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通讯作者:

李兆申(1956-),男,河北宁晋人,中国工程院院士,主要从事消化内镜和胰腺病诊治研究。E-mail:zhaoshenli@hotmail.com

中图分类号:R576

文献标识码:A

文章编号:2096-8965(2020)01-0018-03

DOI:10.12287/j.issn.2096-8965.20200103

参考文献 1
SINGH V K,YADAV D,GARG P K.Diagnosis and management of chronic pancreatitis:a review[J].JAMA,2019,322(24):2422-2434.
参考文献 2
BEYER G,HABTEZION A,WERNER J,et al.Chronic pancreatitis[J].Lancet,2020,396(10249):499-512.
参考文献 3
XIAO A Y,TAN M L,WU L M,et al.Global incidence and mortality of pancreatic diseases:a systematic review,meta-analysis,and meta-regression of population-based cohort studies[J].Lancet Gastroenterol Hepatol,2016,1(1):45-55.
参考文献 4
SELLERS Z M,MACISAAC D,YU H,et al.Nationwide trends in acute and chronic pancreatitis among privately insured children and non-elderly adults in the United States,2007-2014[J].Gastroenterology,2018,155(2):469-478.
参考文献 5
MASAMUNE A,KIKUTA K,KUME K,et al.Nationwide epidemiological survey of chronic pancreatitis in Japan:introduction and validation of the new Japanese diagnostic criteria 2019[J].J Gastroenterol,2020,55(11):1062-1071.
参考文献 6
OH T K,SONG I A.Five-year mortality trends associated with chronic pancreatitis in South Korea:a population based cohort study[J].Pancreatology,2020,20(5):828-833.
参考文献 7
WHITCOMB D C.Pancreatitis:TIGAR-O version 2 risk/etiology checklist with topic reviews,updates,and use primers[J].Clin Trans Gastroenterol,2019,10(6):e00027.
参考文献 8
SCHNEIDER A,LOHR J M,SINGER M V.The MANNHEIM classification of chronic pancreatitis:introduction of a unifying classification system based on a review of previous classifications of the disease[J].J Gastroenterol,2007,42:101-119.
参考文献 9
HUANG H,LIU Y,DANILUK J,et al.Activation of nuclear factor-kappaB in acinar cells increases the severity of pancreatitis in mice[J].Gastroenterology,2013,144(1):202-210.
参考文献 10
MASAMUNE A,KOTANI H,SÖRGEL F L,et al.Variants that affect function of calcium channel TRPV6 are associated with early-onset chronic pancreatitis[J].Gastroenterology,2020,158(6):1626-1641.
参考文献 11
ZOU W B,WANG Y C,REN X L,et al.TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population[J].Hum Mutat,2020,41(8):1351-1357.
参考文献 12
HUANG H,SWIDNICKA-SIERGIEJKO A K,DANILUK J,et al.Transgenic expression of PRSS1R122H sensitizes mice to pancreatitis[J].Gastroenterology,2020,158(4):1072-1082.
参考文献 13
SUN C,LIU M,AN W,et al.Heterozygous spink1 c.194+2T>C mutant mice spontaneously develop chronic pancreatitis[J].Gut,2020,69(5):967-968.
参考文献 14
PATEL V,WILLINGHAM F.The management of chronic pancreatitis[J].Med Clin North Am,2019,103(1):153-162.
参考文献 15
SHELTON C A,UMAPATHY C,STELLO K,et al.Hereditary pancreatitis in the United States:survival and rates of pancreatic cancer[J].Am J Gastroenterol,2018,113(9):1376-1384.
参考文献 16
ZHU X,LIU D,WEI Q,et al.New-onset diabetes mellitus after chronic pancreatitis diagnosis:a systematic review and meta-analysis[J].Pancreas,2019,48(7):868-875.
参考文献 17
PAN J,XIN L,WANG D,et al.Risk factors for diabetes mellitus in chronic pancreatitis:a cohort of 2011 patients[J].Medicine(Baltimore),2016,95(14):e3251.
参考文献 18
LI B R,PAN J,DU T T,et al.Risk factors for steatorrhea in chronic pancreatitis:a cohort of 2 153 Patients[J].Sci Rep,2016,6(1):21381.
参考文献 19
中国医师协会胰腺病专业委员会慢性胰腺炎专委会.慢性胰腺炎诊治指南(2018 广州)[J].中华胰腺病杂志,2018,18(5):289-296.
参考文献 20
GARDNER T B,ADLER D G,FORSMARK C E,et al.ACG clinical guideline:chronic pancreatitis[J].Am J Gastroenterol,2020,115(3):322-339.
参考文献 21
中国医师协会胰腺病专业委员会慢性胰腺炎专委会.胰腺外分泌功能不全诊治规范(2018 年,广州)[J].中华消化杂志,2018,38(12):795.
参考文献 22
ISSA Y,KEMPENEERS M A,BRUNO M J,et al.Effect of early surgery vs.endoscopy-first approach on pain in patients with chronic pancreatitis:the ESCAPE randomized clinical trial[J].JAMA,2020,323(3):237-247.
参考文献 23
QIAN Y Y,HU L H,LIAO Z.Surgery vs.endoscopy for early treatment of chronic pancreatitis[J].JAMA,2020,323(21):2202.
目录contents

    摘要

    慢性胰腺炎是一种由遗传、环境等因素引起的胰腺组织进行性慢性炎症性疾病,近年来在国际上广受学者关注,较为密集的发表了多篇高质量临床指南和研究。该疾病目前发病率逐年增加,病因和机制复杂,临床病程多变,早期诊断困难,临床缺乏有效治疗药物,患者生活质量较低,未来仍有诸多问题有待攻克,基础与临床研究空间大。本文就近年来针对慢性胰腺炎基础与临床研究进展做一回顾,以期为国内胰腺炎研究领域同行提供参考。

    Abstract

    Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas in individuals with genetic, environmental, and/or other risk factors. In recent years, CP has aroused extensive attentions of the researchers worldwide and several high qualified clinical guidelines and studies were published. CP is characterized by increasing incidence, complex etiology and pathogenesis, variable clinical courses, difficult early diagnosis, and low life quality of patients. A plenty of issues in basic and clinical researches of CP need to be explained and solved. This review outlined the important basic and clinical researches of CP currently, to provide some references for this field.

  • 胰腺是一个位于腹膜后的器官,位置隐匿,具有消化食物和调节血糖的重要生理功能。慢性胰腺炎(Chronic Pancreatitis,CP) 是内科中最为疑难的疾病之一,是胰腺的一种进展性炎症纤维化综合征,其发病率逐年上升,病因与机制复杂,临床病程变化多样,并发症种类多,且缺乏有效治疗药物,患者需要终身治疗,生活质量差,导致社会负担重[1, 2]。本文就CP基础与临床的最新研究内容做一概述。

  • 1 CP流行病学

  • 世界范围内,CP的总体发病率为9.62/10万,死亡率为0.09/10万,男性病例数量约为女性的2倍[3]。 最近,多国更新CP流行病学资料,美国报道成人CP发病率为24.7/10万,患病率为91.9/10万[4];日本成人CP发病率为11.6/10万,患病率为44.5/10万[5]; 韩国报道从2002 年至2015 年,CP患病率从0.01%上升至0.07%[6]。总体而言,各国CP发病率呈逐年上升趋势。未来,需要整合资源,全面更新我国CP流行病资料。

  • 2 病因分类

  • 由于CP病因种类复杂,应全面分析患者危险因素,有利于揭示发病机制,预防疾病进展,提供重要治疗靶标和预后信息等。CP主要可分为酒精性和特发性两大类。病因具体可参照TIGAR-O最新版分类系统,分为以下几类:毒性代谢因素(吸烟、饮酒、高钙血症、高脂血症、药物、慢性肾病、糖尿病等)、特发性因素(早发、晚发)、遗传因素(SPINK1、PRSS1、CTRC、CFTR等)、自身免疫性因素(自身免疫性胰腺炎)、复发性急性胰腺炎或重症胰腺炎,以及梗阻性因素(胰腺分裂、 壶腹部狭窄、胰管结石等)[7]。此外,M-ANNHEIM分类系统根据患者疼痛情况、疼痛药物控制情况、 是否行过胰腺手术、胰腺内外分泌功能、胰腺形态改变和有无严重并发症,可对CP进行临床分期和严重程度评估,在临床研究中最常使用[8]

  • 3 致病机制

  • CP目前较为公认的病理过程是从早期腺泡细胞损伤,到引起免疫细胞浸润和活化,并导致胰腺星状细胞增殖与活化。从致病机制来看,胰酶激活通路被公认为CP致病的关键早期步骤,且主要证据来源于该通路相关酶的基因突变。基因突变后导致胰酶异常激活或者抑制胰酶因子功能下降,胞内钙离子信号异常间接激活胰酶,导管分泌功能下降,以及蛋白质错误折叠、内质网应激、自噬异常、炎症信号通路异常等都可能参与CP致病过程。 但是,也有研究证实腺泡细胞可以通过NF-κB通路导致CP发生,而不依赖于胰酶激活[9]。此外,环境因素刺激对慢性激活腺泡内炎症通路起非常重要的作用,大部分突变患者需要环境因素二次打击才表现出CP。

  • 普遍认为CP与遗传因素密切相关,目前发现了10余个易感致病或修饰基因,致病基因突变可显著影响临床病程,对于不明原因的胰腺炎或者复发性胰腺炎,尤其是青少年患者,筛查易感基因可评估CP发生风险。鉴于CP遗传背景存在显著人种差异,以及不断有新的易感基因报道,如钙离子通道相关基因如新型钙离子通道瞬时受体阳离子通道亚家族V成员6(Transient Receptor Potential Cation Channel subfamily V,member 6,TRPV6)[10, 11], 未来结合全外显子或全基因组测序技术,仍有可能发现新易感基因。由于前期易感基因多数停留在细胞水平验证阶段,因此如何在体内构建基因突变模型并证实CP发生机制,成为当前的研究热点。例如,PRSS1 发生突变后可直接导致CP的发生,本团队发现通过转人源PRSS1R122H至小鼠,可促进和加重胰腺炎的发生[12];SPINK1 基因表达胰酶抑制因子,我们通过构建SPINK1 c.194+2T>C点突变敲入小鼠,可引起自发CP[13]

  • 4 临床病程

  • CP患者的主要临床表现为反复腹痛,占比80%~96%[14],部分为反复的胰腺炎急性发作,少数为无痛型患者。研究表明,60%的CP均由急性胰腺炎和复发性胰腺炎进展而来,且携带PRSS1突变基因患者发展为胰腺癌的风险可增至5%~10%[15]。 胰腺内外分泌功能不全可表现为糖尿病、脂肪泻以及营养不良。一项荟萃分析发现,诊断CP后5 年和20年糖尿病的发生率分别为33%和51.5%[16]。我国CP患者诊断后20年、50年糖尿病发生率分别为45.8%和90%[17],诊断后10年、20年脂肪泻的发生率分别为20.44%和30.82%[18]。此外,CP还可出现胆总管狭窄、胰腺假性囊肿、门脉高压、十二指肠狭窄、骨质疏松等合并症。在我国,CP癌变率低于2%,尚无需对CP患者进行胰腺癌侵入性筛查。未来,对CP病程的管理,不仅要围绕疼痛和胰腺功能,而且需要关注罕见合并症的早期识别与防治。

  • 5 临床诊断

  • 目前对于怀疑CP疾病的患者(包括反复腹痛或胰腺炎发作,胰腺外分泌功能不全表现,B超或腹部平片阳性发现等),首选CT或MRI检查,但多数发现时已为进展期CP[19]。实验室检查主要用于评估胰腺内外分泌功能和寻找疾病发生的病因。 由于超声内镜具有一定侵入性,且特异性不高,一般仅在CT检查结果不能确诊或者怀疑癌变时使用。 对于上述检查仍不能明确诊断的患者,国外指南推荐使用促胰液素行MRCP检查[20],该技术在我国尚未推广。胰腺功能的检测分为直接法和间接法,直接法由于具有一定侵入性,临床难以推广,早期国内更多使用粪便脂肪测定,但收集标本难度大,不能反映早期胰腺功能不全。因此,目前国际上常用粪弹力蛋白酶间接评估胰腺外分泌功能[21],该试剂盒正在我国进行多中心临床试验。病理学活检临床应用较少,主要在CP诊断难以确诊或者需要与胰腺癌进行鉴别时使用。目前CP早期诊断仍然缺乏手段,未来,早期诊断CP将是下一步研究的热点和难点,人工智能技术广泛应用于影像和内镜领域,对于CP诊断或许是一个新的结合点。

  • 6 临床治疗

  • CP的临床治疗原则,主要是祛除病因、控制疼痛、维持胰腺功能和治疗合并症。目前对于多数患者,国内外指南较为公认的治疗方式是联合消化内科、胰腺外科、麻醉及营养等多学科进行综合治疗,采取药物—体外震波碎石—内镜微创—外科的升阶梯治疗模式[19],碎石联合内镜微创治疗已成为CP临床治疗的一线方式。针对我国CP患者大多数存在胰腺结石和胰管狭窄,长海医院开展了8 000 余例的体外震波碎石,证实该技术在绝大多数患者中是安全有效的(包括青少年和老年人患者),联合内镜下取石或支架植入术,可有效解除胰管梗阻,缓解患者疼痛症状,并改善胰腺部分功能。 对于部分不适于内科及介入治疗或治疗无效者,尤其是怀疑恶变者,可直接考虑外科手术治疗。关于外科手术与内镜微创治疗疗效的对比,成为近年来争议的话题,从最近一项随机对照实验(Randomized Controlled Trial,RCT)研究来看,外科治疗长期控制疼痛效果更佳,但在整体胰腺功能改善和生活质量上与内镜微创治疗无显著差异,该研究设计可能与临床常规不符,手术的益处或许被高估[22, 23]。鉴于饮酒可持续损害胰腺组织,推荐CP患者一定戒酒治疗,否则临床干预难以取得疗效。关于药物,早期患者可以适当服用抗氧化剂(维生素C、E等),但仍存在一定争议,机制有待阐明。止痛药物的使用遵循WHO提出的疼痛三阶梯治疗原则,止痛药物选择由弱到强,尽量口服给药,强阿片类药物的使用一定要慎重,因存在成瘾性,一般仅在内、外科治疗无效后考虑使用。胰酶制剂可一定程度缓解患者外分泌功能不全的症状,改善患者全身营养状况,但对于疼痛的疗效不确切[21]。未来,对于CP药物治疗的探索仍有非常大的空间, 结合传统中医药,科学探索有效单体或复方,或可为CP患者治疗提供新的希望。

  • 7 小结

  • CP尽管不属于内科常见疾病,但近年来颇受国际同行关注,对其致病机制的认识越来越深入, 临床诊断和治疗方面新增多项高等级研究证据。然而,CP发病率和患病率仍在不断增加,临床尚无根治手段。CP的早期诊断方案国际上仍在讨论中, 有待进一步论证。CP的治疗主要是控制疼痛、维护胰腺功能以及防治并发症,目前体外震波碎石与内镜微创技术已成为一线治疗方式,取得较好的疗效,未来仍需要多学科协作完善CP全病程的管理。

  • 参考文献

    • [1] SINGH V K,YADAV D,GARG P K.Diagnosis and management of chronic pancreatitis:a review[J].JAMA,2019,322(24):2422-2434.

    • [2] BEYER G,HABTEZION A,WERNER J,et al.Chronic pancreatitis[J].Lancet,2020,396(10249):499-512.

    • [3] XIAO A Y,TAN M L,WU L M,et al.Global incidence and mortality of pancreatic diseases:a systematic review,meta-analysis,and meta-regression of population-based cohort studies[J].Lancet Gastroenterol Hepatol,2016,1(1):45-55.

    • [4] SELLERS Z M,MACISAAC D,YU H,et al.Nationwide trends in acute and chronic pancreatitis among privately insured children and non-elderly adults in the United States,2007-2014[J].Gastroenterology,2018,155(2):469-478.

    • [5] MASAMUNE A,KIKUTA K,KUME K,et al.Nationwide epidemiological survey of chronic pancreatitis in Japan:introduction and validation of the new Japanese diagnostic criteria 2019[J].J Gastroenterol,2020,55(11):1062-1071.

    • [6] OH T K,SONG I A.Five-year mortality trends associated with chronic pancreatitis in South Korea:a population based cohort study[J].Pancreatology,2020,20(5):828-833.

    • [7] WHITCOMB D C.Pancreatitis:TIGAR-O version 2 risk/etiology checklist with topic reviews,updates,and use primers[J].Clin Trans Gastroenterol,2019,10(6):e00027.

    • [8] SCHNEIDER A,LOHR J M,SINGER M V.The MANNHEIM classification of chronic pancreatitis:introduction of a unifying classification system based on a review of previous classifications of the disease[J].J Gastroenterol,2007,42:101-119.

    • [9] HUANG H,LIU Y,DANILUK J,et al.Activation of nuclear factor-kappaB in acinar cells increases the severity of pancreatitis in mice[J].Gastroenterology,2013,144(1):202-210.

    • [10] MASAMUNE A,KOTANI H,SÖRGEL F L,et al.Variants that affect function of calcium channel TRPV6 are associated with early-onset chronic pancreatitis[J].Gastroenterology,2020,158(6):1626-1641.

    • [11] ZOU W B,WANG Y C,REN X L,et al.TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population[J].Hum Mutat,2020,41(8):1351-1357.

    • [12] HUANG H,SWIDNICKA-SIERGIEJKO A K,DANILUK J,et al.Transgenic expression of PRSS1R122H sensitizes mice to pancreatitis[J].Gastroenterology,2020,158(4):1072-1082.

    • [13] SUN C,LIU M,AN W,et al.Heterozygous spink1 c.194+2T>C mutant mice spontaneously develop chronic pancreatitis[J].Gut,2020,69(5):967-968.

    • [14] PATEL V,WILLINGHAM F.The management of chronic pancreatitis[J].Med Clin North Am,2019,103(1):153-162.

    • [15] SHELTON C A,UMAPATHY C,STELLO K,et al.Hereditary pancreatitis in the United States:survival and rates of pancreatic cancer[J].Am J Gastroenterol,2018,113(9):1376-1384.

    • [16] ZHU X,LIU D,WEI Q,et al.New-onset diabetes mellitus after chronic pancreatitis diagnosis:a systematic review and meta-analysis[J].Pancreas,2019,48(7):868-875.

    • [17] PAN J,XIN L,WANG D,et al.Risk factors for diabetes mellitus in chronic pancreatitis:a cohort of 2011 patients[J].Medicine(Baltimore),2016,95(14):e3251.

    • [18] LI B R,PAN J,DU T T,et al.Risk factors for steatorrhea in chronic pancreatitis:a cohort of 2 153 Patients[J].Sci Rep,2016,6(1):21381.

    • [19] 中国医师协会胰腺病专业委员会慢性胰腺炎专委会.慢性胰腺炎诊治指南(2018 广州)[J].中华胰腺病杂志,2018,18(5):289-296.

    • [20] GARDNER T B,ADLER D G,FORSMARK C E,et al.ACG clinical guideline:chronic pancreatitis[J].Am J Gastroenterol,2020,115(3):322-339.

    • [21] 中国医师协会胰腺病专业委员会慢性胰腺炎专委会.胰腺外分泌功能不全诊治规范(2018 年,广州)[J].中华消化杂志,2018,38(12):795.

    • [22] ISSA Y,KEMPENEERS M A,BRUNO M J,et al.Effect of early surgery vs.endoscopy-first approach on pain in patients with chronic pancreatitis:the ESCAPE randomized clinical trial[J].JAMA,2020,323(3):237-247.

    • [23] QIAN Y Y,HU L H,LIAO Z.Surgery vs.endoscopy for early treatment of chronic pancreatitis[J].JAMA,2020,323(21):2202.

  • 参考文献

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