difference in the incidence of drug withdrawal (RR = 0.58, 95% CI 0.34–0.97, p = 0.040). ConclusionsOur results demonstrate that hepatoprotective drugs are effective in preventing liver injury in patients receiving anti-TB treatment, to some extent.

Simultaneously Screening for Liver Steatosis and Fibrosis in Romanian Type 2 Diabetes Mellitus Patients Using Vibration-Controlled Transient Elastography with Controlled Attenuation Parameter.

Non-alcoholic fatty liver disease (NAFLD) is a common finding among patients with type 2 diabetes mellitus (T2DM). Between NAFLD and T2DM exist a bidirectional relationship. Patients with T2DM are at high risk for NAFLD, and evidence suggests that T2DM is linked to progressive NAFLD and poor liver outcomes. NAFLD promotes the development of T2DM and leads to a substantial increase in the risk of T2DM complications. This study aimed to assess the prevalence of liver steatosis and fibrosis in patients with T2DM from north-eastern Romania by using Vibration-Controlled Transient Elastography (VCTE) with Controlled Attenuation Parameter (CAP), which is a non-invasive method and can assess simultaneously liver steatosis and fibrosis. In total, 424 consecutive patients with T2DM were enrolled and evaluated using VCTE with CAP from January 2020 to January 2022. Clinical and laboratory data were recorded in all patients. For the CAP score, we used the following cut-offs: mild steatosis (S1)—274 dB/m, moderate steatosis (S2)—290 dB/m, and severe steatosis (S3)—302 dB/m. For liver fibrosis, to differentiate between fibrosis stages, the cut-off values were F ≥ 8.2 kPa for significant fibrosis (F2), F ≥ 9.7 kPa for advanced fibrosis (F3), and F ≥ 13.6 kPa for cirrhosis (F4). In total, 380 diabetic patients (72.6%) had liver steatosis (51.3% females, the mean age of 55.22 ± 10.88 years, mean body mass index (BMI) 29.12 ± 5.64 kg/m2). Among them, 26 (8.4%) patients had moderate liver steatosis (S2) and 242 (78.5%) patients had severe hepatic steatosis (S3). According to VCTE measurements, 176 (57.14%) patients had liver fibrosis, 36 (11.7%) of them had advanced fibrosis (F3), and 42 (13.6%) diabetic patients had cirrhosis (F4). Univariate analyses showed that severe steatosis was significantly associated with ferritin (β = 0.223, p = 0.022), total cholesterol (β = 0.159, p = 0.031), and HDL-cholesterol (β = −0.120, p = 0.006). In multivariate analyses, BMI (β = 0.349, p < 0.001), fasting plasma glucose (β = 0.211, p = 0.006), and triglycerides (β = 0.132, p = 0.044) were predictors of S3. Patients with T2DM have a high prevalence of severe steatosis and advanced fibrosis which can lead to the development and progression of complications with high morbidity and mortality rates. Hence, it is necessary to implement screening strategies to prevent advanced liver disease in patients with T2DM.

Pharmacokinetic Study of Nalbuphine in Surgical Patients Undergoing General Anesthesia with Varying Degrees of Liver Dysfunction.

PurposeThis study aimed to characterize the pharmacokinetics of nalbuphine in patients undergoing general anesthesia with varying degrees of liver dysfunction.Patients and MethodsTwenty-four patients were enrolled and divided into three cohorts based on liver function: normal liver function (n = 13), mild liver dysfunction (n = 5), and moderate/severe liver dysfunction (n = 6). During the induction of anesthesia, they received 15 mg of nalbuphine intravenously. Venous blood samples were collected from each patient. The plasma concentration of nalbuphine was determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of nalbuphine were calculated by non-compartmental analysis (NCA) using Phoenix WinNonlin software.ResultsCompared with the normal liver function group, the plasma elimination half-life (T1/2) of nalbuphine was increased by approximately 33% in the moderate/severe liver dysfunction group (2.66 h vs 3.54 h, P<0.05), and the volume of distribution (Vd) increased by approximately 85% (100.08 L vs 184.95 L, P<0.05). Multivariate analysis revealed that weight and platelet were associated with clearance (CL); total bilirubin as an independent factor was associated with T1/2, and weight associated with area under the curve (AUC(0→∞)) independently.ConclusionThe T1/2, mean residence time, and Vd of nalbuphine in patients with moderate/severe liver dysfunction were prolonged or increased significantly compared with those in the normal liver function group. These data suggest that it may need to be used with caution when nalbuphine is administered to patients with moderate or severe liver dysfunction.

Recipient Comorbidities for Prediction of Primary Graft Dysfunction, Chronic Allograft Dysfunction and Survival After Lung Transplantation.

Since candidates with comorbidities are increasingly referred for lung transplantation, knowledge about comorbidities and their cumulative effect on outcomes is scarce. We retrospectively collected pretransplant comorbidities of all 513 adult recipients transplanted at our center between 1992–2019. Multiple logistic- and Cox regression models, adjusted for donor-, pre- and peri-operative variables, were used to detect independent risk factors for primary graft dysfunction grade-3 at 72 h (PGD3-T72), onset of chronic allograft dysfunction grade-3 (CLAD-3) and survival. An increasing comorbidity burden measured by Charleston-Deyo-Index was a multivariable risk for survival and PGD3-T72, but not for CLAD-3. Among comorbidities, congestive right heart failure or a mean pulmonary artery pressure >25 mmHg were independent risk factors for PGD3-T72 and survival, and a borderline risk for CLAD-3. Left heart failure, chronic atrial fibrillation, arterial hypertension, moderate liver disease, peptic ulcer disease, gastroesophageal reflux, diabetes with end organ damage, moderate to severe renal disease, osteoporosis, and diverticulosis were also independent risk factors for survival. For PGD3-T72, a BMI>30 kg/m2 was an additional independent risk. Epilepsy and a smoking history of the recipient of >20packyears are additional independent risk factors for CLAD-3. The comorbidity profile should therefore be closely considered for further clinical decision making in candidate selection.

Bicyclol ameliorates advanced liver diseases in murine models via inhibiting the IL-6/STAT3 signaling pathway.

Bicyclol, a synthetic hepatoprotective and anti-inflammatory agent approved in China, was widely used to treat various hepatitis accompanied by elevated serum aminotransferases. However, the pharmacological effects and mechanisms of bicyclol on advanced liver diseases, such as fibrosis/cirrhosis and hepatocellular carcinoma (HCC), remain to be explored. Here, we revealed that bicyclol prevents from formatting severe fibrosis, slows the progression of moderate liver fibrosis, accelerates the regression of moderate liver fibrosis, decreases the malignancy of HCC in rat models induced by diethylnitrosamine (DEN), and also blocks steatohepatitis to HCC in mice induced by western diet plus carbon tetrachloride and DEN. The detailed pharmacological mechanism showed that bicyclol alleviates chronic progressive liver diseases by inhibiting the levels of IL-6 and subsequent phosphorylated STAT3. Conclusion: Bicyclol plays significant protective roles in multiply stages of fibrosis/cirrhosis-HCC and nonalcoholic fatty liver disease-related HCC via inhibiting IL-6/STAT3 signaling pathway. Therefore, bicyclol might be a promising therapeutic strategy for treating advanced liver diseases.

Design, synthesis, and biological evaluation of novel pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors for the treatment of TRIM37-amplified breast cancer

Serine/threonine-protein kinase polo-like kinase 4 (PLK4) is a mitosis-associated protein kinase that plays a vital role in the duplication of centrioles in dividing cells and is considered a promising target of synthetic lethality in TRIM37-amplified breast cancer. Herein, based on a rational drug design strategy, we described a series of pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors and dissected the relevant structure-activity relationships (SARs). Most compounds showed potent suppressive activities against PLK4, with IC50 values of < 10 nM. Among them, compound 24j (PLK4 IC50 = 0.2 nM) displayed potent enzyme inhibition and good selectivity in a panel of 35 kinases. At the cellular level, compound 24j exhibited notable antiproliferative activities against MCF-7, BT474, and MDA-MB-231 cells, with IC50 values of 0.36, 1.35, and 2.88 μM, respectively. Compound 24j killed TRIM37-amplified breast cancer cells. Moreover, we evaluated the clone formation, proliferation, cycle arrest, and migration abilities of compound 24j using MCF-7 cells. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 24j showed remarkable plasma stability, moderate liver microsomal stability, and weak inhibitory activity against the main subtypes of human cytochrome P450. Based on in vivo pharmacokinetic studies in Sprague Dawley rats, compound 24j exhibited a relatively high plasma clearance and a low F value (8.03%). Overall, these results support the further development of compound 24j as a potential lead compound to treat TRIM37-amplified breast cancer.

Outcomes In Advance Heart Failure Patients With Biopsy Proven Liver Fibrosis

<h3>Background</h3> There is paucity of data regarding outcomes of stage D heart failure patients undergoing evaluation and treatment with advanced therapies [heart transplant (HTX), left ventricular assist device (LVAD)] in the setting of biopsy-proven liver fibrosis. <h3>Methods</h3> We retrospectively assessed stage D heart failure patients (age>18 years) who had liver biopsy and underwent advanced therapy evaluation from 2017 to 2020. Overall baseline characteristics and 1-year clinical outcomes were compared between mild to moderate (stage 0-2) and severe liver fibrosis (stage 3-4) group. <h3>Results</h3> A total of 136 patients were included. HTX was done in 23 patients, LVAD in 48 patients and 65 did not undergo advance therapies (no therapy group). Patients in no therapy group were older (61 vs 55 vs 57 years; p=0.03) and had more diabetes (60% vs 26% vs 46%; p=0.02) in comparison to HTX and LVAD group, respectively. Whereas HTX group had more non-ischemic cardiomyopathy (83% vs 65% vs 43%; p=0.02) compared to LVAD and no therapy group, respectively (Table 1A). Steatohepatitis was present in 26.1% of HTX, 31.3% of LVAD and 32.3% in no therapy group. Biopsies identified 23 patients with severe liver fibrosis and 113 patients with mild to moderate fibrosis. 1 LVAD patient lost follow-up in mild to moderate fibrosis group. Out of 23 patients in severe fibrosis group, 65% underwent no advanced therapies, only 4% underwent HTX and 30% received LVAD (Table1B). Among patients in the no therapy group, mean PCWP was higher in fibrosis grade 3-4 when compared to fibrosis grade 0-2 group (23 vs 17, p=0.04). No patient died in heart transplant group. There was no significant difference in 1-year mortality in LVAD group (43% vs 20%, p=0.2), whereas no therapy group showed high mortality (60% vs 26%, p=0.02) in severe fibrosis vs mild-moderate fibrosis patients (Tabe1B). The overall 1-year mortality among severe liver fibrosis patients who underwent no advanced therapy was 60% vs 37.5% with advanced therapies. <h3>Conclusions</h3> Liver fibrosis is common among advanced heart failure patients. Mortality is high in end-stage heart failure patients with underlying severe liver fibrosis. As anticipated, patients with severe liver fibrosis were less likely to undergo LVAD or HTX than patients with mild to moderate fibrosis. Therefore, liver biopsy should be considered in patients being evaluated for advanced therapies.

Ultrasound image analysis for detection of fatty liver and grading its severity in buffaloes at Mosul, Iraq

The study aimed to (ⅰ) examines whether quantitative and qualitative digital analysis of hepatic ultrasound images can be used to detect fatty liver and grading its severity, (ⅱ) to estimate the concentration of serum β-hydroxybutyrate content in normal and diseased animals. A total of 50 buffaloes (15 clinically normal and 35 suffered from decreased milk production, loss of appetite, and loss of body weight) 2-4 weeks after parturition were studied. Buffaloes were examined by real-time ultrasound using a 3.5 MHz convex probe. Ultrasound images were saved for qualitative and quantitative analysis, using computer aid Fatty-Liver software (programmed in Matlab language). Based on the digital analysis of ultrasound images, the diseased buffaloes were classified as mild (n=20), moderate (n=7) and severe (n=8) fatty liver affection. Results indicated that the concentration of β-hydroxybutyrate estimated via ELISA were 0.409, 0.735, 0.923, 1.708 mmol/dL in normal, mild, moderate, and severe diseased buffaloes respectively. However, a significant difference has been encountered among normal and diseased animals. It has been concluded that buffaloes at Mosul suffered from fatty liver and digital analysis of ultrasound images was a suitable method for clinical diagnosis, furthermore, estimation of β-hydroxybutyrate was a suitable method for laboratory diagnosis.