Genetic variation and elevated liver enzymes during childhood, adolescence and early adulthood.

BACKGROUND: Genetic factors influence the risk of fatty liver disease (FLD) in adults. The aim of this study was to test if, and when, genetic risk factors known to affect FLD in adults begin to exert their deleterious effects during childhood, adolescence and early adulthood. METHODS: We included up to 4018 British children and adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Three genetic variants known to associate robustly with FLD in adults (PNPLA3 rs738409, TM6SF2 rs58542926 and HSD17B13 rs72613567) were tested for association with plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST) during childhood (mean age: 9.9 years), early adolescence (15.5 years), late adolescence (17.8 years), and early adulthood (24.5 years). We also tested the associations of a 17-variant score and whole-genome polygenic risk scores (PRS) derived from associations in adults with plasma ALT and AST at the same four time points. Associations with elastography-derived liver steatosis and fibrosis were tested in early adulthood. RESULTS: Genetic risk factors for FLD (individually, combined into a 3-variant score, a 17-variant score and as a genome-wide PRS), were associated with higher liver enzymes, beginning in childhood and throughout adolescence and early adulthood. The ALT-increasing effects of the genetic risk variants became larger with increasing age. The ALT-PRS was associated with liver steatosis in early adulthood. No genetic associations with fibrosis were observed. CONCLUSIONS: Genetic factors that promote FLD in adults associate with elevated liver enzymes already during childhood, and their effects get amplified with increasing age.

Transaminitis prevalence among HIV-infected adults eligible for tuberculosis preventive therapy.

OBJECTIVE: To assess the prevalence of severe transaminitis precluding tuberculosis (TB) preventive therapy (TPT) initiation for people with HIV (PWH) in a high TB/HIV burden setting. DESIGN/METHODS: We conducted a secondary analysis of data from a prospective cohort study of PWH with pre-antiretroviral therapy (ART) CD4 + counts 350 cells/µl or less undergoing systematic TB screening from two HIV clinics in Uganda. For this analysis, we excluded patients with culture-confirmed TB and patients without aspartate transaminase (AST) or alanine transaminase (ALT) levels measured within three months of enrollment. We compared the proportion of patients with any transaminitis (AST or ALT greater than one times the upper limit of normal ULN) and severe transaminitis (AST or ALT >3 times ULN) for patients screening negative for TB by symptoms and for those screening negative by C-reactive protein (CRP). We also assessed the proportion of patients with transaminitis by self-reported alcohol consumption. RESULTS: Among 313 participants [158 (50%) women, median age 34 years (IQR 27-40)], 75 (24%) had any transaminitis and six (2%) had severe transaminitis. Of 32 of 313 (10%) who screened negative for TB by symptoms, none had severe transaminitis. In contrast, six-times more PWH screened negative for TB by CRP (194 of 313; 62%), of whom only four (2.1%) had severe transaminitis. Differences in the proportion with any and severe transaminitis according to alcohol consumption were not statistically significant. CONCLUSION: Prevalence of severe transaminitis was low among PWH without culture-confirmed TB in this setting, and is therefore, unlikely to be a major barrier to scaling-up TPT.

Gender Difference in Liver Enzymes in Newly Defined Subgroups of Diabetes Revealed by a Data-Driven Cluster Analysis.

BACKGROUND: Recently, a newly proposed data-driven approach for classifying diabetes has challenged the status quo of the classification of adult-onset patients with diabetes. This study investigated the association between liver injury and diabetes, classified by data-driven cluster analysis, as liver injury is a significant risk factor for diabetes. METHODS: We enrolled 822 adult patients with newly diagnosed diabetes. Two-step cluster analysis was performed using six parameters, including age at diagnosis, body mass index, hemoglobin A1C, homoeostatic assessment model 2 estimates about insulin resistance (HOAM2-IR) and beta-cell function (HOMA2-B), and glutamic acid decarboxylase antibodies (GADA) positivity. Patients were allocated into five clusters. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity were compared as indicators of liver injury among clusters. RESULTS: Serum ALT and AST activities were significantly different among clusters (P=0.002), even among those without GADA positivity (P=0.004). Patients with severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) had a more severe liver injury. Gender dimorphism was also found for serum ALT and AST activities among subgroups. Female patients had better liver function than males with SIRD and MOD. CONCLUSIONS: We verified the feasibility of a newly proposed diabetes classification system and found robust and significant relationship and gender differences between serum ALT and AST activities and diabetes in some specific subgroups. Our findings indicate that more attention should be paid to diabetes subgroups when studying risk factors, indicators, or treatment in diabetic research.

Fibrosis-4 (FIB-4) Index and mortality in COVID-19 patients admitted to the emergency department.

Liver damage worsens the prognosis of coronavirus 19 disease (COVID-19). However, the best strategy to stratify mortality risk according to liver damage has not been established. The aim of this study is to test the predictive value of the validated Fibrosis-4 (FIB-4) Index and compared it to liver transaminases and to the AST-to-Platelet ratio index (APRI). Multicenter cohort study including 992 consecutive COVID-19 patients admitted to the Emergency Department. FIB-4 > 3.25 and APRI > 0.7 were used to define liver damage. Multivariable Cox regression and ROC curve analysis for mortality were performed. Secondary endpoints were (1) need for high-flow oxygen and (2) mechanical ventilation. 240 (24.2%) patients had a FIB-4 > 3.25. FIB-4 > 3.25 associated with an increased mortality (n = 119, log-rank test p < 0.001 and adjusted hazard ratio (HR) 1.72 (95% confidence interval [95%CI] 1.14-2.59, p = 0.010). ROC analysis for mortality showed that FIB-4 (AUC 0.734, 95% CI 0.705-0.761) had a higher predictive value than AST (p = 0.0018) and ALT (p < 0.0001). FIB-4 > 3.25 was also superior to APRI > 0.7 (AUC 0.58, 95% CI 0.553-0.615, p = 0.0008). Using an optimized cut-off > 2.76 (AUC 0.689, 95% CI 0.659-0.718, p < 0.0001), FIB-4 was superior to FIB-4 > 3.25 (p = 0.0302), APRI > 0.7 (p < 0.0001), AST > 51 (p = 0.0119) and ALT > 42 (p < 0.0001). FIB-4 was also associated with high-flow oxygen use (n = 255, HR 1.69, 95% CI 1.25-2.28, p = 0.001) and mechanical ventilation (n = 39, HR 2.07, 95% CI 1.03-4.19, p = 0.043). FIB-4 score predicts mortality better than liver transaminases and APRI score. FIB-4 score may be an easy tool to identify COVID-19 patients at worse prognosis in the emergency department.

Development of nomogram models of inflammatory markers based on clinical database to predict prognosis for hepatocellular carcinoma after surgical resection.

BACKGROUND: Inflammation plays a significant role in tumour development, progression, and metastasis. In this study, we focused on comparing the predictive potential of inflammatory markers for overall survival (OS), recurrence-free survival (RFS), and 1- and 2-year RFS in hepatocellular carcinoma (HCC) patients. METHODS: A total of 360 HCC patients were included in this study. A LASSO regression analysis model was used for data dimensionality reduction and element selection. Univariate and multivariate Cox regression analyses were performed to identify the independent risk factors for HCC prognosis. Nomogram prediction models were established and decision curve analysis (DCA) was conducted to determine the clinical utility of the nomogram model. RESULTS: Multivariate Cox regression analysis indicated that the prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) were independent prognostic factors of OS, and aspartate aminotransferase-to-platelet ratio (APRI) was a common independent prognostic factor among RFS, 1-year RFS, and 2-year RFS. The systemic inflammation response index (SIRI) was an independent prognostic factor for 1-year RFS in HCC patients after curative resection. Nomograms established and achieved a better concordance index of 0.772(95% CI: 0.730-0.814), 0.774(95% CI: 0.734-0.815), 0.809(95% CI: 0.766-0.852), and 0.756(95% CI: 0.696-0.816) in predicting OS, RFS, 1-year RFS, and 2-year RFS respectively. The risk scores calculated by nomogram models divided HCC patients into high-, moderate- and low-risk groups (P < 0.05). DCA analysis revealed that the nomogram models could augment net benefits and exhibited a wider range of threshold probabilities in the prediction of HCC prognosis. CONCLUSIONS: The nomograms showed high predictive accuracy for OS, RFS, 1-year RFS, and 2-year RFS in HCC patients after surgical resection. The nomograms could be useful clinical tools to guide a rational and personalized treatment approach and prognosis judgement.

Cardioprotective potential of Thymus linearis Benth.

In developing countries, myocardial ischemia and the resulting impairments in heart function are the leading cause of illness and mortality. Thymus linearis Benth has been used as an antibiotic, antioxidant, and antihypertensive agent for centuries. The goal of this investigation was to see if Thymus linearis could protect isoproterenol and doxorubicin-induced myocardial ischemia in vivo at doses of 25 mg/kg s.c. and 15 mg/kg i.p., respectively. The level of cardiac enzymes (CK-MB, LDH, and AST) in the serum isolated from the experimental animal's blood was used to determine myocardial ischemia. The anti-ischemic potential was assessed by comparing the levels of the aforementioned cardiac biomarkers in the intoxicated and treated animal groups. The study found substantial increase (p0.0001) in the serum levels of CK-MB, LDH, AST when compared to intoxicated groups, while pretreatment of animals with crude extract of Thymus linearis significantly reduced the rise in serum cardiac indicators. The findings of the study indicated that the aqueous methanolic Thymus linearis crude extract has cardioprotective potential against Isoproterenol and Doxorubicin-induced cardiac necrosis in rats.

Hepatic enzymes and immunoinflammatory response to Bio-C Temp bioceramic intracanal medication implanted into the subcutaneous tissue of rats.

Our purpose was to evaluate the biocompatibility and hepatotoxicity of a new bioceramic intracanal medicament, Bio-C Temp (BIO). The biological properties of BIO were compared with calcium hydroxide-based intracanal medicament (Calen; CAL), used as gold pattern. Polyethylene tubes filled with BIO or CAL, and empty tubes (control group, CG) were implanted into subcutaneous tissue of rats. After 7, 15, 30 and 60 days, the samples were embedded in paraffin for morphological, quantitative and immunohistochemistry analyses. At 7 and 60 days, blood samples were collected for analysis of serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) levels. The data were submitted to two-way ANOVA and Tukey's test (p ≤ 0.05). No significant difference was detected in serum GOT and GPT levels among BIO, CAL and CG specimens. In all periods, BIO specimens exhibited lower number of inflammatory cells and immunoexpression of IL-6, a pro-inflammatory cytokine, than CAL specimens. The reduction of these parameters was accompanied by significant increase in the collagen content and in the immunoexpression of IL-10, a cytokine involved in the tissue repair, over time. Our findings indicate that Bio-C Temp is biocompatible and had no hepatotoxicity effect.

Effect of growth hormone therapy on liver enzyme and other cardiometabolic risk factors in boys with obesity and nonalcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has become the most common causes of liver disease in children and adolescents. Although several reports have confirmed the significant correlation between NAFLD and growth hormone (GH)-insulin-like growth factor 1(IGF-1) axis, no study further investigates whether or not recombinant human GH (rhGH) treatment can improve NAFLD in obese children. METHODS: This study was a randomized, open-label study comprising 44 boys with obesity and NAFLD (11.76 ± 1.67 year) to evaluate the effects of 6 months of rhGH administration for boys with obesity and NAFLD. The subjects were randomized divided into treatment group (subjects with recombinant human GH (rhGH)) and control group for 6 months. RESULTS: After 6 months, IGF-1 increased significantly during rhGH treatment, in comparison with the control group (582.45 ± 133.00 vs. 359.64 ± 129.00 ng/ml; p < 0.001). A significant reduction in serum alanine aminotransferase(ALT) (15.00 vs. 28.00 U/L; p = 0.001), aspartate aminotransferase(AST) (20.00 vs. 24.50U/L; p = 0.004), gamma glutamyl transferase(GGT) (14.50 vs. 28.50 U/L; p < 0.001) was observed in the GH-treated boys. In addition, the rhGH group showed a significant decrease in C reactive protein (CRP) (1.17 ± 0.76 vs. 2.26 ± 1.43 mg/L) and body mass index standard deviation scores (BMI SDS) (2.28 ± 0.80 vs. 2.71 ± 0.61) than the control group (p = 0.003, p = 0.049 respectively). GH treatment also reduced low density lipoprotein cholesterol (LDL-C) (2.19 ± 0.42 vs. 2.61 ± 0.66 mmol/L; p = 0.016) and increased high density lipoprotein cholesterol (HDL-C) (1.30 vs. 1.15 mmol/L; p = 0.005), and there were no changes in total cholesterol (TC), triglycerides (TG) and uric acid(UA) between the treatment group and the control group. CONCLUSION: Our findings suggest that 6 months treatment with rhGH may be beneficial for liver enzyme and can improve obesity-related other cardiovascular and metabolic complications in boys with obesity and NAFLD.

Prognostic and Clinical Significance of Aspartate Aminotransferase-to-Lymphocyte Ratio Index in Individuals with Liver Cancer: A Meta-Analysis.

OBJECTIVE: This study was aimed at exploring the prognostic and clinicopathological roles of aspartate aminotransferase-to-lymphocyte ratio index (ALRI) in patients with hepatocellular carcinoma via a meta-analysis. METHODS: The PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases were comprehensively searched from inception to November 20, 2021. Pooled hazard ratio (HR) and corresponding 95% confidence interval (CI) were used to evaluate the relationship between ALRI and overall survival (OS) as well as progression-free survival (PFS) in patients with hepatocellular carcinoma. Odds ratio (OR) and the corresponding 95% CI were also used to investigate correlations between clinical factors and ALRI in patients with hepatocellular carcinoma. RESULTS: A total of 3914 patients with hepatocellular carcinoma from eleven retrospective cohorts were included in this meta-analysis. The combined results revealed that patients with hepatocellular carcinoma with elevated ALRI tended to have unfavorable OS (HR 1.53 [95% CI 1.25-1.82]; P < 0.001). Pooled HRs revealed that high ALRI was an independent risk factor for inferior PFS in patients with hepatocellular carcinoma (HR 1.36 [95% CI 1.10-1.63]; P < 0.001). In addition, high ALRI was strongly associated with male sex (OR 1.32 [95% CI 1.02-1.70]; P = 0.035), presence of cirrhosis (OR 1.68 [95% CI 1.01-2.81]; P = 0.046), larger tumor size (OR 2.25 [95% CI 1.31-3.88]; P < 0.001), presence of portal vein tumor thrombus (OR 2.50 [95% CI 1.52-4.11]; P < 0.001), and distant metastasis (OR 1.72 [95% CI 1.05-2.82]; P = 0.031). CONCLUSION: Elevated ALRI in patients with hepatocellular carcinoma predicted inferior survival outcomes and was strongly associated with some important features of hepatocellular carcinoma.

Effect of an Extract from the Egyptian Sea Cucumber, Bohadschia marmorata, on Methotrexate-Induced Hepatorenal Toxicity in Male Mice.

BACKGROUND: The sea cucumber, Bohadschia marmorata, is a marine echinoderm consumed and used as a medication. Extract of this species displays a broad spectrum of bioactivity, such as antifungal, antibacterial, immunomodulatory, and cytotoxic properties. This investigation explored sea cucumber extract for hepatorenal protection against the toxicity of methotrexate (MTX). METHODS: Four groups of mice were divided into G1: control, G2: MTX treated, G3: B. marmorata extract-treated daily for 14 days, and G4: B. marmorata extract and MTX treated. RESULTS AND CONCLUSIONS: Biochemical analysis and histopathological examination of liver tissue showed that administration of MTX increased serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), lowered levels of serum albumin, total protein, Superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Administration of B. marmorata extract to MTX- injected mice significantly reversed the increase in serum levels of liver enzymes and induced a significant elevation in serum albumin and total protein levels. SOD, CAT, and GSH levels returned to nearly normal levels. Histopathological examination indicated fewer signs of toxicity in liver and kidney tissues of mice treated with both extract and MTX compared to MTX treatment alone. An extract of B. marmorata will protect mice from hepatorenal toxicity induced by MTX.

The association between elevated lipid profile and liver enzymes: a study on Bangladeshi adults.

Dyslipidemia, a major contributor to cardiovascular diseases, is rapidly increasing in Asian countries including Bangladesh. In addition to the cardiovascular system, abnormal lipid levels are also known to cause complications in renal and hepatic systems. The data regarding dyslipidemia and its relationship with liver enzymes are scarce for the Bangladeshi population. Therefore, this study was conducted to estimate the prevalence of dyslipidemia and determine the relationship between lipid profile and liver enzymes in Bangladeshi adults. A total of 405 participants (318 males and 87 females) were enrolled in the study. Serum levels of TG, TC, LDL, HDL and liver enzymes including ALT, AST, GGT and ALP were analyzed using standard methods. Dyslipidemia and liver function tests abnormalities were defined according to the international standard guidelines. The association between elevated lipid profile markers and liver enzyme abnormalities was assessed by logistic regression analysis. Overall, the prevalence of elevated TG, TC, LDL and low HDL were 30.9%, 23.7%, 26.2% and 78.8%, respectively. On the other hand, the prevalence of elevated liver enzymes ALT, AST, GGT and ALP were 18.8%, 21.6%, 12.9% and 21.9%, respectively. Dyslipidemia and liver enzyme abnormalities were higher in diabetic and hypertensive participants than in the healthy participants. About 61% of participants with dyslipidemia had at least one or more elevated liver enzymes. In regression analysis, an independent association was observed between serum GGT and all lipid components. In conclusion, a high prevalence of dyslipidemia and liver enzyme abnormalities were observed among the study participants. Of the four liver enzymes, the serum levels of GGT showed an independent association with all lipid components. Moreover, this study indicates that subjects with dyslipidemia often have a higher chance of having liver diseases than subjects with no dyslipidemia. However, large-scale prospective studies are needed to understand the underlying mechanisms of lipid-induced hepatic dysfunction in the Bangladeshi population.

Dapagliflozin improves steatohepatitis in diabetic rats via inhibition of oxidative stress and inflammation.

Type-2 diabetes mellitus and NAFLD are considered as one of the greatest worldwide metabolic disorders with growing incidence. It was found that patients with T2DM have two-fold increase to develop NAFLD. Evidence that some antidiabetic agents improve NAFLD/NASH in patients with T2DM is evolving. However, there are no certain pharmacologic therapies. The current study aimed to investigate the underlying mechanisms for the hepatoprotective effect of dapagliflozin against steatohepatitis in diabetic rats. Type-2 diabetes was induced by HFD followed by a single dose of STZ (30 mg/kg I.P). Fifty rats were randomly divided into 5 groups: Group1; normal control, Group 2; diabetic control, Groups (3-5); diabetic rats received daily dapagliflozin (0.75, 1.5, 3 mg/kg, p.o.) respectively for 6 weeks. At the end of the experiment, blood glucose level and serum insulin were measured. Hepatic tissue homogenization was performed for measuring inflammatory and oxidative stress markers. In addition, histopathological investigation of the hepatic tissue was done. Diabetic rats exhibited remarkable increase in liver weight and liver enzymes, along with histopathological changes, significant elevation in MDA, IL-1 ß, TGFß levels and, NF-κB, alpha-SMA expressions. Dapagliflozin treatment decreased liver weight, liver enzymes, together with marked improvement in histopathological changes. Furthermore, dapagliflozin increased antioxidant enzymes, GSH levels. Interestingly, Dapagliflozin reduced IL-1 ß, TGFß levels and, NF-κB, alpha-SMA expressions. Present data show that dapagliflozin represent a viable approach to protect the liver against diabetes-encouraged steatohepatitis through inhibiting oxidative stress, inflammation and fibrosis progression thus conserving liver function.

Camrelizumab plus apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma (CAP 02): a single-arm, open-label, phase 2 trial.

BACKGROUND: Camrelizumab, an anti-PD-1 antibody, has shown moderate efficacy in oesophageal squamous cell carcinoma. Apatinib, a selective inhibitor of VEGFR2, has a synergistic effect with immunotherapy. We aimed to assess the combination of camrelizumab and apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma. METHODS: This single-arm, open-label, phase 2 study was conducted at eight centres in China. Eligible patients were aged 18-75 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had unresectable locally advanced, locally recurrent, or metastatic oesophageal squamous cell carcinoma, and had progressed after or were intolerant to first-line chemotherapy. Patients received intravenous camrelizumab 200 mg once every 2 weeks plus oral apatinib 250 mg once daily for a 28-day cycle until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was investigator-assessed confirmed objective response rate. Efficacy was analysed in patients who had received at least one dose of study drug, and safety was analysed in patients who received the study drug and had at least one post-baseline safety assessment. The study of this cohort is complete and this trial is registered with ClinicalTrials.gov, number NCT03736863. FINDINGS: Between Dec 5, 2019, and Feb 10, 2021, 52 patients were enrolled and included in analyses. At data cutoff (June 20, 2021), median follow-up was 7·5 months (IQR 4·0-11·2). 18 (34·6%, [95% CI 22·0-49·1]) of 52 patients had a confirmed objective response. 23 (44%) of 52 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or worse treatment-related adverse events were increased aspartate aminotransferase (10 [19%]), increased gamma-glutamyltransferase (10 [19%]), and increased alanine aminotransferase (five [10%]). No treatment-related deaths occurred. INTERPRETATION: Camrelizumab combined with apatinib showed promising activity and manageable toxicity, and might be a potential second-line treatment option for patients with advanced oesophageal squamous cell carcinoma. Another cohort of this study, enrolling patients previously treated with first-line immunotherapy, is ongoing. FUNDING: Jiangsu Hengrui Pharmaceuticals.

O-alkyl and o-benzyl hesperetin derivative-1L attenuates inflammation and protects against alcoholic liver injury via inhibition of BRD2-NF-κB signaling pathway.

Alcoholic liver injury (ALI) is a major risk factor for alcoholic liver disease, characterized by excessive inflammatory response and abnormal liver dysfunction. Previous studies have indicated that O-alkyl and o-benzyl hesperetin derivative-1 L (HD-1 L) has anti-inflammatory and hepato-protective effects in CCl4-induced liver injury. However, its effect on ALI and underlying mechanism has not been elucidated. This study was designed to evaluate the protective effects of HD-1 L on alcoholic liver injury and reveal the underlying mechanisms. ALI model was established in male C57BL/6 J mice (aged 6-8 weeks) by Gao-Binge protocol. The mice were received different doses of HD-1 L (25 mg/kg, 50 mg/kg, 100 mg/kg) by daily intragastric administration, respectively. Liver function and inflammation were measured. Mechanism underlying the anti-inflammatory and hepato-protective effect of HD-1 L were studied in RAW264.7 cells. In alcoholic liver injury mice, HD-1 L effectively improved the liver pathology, and remarkably reduced the levels of alanine transaminase (ALT), aspartate transaminase (AST), triglyceride (TG) and total cholesterol (T-CHO) in serum. Moreover, HD-1 L markedly suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro. Our results showed that HD-1 L decreased the activity of Bromodomain-containing Protein 2 (BRD2) and inhibited expression of BRD2 in vivo and in vitro. Furthermore, HD-1 L further alleviated alcohol-induced inflammation after blocking BRD2 with inhibitor (JQ1) or BRD2 small interfering (si)-RNA in RAW264.7 cells. Besides, HD-1 L failed to effectively exert its anti-inflammatory effects after over expression of BRD2. In addition, HD-1 L significantly inhibited the phosphorylation and activation of NF-κB-P65 mediated by BRD2. In conclusion, HD-1 L alleviated liver injury and inflammation mainly by inhibiting BRD2-NF-κB signaling pathway, and HD-1 L may be a potential anti-inflammatory compound in treatment of alcoholic liver disease.

Serum cadmium is associated with hepatic steatosis and fibrosis: Korean national health and nutrition examination survey data IV-VII.

ABSTRACT: Although cadmium (Cd) is correlated with elevated levels of hepatic amino transferases, its influence on the degree of liver steatosis and fibrosis are unknown yet. We aimed to investigate the associations between the serum level of Cd and degree of liver steatosis/fibrosis.Clinical data were obtained from Korean National Health and Nutrition Examination Surveys IV-VII. Alanine aminotransferase (ALT) elevation was defined as ≥ 33 IU/L for men and ≥ 25 IU/L for women. Significant steatosis was defined as a hepatic steatosis index ≥ 36, while significant fibrosis was defined as a fibrosis index (FIB-4) ≥ 2.67 and as an aspartate aminotransferase and platelet ratio index ≥ 0.7. Adjusted odds ratios and 95% confidence intervals were calculated after adjustment.The levels of serum Cd were assessable in 15,783 subjects. The serum cadmium concentrations were significantly associated with ALT elevation, significant liver steatosis and fibrosis. Multivariate logistic regression analysis demonstrated serum Cd level in the forth quartile had a positive correlation with ALT elevation, hepatic steatosis index ≥ 36, FIB-4 ≥ 2.67 and aspartate aminotransferase-to-platelet ratio ≥ 0.7 using the first quartile of serum Cd level as the reference, (adjusted odds ratios 1.90, 1.26, 1.73, and 2.53, respectively; P values <.001).The serum level of Cd was associated with liver steatosis and fibrosis. The evaluation of serum Cd may help for assessing an unexplained liver steatosis and fibrosis, and further prospective studies are needed to confirm our findings.

GP73 level in patients with chronic hepatitis B: Relationship with liver biopsy, levels of ALT, AST and HBV DNA.

BACKGROUND/AIMS: In this study, we investigated the Golgi protein 73 (GP73) level in Hepatitis B and determined the correlation between Hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, and liver histopathology. Materials and. METHODS: GP73 levels were estimated by enzyme-linked immunosorbent assay in serum samples from patients. Liver biopsy specimens were examined by the same pathologist. RESULTS: : This study included a total of 127 patients who underwent liver biopsy. Of patients, 85% were HBeAg negative. HBV DNA level was median 134667 IU/mL (2247-170000000 IU/mL), Liver biopsy results revealed a mean Histological Activity Index (HAI) grade of 7.7 ± 3.4 and a mean fibrosis stage of 2.25 ± 1.06 gr/dL. GP73 was as follows: a mean of 14.8 ± 7.9 ng/mL and a median of 12.9 (4.8-50.1) ng/mL. A weak correlation between GP73 level and AST (r = 0.236, P = 0.11), fibrosis stage (r = 0.287, P = 0.002), and HAI grade (r = 0.218, P = 0.016) was noted. No statistically significant correlation was detected between GP73 and ALT (r = 0.16, P = 0.08), HBV DNA (r = 0.13, P = 0.08). CONCLUSION: Although recent studies revealed a strong correlation and increased GP73 levels in accordance with HAI scores and the fibrosis grade of liver, we detected a weak correlation between serum GP73 levels and HAI scores, fibrosis stage, and AST. This may be due to the insufficient number of patients with higher HAI grading and fibrosis staging in our study. Therefore, we concluded that, in cases of low-moderate fibrosis and HAI grading, GP73 seemed not to be useful and a reliable marker to replace liver biopsy.

Kupffer cells play a crucial role in monocrotaline-induced liver injury by producing TNF-α.

Monocrotaline (MCT), an unsaturated pyrrolizidine alkaloid (PA) in plants, is mainly toxic to the lung and liver of mammals. As a commonly used tool for liver injury model, the mechanism of MCT hepatoxicity has still not been fully clarified. Kupffer cells (KCs) are the liver-resident macrophages and have various responses to different toxicants and liver damage. However, the role of KCs in MCT-induced liver injury remains controversial. In current work, we investigated the effects of KCs on MCT-induced liver injury, especially on MCT-induced hepatocyte death. KCs were depleted in Balb/c mice by liposome-entrapped clodronate (Lip/Clo) (0.2 mL/mouse, i.p.) or GdCl3 (0.7 mg/kg, i.p.) before MCT administration (300 mg/kg, i.p.), we found that the Lip/Clo group showed higher efficiency in KCs depletion and stronger hepatoprotective effects against MCT. We also found TNF-α was remarkably decreased after KCs depletion, the experiment of administering anti-TNF-α antibody (20 µg/mouse, i.p.) to MCT-treated animals generated the similar results. To further elaborate the function of KCs, we compared the ALT levels released from co-culturing murine hepatic parenchymal cells (HPCs) and RAW264.7 cells with that from HPCs alone. After the treatment of MCT, the released ALT levels in co-culture system were shown to be dependent on the number of RAW264.7 cells, while the anti-TNF-α antibody could suppress it. Finally, we discovered RIPK3/MLKL pathway might be activated by TNF-α released from KCs, and subsequently induced hepatocyte necrosis. Noteworthy, the known mechanisms including ER stress and NF-κB pathways were also found to be involved in the activation of KCs. In conclusion, our study reveals a further mechanism to MCT-induced hepatoxicity mediated directly by KCs via producing TNF-α.

Effects of curcumin supplementation on vitamin D levels in women with premenstrual syndrome and dysmenorrhea: a randomized controlled study.

BACKGROUND: Vitamin D has an established role in female reproduction. There is also evidence for an association between vitamin D levels and menstrual problems such as premenstrual syndrome (PMS) and dysmenorrhea. Curcumin, is a bioactive polyphenol constituent of turmeric, that can potentially interact with vitamin D receptors and its molecular targets. This study evaluated the effects of curcumin on vitamin D levels in young women with PMS and dysmenorrhea. METHODS: In this randomized, triple-blind, placebo-controlled trial, women with PMS and dysmenorrhea were divided randomly into experimental and control groups to receive one capsule (500 mg of curcuminoid+ 5 mg piperine, or placebo) daily, from approximately 7 days before until 3 days after menstruation for three consecutive menstrual cycles. Serum vitamin D levels, renal function, and liver enzymes were also measured before and after intervention. RESULTS: A total of 76 subjects (38 in each group) were recruited into the trial. Curcumin significantly increased the median (IQR) serum levels of vitamin D [from 12.8 ng/ml (7.0-24.6) to 16.2 ng/ml (6.4-28.8); P = 0.045], compared with placebo [from 18.6 ng/ml (2.2-26.8) to 21.3 ng/ml (5.2-27.1); P = 0.17]. Serum levels of aspartate aminotransferase and direct bilirubin were reduced by the end of trial in the curcumin group (p < 0.05), but did not change significantly in the control group (p > 0.05). Finally, no significant differences in levels of fasting blood glucose were detected between curcumin and placebo groups. CONCLUSION: Curcumin supplementation in women with PMS and dysmenorrhea led to a significant improvement of vitamin D, liver function enzyme test, but did not affect blood glucose. TRIAL REGISTRATION: The trial was registered on Iranian Registry of Clinical Trials registry (Trial ID: IRCT20191112045424N1 on 23 January 2020; available at https://www.irct.ir ).

Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.

BACKGROUND: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. METHODS: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. FINDINGS: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. INTERPRETATION: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. FUNDING: Bristol Myers Squibb and the US National Institutes of Health.