In silico screening and analysis of single-nucleotide polymorphic variants of the ABCC2 gene affecting Dubin–Johnson syndrome

Background and Study AimsDubin–Johnson syndrome (DJS) is a benevolent genetic disorder of the liver with autosomal inheritance. It is a rare disorder characterized by an increase in conjugated bilirubin and anomaly in coproporphyrin clearance. DJS is caused by deleterious mutations in the ABCC2 gene. A polymorphism in the ABCC2 gene causes malfunctions in its ability to regulate the efflux of different organic anions, such as bilirubin, from hepatocytes to the canaliculi. Multidrug resistance protein 2 (MRP2) encoded by the ABCC2 gene is one of the main regulators of the export of bilirubin to respective sites. ABCC2 gene mutations have widely drawn attention in the pathology of DJS in various populations.Patients and MethodsThe ABCC2 gene was subjected to the National Center for Biotechnology Information (NCBI) database in 2020, and non-synonymous single-nucleotide polymorphisms (nsSNPs) and variants in untranslated regions were studied using different computational servers. SIFT, Protein variation effect analyzer, and PolyPhen-2 were used to retrieve the damaging Single-nucleotide polymorphisms (SNPs); PhD-SNP, SNPs&GO, and Protein Analysis Through Evolutionary Relationships were used to predict the association of nsSNPs with DJS; Mutation3D illustrated the location of variants in the protein; SNAP2, MutPred2, ELASPIC, and HOPE were used to predict the structural and functional effects of these mutations on MRP2; and I-mutant 3.0 and MuPro were used to determine the effects of polymorphism on the function of MRP2.ResultsIn this study, 18,947 SNPs were screened from the NCBI database, followed by a series of refinement of variants using online available servers. We concluded that 41 ABCC2 gene variants are vital etiological candidates for DJS in humans. These 41 variants had highly damaging effects on the MRP2 protein, which may lead to deficient transportation capacity, thereby affecting the efflux of bilirubin across the canalicular membrane.ConclusionIn silico tools are an alternative approach for predicting the target SNPs. Hence, previously unreported variants can be considered strong etiological candidates for diseases related to MRP2.     

Liver dysfunction as a cytokine storm manifestation and prognostic factor for severe COVID-19

Liver damage in severe acute respiratory coronavirus 2 infection occurs in patients with or without preexisting liver disorders, posing a significant complication and mortality risk. During coronavirus disease 2019 (COVID-19), abnormal liver function is typically observed. However, liver injury may occur because of the treatment as well. Ischemia, cytokine storm, and hypoxia were identified as the three major factors contributing to liver damage during COVID-19. Indeed, raised liver enzymes during hospitalizations may be attributed to medications used, as well as sepsis and shock. As a result, the proportion of hospitalized patients afflicted with COVID-19 and pathological liver biomarkers varies from 14% to 53%. Aminotransferases and bilirubin are found most often elevated. Usually, increased gamma-glutamyltransferase, alkaline phosphatase, and decreased serum albumin levels are demonstrated. Additionally, although there is no specific treatment for COVID-19, many of the drugs used to treat the infection are hepatotoxic. In this mini-review, we focus on how liver dysfunction can be one of the features associated with the COVID-19 cytokine storm. Furthermore, data show that liver injury can be an independent predictor of severe COVID-19, the need for hospitalization, and death.     

Total bilirubin trend as a predictor of common bile duct stones in acute cholecystitis and symptomatic cholelithiasis

Background

We hypothesized that trends in total bilirubin in the context of cholecystitis and symptomatic cholelithiasis could be used to guide testing for the presence of common bile duct stones (CBDS).

Plasma acyl-carnitines,bilirubin, tyramine and tetrahydro-21-deoxycortisol in Parkinson's disease and essential tremor. A case control biomarker study

Background and purposeGiven the overlapping clinical manifestations and pathology, the differentiation between essential tremor (ET) and Parkinson's disease (PD) is difficult. Our aims were to examine the plasma metabolomics profiling and their association with motor and non-motor symptoms (NMS) in patients with PD, and to determine differences between de novo PD compared to moderate-advanced PD vs. controls and patients with ET.MethodsPlasma samples were collected from 137 subjects including 35 age matched controls, 29 NOVO-PD, 35 PD and 38 ET patients. PD severity, motor and NMS including cognitive function were assessed using the UPDRS, NMS and PD cognitive rating scales, respectively. Metabolomics analysis was performed by UPLC-ESI-QToF-MS followed by unsupervised multivariate statistics. The area under the curve of the biomarkers according to distribution of their concentrations and the diagnosis of PD (NOVO-PD, advanced PD) vs ET and healthy controls was used as a measurement of diagnostic ability.ResultsSeveral acyl-carnitines, bilirubin, tyramine and tetrahydro-21-deoxycortisol (THS) presented good predictive accuracy (AUC higher than 0.8) for differentiating de novo PD and advanced PD from controls and ET, suggesting an alteration in the lipid oxidation pathway. In multivariate regression analysis, metabolite levels were not significantly associated with motor and NMS severity in PD.ConclusionsDiverse acyl-carnitines, bilirubin, tyramine and some adrenal gland derived metabolites are suggested as potential biomarkers able to distinguish between PD from controls and ET.     

茵栀黄颗粒联合蓝光治疗黄疸疗效及对新生儿肝功能、胆红素、脑功能的影响

目的:研究茵栀黄颗粒口服联合蓝光治疗对新生儿黄疸肝功能、胆红素水平及脑功能的影响。方法:选择120例新生儿黄疸患儿并随机分为观察组和对照组各60例。对照组患儿采用蓝光治疗; 观察组患者在对照组基础上联合茵栀黄颗粒治疗,两组均治疗7 d。比较两组患儿治疗前后肝功能、胆红素水平、炎症反应水平及治疗后脑功能损伤情况和疗效。结果:治疗后观察组谷草转氨酶(AST)和谷丙转氨酶(ALT)水平显著低于对照组(P<0.05); 总胆红素(TBIL)、间接胆红素(IBIL)水平显著低于对照组(P<0.05); 白介素-6(IL-6)、C反应蛋白(CRP)水平显著低于对照组(P<0.05); 脑功能正常率显著高于对照组(P<0.05); 总有效率明显高于对照组(P<0.05)。结论:新生儿黄疸患儿通过茵栀黄颗粒口服联合蓝光治疗对改善肝功能、调节胆红素水平和炎症反应、改善脑功能有积极意义,整体疗效较理想。     

非增生型糖尿病视网膜病变患者循环胆红素水平变化及其预测价值

目的 探讨非增生型糖尿病视网膜病变（non-proliferative diabetic retinopathy,NPDR）患者循环胆红素水平变化及其预测价值。方法 选取2020年5月至2021年12月佳木斯市中医医院收治的100例2型糖尿病患者为研究对象。根据患者人工智能眼底照相筛查情况,将患者分为视网膜病变组（n=41）和非视网膜病变组（n=59）。比较两组患者的循环胆红素指标[直接胆红素（direct bilirubin,DBIL）、间接胆红素（indirect bilirubin,IBIL）、总胆红素（total bilirubin,TBIL）]水平;采用Spearman相关性分析探讨循环胆红素与糖化血红蛋白（glycosylated hemoglobin,HbA1c）的关系;采用Logistic回归分析探讨循环胆红素与NPDR的风险关系;绘制受试者操作特征曲线（receiver operator characteristic curve,ROC曲线）分析循环胆红素对NPDR发生的预测效能。结果 视网膜病变组患者的糖尿病病程、HbA1c、尿蛋白/肌酐比值均显著高于非视网膜病变组（P<0.05）,TBIL、DBIL、IBIL水平均显著低于非视网膜病变组（P<0.05）;Spearman相关性分析结果显示,TBIL、DBIL、IBIL均与HbA1c呈负相关（r=0.457、0.420、0.484,P<0.05）;Logistic回归分析结果显示,HbA1c是发生NPDR的独立危险因素（P<0.05）;TBIL、DBIL、IBIL均是发生NPDR的独立保护因素（P<0.05）;ROC曲线显示,TBIL、DBIL、IBIL预测NPDR发生的曲线下面积（area under the curve,AUC）分别为0.722、0.661、0.825,三者联合预测NPDR发生的AUC为0.913（0.844~0.992）。结论 NPDR患者的血清TBIL、DBIL、IBIL水平下降,其与HbA1c均呈负相关,三者联合检测对预测NPDR的发生具有一定价值。     

Bilirubin,a new therapeutic for kidney transplant?

In patients with end-stage renal disease, kidney transplantation has been associated with numerous benefits, including increased daily activity, and better survival rates. However, over 20% of kidney transplants result in rejection within five years. Rejection is primarily due to a hypersensitive immune system and ischemia/reperfusion injury. Bilirubin has been shown to be a potent antioxidant that is capable of potentially reversing or preventing damage from reactive oxygen species generated from ischemia and reperfusion. Additionally, bilirubin has several immunomodulatory effects that can dampen the immune system to promote organ acceptance. Increased bilirubin has also been shown to have a positive impact on renal hemodynamics, which is critical post-transplantation. Lastly, bilirubin levels have been correlated with biomarkers of successful transplantation. In this review, we discuss a multitude of potentially beneficial effects that bilirubin has on kidney acceptance of transplantation based on numerous clinical trials and animal models. Exogenous bilirubin delivery or increasing endogenous levels pre- or post-transplantation may have therapeutic benefits.     

严重高胆红素血症新生儿急性胆红素脑病危险因素分析

目的 探讨严重高胆红素血症新生儿急性胆红素脑病（ABE）发生的危险因素。方法选择本院2010年1月至2012年12月诊治的胎龄≥35周、血清胆红素（TSB）峰值〉425μmol/L且资料完整、进行了头颅核磁共振及脑干听觉诱发电位检查的患儿,根据是否符合ABE的诊断标准分为病例组和对照组,对一般资料、母孕期情况、合并症、围生期缺氧、黄疸的发生发展过程及实验室指标共22项临床因素进行单因素分析,对其中13项进行多因素Logistic回归分析。结果病例组43例,对照组30例,单因素分析显示,病例组出生后体重下降程度、TSB峰值、平均每日胆红素上升值及B/A值均高于对照组,差异有统计学意义（P〈0.05）;多因素分析提示,严重黄疸诊断日龄、围生期缺氧史及酸中毒与ABE的发生相关,OR（95%可信区间）分别为0.545（0.413~0.962）、36.589（1.114~1202.032）、7.963（1.294~49.010）,P均〈0.05。结论 在严重高胆红素血症新生儿中,严重黄疸诊断日龄越小,曾有围生期缺氧史和（或）伴有酸中毒者,ABE发生风险越高;而母乳喂养、出生后体重下降多、存在母子血型不合溶血、葡萄糖-6-磷酸脱氢酶缺陷则可能是严重高胆红素血症的原因。加强黄疸的监测、对严重高胆红素血症患儿积极纠正酸中毒,可能有助于预防胆红素脑病。