【作者】 刘萍；

【导师】 秦贵军；

【作者基本信息】 郑州大学 ， 内科学（内分泌代谢病专业）（专业学位）， 2024， 硕士

【摘要】 背景肾上腺(adrenal gland,AG)是人体重要的内分泌器官,因其体积小、形态不规则,与肝脏、肾脏等周围脏器关系密切,其相关疾病的诊断仍存在一定困难。已有多个研究表明,肾上腺的计量学指标,包括形状、密度与体积在内的改变在一定程度上可以反映肾上腺功能的变化,可为相关疾病的诊断提供一定依据。既往对肾上腺的研究均较局限,主要局限于肾上腺形态方面,而对肾上腺体积(adrenal gland volume,AGV)的研究相对较少。多层螺旋计算机断层扫描(multislice computed tomography,MSCT)被广泛应用与诊断肾上腺相关疾病,在原发性醛固酮增多症(primary aldosteronism,PA)、肾上腺皮质腺瘤(cortisol producing adenoma,CPA)、嗜铬细胞瘤(pheochromocytoma,PCC)等疾病的诊断中均发挥着重要作用。目前对于AGV的测量,主要通过MSCT三维重建肾上腺体积后利用半自动体积测量法(semi-automated volumetry,SAMV)进行评估,较传统方法而言可更可靠的评估肾上腺形态变化,更能反映肾上腺功能异常,可重复性也更好。原发性醛固酮增多症(primary aldosteronism,PA)是继发性高血压最常见的形式,其特征是单侧或双侧肾上腺自主分泌过多醛固酮。PA亚型可根据肾上腺静脉取血(adrenal venous sampling,AVS)结果分为醛固酮瘤(aldosterone-producing adenoma,APA,约占 35%)和特发性醛固酮增多症(idiopathic hyperaldosteronism,IHA,约占 60%)。AVS 是目前对PA分型最准确的测试,但AVS是一种成本高、技术困难且具有侵入性的手术,术中或术后可发生如肾上腺静脉破裂、出血和血栓栓塞等并发症,受限于专业的中心,因而无法广泛应用。因此,诊断PA的亚型仍存在一定的困难。MSCT被内分泌学会临床实践指南推荐用于PA的诊断评估。研究表明,基于MSCT测量的AGV在PA的诊断及亚型诊断中发挥着重要的作用。因此,本研究基于MSCT三维重建AGV,对正常成人的AGV进行测量,并进一步探讨其影响因素,着重关注AGV与年龄、性别及肥胖指标的相关性。与此同时,对PA患者的AGV进行测量,并探讨其与腹围(waist circumstance,WC)、内脏脂肪组织(visceral adipose tissue,VAT)及皮下脂肪组织(subcutaneous adipose tissue,SAT)等肥胖指标的关系,从而评估PA亚型与肥胖指标的相关性。其次在PA患者中,确定醛固酮瘤(aldosterone-producing-adenoma,APA)的独立影响因素,根据Logistic回归建立模型及评分,为临床中原发性醛固酮增多症亚型的诊断提供新的方法。目的1.MSCT三维重建肾上腺,测量AGV并探讨其影响因素;同时讨论PA患者的AGV与肥胖指标的关系,从而评估PA亚型与肥胖指标的相关性。2.在PA患者中,确定PA亚型中APA的独立影响因素,建立评分,为临床中PA亚型的诊断提供新的方法,并评估这一评分的作用及临床意义。方法第一部分收集2021年7月至2024年1月就诊于郑州大学第一附属医院内分泌科行功能试验并成功进行肾上腺静脉取血结果(adrenal venous sampling,AVS)的原发性醛固酮增多症(primary aldosteronism,PA)患者338例,按照排除标准排除后共纳入285例患者。同时选取2017年1月至2024年1月于郑州大学第一附属医院体检中心进行健康体检的健康成人作为研究对象2295例纳入正常成人(normal control,NC)组。通过医院PACS系统收集所有研究对象包括性别、年龄、身高、体重等在内的人口学资料,包括血压、空腹血糖(FBG)、糖化血红蛋白(HbA1c)、肝肾功能、血脂等在内的临床资料,影像学资料如肾上腺(或腹部)MSCT图像,采用SAMV测量左侧肾上腺体积(left adrenal gland volume,LAGV)与右侧肾上腺体积(right adrenal gland volume,RAGV),同时测量NC组215例及PA组285例研究对象的腹围(waist circumstance,WC),内脏脂肪组织(visceral adipose tissue,VAT),皮下脂肪组织(subcutaneous adipose tissue,SAT)等肥胖指标。收集PA组患者的肾上腺激素相关数据。第二部分将PA组按照7:3分为开发队列(n=201)及验证队列(n=84),在开发队列中应用Logistic回归建模,根据多因素Logistic回归系数计算评分,在验证队列中进行验证。计算受试者工作特征曲线分析(ROC)和ROC曲线下面积(AUC),以评估肾上腺体积与相关指标结合对APA的预测能力和诊断性能。在分析诊断APA的准确性时,使用最大Youden指数确定每个参数的ROC曲线切点值。Youden指数通过以敏感性和特异性的总和减去1来计算。以上检验的检验水准α均为0.05,所有P值均为双侧检验结果。结果1.将NC组按照年龄分组发现,AGV随着年龄增加呈现先增后减的趋势,其中28～37岁组NC组的AGV最大,而后随着年龄增加,AGV逐步减小。2.NC组年龄在18～67岁之间的男性AGV均显著大于同年龄段女性,差异具有统计学意义(均P<0.001);而年龄在68～77岁组及78～80岁组中,男性AGV大于女性,但差异统计学意义不显著(均P>0.05)。3.NC组AGV与WC、VAT、VAT/SAT均呈正相关(均P<0.001),但与SAT未观察到相关性(P>0.05)。4.PA组患者AGV均显著高于NC组(均P<0.001);NC组与PA组两组间WC差异具有统计学意义(P<0.001),PA组患者的VAT、SAT均表现出高于NC组的趋势,但差异统计学意义不显著(均P>0.05)。5.APA患者的最低血钾、PRA水平显著低于IHA患者(P<0.001与P=0.008),PAC、ARR显著高于IHA患者,且差异有统计学意义(均P<0.001)。6.APA患者的AGV高于IHA患者(均P<0.05);APA患者的WC、VAT、SAT低于IHA患者,差异有统计学意义(均P<0.05)。7.男性PA患者的AGV、WC、VAT、VAT/SAT均高于女性PA患者,且差异有统计学意义(均P<0.001)。8.校正后AGV比值、ARR及最低血钾是APA的独立影响因素,多因素Logistic回归建模显示该模型在开发队列中的AUC=0.805(95%CI,0.743-0.857),显示出良好的诊断性能。9 根据多因素Logistic回归模型相关系数建立评分,高校正后AGV比值(>1.4646 赋 2 分)、高ARR(>267.9167 赋 7 分)且血钾低(≤3.06mmol/L赋 2 分)的PA患者有较高的APA风险,该评分可为临床中原发性醛固酮增多症亚型的诊断提供新的方法。结论1.正常成人肾上腺体积左侧大于右侧,同年龄阶段男性的肾上腺体积大于女性,且与年龄相关。在正常成人及原发性醛固酮增多症患者中观察到肾上腺体积与肥胖指标的正相关。2.在原发性醛固酮增多症患者中,醛固酮瘤患者的肾上腺体积高于特发性醛固酮增多症患者;特发性醛固酮增多症患者与肥胖指标的相关性更强;男性原发性醛固酮增多症患者的肾上腺体积及肥胖指标均显著高于女性。3.高校正后肾上腺体积比值、高ARR及低血钾的原发性醛固酮增多症患者患醛固酮瘤风险较高。该评分可为原发性醛固酮增多症亚型的诊断提供新的方法,辅助临床决策,弥补AVS的局限性。更多还原

【Abstract】 BackgroundAdrenal gland(adrenal gland,AG)is an important endocrine organ of human body.Due to its small size,irregular morphology and close relationship to surrounding organs,the diagnosis of adrenal related diseases is still difficult.Several studies have shown that the measurements of the adrenal gland,including changes in shape,density and volume,can reflect changes in its function to some extent and could provide some evidence for the diagnosis of related disease.Previous studies on the adrenal gland were limited,mainly on adrenal morphology,while relatively few studies on adrenal gland volume(AGV).Multislice computed tomography(MSCT)is still the main method to diagnosis adrenal related diseases and plays an important role in the diagnosis of primary aldosteronism(PA),adrenocortical adenoma cortisol producing adenoma(CPA),pheochromocytoma(PCC)and other diseases.At present,the semi-automated volumetry(SAMV)is the main method to measure AGV.It is more reliable than the traditional method of assessing adrenal morphology and can better reflect abnormal adrenal function and better repeatability.PA is the most common form of secondary hypertension and is characterized by excessive aldosterone secretion by unilateral or bilateral adrenal autonomy.PA subtypes can be divided into aldosterone-producing-adenoma(APA,approximately 35%)and idiopathic aldosteronism(IHA,approximately 60%).Adrenal venous sampling(AVS)is the most accurate test for subtype diagnosis of PA.But AVS is a costly,technically difficult and invasive procedure,which can cause intraoperative or postoperative complications such as adrenal vein rupture,hemorrhage and thromboembolism,so it cannot be widely used.MSCT is recommended by the Endocrine Society clinical practice guidelines to diagnosis PA.Previous studies have shown that AGV plays an important role in the diagnosis of and subtype diagnosis of PA.Therefore,basing on the three-dimensional reconstruction of AGV by MSCT,this study aims to measure the normal adult AGV and explore the influencing factors,focusing on the correlation of AGV with age,sex,and obesity measures.Meanwhile,we also discuss the correlation between AGV and waist circumstance(WC),visceral adipose tissue(VAT)and subcutaneous adipose tissue(SAT)in patients with PA,so as to evaluate the association between PA subtypes and obesity measures.According to Logistic regression,we also establish a predictive model and a prediction score that can provide a new method for subtype diagnosis of PA.Objective:1.After the three-dimensional reconstruction of adrenal morphology by MSCT,we aim to measure AGV and explore the influencing factors.Discussing the correlation between AGV and obesity measures including VAT and SAT in patients with PA and the association between PA subtypes.2.In patients with PA,identifying independent risk factors of APA.Basing on the risk factors,we developed a prediction score to provide a new method for subtype diagnosis of PA.MethodsWe evaluated a total cohort of 338 PA patients referred to the Department of Endocrinology of the First Affiliated Hospital of Zhengzhou University spanning from July 2021 to January 2024.After excluding patients with data missing,285 patients had successful results of adrenal venous sampling(AVS)and available data were include in the study.At the same time,2295 healthy adults who underwent physical examination in the Physical Examination Center of the First Affiliated Hospital of Zhengzhou University from January 2017 to January 2024 were included in the normal control(NC)group.Demographic data of all patients were collected through the hospital PACS system,including gender,age,height,body weight,clinical data such as blood pressure,fasting blood glucose(FBG),glycated hemoglobin(HbA1c)and other clinic indicators and imaging data such as MSCT images of the adrenal gland(or abdomen).The left adrenal gland volume(LAGV)and right adrenal gland volume(RAGV)were measured by SAMV.The obesity measures of the 215 patients in the NC group and 285 of the PA group was also measured,including WC,VAT,SAT.The adrenal hormone-related data were collected in PA patients.The PA group was divided into development cohort(n=201)and validation cohort(n=84),according to the ratio of 7:3.The model and a prediction score were developed in the developing cohort with logistic regression analyses and validated in the validation cohort.Area under the receiver operating characteristics curve(AUC)was used to determine the performance.The cutoffs for the independent risk factors were determined by Youden’s index(specificity+sensitivty-1).The test level a of the above tests were all 0.05,and all P values were two-sided.Results1 In the NC group by age,the AGV showed a trend of first increased and then decreased with age,among which the 28-37 years old group had the largest AGV and then the AGV gradually decreased with age.2 In the NC group,AGV of men aged between 18-67 years was significantly larger than that of women of the same age(all P<0.001),while in the group aged 68-80 years,the difference was not significant(all P>0.05).3 The AGV of NC group were positively associated with WC,VAT,and VAT/SAT(all P<0.001),but no association was observed with SAT(P>0.05).4 The AGV of PA group was significantly higher than the NC group(all P<0.001).The difference in WC between the two groups was statistically significant(P<0.001),while VAT and SAT in PA group showed a higher trend than that in the NC control group,but the difference was not significant(all P>0.05).5 The serum potassium and PRA levels in PA patients were significantly lower than IHA patients(P<0.001 and P=0.008),PAC and ARR were significantly higher than IHA patients,and the differences showed significant significance(all P<0.001).6 The AGV in APA patients was higher than that in IHA patients(all P<0.05);the WC,VAT,and SAT in APA patients were lower than that in IHA patients with significant difference(all P<0.05).7 In PA patients,the AGV,WC,VAT,VAT/SAT were higher in male than that in female,and the difference was statistically significant(all P<0.001).8 Adrenal gland volume ratio,ARR and lowest potassium were independent predictors of APA.Multivariate logistic regression model showed that the AUC=0.805(95%CI,0.743-0.857)in the development cohort.Our model showed favorable diagnostic performance.9 The prediction score was developed according to the β coefficients of the multivariate logistic regression model,a PA patient showed that high adjusted adrenal gland volume ratio(>1.4646 will gain 2 points),high ARR(>267.9167 will gain 7 points)and low serum potassium(≦3.06 mmol/L will gain 2 points)has a higher risk of APA.The prediction score could provide a new method for subtype diagnose of PA.Conclusions1 The left adrenal gland volume was larger compared with the right adrenal gland.The adrenal gland volumes were larger in men than in women.The adrenal gland volumes increase first and then decrease with age.A positive correlation between adrenal gland volume and obesity measures was observed in both NC and PA groups.2 In patients with primary aldosteronism,the adrenal gland volumes were larger than those with idiopathic aldosteronism.The patients with idiopathic aldosteronism have stronger correlation with obesity measures than the patients with aldosterone-producing adenoma.In patients with primary aldosteronism,the adrenal gland volume and obesity measures in male were significantly higher than those in female.3 Patients with high adrenal gland volume ratio,high ARR and low serum potassium had a higher risk of APA.The prediction score could provide a new method for the identification of primary aldosteronism subtypes and could help avoid AVS of several patients.更多还原