Nonselective beta-blockers in cirrhotic patients with no or small varices:A meta-analysis

AIM:To explore effects of nonselective beta-blockers(NSBBs) in cirrhotic patients with no or small varices.METHODS:The Pub Med,EMBASE,Science Direct,and Cochrane library databases were searched for relevant papers.A meta-analysis was performed using ORs with 95%CI as the effect sizes.Subgroup analysis was conducted according to the studies including patients without varices and those with small varices.RESULTS:Overall,784 papers were initially retrieved from the database searches,of which six randomized controlled trials were included in the meta-analysis.The incidences of large varices development(OR = 1.05,95%CI:0.25-4.36;P = 0.95),first upper gastrointestinal bleeding(OR = 0.59,95%CI:0.24-1.47;P = 0.26),and death(OR = 0.70,95%CI:0.45-1.10;P = 0.12) were similar between NSBB and placebo groups.However,the incidence of adverse events was significantly higher in the NSBB group compared with the placebo group(OR = 3.47,95%CI:1.45-8.33;P = 0.005).The results of subgroup analyses were similar to those of overall analyses.CONCLUSION:The results of this meta-analysis indicate that NSBBs should not be recommended for cirrhotic patients with no or small varices.     

肝硬化门静脉高压合并食管静脉曲张出血的风险评估

食管静脉曲张破裂出血是肝硬化门静脉高压常见及最严重的并发症之一,常危及患者的生命。据报道,每年约7%的肝硬化患者发生食管静脉曲张破裂出血。因此,评估食管静脉曲张出血风险对于临床防治具有重要意义。目前,内镜、一些血清标志物、影像学检查及肝静脉压力梯度(HVPG)等对曲张静脉出血风险的预测具有一定价值。本文将对预测肝硬化门静脉高压所致食管静脉曲张出血风险研究进展作一概述。     

Platelet count/spleen diameter ratio for non-invasive prediction of high risk esophageal varices in cirrhotic patients

Background and objective. Prophylaxis therapy is indicated in cirrhotic patients with large esophageal varices or small varices with red wale signs (high risk esophageal varices; HREV). Endoscopic surveillance to detect HREV is currently recommended. The objective of this study is to identify non-invasive predictors of HREV in cirrhotic patients.Design and methods. Adult cirrhotic patients without previous variceal bleeding were prospectively included. All patients underwent a complete biochemical workup, upper digestive endoscopy, and ultrasonographic measurement of spleen bipolar diameter. Platelet count/spleen diameter ratio (PC/SD) was calculated for all patients. The association of these variables with the presence of HREV in upper endoscopy was tested using univariate and multivariate analysis. Receiver operating characteristic (ROC) curves were constructed for variables associated with HREV.Results. Sixty-seven patients were included. The prevalence rate of HREV was 50%. Age, gender (female), platelet count, spleen diameter, PC/ SD ratio, total bilirrubin, prothrombin activity (INR), Child-Pugh score, clinical and ultrasonographic ascites were significantly associated with presence of HREV in univariate analysis. Age and PC/SD ratio were the parameters independently associated with HREV in a multivariate analysis, with OR 8.81 (CI 95%: 1.7-44.9) and OR 11.21 (CI 95%: 2.8-44.6) respectively. A PC/SD ratio cut-off value under 830.8 predicted HREV with 76.9% sensitivity, 74.2% specificity and 77.8% negative predictive value (ROC curve area: 0.78).Conclusions. The PC/SD ratio was significantly associated with HREV, but with suboptimal sensitivity and specificity. Therefore, the results of this study do not support the routine clinical use of PC/SD ratio for screening of HREV.     

Role of portal haemodynamic parameters in prediction of oesophageal varices in cirrhotic patients

Background and study aimsScreening all cirrhotic patients by endoscopy for detection of varices is not cost-effective as the number of patients increases by time and half of them still would not have developed varices 10 years after being diagnosed with cirrhosis. Therefore, this study aimed to evaluate hepatic haemodynamic Doppler parameters in predicting the presence of oesophageal varices (OVs) in cirrhotic patients for better selection of those actually needed for screening endoscopy.Patients and methodsEighty-one patients with liver cirrhosis, 32 females and 49 males, with a mean age of 50.7 ± 11.7 years were recruited for the study. They included 61 patients with OVs and 20 patients without varices. The diagnosis of liver cirrhosis was based on clinical history, examination, and investigations. Liver function and kidney function tests and complete blood count (CBC) were performed for all patients. All patients underwent abdominal ultrasound (US), upper endoscopy, and hepatic Doppler US examination.ResultsThe portal vein velocity (PVV) and liver vascular index (LVI) showed statistically significantly lower values in patients with OVs than those without OVs (p value = 0.02 and 0.000, respectively). The congestion index (CI) of the portal vein, the portal hypertension index (PHI), and the splenoportal index (SPI) showed statistically significantly higher values in patients with OVs than those without OVs (p value = 0.006, 0.001, and 0.001, respectively). CI and SPI were the best parameters that could predict the presence of OVs with high sensitivity, specificity, and diagnostic accuracy when cutoff values were set at >0.069 and 3.57, respectively (area under the curve = 0.864 and 0.894, respectively).ConclusionsThe CI of the portal vein and SPI are good predictors for the presence of OVs in cirrhotic patients, and could be used noninvasively to decrease the burden on the upper endoscopy unit by proper selection of those who are candidates for screening endoscopy.     

肝硬化高危食管曲张静脉出血无创性预测指标的临床研究

目的分析血小板计数、脾脏直径、血小板计数/脾脏直径比值与肝硬化高危食管曲张静脉的关系及其临床价值。方法连续收集近3年肝硬化合并食管静脉曲张住院患者272例。出血组113例,其中行胃镜检查并明确静脉曲张分级的共94例,非出血组159例,其中101例既往无出血史。以胃镜检查发现重度食管曲张静脉和/或红色征作为高危食管曲张静脉标准,将非出血组分为高危组77例,非高危组24例。分析出血组与非出血组、高危组与非高危组之间血小板计数、脾脏直径和血小板计数/脾脏直径比值,并通过绘制受试者工作特征(ROC)曲线计算脾脏直径,预测肝硬化合并高危食管曲张静脉的敏感度、特异度、阳性预测值和阴性预测值。结果出血组与非出血组之间血小板计数、脾脏直径、血小板计数/脾脏直径比较差异均无统计学意义(P>0.05)。高危组脾脏直径大于非高危组(161.96±33.64 vs 139.15±24.29,P=0.024);经ROC曲线分析,脾脏直径预测肝硬化患者合并高危食管曲张静脉的灵敏度为87.9%,特异度为53.8%,阳性预测值为85.9%,阴性预测值为58.1%,ROC曲线下面积为0.71。结论脾脏直径可以作为预测肝硬化高危食管曲张静脉的指标,其灵敏度较好,诊断效率较高,但特异度欠佳。     

Egyptian revalidation of non-invasive parameters for predicting esophageal varices in cirrhotic patients: A retrospective study

Background and study aimsIn resource-limited countries, non-invasive tests for assessing liver fibrosis are a potential alternative to costly endoscopic screening for esophageal varices. We aimed to validate several non-invasive parameters for predicting the presence of varices.Patients and methodsBetween September 2006 and August 2017, a total of 46,014 patients who underwent upper gastrointestinal endoscopy as one of the perquisites for receiving hepatitis C virus (HCV) therapy were enrolled and divided into group I (without varices) and group II (with varices). Non-invasive parameters of fibrosis, namely Lok index, Bonacini score, liver stiffness, FIB-4, Baveno, and extended Baveno criteria, were validated.ResultsLok index, Bonacini score, liver stiffness, and FIB-4 had areas under the receiver operating characteristic curve (AUCs) of >0.6 (all P < 0.01 for the null hypothesis that the AUC was 0.5) for determination of the presence/absence of varices, with cutoff values of 0.80, 6.5, 21.9 kPa, and 2.94, and sensitivities of 74%, 74%, 66%, and 83%, respectively. The expanded Baveno VI criteria performed better than the Baveno VI criteria (spared endoscopy rate 81% versus 63%).ConclusionThe use of non-invasive methods is of limited value in predicting esophageal varices. The limited accuracy of ≤60% may delay the use of appropriate primary prophylaxis against variceal bleeding in a large proportion of cirrhotic patients.     

Elastography-based screening for esophageal varices in patients with advanced chronic liver disease

Elastography-based liver stiffness measurement(LSM) is a non-invasive tool for estimating liver fibrosis but also provides an estimate for the severity of portal hypertension in patients with advanced chronic liver disease(ACLD). The presence of varices and especially of varices needing treatment(VNT) indicates distinct prognostic stages in patients with compensated ACLD(cACLD). The Baveno VI guidelines suggested a simple algorithm based on LSM < 20 kPa(by transient elastography, TE) and platelet count > 150 G/L for ruling-out VNT in patients with cACLD. These(and other) TE-based LSM cut-offs have been evaluated for VNT screening in different liver disease etiologies. Novel point shear-wave elastography(pSWE) and two-dimensional shear wave elastography(2D-SWE) methodologies for LSM have also been evaluated for their ability to screen for "any" varices and for VNT. Finally, the measurement of spleen stiffness(SSM) by elastography(mainly by pSWE and 2D-SWE) may represent another valuable screening tool for varices. Here, we summarize the current literature on elastography-based prediction of "any" varices and VNT. Finally,we have summarized the published LSM and SSM cut-offs in clinically useful scale cards.     

Endoprosthetics for bleeding esophageal varices

Refractory esophageal hemorrhage and early rebleeding following endoscopic therapy remain challenging conditions to treat and are associated with a high mortality. Techniques such as balloon tamponade (BT) and transjugular intrahepatic portosystemic shunt (TIPS) are highly effective at controlling refractory bleeding, but they can be associated with a high rate of complications and, in the case of TIPS, may not be immediately available outside specialist centers. Recently, removable self-expanding metal stents (SEMSs) have been introduced in clinical practice for the management of esophageal variceal bleeding. SEMSs control bleeding by tamponade of varices in the distal esophagus and can remain in situ for a number of days, thus preventing early rebleeding. The use of SEMSs does not require the transfer of the patient to a specialist center, and unlike TIPS, it is not associated with deterioration in liver function. The use of SEMSs has been described in small series of patients with refractory bleeding. These series report high rates of hemostasis with low complication rates, suggesting that SEMSs may have an important role in the management of refractory bleeding either as an alternative to BT or where TIPS is contraindicated. SEMSs may also have a role in treating complications of therapy for bleeding esophageal varices, such as postbanding ulceration and BT-induced esophageal tears. The aim of this review is to summarize the published data on the efficacy of SEMSs and suggest future studies that may clarify its role in the management of esophageal variceal hemorrhage.     

肝硬化食管静脉曲张患者门静脉血栓形成的危险因素分析

目的旨在识别肝硬化食管静脉曲张患者中门静脉血栓(PVT)形成的独立危险因素,并建立一个预测PVT发生风险的列线图。方法回顾性分析2013年12月—2018年12月于山东大学附属省立医院就诊的283例肝硬化食管静脉曲张患者资料,根据影像学检查将其分为PVT组(n=119)和非PVT组(n=164)。计量资料两组间比较采用t检验或Mann-Whitney U检验,计数资料两组间比较采用χ2检验。利用多因素logistic回归分析筛选独立危险因素,基于多因素回归结果建立并检验列线图,应用C指数(C-index)、校准曲线评价其性能。结果单因素分析显示,PVT组在Child-Pugh分级(χ^2=9.388,P=0.009)、脾切除史(χ^2=26.805,P<0.001)、WBC(Z=-2.248,P=0.025)、PLT(Z=-3.323,P=0.001)、D-二聚体水平(Z=-6.236,P<0.001)及脾脏厚度(Z=-2.432,P=0.015)方面高于非PVT组,而TG水平低于非PVT组(Z=-4.150,P<0.001)。多因素分析显示,TG水平(OR=0.441,95%CI:0.190~0.889)、D-二聚体水平升高(OR=1.151,95%CI:1.041~1.272)、PT延长(OR=1.160,95%CI:1.025~1.313)、有脾切除史(OR=2.933,95%CI:l.164~7.389)是肝硬化食管静脉曲张患者PVT形成的独立风险因素。基于多因素回归结果,建立了列线图,其C指数值为0.745,校准曲线显示PVT发生的观测值和预测值之间有较好的一致性。结论TG水平降低、有脾切除史、D-二聚体水平升高、PT延长是肝硬化食管静脉曲张患者PVT形成的独立危险因素,基于此所建立的列线图,为临床医生评估PVT形成风险提供了一个定量、直观的工具。     

Role of echo Doppler ultrasonography in the evaluation of postprandial hyperemia in cirrhotic patients

AIM： TO assess the role of echo-Doppler ultrasonography in postprandial hyperemia in cirrhotic patients by comparing the results with the hepatic vein catheterization technique.
METHODS： Patients with cirrhosis, admitted to the portal hemodynamic laboratory were included into the study. After an overnight fast, echo-Doppler ultrasonography （basal and 30 min after a standard meal） and hemodynamic studies by hepatic vein catheterization （basal, 15 min and 30 min after a standard meal） were performed. Ensure Plus （Abbot Laboratories, North Chicago, IL） was used as the standard liquid meal. Correlation analysis of the echo- Doppler and hepatic vein catheterization measurements were done for the basal and postprandial periods.
RESULTS： Eleven patients with cirrhosis （5 Child A, 4 Child B, 2 Child C） were enrolled into the study. After the standard meal, 8 of the 11 patients showed postprandial hyperemia with increase in portal blood flow, portal blood velocity and hepatic venous pressure gradient. Hepatic venous pressure gradient in the postprandial period correlated positively with postprandial portal blood velocity （r = 0.8, P 〈 0.05） and correlated inversely with postprandial superior mesenteric artery pulsatility index （r = -1, P 〈 0.01）.
CONCLUSION： Postprandial hyperemia can be efficiently measured by echo-Doppler ultrasonography and the results are comparable to those obtained with the hemodynamic studies.     

Portal hemodynamics as predictors of high risk esophageal varices in cirrhotic patients

AIM： To evaluate portal hypertension parameters in liver cirrhosis patients with and without esophageal varices （EV）. METHODS： A cohort of patients with biopsy confirmed liver cirrhosis was investigated endoscopically and with color Doppler ultrasonography as a possible noninvasive predictive tool. The relationship between portal hemodynamics and the presence and size of EV was evaluated using uni- and multivariate approaches. RESULTS： Eighty five consecutive cirrhotic patients （43 men and 42 women） were enrolled. Mean age （± SD） was 47.5 （± 15.9）. Portal vein diameter （13.88 ± 2.42 vs 12.00 ± 1.69, P 〈 0.0005） and liver vascular index （8.31 ± 2.72 vs 17.8 ± 6.28, P 〈 0.0005） were found to be significantly higher in patients with EV irrespective of size and in patients with large varices （14.54 ± 1.48 vs 13.24 ± 2.55, P 〈 0.05 and 6.45 ± 2.78 v$10.96 ± 5.05, P 〈 0.0005, respectively）, while portal vein flow velocity （13.25 ± 3.66 vs 20.25 ± 5.05, P 〈 0.0005）, congestion index （CI） （0.11 ± 0.03 vs 0.06 ± 0.03, P 〈 0.0005）, portal hypertensive index （2.62 ± 0.79 vs 1.33 ± 0.53, P 〈 0.0005）, and hepatic （0.73 ± 0.07 vs 0.66 ± 0.07, P 〈 0.001） and splenic artery resistance index （R/） （0.73 ± 0.06 vs 0.62 ± 0.08, P 〈 0.0005） were significantly lower. A logistic regression model confirmed spleen size （P = 0.002, AUC 0.72） and portal hypertensive index （P = 0.040, AUC 0.79） as independent predictors for the occurrence of large esophageal varices （LEV）. CONCLUSION： Our data suggest two independent situations for beginning endoscopic evaluation of compensated cirrhotic patients： Portal hypertensive index 〉 2.08 and spleen size 〉 15.05 cm. These factors may help identifying patients with a low probability of LEV who may not need upper gastrointestinal endoscopy.     

Per rectal portal scintigraphy as a useful tool for predicting esophageal variceal bleeding in cirrhotic patients

AIM： To investigate potential roles of per rectal portal scintigraphy in diagnosis of esophageal varices and predicting the risk of bleeding. METHODS： Fifteen normal subjects and fifty cirrhotic patients with endoscopically confirmed esophageal varices were included. Patients were categorized into bleeder and non-bleeder groups according to history of variceal bleeding. All had completed per rectal portal scintigraphy using ^99mTechnetium pertechnetate. The shunt index was calculated from the ratio of ^99mTechnetium pertechnetate in the heart and the liver. Data were analyzed using Student＇s t-test and receiver operating characteristics. RESULTS： Cirrhotic patients showed a higher shunt index than normal subjects （63.80 ± 25.21 vs 13.54 ± 6.46, P 〈 0.01）. Patients with variceal bleeding showed a higher shunt index than those without bleeding （78.45 ± 9.40 vs 49.35 ± 27.72, P 〈 0.01）. A shunt index of over 20% indicated the presence of varices and that of over 60% indicated the risk of variceal bleeding. CONCLUSION： In cirrhotic patients, per rectal portal scintigraphy is a clinically useful test for identifying esophageal varices and risk of variceal bleeding.     

Comparison of esophageal capsule endoscopy and esophagogastroduodenoscopy for diagnosis of esophageal varices

AIM： To investigate the utility of esophageal capsule endoscopy in the diagnosis and grading of esophageal varices.
METHODS： Cirrhotic patients who were undergoing esophagogastroduodenoscopy （EGD） for variceal screening or surveillance underwent capsule endoscopy. Two separate blinded investigators read each capsule endoscopy for the following results： variceal grade, need for treatment with variceal banding or prophylaxis with beta-blocker therapy, degree of portal hypertensive gastropathy, and gastric varices.
RESULTS： Fifty patients underwent both capsule and EGD. Forty-eight patients had both procedures on the same day, and 2 patients had capsule endoscopy within 72 h of EGD. The accuracy of capsule endoscopy to decide on the need for prophylaxis was 74%, with sensitivity of 63% and specificity of 82%. Interrater agreement was moderate （kappa = 0.56）. Agreement between EGD and capsule endoscopy on grade of varices was 0.53 （moderate）. Inter-rater reliability was good （kappa = 0.77）. In diagnosis of portal hypertensive gastropathy, accuracy was 57%, with sensitivity of 96% and specificity of 17%. Two patients had gastric varices seen on EGD, one of which was seen on capsule endoscopy. There were no complications from capsule endoscopy.
CONCLUSION： We conclude that capsule endoscopy has a limited role in deciding which patients would benefit from EGD with banding or beta-blocker therapy. More data is needed to assess accuracy for staging esophageal varices, PHG, and the detection of gastric varices.     

New index to predict esophageal variceal bleeding in cirrhotic patients

AIM:To develop a safe,simple,noninvasive and affordable system to predict esophageal variceal bleeding(EVB)in decompensated cirrhosis patients.METHODS:Four hundred and eighty-six patients with decompensated cirrhosis(238 males and 248 females),with a mean age of 63.1±11.2 years,were admitted to Changshu Affiliated Hospital of Suzhou University between May 2008 and March 2011.Patients enrolled in this study underwent ultrasound-Doppler(US-Doppler)to assess left gastric vein(LGV)blood flow velocity(LGVV)and blood flow direction(LGVBFD),and were evaluated by the Model For End-Stage Liver Disease(MELD)scoring system.All patients received followup evaluations every three months.The resulting data were entered into a database after each time point collection.RESULTS:Four hundred and sixteen patients com-pleted follow-up evaluations for an average of 31.6mo(range:12 to 47 mo).Fifty-one(12.3%)patients experienced EVB.The change in the MELD score over three months(ΔMELD),LGVV and LGVBFD were independently associated with EVB occurrence.MELDUS-Doppler Index(MUI),a new index,was developed and calculated using the following logistic regression equation:MUI=Logit(P)=1.667(ΔMELD)+2.096(LGVV)-3.245(LGVBFD)-1.697.The area under the receiver operating characteristic curve for prediction of EVB occurrence was significantly higher for the MUI[0.858(95%CI:0.774-0.920)]than forΔMELD[0.734(95%CI:0.636-0.817);P<0.05],LGVV[0.679(95%CI:0.578-0.769);P<0.05]or LGVBFD[0.726(95%CI:0.627-0.810);P<0.05]alone.When the MUI was set at 46,the index had high diagnostic accuracy(85.8%),with high specificity(80%)and sensitivity(87.27%).CONCLUSION:The MUI,a noninvasive and affordable index,can predict EVB occurrence in decompensated cirrhotic patients and serve as an alternative when conventional endoscopic screening is declined.     

A pilot study of capsule endoscopy after a standard meal for the detection and grading of oesophageal varices in cirrhotic patients

Background

Capsule endoscopy has been proposed as an alternative to fibreoptic endoscopy for oesophageal varices evaluation in cirrhotics. However, it shows only moderate sensitivity compared to fibreoptic endoscopy.

Aim

To compare post-meal capsule endoscopy to fibreoptic endoscopy, based on the hypothesis that meal-induced increase of portal pressure can enhance its sensitivity.

Methods

Twenty-five patients were submitted to fibreoptic endoscopy and, after a standard meal, capsule endoscopy.

Results

Post-meal capsule endoscopy detected varices in the 18 patients in whom fibreoptic endoscopy detected varices plus 3 more subjects (sensitivity 100%, specificity 70%); large varices in the 4 patients in whom fibreoptic endoscopy graded varices as large, plus 5 more subjects; red markers in the 5 patients in whom fibreoptic endoscopy detected red markers, plus 3 more subjects. High-risk varices were identified in 11 patients by post-meal capsule endoscopy and in 10 by fibreoptic endoscopy (sensitivity 100%, specificity 93.8%).

Conclusions

Post-meal capsule endoscopy identified more varices, large varices and red markers than fibreoptic endoscopy. The two methods detected similar proportions of high-risk varices. These data suggest that a standard meal can enhance the sensitivity of capsule endoscopy in the detection and grading of oesophageal varices in cirrhotics.     

Sonographic gallbladder wall thickness measurement and the prediction of esophageal varices among cirrhotics

Acute variceal bleeding in patients with liver cirrhosis and portal hypertension (PHT) is the most serious emergency complication among those patients and could have catastrophic ‎outcomes if not timely managed. ‎Early screening by esophago-gastro-duodenoscopy (EGD) for the presence of esophageal varices (EVs) is ‎‎currently recommended by the practice guidelines for all cirrhotic patients. Meanwhile, EGD is not readily accepted or preferred by many patients. The literature is rich in ‎studies to investigate and validate ‎ non-invasive markers of EVs prediction aiming at reducing the unneeded endoscopic procedures. Gallbladder (GB) wall thickness (GBWT) ‎measurement has been found promising in many published research ‎articles. We aim to highlight the validity of sonographic GBWT measurement in the ‎prediction of EVs based on the available evidence.‎ We searched databases including Cochrane library, PubMed, Web of Science and many others for relevant articles. GBWT is associated with the presence of EVs in cirrhotic patients with PHT of different etiologies. The cut-off of GBWT that can predict the presence of EVs varied in the literature and ranges from 3.1 mm to 4.35 mm with variable sensitivities of 46%-90.9% and lower cut-offs in viral cirrhosis compared to non-viral, however GBWT > 4 mm in many studies is associated with acceptable sensitivity up to 90%. Furthermore, a relation was also noticed with the degree of varices and portal hypertensive gastropathy. Among cirrhotics, GBWT > 3.5 mm predicts the presence of advanced (grade III-IV) EVs with a sensitivity of 45%, the sensitivity increased to 92% when a cut-off ≥ 3.95 mm was used in another cohort. Analysis of these results should carefully be revised in the context of ascites, hypoalbuminemia and other intrinsic GB diseases among cirrhotic patients. The sensitivity for prediction of EVs improved upon combining GBWT measurement with other non-invasive predictors, e.g., platelets/GBWT.     

门脉高压患者内镜下胃静脉曲张分类及其发病分析

目的 对肝硬化患者内镜下胃静脉曲张进行分类，并分析其出血的好发因素。方法 确诊肝硬化门静脉高压患者139例，采用Soehendra和Sarin标准进行食管-胃静脉曲张分类，分析各类型的发生率、出血率、静脉曲张间的关系及出血与肝功能的关系。结果胃静脉曲张的发生率为35％，以GOV1发生率最高，多见于重度食管静脉曲张患者；胃静脉曲张出血率为12％，见于肝功能B级以上患者及GOV2和IOV1，显著低于食管静脉曲张出血率，食管静脉曲张出血见于中度以上静脉曲张、肝功能B级以上患者。结论胃静脉曲张在中国人群中有较高的发病率，出血多发生于胃底部位的曲张静脉，与肝功能差有关；食管静脉曲张出血发生率高于胃静脉曲张，与曲张静脉和肝功不良严重程度有关。