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Article(id=1198200258640572942, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198200256912519683, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.0236.2024.0924, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1708963200000, receivedDateStr=2024-02-27, revisedDate=null, revisedDateStr=null, acceptedDate=1720886400000, acceptedDateStr=2024-07-14, onlineDate=1763602803143, onlineDateStr=2025-11-20, pubDate=1732723200000, pubDateStr=2024-11-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763602803143, onlineIssueDateStr=2025-11-20, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763602803143, creator=13701087609, updateTime=1763602803143, updator=13701087609, issue=Issue{id=1198200256912519683, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='11', pageStart='1221', pageEnd='1342', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763602802732, creator=13701087609, updateTime=1763603918291, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1198204935973204862, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198200256912519683, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198204935973204863, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198200256912519683, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1244, endPage=1250, ext={EN=ArticleExt(id=1198200258934174226, articleId=1198200258640572942, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Advances in the diagnosis and treatment of Cushing's disease, columnId=1198200258858676753, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Special Issue on Diagnosis, Treatment and Management of Pituitary Diseases, runingTitle=null, highlight=null, articleAbstract=

Cushing's disease is a severe endocrine disorder caused by excess secretion of adrenocorticotropic hormone from pituitary. Due to its subtle early clinical manifestations , the diagnosis of Cushing's disease is often delayed, and differentiating it from ectopic adrenocorticotropic hormone syndrome is a challenge. Combined functional tests can improve the diagnostic accuracy of Cushing's disease. The primary treatment for Cushing's disease is surgical removal of pituitary adenoma. However, about 1/3 of patients do not respond or experience recurrence after surgery, necessitating second-line treatments including medication. The development of novel drugs has enhanced the role of pharmacotherapy in the management of Cushing's disease. The review discusses the classic and emerging diagnostic methods and treatment strategies of Cushing's disease to deepen clinicians' understanding of its current treatment status and prospects.

, correspAuthors=Wei-Jun Gu, authorNote=null, correspAuthorsNote=
E-mail:
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库欣病是一种由垂体分泌过量的促肾上腺皮质激素引起的严重内分泌疾病，其早期临床表现隐匿，诊断常被延误，与异位促肾上腺皮质激素综合征的鉴别是临床诊断的难点之一。联合功能试验可提高库欣病的诊断准确度。目前针对库欣病的首选治疗方式为手术切除垂体腺瘤，但仍有1/3的患者术后未缓解或复发，需启动包括药物治疗在内的二线治疗。新型药物的研发提高了药物治疗在库欣病治疗中的地位。本文对库欣病的经典和新兴诊断方法及治疗策略进行讨论，以期加深临床医师对库欣病治疗现状及前景的了解。

, correspAuthors=谷伟军, authorNote=null, correspAuthorsNote=
谷伟军，E-mail：
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王岳鹏，硕士研究生，主要从事糖尿病及其并发症方面的研究

谷伟军，解放军总医院第一医学中心内分泌科主任医师，教授，博士研究生导师。长期从事垂体、性腺、肾上腺、糖尿病等内分泌代谢疾病的临床工作。现为中华医学会内分泌学分会全国委员兼副秘书长，北京医学会糖尿病学分会常委，北京医师学会内分泌分会副会长，中国女医师协会内分泌分会委员，曾任中华医学会内分泌学分会青年委员会副主任委员，中国医师协会内分泌学分会青年委员会副主任委员。现为《中华内分泌代谢杂志》《临床内科杂志》通信编委及多个外文期刊审稿人。

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王岳鹏，硕士研究生，主要从事糖尿病及其并发症方面的研究

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王岳鹏，硕士研究生，主要从事糖尿病及其并发症方面的研究

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谷伟军，解放军总医院第一医学中心内分泌科主任医师，教授，博士研究生导师。长期从事垂体、性腺、肾上腺、糖尿病等内分泌代谢疾病的临床工作。现为中华医学会内分泌学分会全国委员兼副秘书长，北京医学会糖尿病学分会常委，北京医师学会内分泌分会副会长，中国女医师协会内分泌分会委员，曾任中华医学会内分泌学分会青年委员会副主任委员，中国医师协会内分泌学分会青年委员会副主任委员。现为《中华内分泌代谢杂志》《临床内科杂志》通信编委及多个外文期刊审稿人。

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谷伟军，解放军总医院第一医学中心内分泌科主任医师，教授，博士研究生导师。长期从事垂体、性腺、肾上腺、糖尿病等内分泌代谢疾病的临床工作。现为中华医学会内分泌学分会全国委员兼副秘书长，北京医学会糖尿病学分会常委，北京医师学会内分泌分会副会长，中国女医师协会内分泌分会委员，曾任中华医学会内分泌学分会青年委员会副主任委员，中国医师协会内分泌学分会青年委员会副主任委员。现为《中华内分泌代谢杂志》《临床内科杂志》通信编委及多个外文期刊审稿人。

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库欣病的诊治进展
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王岳鹏 1, 2 , 李冰 1 , 吕朝晖 1 , 谷伟军 1, *
解放军医学杂志 | 垂体疾病诊疗及管理专题 2024,49(11): 1244-1250
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解放军医学杂志 | 垂体疾病诊疗及管理专题 2024, 49(11): 1244-1250
库欣病的诊治进展
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王岳鹏1, 2, 李冰1, 吕朝晖1, 谷伟军1, *
作者信息
  • 1解放军总医院第一医学中心内分泌科，北京 100853
  • 2南开大学医学院，天津 300071

    • 王岳鹏，硕士研究生，主要从事糖尿病及其并发症方面的研究

    谷伟军，解放军总医院第一医学中心内分泌科主任医师，教授，博士研究生导师。长期从事垂体、性腺、肾上腺、糖尿病等内分泌代谢疾病的临床工作。现为中华医学会内分泌学分会全国委员兼副秘书长，北京医学会糖尿病学分会常委，北京医师学会内分泌分会副会长，中国女医师协会内分泌分会委员，曾任中华医学会内分泌学分会青年委员会副主任委员，中国医师协会内分泌学分会青年委员会副主任委员。现为《中华内分泌代谢杂志》《临床内科杂志》通信编委及多个外文期刊审稿人。

通讯作者:

谷伟军，E-mail：
Advances in the diagnosis and treatment of Cushing's disease
Yue-Peng Wang1, 2, Bing Li1, Zhao-Hui Lyu1, Wei-Jun Gu1, *
Affiliations
  • 1Department of Endocrinology, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
  • 2School of Medicine, Nankai University, Tianjin 300071, China
出版时间: 2024-11-28 doi: 10.11855/j.issn.0577-7402.0236.2024.0924
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摘要
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库欣病是一种由垂体分泌过量的促肾上腺皮质激素引起的严重内分泌疾病，其早期临床表现隐匿，诊断常被延误，与异位促肾上腺皮质激素综合征的鉴别是临床诊断的难点之一。联合功能试验可提高库欣病的诊断准确度。目前针对库欣病的首选治疗方式为手术切除垂体腺瘤，但仍有1/3的患者术后未缓解或复发，需启动包括药物治疗在内的二线治疗。新型药物的研发提高了药物治疗在库欣病治疗中的地位。本文对库欣病的经典和新兴诊断方法及治疗策略进行讨论，以期加深临床医师对库欣病治疗现状及前景的了解。

库欣病  /  异位促肾上腺皮质激素综合征  /  促肾上腺皮质激素  /  皮质醇

Cushing's disease is a severe endocrine disorder caused by excess secretion of adrenocorticotropic hormone from pituitary. Due to its subtle early clinical manifestations , the diagnosis of Cushing's disease is often delayed, and differentiating it from ectopic adrenocorticotropic hormone syndrome is a challenge. Combined functional tests can improve the diagnostic accuracy of Cushing's disease. The primary treatment for Cushing's disease is surgical removal of pituitary adenoma. However, about 1/3 of patients do not respond or experience recurrence after surgery, necessitating second-line treatments including medication. The development of novel drugs has enhanced the role of pharmacotherapy in the management of Cushing's disease. The review discusses the classic and emerging diagnostic methods and treatment strategies of Cushing's disease to deepen clinicians' understanding of its current treatment status and prospects.

Cushing's disease  /  ectopic adrenocorticotropic hormone syndrome  /  adrenocorticotropic hormone  /  cortisol
王岳鹏, 李冰, 吕朝晖, 谷伟军. 库欣病的诊治进展. 解放军医学杂志, 2024 , 49 (11) : 1244 -1250 . DOI: 10.11855/j.issn.0577-7402.0236.2024.0924
Yue-Peng Wang, Bing Li, Zhao-Hui Lyu, Wei-Jun Gu. Advances in the diagnosis and treatment of Cushing's disease[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (11) : 1244 -1250 . DOI: 10.11855/j.issn.0577-7402.0236.2024.0924
正文
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库欣病为内源性库欣综合征(Cushing's syndrome，CS)的常见形式，主要是由垂体腺瘤分泌过多的促肾上腺皮质激素(adrenocorticotropic hormone，ACTH)刺激肾上腺皮质过度分泌皮质醇而引起的一种代谢性疾病，其发病率为(1.2~2.4)/100万，患病率为39.1/100万[1-3]。库欣病可引起代谢综合征、骨质疏松、机会性感染、精神神经障碍及认知障碍等多种并发症，严重影响患者的生活质量。研究发现，未治疗的库欣病患者标准化死亡比为2.8；术后生化治愈者的标准化死亡比为1.8，而术后未缓解者的标准化死亡比为4.6[4]。此外，库欣病与异位ACTH综合征(ectopic ACTH-dependent CS，EAS)的鉴别是临床诊疗的难点之一，尽管传统的内分泌试验具有一定的诊断价值，但均存在局限性，故两者的鉴别诊断仍存在诸多挑战。对于库欣病患者，虽然经蝶手术可实现80%微腺瘤及60%大腺瘤的缓解，但术后复发率较高。因此，对于复发性、难治性以及不适合手术的库欣病患者，其治疗仍是临床亟须解决的问题。本文就近年来库欣病的诊治热点及难点问题进行阐述，以期加深临床医师对库欣病的了解。
1 库欣病与EAS的鉴别诊断方法
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库欣病的临床诊断通常延迟数年，这与患者早期症状不典型、疾病的隐匿性进展有关。当临床怀疑CS时，通过24 h尿皮质醇(urinary free cortisol，UFC)、午夜1 mg地塞米松抑制试验及低剂量地塞米松抑制试验(low-dose dexamethasone-suppression test，LDDST)等明确CS的诊断相对容易。在皮质醇增多的状态下，ACTH水平异常升高可考虑为ACTH依赖性CS。库欣病及EAS均属于ACTH依赖性CS，临床的难点在于这两种疾病的鉴别诊断。侵袭性ACTH大腺瘤与恶性程度高的异位肿瘤容易鉴别，但对于ACTH微腺瘤与分化较好的神经内分泌肿瘤/隐匿性EAS，由于二者的临床表现、生化指标有较多重叠，影像学定位也相对困难，因而极易混淆。
1.1 库欣病鉴别诊断的传统方法
大剂量地塞米松抑制试验(high-dose dexamethasone-suppression test，HDDST)是鉴别库欣病与EAS的经典方法，但其敏感度仅为70.3%，特异度为77.8%，准确性欠佳[5]。此外，1-脱氨-8-精氨酸血管升压素(1-deamino-8-D-arginine vasopressin，DDAVP)刺激试验及促肾上腺皮质激素释放激素(corticotropin releasing hormone，CRH)刺激试验也可用于区分库欣病与EAS。DDAVP是一种长效抗利尿激素类似物，与肾脏加压素受体2(vasopressin receptor 2，VR-2)的亲和力较高，而库欣病中ACTH肿瘤细胞表达VR-2和VR-3，EAS则几乎不表达此受体。外源性给予DDAVP后，观察血浆中ACTH水平的变化可区分库欣病与EAS。需要注意的是，DDAVP试验应在HDDST及LDDST之前，或HDDST及LDDST完成后至少14 d再进行。然而，一些分化良好的神经内分泌EAS也可能表达VR-2，从而使试验结果存在假阳性和假阴性的可能。解放军总医院内分泌科的一项研究显示，外周DDAVP刺激后，以ACTH升高≥33.6%作为诊断切点时，鉴别库欣病与EAS的敏感度为98.9%，特异度为55.6%[6]。国内另一项研究显示，外周DDAVP刺激后，当ACTH水平升高幅度为基础值3倍以上时，可诊断为库欣病；以ACTH水平升高到基础值1.5倍作为诊断切点时，敏感度为82.0%，而特异度仅为38.0%[7]。因此，DDAVP试验的信效度并不能完全满足鉴别诊断的需求[8]。关于CRH刺激试验的荟萃分析显示，在单独的内分泌功能试验中，采用外周CRH刺激试验诊断库欣病时敏感度最高，但仍有约14%的库欣病患者无法做出预期反应[9]，且国内没有CRH，限制了该试验的开展。
岩下窦取血(inferior petrosal sinus sampling，IPSS)是目前公认的鉴别诊断库欣病的金标准。CRH刺激的IPSS试验中，基线中枢/外周ACTH梯度≥2.0或刺激后≥3.0时，诊断敏感度为92.0%，特异度为96.0%[10]。但国内无CRH制剂，采用DDAVP替代刺激后，中枢/外周ACTH比值≥3.0可考虑为库欣病，该试验的敏感度为95%~99%，特异度为95%~100%[11]，与CRH刺激的效果相当。IPSS无法正确定位的常见原因包括置管失败、置管位置不当、异常静脉回流、因药物或肾上腺切除致皮质醇水平正常或异位CRH分泌肿瘤等。IPSS在诊断库欣病时也可能存在假阴性结果，多由双侧垂体静脉分流异常引起，对无中枢优势的IPSS，可通过回顾插管影像来明确采样是否恰当。垂体发育不良或岩下窦血管丛异常分布也可能导致试验结果出现假阴性，而EAS患者有时会出现假阳性结果[12]。
目前，磁共振成像(MRI)仍是分泌ACTH垂体腺瘤的首选成像方式。有10%的普通人群存在垂体腺瘤，因此，在EAS患者中也可合并垂体无功能腺瘤而导致MRI出现假阳性结果；部分库欣病患者因垂体腺瘤较小或蝶鞍-蝶骨-空气界面处的信噪比低，导致垂体MRI为假阴性表现。MRI对于库欣病定位的总体敏感度为73.4%[13]。目前认为，如果MRI检测到垂体腺瘤≥10 mm且功能试验结果与库欣病一致，则库欣病的诊断不需要行IPSS；对于病变6 mm的患者，建议均应行IPSS；对于6~9 mm的垂体腺瘤，目前存在争议，但国际垂体协会2021年版的《库欣病的诊断和管理共识》仍建议行IPSS[14]。
1.2 联合试验诊断库欣病的价值
目前单一的功能试验很难精确诊断库欣病，而研究发现联合功能试验可提高库欣病的诊断准确度，其中最常用的为HDDST联合DDAVP试验，华西医院的研究显示其诊断库欣病的敏感度为95.5%，阳性预测值为98.4%[15]。此外，Elenius等[16]的研究显示，HDDST联合CRH兴奋试验诊断库欣病的敏感度为93.0%，特异度为98.0%。研究发现，垂体MRI联合功能试验也可提高诊断的准确性，动态增强MRI与HDDST试验联合诊断库欣病的阳性预测值为98.6%[17]。
1.3 新型鉴别诊断方法
天津医科大学总医院的Ding等[18]开发了无须功能试验的“ACTH-UFC指数”，该指数是由基线ACTH(pmol/L)和24 h UFC(nmol，ACTH和UFC通过化学发光法测算)的乘积除以10 000计算而来，以ACTH-UFC指数≤11作为诊断库欣病的切点时，研究队列的敏感度为96.0%，特异度为87.5%。但该指数可否进一步向其他中心推广应用尚需进一步临床验证。
近年来，新型检测方法如蛋白质组学和基因检测等在临床中得到了广泛应用，这些方法能够帮助临床医师更准确地进行疾病的鉴别诊断，对于病因的探究也具有重要意义。不同的CS亚型显示出各自独特的类固醇代谢谱特征，或可成为疾病特有的“指纹”。Eisenhofer等[19]发现，对CS患者10种血浆类固醇液相色谱串联质谱的特征进行分析，可实现对88%的库欣病及全部EAS患者的正确分类。该方法简单易行，具有潜在的应用前景。但目前临床上尚未广泛开展类固醇质谱检测，对于疾病的类固醇谱特征认识不够清晰，且缺乏明确的疾病诊断切点，因此，对包括库欣病在内的类固醇激素异常疾病仍需深入研究。
微RNA(microRNA，miRNA)是一类非编码RNA，可与非编码区或编码区序列结合作为转录后基因调节剂，也是目前研究的热点。Belaya等[20]发现，库欣病与EAS患者的血浆miRNA表达水平不同，尤其是miR-16-5p、miR-145-5p和miR-7g-5p，有望成为区分ACTH依赖性库欣综合征有前途的生物标志物。
此外，新型的影像学技术有助于提高库欣病的诊断准确性。68Ga生长抑素受体正电子发射计算机体层显像(PET)/计算机断层成像(CT)可识别约65%的EAS；68Ga CRH PET-CT靶向于CRH受体，能够全部正确识别包括直径6 mm的ACTH瘤，且对于肿瘤侧别的识别优于IPSS[21]。11C-甲硫氨酸PET-MRI对ACTH瘤的正确检出率约为89%，而半衰期更长的18F-乙基酪氨酸PET-MRI可实现对全部ACTH瘤的正确诊断和侧别定位，为外科手术中的肿瘤导航提供了有价值的信息[22]。但上述新的诊断标志物及影像学研究的样本量较小，尚需在临床开展更大规模或多中心的前瞻性研究，以验证其鉴别诊断的可靠性。
2 库欣病的治疗进展
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库欣病治疗的主要目标包括皮质醇水平及节律正常、临床症状缓解、并发症的预防及控制，以及对复发的早期监测和防治。然而，这些目标在临床实践中使用单一手段通常难以实现，需要施行包括手术、放疗以及药物治疗等在内的综合管理。
2.1 手术治疗
库欣病的首选治疗方式为手术切除垂体腺瘤，其中经蝶手术是主要的手术方式。最常见的手术并发症为新发前叶垂体功能减退症，发生率约为10%，其次为尿崩症、脑脊液漏和血栓事件[14]。围手术期病死率为0~7.1%，手术缓解率约为78.0%，术后复发率为5.0%~33.0%，中位复发时间为13.6~66.0个月[23]。复发后首选的二线治疗为再次手术，但再次手术3个月后的中位缓解率降低到58.0%[24]。
垂体手术结局的主要预测因素包括患者及肿瘤特征、术前影像、手术和病理结果以及手术特征。库欣病的不良预后与男性、术前肿瘤直径2 cm、肿瘤占位效应、Knosp分级3~4级、肿瘤残余、肿瘤病理的高风险亚型等因素有关[25]。近年来，人工智能技术广泛应用于临床，基于机器学习的库欣病复发模型也提升了肿瘤复发的预测能力。国外一项基于人工神经网络分析的研究开发了预测库欣病术后3年复发的风险计算器，该模型的敏感度为75%，特异度为97%，总体准确度为92%[26]；国内也有类似的研究探索[27]，但尚需进一步建立我国库欣病患者的大型临床及病理数据集，以指导库欣病患者的术后管理。
库欣病术后早期进行生化检测可能有助于预后判断，如术后ACTH水平较低或需要糖皮质激素替代治疗的患者复发风险较低[28]。午夜唾液皮质醇识别库欣病复发的敏感度及特异度高于UFC，而CRH兴奋试验、DDAVP兴奋试验以及地塞米松抑制联合DDAVP兴奋试验也可帮助预测疾病复发[14]。需要注意的是，约10%的患者在术后1个月内出现肾上腺功能不全的延迟缓解或进展，与术后立即缓解的患者相比，缓解延迟显著增加了复发风险。近30%的库欣病患者术后复发，且复发甚至可能出现在术后数十年[29]。因此，库欣病患者需终身随访。
2.2 放射治疗
垂体放射治疗主要用于术后持续或复发性库欣病患者的辅助治疗，或用于侵袭性垂体腺瘤的治疗。库欣病立体定向放射治疗是目前最常见的放射治疗方法，对于皮质醇增多症患者，其10年控制率为64%[30]，影像学改善率为95%[31]。但放射治疗的缺点是治疗起效的潜伏期较长，且发生垂体功能减退的风险较高。因此，在放射治疗后的缓解前期，需要辅助药物治疗来控制皮质醇增多症。垂体功能减退症是垂体放射治疗最常见的不良反应，发生率为25%~50%，且可随时间的推移不断增高[14]。因此，接受放射治疗的患者需终身监测垂体激素水平，以明确是否存在垂体激素缺乏或库欣病复发。
2.3 药物治疗
药物治疗可用于复发性库欣病，以及不适合手术的高皮质醇血症患者，并可用于控制放射治疗患者的皮质醇水平。为缓解高皮质醇血症对机体的损害，药物治疗作为二线治疗是必不可少的手段。随着新药的研发及应用，药物疗法在库欣病治疗策略中的地位有所提高。目前，库欣病的治疗药物可大致分为3类：(1)抑制类固醇生成的药物(adrenal inhibitors)，作用于肾上腺；(2)拮抗皮质醇作用的药物(reverse cortisol effect)，即糖皮质激素受体拮抗剂，作用于外周组织；(3)抑制ACTH合成及分泌的药物(suppressors of ACTH)，作用于垂体。
2.3.1 抑制类固醇生成的药物
类固醇合成抑制剂包括美替拉酮(甲吡酮)、酮康唑、米托坦、依托咪酯、奥西卓司他(osilodrostat)等。美替拉酮可抑制11β-羟化酶，减少皮质酮、皮质醇以及醛固酮的生成，其不良反应包括女性的高雄激素血症、头晕、关节痛、低钾血症，而肾上腺皮质功能不全相对较少。奥西卓司他是一种新型的类固醇生成抑制剂，可通过抑制11β-羟化酶来减少醛固酮和皮质醇的合成。奥西卓司他在欧洲及美国于2020年被批准用于治疗无法接受垂体手术，或已接受垂体手术但未缓解的库欣病患者。在一项Ⅲ期随机对照研究中，接受奥西卓司他治疗12周时，71.5%的患者UFC恢复正常，48周时66.0%的患者UFC仍处于正常范围[32]。有研究发现，在应用奥西卓司他期间，肿瘤体积有所增大，因此需要额外关注肿瘤体积的变化情况。奥西卓司他的不良反应包括肾上腺皮质功能减退及女性的高雄激素血症。
酮康唑可抑制类固醇合成的多个步骤，但因肝毒性较明显，在我国已退市。左旋酮康唑是外消旋酮康唑的2S、4R对映体，半衰期较长，体外抑制皮质醇的效力是酮康唑的2倍，且肝毒性低于酮康唑。左旋酮康唑已在美国获批用于治疗无法接受手术或无法治愈的CS成年患者的高皮质醇血症。有临床研究显示，接受左旋酮康唑治疗6个月后有30.0%的患者UFC水平仍正常，继续随访6个月，90.3%的库欣病患者肿瘤最大直径未继续增加[33]；痤疮、多毛症和代谢参数等临床体征在治疗后也得到明显缓解[34]。因此，左旋酮康唑可作为库欣病药物治疗的潜在选择之一，但需关注左旋酮康唑使用相关的肝损害、QT间期延长和药物相互作用。
2.3.2 拮抗皮质醇作用的药物
类固醇生成抑制剂可有效、快速地控制皮质醇水平，但这些药物均不能直接抑制ACTH的分泌，也不能恢复ACTH-皮质醇节律。目前，我国可获得的作用于糖皮质激素受体的药物主要为米非司酮。一项Ⅲ期临床研究显示，米非司酮300~1200 mg/d可有效控制皮质醇增多症带来的影响，包括血糖及血压的改善；不良反应包括低钾血症、阴道出血及肾上腺皮质功能不全等[35]。由于服用米非司酮后外周血的皮质醇浓度依然很高，目前尚缺少监测米非司酮治疗有效性的标志物，因此，临床应用难度较大，需密切关注低钾血症及肾上腺皮质功能不全的发生风险。此外，应用米非司酮时应考虑到潜在的药物间相互作用[36]。
2.3.3 抑制ACTH合成及分泌的药物
帕瑞肽是目前唯一被批准用于治疗库欣病的生长抑素类似物。有研究显示，帕瑞肽900 μg(2次/d)可使约26%的库欣病患者UFC恢复正常；每个月服用1次长效剂型帕瑞肽可使约40%的库欣病患者UFC恢复正常，且40%的患者肿瘤体积缩小[37]。值得关注的是，帕瑞肽可使68.4%~73.0%的库欣病患者出现高血糖，联合应用胰高血糖素样肽-1(GLP-1)受体激动剂可能有助于改善患者的血糖水平[14]。其他不良事件包括胆结石、腹泻等。卡麦角林是一种多巴胺2受体激动剂，可阻止ACTH细胞的激活及ACTH的分泌，但总体有效率低，仅25%~40%的患者可达到生化缓解[38]，且长期高剂量应用存在瓣膜反流增加的风险[39]。
2.3.4 库欣病的药物治疗策略
2021年《库欣病的诊断和管理共识》建议根据临床情况对库欣病患者进行个体化药物治疗[14]。通常首选肾上腺类固醇生成抑制剂，如酮康唑、奥西卓司他或美替拉酮；对于轻中度库欣病和残留肿瘤的患者，可考虑选择具有潜在缩小肿瘤效果的卡麦角林或帕瑞肽，其中卡麦角林效果相对较差且起效缓慢，但可用于怀孕的年轻女性[38]；对于患有严重多毛症伴轻度高皮质醇血症的女性，酮康唑和左旋酮康唑可能是最佳的初始治疗方案[23]。如果最大耐受剂量治疗2~3个月，患者的皮质醇水平仍持续升高，应考虑改变治疗方案；对于皮质醇增高有所缓解但未恢复正常，或临床症状缓解的患者，则可考虑联合治疗，但必须警惕药物间的相互作用和重叠毒性的风险[14]。目前国内库欣病的治疗药物可及性差，且价格相对昂贵，对于手术无法根治且皮质醇增多症较严重，药物治疗无法实施或对药物治疗没有反应的患者，可考虑双侧肾上腺切除[14]。
2.3.5 库欣病治疗药物研发的新靶点
既往库欣病的治疗药物主要针对ACTH及皮质醇作用途径，而缺少真正的靶向性药物。库欣病的发病与促黑素细胞皮质素原(proopiomelanocortin，POMC)启动子激活的改变、皮质醇负反馈的减少以及肿瘤细胞周期的破坏等机制有关[40]。目前已发现，USP8、NR3C1、BRAF、TP53等基因突变在库欣病的进展中也发挥了作用[41]。随着分子靶向治疗研究的进展，部分靶向药物表现出了较好的抗肿瘤作用。例如，ACTH肿瘤中的表皮生长因子受体(epidermal growth factor receptor，EGFR)表达水平与ACTH水平及肿瘤复发呈正相关，而EGFR过表达参与了ACTH瘤的形成与增殖、POMC的表达及ACTH的分泌。吉非替尼是一种针对EGFR的酪氨酸激酶抑制剂，可减弱ACTH肿瘤细胞中POMC的表达和ACTH的分泌，对库欣病具有潜在的治疗价值[42]。Nur77是POMC的正转录调节因子，可与类视黄酸X受体α(retinoid X receptor α，RXRα)信号通路相互作用。国内的一项研究显示，EGFR抑制剂拉帕替尼与RXRα激动剂贝沙罗汀联合应用时，可促进Nur77-RXRα二聚体的形成，并协同抑制PI3K-Akt通路。在小鼠模型中，拉帕替尼与贝沙罗汀联合应用可抑制ACTH瘤的生长及ACTH水平[43]。该研究通过对已有药物的合理组合，实现了对库欣病的精准靶向治疗。
ACTH瘤的细胞周期蛋白E(cyclin E)呈过表达，且细胞周期抑制剂p27呈低表达，这与细胞周期G1/S被破坏相关。Seliciclib是一种小分子、细胞周期蛋白依赖性激酶2/cyclin E的抑制剂，可抑制动物ACTH肿瘤模型中ACTH的表达[44]。一项纳入9例库欣病患者的Ⅱ期临床研究显示，在服用4周seliciclib后，患者的UFC水平降低了42%，ACTH水平的降幅达48%~57%[45]。此外，有研究发现，16.5%的库欣病患者存在BRAF V600E突变，而BRAF抑制剂vemurafenib对BRAF V600E突变的ACTH腺瘤具有潜在的治疗价值[46]，未来可能用于肿瘤的分子亚型分型，并指导靶向分子治疗。这些靶向药物目前大多处于研发及试验阶段，未来有可能成为库欣病的潜在治疗手段。
3 总结及展望
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虽然目前库欣病的诊治已取得了一定进展，但仍存在许多挑战和问题需要解决。库欣病由于起病隐匿，其诊断常被延迟。临床上需注意与EAS鉴别；ACTH小腺瘤与隐匿性EAS之间的鉴别是临床的难点，传统单一的内分泌功能试验准确性相对不高，而IPSS操作难度大，采取HDDST与DDAVP的联合诊断试验有助于疑难ACTH依赖性CS的诊断。此外，开发新的指数、类固醇质谱分析以及新型影像学技术有助于提高库欣病的诊断准确性。在库欣病的治疗方面，手术仍是其一线治疗手段，放射治疗可用于持续性或复发性库欣病患者。药物疗法在库欣病治疗策略中的地位有所提高，但目前已有的3类药物仍然不能满足临床需求，且在国内可及性较差。新的靶向药物如EGFR抑制剂等的研发正在取得积极进展。
总之，库欣病的诊断手段将朝着更简洁、精准的方向发展。未来应继续着眼于提升库欣病的早期诊断水平，简化库欣病的诊断流程，加强库欣病的发病机制研究，研发或引进更有效的药物治疗手段，积极开发靶向治疗药物，最终降低库欣病的病死率，提高患者的生活质量。
基金
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  • 北京市自然科学基金(7232155)
文献
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参考文献 引证文献
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2024年第49卷第11期
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doi: 10.11855/j.issn.0577-7402.0236.2024.0924
  • 接收时间：2024-02-27
  • 首发时间：2025-11-20
  • 出版时间：2024-11-28
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  • 收稿日期：2024-02-27
  • 录用日期：2024-07-14
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Beijing Natural Science Foundation(7232155)
北京市自然科学基金(7232155)
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    1解放军总医院第一医学中心内分泌科，北京 100853
    2南开大学医学院，天津 300071

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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