乙型肝炎病毒对不同ALT状态下慢性乙型肝炎患者T淋巴细胞及其亚群的影响

目的：探讨乙型肝炎病毒（HBV）在不同丙氨酸氨基转移酶（ALT）状态下对T淋巴细胞及其亚群的影响,阐明以ALT分组抗病毒治疗乙型肝炎（乙肝）的免疫学机制。方法：选取慢性乙肝患者363例作为研究对象,根据ALT异常情况分为ALT正常组（131例）、ALT大于等于正常上限且小于2倍增高组（110例）和ALT大于等于正常上限2倍增高组（122例）。对ALT大于等于正常上限2倍增高组患者给予恩替卡韦治疗,随访24周。采用化学发光免疫分析仪检测乙肝抗原抗体指标,采用全自动生化分析仪检测肝功能指标,采用全自动荧光定量PCR分析仪检测被测者的病毒载量,采用流式细胞仪检测T淋巴细胞分类,酶联免疫吸附实验（ELISA）法检测患者血清中白细胞介素12（IL-2）、干扰素γ（IFN-γ）、白细胞介素4（IL-4）和白细胞介素10（IL-10）水平,检测不同组别中不同载量HBV对机体免疫学指标的影响及抗病毒治疗前后患者病毒学及免疫学指标的变化。结果：在ALT正常组中,不同载量HBV患者T淋巴细胞总数、Th/i淋巴细胞数、Ts/c淋巴细胞数及血清中IL-2、IFN-γ、IL-4和IL-10水平比较差异无统计学意义（P>0.05）;在ALT大于等于正常上限2倍增高组,随着病毒载量的增加,患者T淋巴细胞总数和Th/i淋巴细胞数明显下降（P<0.05）,Ts/c淋巴细胞数明显升高（P<0.05）,反映Th1细胞的细胞因子IL-2和IFN-γ水平明显升高（P<0.05）,反映Th2细胞的细胞因子IL-4和IL-10水平明显下降（P<0.05）。与治疗前比较,恩替卡韦治疗24周后,患者HBVDNA明显下降（P<0.05）,T淋巴细胞总数和Th/i淋巴细胞数明显升高（P<0.05）,Ts/c淋巴细胞数明显下降（P<0.05）,血清中IL-2和IFN-γ水平明显下降（P<0.05）,IL-4和IL-10水平明显升高（P<0.05）。结论：HBV在不同ALT状态下对机体免疫功能有不同的影响,对于ALT大于等于正常上限2倍增高的乙肝患者进行抗病毒治疗可明显改变机体的免疫状态。     

Effects of sodium-glucose co-transporter-2 inhibitors on serum alanine aminotransferase levels in people with type 2 diabetes: A multi-institutional cohort study

Clinical trials have indicated that sodium-glucose co-transporter-2 (SGLT2) inhibitors have a favourable effect on serum alanine aminotransferase (ALT) levels in people with type 2 diabetes (T2D), but supporting evidence from real-world studies is lacking. We identified patients with T2D who initiated SGLT2 inhibitors during the period 2016 to 2017 from Chang Gung Research Database, which covers 1.3 million individuals from seven hospitals (6% of the Taiwan population). We classified patients by baseline ALT level and evaluated changes in ALT values from baseline to 1 year after initiation of SGLT2 inhibitors. We identified 11 690 new users of SGLT2 inhibitors with a mean (SD) age of 59.3 (11.8) years. The mean (SD) glycated haemoglobin and ALT levels were 8.9 (1.7)% and 34.7 (28.9) U/L at baseline, respectively. The mean change in ALT levels was −5.0 U/L (95% confidence interval [CI] –6.4, −3.5) 1 year after initiation of SGLT2 inhibitors. In patients with ALT levels ≤1× the upper limit of normal (ULN), the change in ALT levels was 1.6 U/L (95% CI –0.1, 3.4), while in those with ALT levels >1× ULN, the change in ALT levels was −26.5 U/L (95% CI –28.6, −24.3). The higher the baseline ALT level, the greater the decline after SGLT2 inhibitor treatment. Our findings suggest the initiation of SGLT2 inhibitors for T2D management could improve serum ALT levels in clinical practice, particularly in patients with especially high ALT levels.     

Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa‐2a/ribavirin

Summary. It is unclear whether the current threshold for ‘high’ hepatitis C virus (HCV) RNA level (800 000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono‐infected and 176 HIV–HCV co‐infected patients treated with peginterferon alfa‐2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono‐infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400 000 IU/mL was used and 16% (59%vs 43%) when 800 000 IU/mL was used. In HIV–HCV genotype 1 co‐infected patients, the difference was 51% (71%vs 20%) when 400 000 IU/mL was used and 43% (61%vs 18%) when 800 000 IU/mL was used. A lower threshold (200 000 IU/mL) was identified for genotype 1 mono‐infected patients with ‘normal’ alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400 000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1‐infected individuals with elevated ALT.     

Fish to meat intake ratio and cooking oils are associated with hepatitis C virus carriers with persistently normal alanine aminotransferase levels

Aim: Dietary habits are involved in the development of chronic inflammation; however, the impact of dietary profiles of hepatitis C virus carriers with persistently normal alanine transaminase levels (HCV‐PNALT) remains unclear. The decision‐tree algorithm is a data‐mining statistical technique, which uncovers meaningful profiles of factors from a data collection. We aimed to investigate dietary profiles associated with HCV‐PNALT using a decision‐tree algorithm. Methods: Twenty‐seven HCV‐PNALT and 41 patients with chronic hepatitis C were enrolled in this study. Dietary habit was assessed using a validated semiquantitative food frequency questionnaire. A decision‐tree algorithm was created by dietary variables, and was evaluated by area under the receiver operating characteristic curve analysis (AUROC). Results: In multivariate analysis, fish to meat ratio, dairy product and cooking oils were identified as independent variables associated with HCV‐PNALT. The decision‐tree algorithm was created with two variables: a fish to meat ratio and cooking oils/ideal bodyweight. When subjects showed a fish to meat ratio of 1.24 or more, 68.8% of the subjects were HCV‐PNALT. On the other hand, 11.5% of the subjects were HCV‐PNALT when subjects showed a fish to meat ratio of less than 1.24 and cooking oil/ideal bodyweight of less than 0.23 g/kg. The difference in the proportion of HCV‐PNALT between these groups are significant (odds ratio 16.87, 95% CI 3.40–83.67, P = 0.0005). Fivefold cross‐validation of the decision‐tree algorithm showed an AUROC of 0.6947 (95% CI 0.5656–0.8238, P = 0.0067). Conclusion: The decision‐tree algorithm disclosed that fish to meat ratio and cooking oil/ideal bodyweight were associated with HCV‐PNALT.     

术中麻醉管理对肝癌患者术后丙氨酸转氨酶恢复的影响

目的 探讨术中影响肝癌患者术后丙氨酸转氨酶（ALT）恢复的麻醉相关因素。方法 收集接受根治性手 术治疗的177例肝癌患者临床资料。术后第5天ALT恢复正常或小于术前值的患者归为ALT恢复组（n＝78）,ALT 未恢复正常且高于术前值的患者归为ALT未恢复组（n＝99）。使用单因素分析及Logistic回归,筛选出影响术后ALT 恢复的独立危险因素。结果 ALT恢复组中术后第5天ALT值、中心静脉压（CVP）降低值和乳酸升高值低于ALT未 恢复组,ALT恢复组中切除范围超过3个肝段和术后体温＜35.5 ℃的患者占比低于ALT未恢复组,而手术时间≤180 min 的患者占比高于 ALT 未恢复组（P＜0.05）。Logistic 回归分析显示,术后乳酸升高值较高（OR=1.526,95%CI： 1.105~2.107）、CVP 降低值较高（OR=1.170,95%CI：1.017~1.346）、手术切除范围较高超过 3 个肝段（OR=2.487, 95%CI：1.185~5.216）是ALT未恢复的独立危险因素。结论 术后乳酸升高值、手术切除范围超过3个肝段、CVP降 低值影响肝癌患者术后ALT恢复。     

Osteopontin is an initial mediator of inflammation and liver injury during obstructive cholestasis after bile duct ligation in mice

Osteopontin (OPN) is a chemotactic factor which can be cleaved to the pro-inflammatory form by matrix metalloproteinases (MMPs). To test the hypothesis that OPN can modulate inflammatory liver injury during cholestasis, wild-type (WT) C57BL/6 and OPN knockout (OPN-KO) mice underwent bile duct ligation (BDL). OPN-KO mice showed significant reduction in liver injury (plasma ALT and necrosis) and neutrophil recruitment compared with WT animals at 24 h but not 72 h after BDL. In WT mice, a 4-fold increase in hepatic MMP-3 mRNA and elevated MMP activities and cleaved OPN levels were observed in bile. WT mice subjected to BDL in the presence of the MMP inhibitor BB-94 showed reduced liver injury, less neutrophil extravasation and diminished levels of cleaved OPN in bile. Thus, during obstructive cholestasis, OPN released from biliary epithelial cells could be cleaved by MMPs in bile. When the biliary system leaks, cleaved OPN enters the parenchyma and attracts neutrophils. In the absence of OPN, other chemoattractants, e.g. chemokines, mediate a delayed inflammatory response and injury. Taken together, our data suggest that OPN is the pro-inflammatory mediator that initiates the early neutrophil-mediated injury phase during obstructive cholestasis in mice.