Liver Function Injury Research Articles

Fasudil alleviates acetaminophen-induced liver injury via targeting Rhoa/ROCK signal pathway.

Fasudil is an inhibitor of Rhoa/ROCK signaling, which is involved in anti-inflammatory and anti-injury effects. The purpose of this study was to explore the effects of Fasudil on acetaminophen (APAP)-induced liver injury and reveal its potential molecular mechanism. In this study, C57BL/6 J mice were divided into different groups and treated with APAP and specified dose of Fasudil. HE staining was used to detect the changes of liver pathological tissues induced by APAP. ELISA assay was performed to detected the level of related factors. Western blot was used to detect the expressions of Rhoa, ROCK1, ROCK2. CD86 and CD6 were determined by RT-PCR and immunohistochemical staining detected the difference in CD86 expression. Rhoa/ROCK expression was increased in APAP-induced liver injury, and Fasudil targeted the expression of Rhoa/ROCK. Fasudil inhibits APAP-induced hepatic pathological changes and liver function injury. Fasudil inhibits the release of APAP-induced systemic inflammatory factors in liver tissue. Fasudil inhibits the activity of antioxidant enzymes, lipid peroxidation and macrophage infiltration induced by APAP in liver tissues. Fasudil alleviates APAP-induced liver injury via targeting Rhoa/ROCK signal pathway, indicating the possibility for clinical use of Fasudil in APAP-induced liver injury.

The laboratory results of blood samples from 78 cases of COVID-19 in Shenzhen

Objective To analyze the hematological characteristics of COVID-19, which may provide a foundation for clinical diagnosis and treatment. Methods The blood samples from 78 cases of different clinical types of COVID-19 were tested for the indexes of hematocyte and clinical chemistry. The dynamic changes of early (0 -<10 d), middle (10 -<20 d) and late (≥20 d) stage were observed in 10 cured cases and 3 death cases. Results The 78 cases were divided into mild group ( n = 7), common group ( n =50) , severe group ( n =9) and critical group ( n =12). Compared to mild group and common group, lympho⁃ cyte count (LYM) and T lymphocyte subsets (CD3 + , CD4 + , CD8 + ) of early stage were decreased significantly in the severe and critical groups, while CK was increased ( P <0.05). Procalcitionin (PCT), D-Dimer, AST, ALT and MYO were also increased sig⁃ nificantly in critical group ( P <0.05). For the 10 cured cases, IL-6 and CRP were increased significantly in some of patients in early stage (0-<10 d) , lymphocyte count (LYM) (was decreased while neutrophil count (NEUT) and D-Dimer were increased in some of patients in middle stage 10-<20 d. In the late stage (≥20 d), except for CRP , D-Dimer and IL-6 , the other indexes gradually returned to normal level. CK and MYO had no significant change in the whole stage. For the 3 death cases, neutrophil count (NEUT), procalcitionin (PCT), D-Dimer, IL-6, CK and CRP was increased significantly, while lymphocyte count (LYM) was decreased in early stage (0-<10 d). D-Dimer, procalcitionin (PCT), AST, ALT, CK, MYO and IL-6 were still much higher than the normal level until the late stage (≥20 d). MYO and IL-6 were increased progressively in the whole stage ( P <0.05). Conclusion COVID-19 patients in severe and critical type are more serious in inflammatory reaction, and more prone to myocardial and liver function injury. CK, MYO, IL-6 and CRP continue to increase significantly in the early stage , which may be useful in predicting severity and outcome for patients with COVID-19. 摘要：目的 分析新型冠状病毒患者血液中各指标特点, 为临床诊治提供理论依据。 方法 以明确诊断为新型冠 状病毒肺炎的不同临床分型的 78 例患者为研究对象, 分析其外周血白细胞、血清生化等指标检测结果, 并对其中 10 例 痊愈患者和 3 例死亡患者在病程早 期 (0~<10 d) 、中 期 (10~<20 d) 和 后 期 (≥20 d) 的 上述各项指标进行动态观察。 结果 78 例患者中, 轻型 7 例, 普通型 50 例, 重型 9 例, 危重型 12 例。与轻型和普通型患者相比, 重型和危重型患者病程 早期的淋巴细胞绝对值、T 淋巴细胞亚群 (CD3 + 、CD4 + 、CD8 + ) 明显降低, 而 CK 显著升高 ( P <0.05), 危重型患者的 PCT、D- 二聚体、AST、ALT 以及 MYO 等指标均显著升高 ( P <0.05)；10 例痊愈患者中, 部分患者早期 (0~<10 d) IL-6 和 30% 的 C 反 应蛋白明显升高, 病程中期 (10~<20 d) 部分患者出现 LYM 降低, NEUT 和 D-二聚体升高, 病程后期 (≥20 d) 除 C 反应蛋 白、D-二聚体和 IL-6 外, 其余各项指标逐步恢复至正常水平。CK 指标在整个病程过程中无明显变化。3 例死亡患者病 程早期 (0~<10 d) 的 NEUT、PCT、D-二聚体、IL-6、CK、MYO、C 反应蛋白等指标明显高于正常水平, LYM 降低, 一直到病 程晚期 (≥20 d) 仍远高于正常水平的指标有 D-二聚体、PCT、ALT、AST、CK、MYO 和 IL-6。MYO 和 IL-6 在整个病程中呈 进行性升高 (( P <0.05)。 结论 新型冠状病毒肺炎重型和危重型患者的炎症反应比轻型和普通型患者重, 更易出现心肌 和肝功能损伤；CK、MYO、IL-6、C 反应蛋白等指标在病程早期的持续明显升高, 可作为临床上判断患者病情程度, 提示 预后的重要参考指标。

Clinical characteristics of coronavirus disease 2019 patients complicated with liver injury.

To analyze the clinical characteristics in patients of coronavirus disease 2019 (COVID-19) complicated with liver injury, to explore the relationship between COVID-19 clinical classification and liver injury, and to elucidate whether COVID-19 complicated with hepatitis B virus can aggravate liver injury. The abnormal liver function in 110 patients in the First Hospital of Changsha, who were confirmed COVID-19 and admitted to the designated hospital from January 17, 2020 to February 20, 2020, wereretrospectively analyzed. The detection indexes included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), and total bilirubin (TBIL). A total of 49.1% of the COVID-19 patients had liver injury. There were significant difference in the ALT, AST, ALB (all P<0.05), but there was no significant difference in the TBIL (P>0.05) between the severe (critical) patients and the general (light) patients. There was also no significant difference in the liver function injury between the HBsAg-positive COVID-19 patients and HBsAg-negative COVID-19 patients (P>0.05). Acute liver injury was not found to be a direct cause of death in the patients. In the COVID-19 patients, the incidence of liver injury is high with the increase of ALT and AST and the decrease of ALB. Severe and critical patients have obvious liver injury, and those patients complicated with hepatitis B virus infection don't show aggravated liver injury.

Clinical characteristics and outcomes of 2019 novel coronavirus disease patients presenting with initial gastrointestinal symptoms in Wuhan, China: A retrospective cohort study.

Patients with 2019 novel coronavirus disease (COVID-19) could present with gastrointestinal symptoms without fever or respiratory manifestations, which could be overlooked by health-care providers. We aimed to evaluate the clinical characteristics of COVID-19 in patients presenting with initial gastrointestinal symptoms. We evaluated all confirmed cases of COVID-19 in Zhongnan Hospital of Wuhan University between January 10 and February 29, 2020. We divided these patients into two groups: patients with initial gastrointestinal symptoms (group A, n=183) and patients with respiratory syndrome and/or fever (group B, n=1228). The clinical characteristics, radiological features, and laboratory data were assessed. The clinical procedures of both groups underwent 1-2weeks rising period and were downward trend at 3weeks; less than 5% of patients progressed to critical illness. In both groups, mean leukocyte count (P=0.354) and lymphocyte count (P=0.386) were below normal, and C-reactive protein level was elevated (P=0.412). There was mild liver function injury (aspartate aminotransferase, 65.8±12.7 vs 67.4±9.3U/L, P=0.246; alanine aminotransferase, 66.4±13.2 vs 69.6±12.7U/L, P=0.352), and normal renal function was intact (blood urea nitrogen 6.4±2.5 vs 5.6±2.8mmol/L P=0.358; creatinine 85.7±37.2, 91.2±32.6μmol/L, P=0.297). After a series of treatment, 176 and 1169 were stable and alive in groups A and B, respectively. The survival rate did not differ significantly between the groups (P=0.313). COVID-19 patients presented with initial gastrointestinal symptoms had similar clinical characteristics and outcomes, when compared with patients with fever and respiratory symptoms.

Analysis of metastatic colorectal cancer patients treated with regorafenib in real-world practice

Objective: To evaluate the dose, efficacy and tolerability of regorafenib in a real-world clinical setting of metastatic colorectal cancer patients. Methods: The clinical data of patients with metastatic colorectal cancer who had received at least two previous treatment lines treated with regorafenib from May 2018 to December 2019 at National Cancer Center/Cancer Hospital was retrospectively analyzed. Patients'demographics, treatment, dosimetry, safety and survival data were collected. The primary endpoint was overall survival (OS). Results: A total of 114 patients were enrolled in this study, including male 83 and female 31, with a median age of 61.Of all patients, 83 were treated with regorafenib and 31 were given combination therapy with regorafenib. Starting dose was 80 mg in 57 (50.0%) patients, 120 mg in 24 (21.1%) patients, and 160 mg in 28 (24.6%) patients. Dose increases were observed in 30.9% (25/81) of patients receiving 80 mg and 120 mg as the initial dose. Forty-five (39.5%) and 36 (31.6%) patients took the last daily dose of 80 mg and 120 mg, respectively. Median follow-up time was 8.5 months.Objective response rate (ORR) and disease control rate(DCR) were 1.0% and 52.1%, respectively. The median progression free survivalrate (PFS) was 2.4 moths (95%CI: 0.80-10.57), median OS was 11.0 moths(95%CI: 9.03-not available). The difference of the PFS and OS in the different dose groups was not statistically significant. But patients who received 120 mg regorafenib showed much longer survival with a median OS of 16.7 month. The difference of survival between the regorafenib group and combination group was not statistically significant either. Twenty patients continued with regorafenib as treatment even after progression. These patients had longer survival compared with those (n=52) who stopped regorafenib with median OS of 16.7 month vs 9.1 month (χ(2)=2.305, P=0.116), respectively.There were 7.9%(9/114) of the patients who discontinued regorafenib therapy because of the adverse event, such as hand-foot skin reaction (HFSR), gastrointestinal bleeding, proteinuria and liver function injury. Conclusions: Patients with advanced colorectal cancer who failed to respond to standard therapy have a good survival benefit. The initial dose of 120 mg of regorafenib has a better risk/benefit ratio and is more suitable for patients with advanced colorectal cancer.

A Novel Pathological Scoring System for Hepatic Cirrhosis with Hepatocellular Carcinoma.

PurposeThis study aimed to propose an effective quantitative pathological scoring system and to establish nomogram to assess the stage of cirrhosis and predict postoperative survival of hepatocellular carcinoma (HCC) with cirrhosis patients after hepatectomy.MethodsThe scoring system was based on a retrospective study on 163 patients who underwent partial hepatectomy for HCC with cirrhosis. The clinicopathological and follow-up data of 163 HCC with cirrhosis patients who underwent hepatectomy in our hospital from 2010 to 2014 were retrospectively reviewed. A scoring system was established based on the total value of independent predictive factors of cirrhosis. The results were validated using 97 patients operated on from 2011 to 2015 at the same institution. Nomogram was then formulated using a multivariate Cox proportional hazards model to analyze.ResultsThe scoring system was ultimately composed of 4 independent predictive factors and was divided into 3 levels. The new cirrhosis system score strongly correlated with Child–Pugh score (r=0.8058, P<0.0001) 3 months after surgery; higher cirrhosis system scores predicted poorer liver function and stronger liver damage 3 months after surgery. Then, a four-factor nomogram for survival prediction was established. The concordance indices were 0.79 for the survival-prediction nomogram. The calibration curves showed good agreement between predictions by the nomogram and actual survival outcomes.ConclusionThis new scoring system of cirrhosis can help us predict the liver function and liver injury 3 months after surgery, and the nomogram enabled accurate predictions of risk of overall survival in patients of HCC with cirrhosis after hepatectomy.

Effect and mechanism of gdolinium chloride on hepatic ischemia/reperfusion injury in Sprague Dawley rats

Objective To analyze the effect and mechanism of gadolinium chloride on hepatic ischemia-reperfusion injury (HIRI) in Sprague Dawley (SD) rats. Methods Thirty six eight weeks special pathogen free SD rats, were included in the project. The body weight ranged from 200 to 250 g. Thirty six rats were randomly divided into sham operation group, model group and gadolinium chloride group with 12 rats/group. Model of ischemia-reperfusion injury was generated in the rats of model group; In the gadolinium chloride group, preoperative intraperitoneal injection of gadolinium chloride was performed before the model of HIRI was established; In the sham operation group, only the abdomen was opened and closed and the hilum was dissected. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected in the three groups. The relative expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1 β (IL-1β) mRNA were detected by Q-PCR. Western blot was used to detect the expression of markers involved in the Toll like receptor 2/myeloid differentiation factor 88 (MyD88) signaling pathway. Immunohistochemistry staining was used to detect the expression of Fas and Fas ligands in hilar bile duct epithelial cells. Results ALT and AST were (55±8) U/L, (92±22) U/L in sham operation group, lower than those in model group (1 247±62) U/L, (1 117±60) U/L, respectively, and ALT and AST in gadolinium chloride group were (622±50) U/L and (552±41) U/L, lower than those in model group (all P<0.05). Compared with the sham operation group, the relative expression of TNF-α, IL-1 β, IL-6 mRNA in the model group was significantly higher (all P<0.05), but the expression of those markers were higher than gadolinium chloride group (all P<0.05). Gadolinium chloride down-regulated the expression of Toll like receptor 2/MyD88 signaling pathway in rat with liver ischemia-reperfusion. The percentage of Fas protein positive cells in model group was (40.2±3.8)%, and the percentage of Fas ligand positive cells was (36.9±2.9)%, which was higher than those in gadolinium chloride group (29.7±2.3)% and (23.6±2.1)% with statistically significant differences (all P<0.05). Conclusion Gadolinium chloride can reduce the injury of liver function and inhibit the expression of inflammatory factors in liver tissue of SD rats with hepatic ischemia-reperfusion, which may play a protective role by down regulating the expression of relative protein in Toll like receptor 2/MyD88 signaling pathway. Key words: Reperfusion injury; Gdolinium chloride; Liver; Toll-like receptor 2; Myeloid differentiation factor 88

Effect of compromised liver function and acute kidney injury on the pharmacokinetics of thymoquinone in a rat model

The current research explored the effect of hepatic and renal dysfunctions on the pharmacokinetics of thymoquinone (TQ) in a rat model.An acute kidney injury was induced using gentamicin and a liver damage was elicited using a single dose of d-galactosamine. For the pharmacokinetic studies, TQ was administered as IV injection or and PO route to rats.The concentrations of TQ and pharmacokinetic parameters were calculated using a non-compartmental analysis. The systemic clearance (Cl) of TQ after IV dosing was slightly reduced in the liver dysfunction group compared to healthy controls (p = 0.0013). Similarly, the estimated volume of distribution at steady state (Vss) was marginally decreased (p = 0.001). However, in rats with acute kidney injury exhibited a larger Vss as opposed to normal renal function (511.28 ± 21.03 ml/kg vs. 442.25 ± 31.43 ml/kg; p = 0.0001). Whereas oral Cl and terminal volume of distribution (Vz) of TQ were reduced by ∼50% in the liver dysfunction group (p = 0.0001). These changes were associated with more systemic exposure as measured by AUC0–∞ in rats with compromised liver functions. The estimated plasma protein binding TQ was 99.84 ± 0.03% in healthy controls, 97.05 ± 0.57% with kidney injury rats, and 95.75 ± 0.64% in liver dysfunctionThe findings of the present study suggest that liver dysfunction could potentially modify the disposition of TQ administered orally, and therefore, a smaller maintenance dose is probably required to avoid accumulation.

Clinical characteristics and influencing factors of patients with novel coronavirus pneumonia combined with liver injury in Shaanxi region

Objective: To understand the clinical characteristics, change of liver function, influencing factors and prognosis in hospitalized patients with coronavirus disease-19 (COVID-19) combined with liver injury. Methods: The general conditions, biochemical indicators of liver, blood clotting mechanism, routine blood test, UGT1A1 * 28 gene polymorphism and other data of 40 cases with COVID-19 admitted to the isolation ward of Tangdu Hospital were retrospectively analyzed. The clinical characteristics, influencing factors and prognosis of liver injury in patients with liver injury group and those with normal liver function group were compared. The mean of two samples in univariate analysis was compared by t-test and analysis of variance. The counting data was measured by χ(2) tests. The non-normal distribution measurement data were described by the median, and the non-parametric test was used. Statistically significant influencing factors were used as the independent variables in univariate analysis. Multiple logistic regression analysis was used to analyze the main influencing factors of liver injury. Results: Of the 40 cases, 25 were male (62.5%) and 15 were female (37.5%), aged 22 to 83 (53.87 ± 15.84) years. Liver injury was occurred in 22 cases (55%) during the course of the disease. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level was initially increased (4.4 to 3.5 times of the normal value) along with decrease of albumin in the second week, and the difference was statistically significant (P < 0.001). Ten cases (43.5%) had highest abnormal total blood bilirubin (54.1 μmol/ L). There was no correlation between the increase in transaminase and the increase in total blood bilirubin (R = -0.006, P = 0.972). Three cases had prothrombin activity (PTA) of ≤50%, 10 cases had elevated FDP, and 13 cases had elevated D-dimer, all of whom were severe or critically ill. Liver function injury was more likely to occur in patients who used many types of drugs and large amounts of hormones (P = 0.002, P = 0.031), and there was no correlation with the TA6TA7 mutation in the UGT1A1 * 28 gene locus. Multiple regression analysis showed that the occurrence of liver injury was only related to critical illness. The liver function of all patients had recovered within one week after conventional liver protection treatment. Conclusion: COVID-19 combined with liver function injury may be due to the slight elevation of transaminase, mostly around the second week of the disease course. Severe patients have a higher proportion of liver injury, and critical type is an independent risk factor for liver injury.

Comparative Study on Effect of Mesenchymal Stem Cells and Endothelial Progenitor Cells on Treatment of Experimental CCL4 Induced Liver Fibrosis

Abstract Background Bone marrow mesenchymal stem cells (BM-MSCs) and human umbilical cord endothelial progenitor cells (UC-EPCs) have several benefits for liver regeneration. We speculate huge impacts of rat BM-MSCs and UC-EPCs on reversal of hepatic injury and improvement of liver function in liver fibrosis induced by carbon tetrachloride (CCl4). Methods Forty adult rats were divided into 4 groups; control group, CCl4 group, CCl4/BM-MSCs group and CCl4/UCEPCs group. Blood samples were driven from rats at 1, 2 and 3months to measure serum concentration of albumin and alanine aminotransferase (ALT). Quantitative expression of HGF,TGF-β, MMP-2, and VEGF were assessed by polymerase chain reaction. Histological examination of the liver tissue was performed. α-SMA immunohistochemistry to identify the myoepithelial cells (MECs) and Ki-67 to identify cell prolifration immunohistochemistry are detected in groups injected with cells to confirm cells regeneration. Results Regarding liver function, there was elevating albumin (P &amp;lt; 0.05) and reducing ALT (P &amp;lt; 0.05) concentrations in groups treated with BM-MSCs and UC-EPCs effect compared to untreated CCL4 group. Concerning gene expression, UC-EPCs treated group have significantly higher MMP-2 and VEGF (P &amp;lt; 0.01) genes expression than BM-MSCs treated group. Furthermore, UC-EPCs were more valuable than BM-MSCs in increasing gene expression of HGF (P &amp;lt; 0.05) and immunohistochemistry of α-SMA and Ki-67 (P &amp;lt; 0.01). BM-MSCs have significantly lower TGF- β (P &amp;lt; 0.00) compared to UC-EPCs. Conclusion This study highlighted on liver regeneration role of both human UC-EPCs and BM-MSCs in liver fibrosis by different signaling mechanistic.

Liver Function of Male Rats Exposed to Manganese at Different Time Points.

As an essential trace element in the human body, manganese (Mn) is involved in many important biochemical reactions. However, excessive exposure to manganese can cause multiple systematic damages to the body. This study aims to investigate the effects of manganese exposure on serum hepatic enzymes in male rats at different time points. After adaptive feeding for 7days, male Sprague-Dawley (SD) rats were injected intraperitoneally with 30mg/kg MnCl2·4H2O once a day for 21days at zeitgeber time point 2 (ZT2), ZT8, ZT14, and ZT20, respectively. We found that short-term repeated exposure to manganese caused slower body weight gain and increased relative liver and spleen weight index in male rats at different time points. Moreover, serum total bile acid (TBA) increased while aspartate aminotransferase (AST) decreased at ZT2, ZT8, and ZT20. Cholinesterase (ChE) decreased at ZT2 and ZT20, lactic dehydrogenase (LDH) decreased at ZT2, ZT14, and ZT20, and acid phosphatase (ACP) decreased at ZT2 and ZT14. Alkaline phosphatase (ALP) decreased at ZT2, ZT14, and ZT20, but increased at ZT8. Alanine amino transferase (ALT) decreased at ZT2 and ZT20, but increased at ZT8. There was a negative correlation between relative liver weight index with AST, ACP, ALP, and LDH, while a positive correlation with TBA. However, relative spleen weight index had a positive correlation with relative liver weight index and TBA, while a negative correlation with ALT, AST, ACP, ALP, LDH, and ChE. Our study shows that the injury of liver function is caused by short-term repeated manganese exposure at different time points. The time effect should be considered in manganese toxicity evaluation.

Side Effects of PTU and MMI in the Treatment of Hyperthyroidism: A Systematic Review and Meta-Analysis

Objective: The present study aimed to investigate the adverse effects of the antithyroid drugs propylthiouracil (PTU) and methimazole (MMI)/carbimazole (CMZ) in treating hyperthyroidism. Methods: Qualitative analysis was performed for studies identified in a literature search up to April 20, 2019, and 30 studies were selected for meta-analysis. The study designs included case-control, randomized controlled, and retrospective cohort. Patients were in four age groups: childhood, gestating mothers, older adults, and other ages, and all were receiving PTU or MMI/CMZ. Adverse reactions to MMI/CMZ and PTU were evaluated and compared. Results: Odds of liver function injury were higher in the PTU group than in the MMI/CMZ group (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.16 to 4.96; P = .02). Odds of elevated transaminase were much higher in the PTU group than in the MMI/CMZ group (OR, 3.96; 95% CI, 2.49 to 6.28; P<.00001). No significant between-group differences were found in odds of elevated bilirubin, agranulocytosis, rash, or urticaria; incidence of other adverse events; or in children. Odds of birth defects during the first trimester of pregnancy were higher in the MMI/CMZ group than in the PTU group (OR, 1.29; 95% CI, 1.09 to 1.53; P = .003). Conclusion: The impact of PTU on liver injury and transaminase levels is greater than that of MMI/CMZ, but no significant between-group differences are found in the drugs' effects on bilirubin, agranulocytosis and rash, urticaria, or in children. In treating pregnancy-related hyperthyroidism, PTU should be used in the first trimester and MMI reserved for use in late pregnancy. Abbreviations: ALT = alanine aminotransferase; ATD = antithyroid drug; CI = confidence interval; CMZ = carbimazole; GD = Graves disease; MMI = methimazole; MTU = methylthiouracil; NOS = Newcastle-Ottawa Scale; OR = odds ratio; PTU = propylthiouracil; RAI = radioactive iodine.

Acute kidney injury and hepatitis associated with energy drink consumption: a case report

IntroductionIn the USA, energy drinks are commonly consumed among adults. The side effects of these drinks are not well studied but consumers have reported multiple adverse events to the US Food and Drug Administration including acute kidney injury and acute hepatitis.Case presentationA 62-year-old white woman presented with progressive weakness, fatigue, confusion, and delirium secondary to acute kidney injury and acute hepatitis associated with excessive energy drink use. Clinical improvement occurred with supportive care and discontinuation of energy drinks, with resolution of acute kidney injury and progressive improvement of liver function. The defined mechanism of injury is unknown but thought due to energy drink ingredients.ConclusionMultiple cases of energy drink-induced acute kidney injury or acute hepatitis are reported in the literature but this case is the first to report them simultaneously. Ingredients and presumed doses to cause these events are outlined in this case report.

Value of the gadoxetic acid-enhanced magnetic resonance imaging on oxaliplatin-induced liver function injury in C57BL/6 mice

Objective To investigate the value of gadoxetic acid-enhanced magnetic resonance imaging (MRI) on oxaliplatin-induced liver function injury in C57BL/6 mice. Methods Forty male and six weeks old C57BL/6 mice without specific pathogens were included and the body weght ranged from 19 to 23 g. They were randomly assigned into control group, experimental group A, experimental group B and experimental group C (10 mice/group). The mice in the control group was intraperitoneally injected with saline solution. The mice in the experimental groups were intraperitoneally injected with oxaliplatin twice a week. The experimental group A, B and C were administered for 2 weeks, 4 weeks and 6 weeks, respectively. The T1 relaxation time on the hepatobiliary phase and the first rapid enhancement slope percentage (ESP) in liver parenchyma were measured and calculated. Serum albumin and bilirubin values were measured and albumin and bilirubin (ALBI) scores were calculated. Pathological staining was used to observe liver tissue damage and fibrosis. The receiver operating characteristic (ROC) curve evaluated the ALBI score, ESP and T1 relaxation time on hepatobiliary phase for the diagnosis of liver function. Results Sixteen mice in the experimental groups (including group A, B and C) were included in the hepatic degeneration group (hepatocyte degeneration without fibrosis). Fourteen mice were included in the hepatic fibrosis group. T1 relaxation time on hepatobiliary phase in the hepatic fibrosis group was higher than that in the control group and in the hepatic degeneration group. The differences were statistically significant (P<0.05). The ESP of the control group, the hepatic degeneration group and the hepatic fibrosis group was increased, with statistically significant differences (all P<0.05). Compared with the control group, ALBI scores of the hepatic degeneration group and the hepatic fibrosis group were both decreased, with statistically significant differences (P<0.05). In the hepatic fibrosis group, the areas under the curve of ALBI scores, the T1 relaxation time on hepatobiliary phase and the ESP were 0.734, 0.962 and 0.989, respectively. Conclusion The T1 relaxation time on hepatobiliary phase and the ESP of gadoxetic acid-enhanced MRI can effectively evaluate the hepatic function reduction induced by oxaliplatin-induced hepatic tissue injury in C57BL/6 mice. Key words: Magnetic resonance imaging; Gadoxetic acid; Albumin-bilirubin; Liver function

Yinchenhao decoction attenuates obstructive jaundice-induced liver injury and hepatocyte apoptosis by suppressing protein kinase RNA-like endoplasmic reticulum kinase-induced pathway.

BACKGROUNDChronic biliary obstruction results in ischemia and hypoxia of hepatocytes, and leads to apoptosis. Apoptosis is very important in regulating the homeostasis of the hepatobiliary system. Endoplasmic reticulum (ER) stress is one of the signaling pathways that induce apoptosis. Moreover, the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-induced apoptotic pathway is the main way; but its role in liver injury remains unclear. Yinchenhao decoction (YCHD) is a traditional Chinese medicine formula that alleviates liver injury and apoptosis, yet its mechanism is unknown. We undertook this study to investigate the effects of YCHD on the expression of ER stress proteins and hepatocyte apoptosis in rats with obstructive jaundice (OJ).AIMTo investigate whether YCHD can attenuate OJ-induced liver injury and hepatocyte apoptosis by inhibiting the PERK-CCAAT/enhancer-binding protein homologous protein (CHOP)-growth arrest and DNA damage-inducible protein 34 (GADD34) pathway and B cell lymphoma/leukemia-2 related X protein (Bax)/B cell lymphoma/leukemia-2 (Bcl-2) ratio.METHODSFor in vivo experiments, 30 rats were divided into three groups: control group, OJ model group, and YCHD-treated group. Blood was collected to detect the indicators of liver function, and liver tissues were used for histological analysis. For in vitro experiments, 30 rats were divided into three groups: G1, G2, and G3. The rats in group G1 had their bile duct exposed without ligation, the rats in group G2 underwent total bile duct ligation, and the rats in group G3 were given a gavage of YCHD. According to the serum pharmacology, serum was extracted and centrifuged from the rat blood to cultivate the BRL-3A cells. Terminal deoxynucleotidyl transferase mediated dUTP nick end-labelling (TUNEL) assay was used to detect BRL-3A hepatocyte apoptosis. Alanine aminotransferase (ALT) and aspartate transaminase (AST) levels in the medium were detected. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) analyses were used to detect protein and gene expression levels of PERK, CHOP, GADD34, Bax, and Bcl-2 in the liver tissues and BRL-3A cells.RESULTSBiochemical assays and haematoxylin and eosin staining suggested severe liver function injury and liver tissue structure damage in the OJ model group. The TUNEL assay showed that massive BRL-3A rat hepatocyte apoptosis was induced by OJ. Elevated ALT and AST levels in the medium also demonstrated that hepatocytes could be destroyed by OJ. Western blot or qRT-PCR analyses showed that the protein and mRNA expression levels of PERK, CHOP, and GADD34 were significantly increased both in the rat liver tissue and BRL-3A rat hepatocytes by OJ. The Bax and Bcl-2 levels were increased, and the Bax/Bcl-2 ratio was also increased. When YCHD was used, the PERK, CHOP, GADD34, and Bax levels quickly decreased, while the Bcl-2 levels increased, and the Bax/Bcl-2 ratio decreased.CONCLUSIONOJ-induced liver injury and hepatocyte apoptosis are associated with the activation of the PERK-CHOP-GADD34 pathway and increased Bax/Bcl-2 ratio. YCHD can attenuate these changes.

Liver function, tolerability and satisfaction during treatment with ulipristal acetate in women with fibroids: a single center experience

The aim of the study was to evaluate liver function in women treated with ulipristal acetate (UPA) and to assess the tolerability and satisfaction during treatment. This Cross-sectional study included women with symptomatic uterine fibroids subjected to one or more 3-month treatment courses of 5 mg UPA daily. Following European Medical Agency’s prescriptions, women were asked about symptoms potentially related to liver damage and had blood tests done, to assess serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Data on side effects, tolerability and satisfaction with the therapy were obtained during a phone interview. A total of 162 women completed the study with a mean treatment duration of 1.8 ± 0.9 cycles. No increased AST and ALT serum levels were detected and no woman reported symptoms suggestive of liver injury. The majority of women reported improvement of fibroids-related symptoms and a high degree of satisfaction with treatment. More than half of women had side effects, in most cases not as severe as to discontinue therapy. Ulipristal acetate did not worsen liver function or cause severe organ injury and showed high tolerability and satisfaction profiles. Therefore, we believe that it can still be considered a valuable option in the treatment of uterine fibroids.

Prenatal dexamethasone exposure-induced a gender-difference and sustainable multi-organ damage in offspring rats via serum metabolic profile analysis

Prenatal dexamethasone exposure (PDE) induces developmental toxicities of multiple organs in offspring, but its serum metabolic profile changes before and after birth are unclear. Here, we employed a LC–MS-based metabolomic approach to detect serum metabolites of PDE offspring rats in utero and adulthood, and explore its change characteristics and toxicological significances. Meanwhile, the bodyweight, serum index related to hepatic and renal function were detected. As compared to healthy control rats, PDE reduced offspring birthweight but caused postnatal catch-up growth accompanied by adult liver and kidney function injury. In utero, the differential metabolites in response to PDE were mainly manifested as enhanced glycolysis, increased protein breakdown and disordered lipid metabolism, and multiple metabolic pathways were changed, which displayed gender differences. In adulthood, PDE offspring showed fewer and inconsistent types of differential metabolites compared to those in utero, which exhibited significant gender differences. The main differential metabolites induced by PDE included lactic acid, carnitine, cortexolone, bile acid, phosphatidylcholine, uric acid and platelet activating factor, which may participate in dexamethasone multi-organ toxicities and multi-disease susceptibility. In conclusion, PDE could induce a gender-difference and sustainable multi-organ damage in the offspring rats via serum metabolic profile analysis, which will enhance offspring susceptibility to multiple adult diseases.

Analysis of adverse effects of infliximab treatment in 486 patients with Crohn′s disease

Objective To assess the safety of infliximab(IFX) treatment in patients with Crohn′s disease(CD). Methods From January 2009 to May 2018, at inflammatory bowel disease (IBD) center of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 486 CD patients received the treatment of IFX were enrolled and their clinical data were collected. Univariate and multivariate regression of binary logistic were performed for statistical analysis. Results The median follow-up duration was 31.1 months (12.0 months to 40.0 months). The median duration of IFX therapy was 13.0 months (7.0 months to 21.0 months). Among 486 patients, 98 (20.16%) patients reported adverse effects, and 12 (2.47%) patients discontinued the therapy because of adverse effects. Acute infusion reaction was the most common adverse effect in CD patients who received IFX treatment accounting for 41.84%(41/98)of all the adverse effects, and the incidence was 8.44%. Thirty-nine patients had mild and moderate infusion reaction, and all improved after symptomatic treatment (eight patients discontinued IFX therapy because of recurrent infusion reaction). Two patients developed severe infusion reaction as allergic shock, and both relieved after emergency rescue. Four patients developed late-phase allergic reactions. Among 486 patients, 39 (8.02%) patients had infections, including infections of Clostridium difficile, cytomegalovirus, herpeszoster virus, Mycobacterium tuberculosis, and other opportunistic pathogens. There was no cases of infection related death. Thirty-six patients continued with IFX treatment after infection controlled. Among 486 patients, 14(2.88%) patients had severe infection, and all the cases improved after anti-infection treatment. Twenty-seven CD patients with hepatitis B virus (HBV) infection received anti-viral treatments, no active HBV infection was observed. Colon adenocarcinoma was found in one patient under colonoscopy at 22 months after discontinuation of IFX therapy. There were six patients with the history of benign tumors, and no evidence of recurrence, progress or malignancy during treatment. In terms of other rare adverse effects in 486 patients, there were eight (1.64%) patients with liver function injury, two (0.41%) patients with anemia, one (0.21%) patient with peripheral neuropathy, and four (0.82%) patients with skin lesion. Prolonged duration of IFX therapy, without combination of immune-suppressors and with increased baseline body mass index (BMI) were the risk factors of acute infusion reactions. Prolonged duration of IFX therapy and with low baseline albumin level were the risk factors of infections. Conclusions IFX is generally safe as the treatment for CD patients, and its adverse effects can be clinically controlled. Screening before therapy and monitoring during therapy may reduce the risks of adverse effects. Key words: Crohn disease; Infection; Neoplasms; Infliximab; Adverse effects; Infusion reaction

Therapeutic effect of human umbilical cord blood mesenchymal stem cells combined with G-CSF on rats with acute liver failure

Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) have been used to facilitate healing in animal models of liver injury, while granulocyte colony-stimulating factor (G-CSF) has been shown to stimulate stem cell mobilization and these cells may contribute to liver repair. hUCB-MSCs were characterized by flow cytometry, and transplanted into rats with d-galactosamine (D-GalN)/lipopolysaccharides (LPS)-induced acute liver failure (ALF) together with granulocyte colony-stimulating factor (G-CSF). Liver function, oxidative stress and pro-inflammatory cytokines expressions were examined using enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was used to observe the morphological changes. Apoptosis was investigated by terminal dUTP nick end labeling (TUNEL) staining. Bromodeoxyuridine (BrdU) cell proliferation assay was analyzed by immunofluorescence and immunohistochemistry. In the results, cultured hUCB-MSCs displayed proliferation and adipogenic and osteogenic differentiation potentials. hUCB-MSCs in combination with G-CSF significantly attenuated ALF-induced liver function injury. Furthermore, hUCB-MSCs and G-CSF treatment remarkably suppressed the secretions of pro-inflammatory cytokines and MDA activation induced by ALF. In addition, inflammation, lesions and cell apoptosis in liver tissues were obviously ameliorated by application of hUCB-MSCs and G-CSF. In conclusion, hUCB-MSCs, alone or co-treatment with G-CSF could ameliorate ALF in rats by inhibiting liver function injury, production of pro-inflammatory cytokines, oxidative stress, and liver cell apoptosis.

Human amniotic mesenchymal stromal cells alleviate acute liver injury by inhibiting the pro-inflammatory response of liver resident macrophage through autophagy.

The activation and polarization of macrophages are crucial during the pathogenesis of liver injury induced by the toxin. Human amniotic mesenchymal stromal cells (hAMSCs) are newly identified mesenchymal stem cells and have been shown to have an immunoregulatory ability for multiple autoimmune diseases. Mice were intraperitoneally injected with Acetaminophen (APAP) to establish a liver injury model. hAMSCs were injected through the tail vein, and the liver function was observed through a liver function and pathology analysis. To test the regulative ability of hAMSCs in vitro, the supernatant of hAMSCs were collected and co-cultured with Kupffer cells (KCs). Liposome was used to abolish the function of KCs in vivo. Infusion of hAMSCs reduced the level of liver function injury and inflammation expression in APAP-induced liver injury. hAMSCs markedly promoted M2 polarization of KCs instead of M1 polarization in vitro. Furthermore, the mechanism study also proved that hAMSCs reduced autophagy, as revealed by down-regulated LC3B-II levels. The elimination of KCs in vivo abolished the protective ability of hAMSCs in liver injury, which resulted in a significant increase of liver pathogenesis along with an increase in alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) levels. Our results proved that hAMSCs suppressed M1 polarization and promoted M2 polarization of KCs through regulating autophagy in the model of APAP-treated livers. Thus, the injury of the liver was attenuated. This study provides us a new therapeutic strategy for the disease of acute liver injury.