Drug-induced liver injury: A 2-year retrospective study of 1169 hospitalized patients in a single medical center

BackgroundAlthough herbal medicines (HMs) are widely used in Asian and Western countries, medicinal information concerning their hepatic toxicity or interaction with conventional medicines (CMs) is sparse.PurposeThe aim of our study was to estimate the prevalence of drug-induced liver injury (DILI) among total inpatients prescribed HMs or CMs. Furthermore, we noted all medications suspected to be associated with hepatotoxicity in the liver injury group during the period of hospitalization.Study designWe retrospectively observed medical records of 1169 inpatients in a single medical center from January 2012 to July 2014.MethodsBased on a database of the 1169 inpatients at a single medical center, we researched the occurrence rate and type of liver injury according to the criteria of the Council for International Organization of Medical Science (CIOMS). We also utilized a simplified Roussel Uclaf Causality Assessment Method (RUCAM) score for probable causality assessment between drugs and liver injury.ResultsAmong a total of 1169 inpatients, 13 cases whose baseline LFTs had been in the normal range at admission had abnormal liver parameters at the time of follow-up, and 11 of them (0.94%) were attributed to drugs: 0.43% (5 of 1169) to HMs, 0.43% (5 of 1169) to CMs, and 0.09% (1 of 1169) to combined drug classes. Two of them were found to have liver injury because of pneumonia and sepsis. As for liver injury type, 8 cases were hepatocellular, 2 were cholestatic, and 1 was of mixed pattern. The common causative HMs for hepatotoxicity were Ephedrae Herba and Scutellariae Radix, while CMs included antidepressants, antihistamines, and antibacterials.ConclusionsWe investigated approximate incidence rates and analyzed suspicious drugs associated with liver damage, which revealed a low frequency of liver injury induced by HMs. However, further study, based on a well-designed, long-term, multicenter prospective study, will be required to determine the safety of HMs.     

Hospital Admissions for Drug-Induced Liver Injury: Clinical Features, Therapy, and Outcomes

We investigated clinical features, therapy, and outcomes of patients hospitalized for drug-induced liver injury (DILI). DILI resolution was defined as liver biochemistry values back to normal or lower than CIOMS laboratory criteria; Chronicity was defined as persistent biochemical abnormality for >6?months after drugs?? withdrawal. Three-hundred cases were reviewed retrospectively; mean age 51 (13?C86) years, and 204 (68?%) were females. It included 267 (89?%) hepatocellular injury, 16 (5.3?%) cholestatic injury, and 17 (5.7?%) mixed injury cases. In hepatocellular injury group, 197 (73.8?%) patients with TBIL?<?10× ULN included 142 (72.1?%) females and 70 (26.2?%) patients with TBIL????10× ULN included 39 (55.7?%) females (P?=?0.012). Of 70 patients (TBIL????10× ULN), 20 were treated with steroid step-down therapy (79?±?26?days) and others with non-steroid therapy. The steroid therapy group showed higher DILI resolution rate (P?=?0.029) and shorter recovery time (P?=?0.012). Notably, 274/300 (91.3?%) patients resolved, 18/300 (6?%) developed chronic liver injury, 7/300 (2.3?%) died, and one patient received liver transplantation. In death group, TBIL, ALB, PT, and PTA revealed more severe abnormality than in recovery group. In 121/300 (40.3?%) patients, use of herbal medicines was the leading cause of liver injury, followed by antibiotics, cardiovascular drugs, and endocrine drugs. We concluded that step-down steroid therapy for DILI improved curative effect, shortened disease course, and was safe.     

Liver enzyme abnormalities and associated risk factors in HIV patients on efavirenz-based HAART with or without tuberculosis co-infection in Tanzania

Objectives

To investigate the timing, incidence, clinical presentation, pharmacokinetics and pharmacogenetic predictors for antiretroviral and anti-tuberculosis drug induced liver injury (DILI) in HIV patients with or without TB co-infection.

Methods and Findings

A total of 473 treatment naïve HIV patients (253 HIV only and 220 with HIV-TB co-infection) were enrolled prospectively. Plasma efavirenz concentration and CYP2B6*6, CYP3A5*3, *6 and *7, ABCB1 3435C/T and SLCO1B1 genotypes were determined. Demographic, clinical and laboratory data were collected at baseline and up to 48 weeks of antiretroviral therapy. DILI case definition was according to Council for International Organizations of Medical Sciences (CIOMS). Incidence of DILI and identification of predictors was evaluated using Cox Proportional Hazards Model. The overall incidence of DILI was 7.8% (8.3 per 1000 person-week), being non-significantly higher among patients receiving concomitant anti-TB and HAART (10.0%, 10.7per 1000 person-week) than those receiving HAART alone (5.9%, 6.3 per 1000 person-week). Frequency of CYP2B6*6 allele (p = 0.03) and CYP2B6*6/*6 genotype (p = 0.06) was significantly higher in patients with DILI than those without. Multivariate cox regression model indicated that CYP2B6*6/*6 genotype and anti-HCV IgG antibody positive as significant predictors of DILI. Median time to DILI was 2 weeks after HAART initiation and no DILI onset was observed after 12 weeks. No severe DILI was seen and the gain in CD4 was similar in patients with or without DILI.

Conclusions

Antiretroviral and anti-tuberculosis DILI does occur in our setting, presenting early following HAART initiation. DILI seen is mild, transient and may not require treatment interruption. There is good tolerance to HAART and anti-TB with similar immunological outcomes. Genetic make-up mainly CYP2B6 genotype influences the development of efavirenz based HAART liver injury in Tanzanians.     

Pharmacogenetic & pharmacokinetic biomarker for efavirenz based ARV and rifampicin based anti-TB drug induced liver injury in TB-HIV infected patients

Background

Implication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI) has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI) in HIV and tuberculosis (TB) co-infected patients.

Methods and Findings

Newly diagnosed treatment naïve TB-HIV co-infected patients (n = 353) were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p = 0.001), higher plasma efavirenz level (p = 0.009), efavirenz/8-hydroxyefavirenz ratio (p = 0.036), baseline AST (p = 0.022), ALT (p = 0.014), lower hemoglobin (p = 0.008), and serum albumin (p = 0.007), NAT2 slow-acetylator genotype (p = 0.039) and ABCB1 3435TT genotype (p = 0.001).

Conclusion

We report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification of patients at risk of DILI.     

Polymorphisms in CTLA4 Influence Incidence of Drug-Induced Liver Injury after Renal Transplantation in Chinese Recipients

Genetic polymorphisms in cytotoxic T lymphocyte-associated antigen 4 (CTLA4) play an influential role in graft rejection and the long-term clinical outcome of organ transplantation. We investigated the association of 5 CTLA4 single-nucleotide polymorphisms (SNPs) (rs733618 C/T, rs4553808 A/G, rs5742909 C/T, rs231775 A/G, and rs3087243 G/A) with drug-induced liver injury (DILI) in Chinese renal transplantation (RT) recipients. Each recipient underwent a 24-month follow-up observation for drug-induced liver damage. The CTLA4 SNPs were genotyped in 864 renal transplantation recipients. A significant association was found between the rs231775 genotype and an early onset of DILI in the recipients. Multivariate analyses revealed that a risk factor, recipient rs231775 genotype (p = 0.040), was associated with DILI. Five haplotypes were estimated for 4 SNPs (excluding rs733618); the frequency of haplotype ACGG was significantly higher in the DILI group (68.9%) than in the non-DILI group (61.1%) (p = 0.041). In conclusion, CTLA4 haplotype ACGG was partially associated with the development of DILI in Chinese kidney transplant recipients. The rs231775 GG genotype may be a risk factor for immunosuppressive drug-induced liver damage.     

mTOR信号通路诱导的自噬在心肌细胞缺氧损伤中的作用研究

目的:探讨自噬在心肌细胞缺氧损伤中的作用及分子机制。方法:体外分离培养乳鼠心肌细胞,体外建立缺氧/去血清(H/SD)模型以模拟在体的缺血环境。分别给予自噬抑制剂3-甲基腺嘌呤(3MA,5 mM)和mTOR抑制剂雷帕霉素(1.0μg/L)调节心肌细胞自噬水平。分别采用TUNEL染色检测心肌细胞凋亡,Western blot方法检测心肌细胞蛋白表达水平。结果:H/SD损伤可以显著诱导心肌细胞自噬水平(P0.05),并且细胞自噬水平可以被3-MA及雷帕霉素调节。同时,H/SD可以显著增加心肌细胞凋亡(P0.05),而给予3-MA抑制自噬水平可以减少细胞凋亡(P0.05)。相反,雷帕霉素增加自噬同样可以加重缺氧导致的心肌细胞凋亡(P0.05)。H/SD损伤过程中,心肌细胞mTOR信号通路被激活,而自噬抑制剂3-MA可以显著提高缺氧条件下心肌细胞中p-mTOR(Ser2448)的表达水平(P0.05),并增加mTOR下游分子p-p70S6k(P0.05)和p-S6(P0.05)的表达。结论:mTOR信号通路诱导的细胞自噬可能参与了缺氧损伤诱导的心肌细胞凋亡。     

HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity

Background and Aim

The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases.

Methods

High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls.

Results

The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy’s Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07).

Conclusions

HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.     

Association between use of Qingfei Paidu Tang and mortality in hospitalized patients with COVID-19: A national retrospective registry study

BackgroundQingfei Paidu Tang (QPT), a formula of traditional Chinese medicine, which was suggested to be able to ease symptoms in patients with Coronavirus Disease 2019 (COVID-19), has been recommended by clinical guidelines and widely used to treat COVID-19 in China. However, whether it decreases mortality remains unknown.PurposeWe aimed to explore the association between QPT use and in-hospital mortality among patients hospitalized for COVID-19.Study designA retrospective study based on a real-world database was conducted.MethodsWe identified patients consecutively hospitalized with COVID-19 in 15 hospitals from a national retrospective registry in China, from January through May 2020. Data on patients’ characteristics, treatments, and outcomes were extracted from the electronic medical records. The association of QPT use with COVID-19 related mortality was evaluated using Cox proportional hazards models based on propensity score analysis.ResultsOf the 8939 patients included, 28.7% received QPT. The COVID-19 related mortality was 1.2% (95% confidence interval [CI] 0.8% to 1.7%) among the patients receiving QPT and 4.8% (95% CI 4.3% to 5.3%) among those not receiving QPT. After adjustment for patient characteristics and concomitant treatments, QPT use was associated with a relative reduction of 50% in-hospital COVID-19 related mortality (hazard ratio, 0.50; 95% CI, 0.37 to 0.66 p < 0.001). This association was consistent across subgroups by sex and age. Meanwhile, the incidences of acute liver injury (8.9% [95% CI, 7.8% to 10.1%] vs. 9.9% [95% CI, 9.2% to 10.7%]; odds ratio, 0.96 [95% CI, 0.81% to 1.14%], p = 0.658) and acute kidney injury (1.6% [95% CI, 1.2% to 2.2%] vs. 3.0% [95% CI, 2.6% to 3.5%]; odds ratio, 0.85 [95% CI, 0.62 to 1.17], p = 0.318) were comparable between patients receiving QPT and those not receiving QPT. The major study limitations included that the study was an observational study based on real-world data rather than a randomized control trial, and the quality of data could be affected by the accuracy and completeness of medical records.ConclusionsQPT was associated with a substantially lower risk of in-hospital mortality, without extra risk of acute liver injury or acute kidney injury among patients hospitalized with COVID-19.     

Necrotic cell death and suppression of T-cell immunity characterized acute liver failure due to drug-induced liver injury

Background & aims: The aim of this study was to investigate the clinical characteristics and pathophysiology of drug-induced liver injury (DILI) – acute liver failure (ALF). Methods: The patients with acute liver injury (ALI) including ALF from 2009 to 2014 were analyzed. The hepatic encephalopathy (HE) development rate was compared with the findings from a national survey in Japan. The serum cytokines levels and the findings of a liver function test were evaluated in the DILI patients. Results: The HE development rate substantially decreased for autoimmune hepatitis (AIH) – and undetermined cause-induced ALI owing to the early prediction system, but not in DILI-ALI. Among the DILI-ALF and AIH-ALF cases, the CK-18 fragment (1480.1 U/L, 3945.4 U/L), IL-8 (82.9 pg/mL, 207.5 pg/mL), IP-10 (1379.6 pg/mL, 3731.2 pg/mL) and MIP-1β (1017.7 pg/mL, 2273.3 pg/mL) levels were lower in the DILI-ALF cases. Among the DILI-ALI and DILI-ALF cases, IL-4 (19.8 pg/mL, 25.4 pg/mL) and RANTES (14028.0 pg/mL, 17804.7 pg/mL) were higher in DILI-ALI, and HMGB-1 (397.1 pg/μL, 326.2 pg/μL) and HGF (2.41 ng/mL, 0.55 ng/mL) were higher in DILI-ALF. We observed that HGF independently associated with DLI-ALF development. Conclusions: Despite the low grade apoptosis and inflammation, DILI patients progressed to ALF comparable with that of the AIH patients.     

Selected ABCB1, ABCB4 and ABCC2 Polymorphisms Do Not Enhance the Risk of Drug-Induced Hepatotoxicity in a Spanish Cohort

Background and Aims

Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort.

Methods

A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (−1774G>del, −1549A>G, −24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5′ allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed.

Results

None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 −1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 −1774G/−1549A/−24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI.

Conclusions

Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 −1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility.     

Evaluation of Patterns of Liver Toxicity in Patients on Antiretroviral and Anti-Tuberculosis Drugs: A Prospective Four Arm Observational Study in Ethiopian Patients

Objectives

To evaluate the incidence, type, severity and predictors of antiretroviral and/or anti-tuberculosis drugs induced liver injury (DILI).

Methods

A total of 1,060 treatment naive patients were prospectively enrolled into four treatment groups: HIV patients receiving efavirenz based HAART alone (Arm-1); TB-HIV co-infected patients with CD4≤200 cells/μL, receiving concomitant rifampicin based anti-TB and efavirenz based HAART (Arm-2); TB-HIV co-infected patients with CD4>200 cells/μL, receiving anti-TB alone (Arm-3); TB patients taking rifampicin based anti-TB alone (Arm-4). Liver enzyme levels were monitored at baseline, 1st, 2nd, 4th, 8th, 12th and 24th weeks during treatment. CD4 and HIV viral load was measured at baseline, 24th and 48th weeks. Data were analyzed using multivariate Cox Proportional Hazards Model.

Results

A total of 159 patients (15%) developed DILI with severity grades 1, 2, 3 and 4 of 53.5%, 32.7%, 11.3% and 2.5% respectively. The incidence of cholestatic, hepatocellular or mixed pattern was 61%, 15% and 24%, respectively. Incidence of DILI was highest in Arm-2 (24.2%)>Arm-3 (10.8%)>Arm-1 (8.8%)>Arm-4 (2.9%). Concomitant anti-TB-HIV therapy increased the risk of DILI by 10-fold than anti-TB alone (p<0.0001). HIV co-infection increased the risk of anti-TB DILI by 4-fold (p = 0.004). HAART associated DILI was 3-fold higher than anti-TB alone, (p = 0.02). HAART was associated with cholestatic and grade 1 DILI whereas anti-TB therapy was associated with hepatocellular and grade ≥ 2. Treatment type, lower CD4, platelet, hemoglobin, higher serum AST and direct bilirubin levels at baseline were significant DILI predictors. There was no effect of DILI on immunologic recovery or virologic suppression rate of HAART.

Conclusion

HAART associated DILI is mainly cholestatic and mild whereas hepatocellular or mixed pattern with high severity grade is more common in anti-tuberculosis DILI. TB-HIV co-infection, disease severity and concomitant treatment exacerbates the risk of DILI.     

Liver enzyme abnormalities during concurrent use of herbal and conventional medicines in Korea: A retrospective study

Concurrent use of herbal medicine (HM) and conventional medicine (CM) is increasing. However, little is known about the prevalence of drug-induced liver injury (DILI) related to this concurrent use. In order to investigate changes in liver enzymes during concurrent use of HM and CM and to assess the prevalence of DILI related to their concurrent use, we screened for liver injury among inpatients at our institution who were administered both HM and CM for at least 14 days while hospitalized between 2006 and 2010. We used the Council for International Organization of Medical Science (CIOMS) laboratory criteria to define liver injury. Of the 892 patients included in the study, 34 (3.81%) had liver injury on admission and 21 (2.35%) had liver injury at discharge. Of the 48 cases that fulfilled the CIOMS laboratory criteria for liver injury, 34 had preexisting liver injury. The remaining 14 were analyzed, and five were concluded to have DILI, resulting in a prevalence of 5/892 (0.56%, with a 95% confidence interval of 0.07-1.05%). Overall, clinical symptoms of liver injury were mild. We thus contend that concurrent use of HM and CM is relatively safe.     

Prediction models for drug-induced hepatotoxicity by using weighted molecular fingerprints

Background

Drug-induced liver injury (DILI) is a critical issue in drug development because DILI causes failures in clinical trials and the withdrawal of approved drugs from the market. There have been many attempts to predict the risk of DILI based on in vivo and in silico identification of hepatotoxic compounds. In the current study, we propose the in silico prediction model predicting DILI using weighted molecular fingerprints.

Results

In this study, we used 881 bits of molecular fingerprint and used as features describing presence or absence of each substructure of compounds. Then, the Bayesian probability of each substructure was calculated and labeled (positive or negative for DILI), and a weighted fingerprint was determined from the ratio of DILI-positive to DILI-negative probability values. Using weighted fingerprint features, the prediction models were trained and evaluated with the Random Forest (RF) and Support Vector Machine (SVM) algorithms. The constructed models yielded accuracies of 73.8% and 72.6%, AUCs of 0.791 and 0.768 in cross-validation. In independent tests, models achieved accuracies of 60.1% and 61.1% for RF and SVM, respectively. The results validated that weighted features helped increase overall performance of prediction models. The constructed models were further applied to the prediction of natural compounds in herbs to identify DILI potential, and 13,996 unique herbal compounds were predicted as DILI-positive with the SVM model.

Conclusions

The prediction models with weighted features increased the performance compared to non-weighted models. Moreover, we predicted the DILI potential of herbs with the best performed model, and the prediction results suggest that many herbal compounds could have potential to be DILI. We can thus infer that taking natural products without detailed references about the relevant pathways may be dangerous. Considering the frequency of use of compounds in natural herbs and their increased application in drug development, DILI labeling would be very important.

     

The HepaRG cell line,a superior in vitro model to L-02, HepG2 and hiHeps cell lines for assessing drug-induced liver injury

Drug-induced liver injury (DILI) is a leading cause of discontinuation of new drug approval or withdrawal of marketed medicine based on safety due to organ vulnerability. The aim of this research is to investigate the potential abilities of four different in vitro cell models (L-02, HepG2, HepaRG, and hiHeps cell lines) in assessing marketed drugs labeled with apparently different types of liver injury. A total of 17 drugs with versatile pharmacological profiles were chosen, of which, 14 drugs are recognized as DILI agents and 3 drugs are DILI irrelevant. Preliminary cellular screening assays indicated that the HepaRG cell line had an advantage over other cell lines in predicting drugs associated with DILI in vitro as it had the highest Youden’s index (71.4 %). A multi-parametric screening assay showed that oxidative stress, mitochondrial damage, and disorders of neutral lipid metabolism were changed notably in the HepaRG cell line after DILI-related drugs exposure, accounting for its high sensitivity in comparison with other three cell lines. In addition, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and malate dehydrogenase (MDH) all correlated with the cytotoxic effects of diclofenac sodium (p?<?0.05), buspirone hydrochloride (p?<?0.01), and danazol (p?<?0.01) in the HepaRG cell line. We conclude that the HepaRG cell line is a superior in vitro cell model to other three cell lines for evaluating drugs with DILI potential.     

Clinical Features of Brain Metastases in Small Cell Lung Cancer: an Implication for Hippocampal Sparing Whole Brain Radiation Therapy

PURPOSE: To assess the clinical features and distribution of brain metastases (BMs) of small cell lung cancer (SCLC) in the hippocampal and perihippocampal region, with the purpose of exploring the viability of hippocampal-sparing whole-brain radiation therapy (HS-WBRT) on reducing neurocognitive deficits. METHODS: This was a retrospective analysis of the clinical characteristics and patterns of BMs in patients with SCLC. Associations between the clinical characteristics and hippocampal metastases (HMs)/perihippocampal metastases (PHMs) were evaluated in univariate and multivariate regression analyses. RESULTS: A total of 1594 brain metastatic lesions were identified in 180 patients. Thirty-two (17.8%) patients were diagnosed with BMs at the time of primary SCLC diagnosis. The median interval between diagnosis of primary SCLC and BMs was 9.3 months. There were 9 (5.0%) and 22 (12.2%) patients with HMs and PHMs (patients with BMs located in or within 5 mm around the hippocampus), respectively. In the univariate and multivariate analysis, the number of BMs was the risk factor for HMs and PHMs. Patients with BMs ≥ 5 had significantly higher risk of HMs (odds ratio [OR] 7.892, 95% confidence interval [CI] 1.469-42.404, P = .016), and patients with BMs ≥ 7 had significantly higher risk of PHMs (OR 5.162, 95% CI 2.017-13.213, P = .001). Patients with extracranial metastases are also associated with HMs. CONCLUSIONS: Our results indicate that patients with nonoligometastatic disease are significantly associated with HMs and PHMs. The incidence of PHMs may be acceptably low enough to perform HS-WBRT for SCLC. Our findings provide valuable clinical data to assess the benefit of HS-WBRT in SCLC patients with BMs.     

The para isomer of dinitrobenzene disrupts redox homeostasis in liver and kidney of male wistar rats

BackgroundPara-Dinitrobenzene (p-DNB) is one of the isomers of dinitrobenzene which have been detected as environmental toxicants. Skin irritation and organ toxicities are likely for industrial workers exposed to p-DNB. This study evaluated the effect of sub-chronic exposure of rats to p-DNB on cellular redox balance, hepatic and renal integrity.MethodsForty eight male Wistar rats weighing 160–180 g were administered 50, 75, 1000 and 2000 mg/kg b.wt (body weight) of p-DNB or an equivalent volume of vehicle (control) orally and topically for 14 days. After the period of treatment, the activities of kidney and liver catalase (CAT), alkaline phosphatase (ALP) and superoxide dismutase (SOD) as well as extent of renal and hepatic lipid peroxidation (LPO) were determined. Serum ALP activity and plasma urea concentration were also evaluated.ResultsCompared with control animals, p-DNB -administered rats showed decrease in the body and relative kidney and liver weights as well as increased renal and hepatic hydrogen peroxide and lipid peroxidation levels accompanied by decreased superoxide dismutase and catalase activities. However, p-DNB caused a significant increase in plasma urea concentration and serum, liver and kidney ALP activities relative to control. In addition, p-DNB caused periportal infiltration, severe macro vesicular steatosis and hepatic necrosis in the liver.ConclusionsOur findings show that sub-chronic oral and sub-dermal administration of p-DNB may produce hepato-nephrotoxicity through oxidative stress.     

A longitudinal assessment of miR-122 and GLDH as biomarkers of drug-induced liver injury in the rat

Context: There is an ongoing search for specific and translational biomarkers of drug-induced liver injury (DILI). MicroRNA-122 (miR-122) has previously shown potential as a sensitive, specific, and translational biomarker of DILI in both rodent, and human studies.

Objective: To build on previous work within the field, we examined biomarker kinetics in a rat model of acetaminophen (APAP)-induced liver injury to confirm the sensitivity, and specificity of miR-122 and glutamate dehydrogenase (GLDH).

Materials and methods: qRT-PCR and a standard enzymatic assay were used for biomarker analysis.

Results: Both miR-122 and GLDH were demonstrated to be more readily-detectable biomarkers of APAP-DILI than alanine aminotransferase (ALT). Peak levels for all biomarkers were detected at 2 days after APAP. At day 3, miR-122 had returned to baseline; however, other biomarkers remained elevated between 3 and 4 days. We were also able to demonstrate that, although miR-122 is present in greater quantities in exosome-free form, both exosome-bound and non-vesicle bound miR-122 are released in a similar profile throughout the course of DILI.

Discussion and conclusions: Together, this study demonstrates that both GLDH and miR-122 could be used during preclinical drug-development as complementary biomarkers to ALT to increase the chance of early detection of hepatotoxicity.     

Red algae natural products for prevention of lipopolysaccharides (LPS)-induced liver and kidney inflammation and injuries

Background: The liver and kidney inflammation due to bacterial infection is one of the most common pathological problems leading to tissue damage or disease. In many liver and kidney disorders, which represent serious global health burden with a high economic cost, oxidative stress-related inflammation and apoptosis are important pathogenic components, finally resulting in acute liver and/or kidney failure. Erythropoietin and its analogues are well known to influence the interaction between apoptosis and inflammation in liver and kidney. Objective: The aim of the present study is to investigate and clarify the effect of Galaxaura oblongata (G. oblongata) red algae on lipopolysaccharides (LPS)-induced acute liver and kidney injury of mice with endotoxemia and associated molecular mechanism from inflammation, apoptosis and oxidative stress levels. Results: The current study cleared out that treatment of rats with the G. oblongata extract prior to LPS injection significantly lowered serum cytokines, including NF-κB, MPO and LPO, and improved liver apoptosis through suppressing protein tyrosine kinase signaling pathway, and that may be due to antibacterial activity as well antioxidant capacity of G. oblongata extract. Conclusion: The present study was cleared out the possibility of administration of G. oblongata red algae as a multi products source for biotechnological, medical, nutraceutical and pharmaceutical applications due to highly antioxidant and anti-inflammatory capacities even although more investigations are required for separating, purifying and characterizing these bioactive compounds.     

Overexpression of c-myc in hepatocytes promotes activation of hepatic stellate cells and facilitates the onset of liver fibrosis

BackgroundLiver fibrosis is a consequence of chronic liver injury and can further progress to hepatocellular carcinoma (HCC). Fibrogenesis involves activation of hepatic stellate cells (HSC) and proliferation of hepatocytes upon liver injury. HCC is frequently associated with overexpression of the proto-oncogene c-myc. However, the impact of c-myc for initiating pathological precursor stages such as liver fibrosis is poorly characterized. In the present study we thus investigated the impact of c-myc for liver fibrogenesis.MethodsExpression of c-myc was measured in biopsies of patients with liver fibrosis of different etiologies by quantitative real-time PCR (qPCR). Primary HSC were isolated from mice with transgenic overexpression of c-myc in hepatocytes (alb-myc^tg) and wildtype (WT) controls and investigated for markers of cell cycle progression and fibrosis by qPCR and immunofluorescence microscopy. Liver fibrosis in WT and alb-myc^tg mice was induced by repetitive CCl₄ treatment.ResultsWe detected strong up-regulation of hepatic c-myc in patients with advanced liver fibrosis. In return, overexpression of c-myc in alb-myc^tg mice resulted in increased liver collagen deposition and induction of α-smooth-muscle-actin indicating HSC activation. Primary HSC derived from alb-myc^tg mice showed enhanced proliferation and accelerated transdifferentiation into myofibroblasts in vitro. Accordingly, fibrosis initiation in vivo after chronic CCl₄ treatment was accelerated in alb-myc^tg mice compared to controls.ConclusionOverexpression of c-myc is a novel marker of liver fibrosis in man and mice. We conclude that chronic induction of c-myc especially in hepatocytes has the potential to prime resident HSC for activation, proliferation and myofibroblast differentiation.     

Anemia in Patients With Diabetes and Prediabetes With Normal Kidney Function: Prevalence and Clinical Outcomes

ObjectiveAnemia is a known complication of diabetes mellitus (DM); however, its prevalence and prognostic relevance in patients with DM and pre-DM with normal kidney function have not been well defined. This study assessed the prevalence of anemia in patients with DM and pre-DM and evaluated its association with clinical outcomes during a 4-year follow-up period.MethodsThis retrospective analysis included patients with DM and pre-DM referred to the Meir Medical Center Endocrine Institute in 2015. Patients with an estimated glomerular filtration rate (eGFR) of <60 mL/min or any other recognized cause of anemia were excluded. The risk of developing microvascular or macrovascular complications or of death during the 4-year follow-up period was determined.ResultsA total of 622 patients (408 with DM and 214 with pre-DM) were included. The mean age of the patients was 64 ± 10.6 years, and 70% were women. The baseline hemoglobin A1C level was 7.1% ± 1.7% (54 mmol/mol), and the eGFR was 86.1 ± 15.3 mL/min. At the time of inclusion, 77 patients (19%) with DM and 23 (11%) with pre-DM had anemia (hemoglobin level 11.9 ± 0.8 and 11.8 ± 0.8 g/dL, respectively), compared with normal hemoglobin levels of 13.8 ± 0.9 and 13.7± 0.9 g/dL, respectively, in the others. A multivariable analysis demonstrated an inverse correlation between baseline hemoglobin (as a continuous variable) and mortality (P = .035), microvascular complications (P = .003), and eGFR decline (P < .001) but not between baseline hemoglobin and macrovascular complications (P = .567).ConclusionThis study found a significant prevalence of anemia unrelated to renal failure, both in patients with DM and pre-DM. Anemia in these patients is associated with the development of microvascular complications, eGFR decline, and mortality. These results underscore the need for intensive lifestyle and pharmacologic interventions in these patients.