背侧胰腺发育不全的研究进展

Recent advances in agenesis of the dorsal pancreas

摘要

背侧胰腺发育不全（ADP）是一种极为罕见的先天性胰腺发育异常，其核心特征为胰体及胰尾缺如或发育不全。该疾病的发生与胚胎期腹背胰芽发育异常密切相关，受多基因调控网络影响，其中HLXB9、HNF1B、PDX1、PTF1A、GATA4和GATA6等关键转录因子在胰腺形态建成过程中发挥重要作用。ADP患者的临床表现差异较大，可无症状，也可表现为腹痛、糖尿病或胰腺炎等。影像学检查（包括超声、CT、磁共振胆胰管成像及经内镜逆行胆胰管造影）是确诊的主要手段，特征性表现为胰体尾缺如及胰头代偿性增大。ADP常合并肾、胆道、心血管或生殖系统等多器官发育异常。治疗以对症支持为主，糖尿病患者需胰岛素替代治疗，外分泌功能不足者可予胰酶补充。随着基因测序及干细胞技术的发展，对ADP的发病机制、遗传背景及潜在干预手段的研究不断深入。本文综述ADP的胚胎学与遗传学基础、临床表现、诊断及治疗进展，以期为临床诊治和未来研究提供参考。

Abstract

Agenesis of the dorsal pancreas (ADP) is an extremely rare congenital pancreatic malformation characterized by the absence or hypoplasia of the pancreatic body and tail. Its pathogenesis is closely related to abnormal embryonic development of the ventral and dorsal pancreatic buds, governed by a complex network of transcription factors, including HLXB9, HNF1B, PDX1, PTF1A, GATA4, and GATA6. The clinical spectrum of ADP is highly variable, ranging from asymptomatic cases to manifestations such as abdominal pain, diabetes mellitus, or pancreatitis. Imaging modalities-including ultrasonography, CT, magnetic resonance cholangiopancreatography, and endoscopic retrograde cholangio-pancreatography-serve as the main diagnostic tools, with characteristic findings of absent pancreatic body and tail accompanied by compensatory enlargement of the pancreatic head. ADP is frequently associated with congenital anomalies of the kidney, biliary tract, cardiovascular system, or genital organs. Management is primarily symptomatic, with insulin replacement for diabetes and pancreatic enzyme supplementation for exocrine insufficiency. Advances in genetic sequencing and stem cell research have deepened understanding of the pathogenesis, genetic background, and potential therapeutic strategies of ADP. This review summarizes current progress in embryology, genetics, clinical features, diagnosis, and treatment of ADP, aiming to improve clinical recognition and guide future investigations.

Graphical abstract

关键词

胰腺疾病 / 先天畸形 / 糖尿病 / 胰腺炎 / 胰腺肿瘤 / 综述

Key words

Pancreatic Diseases / Congenital Abnormalities / Diabetes Mellitus / Pancreatitis / Pancreatic Neoplasms / Review

背侧胰发育不全（agenesis of dorsal pancreas，ADP）是一种罕见先天性胰腺发育畸形，又称“短胰腺”“球形胰腺”，其核心特征为胰体和胰尾缺失或发育不全。1911年Heiberg首次报道该疾病，目前发表文章中报告病例不足150例^[1]，属于胰腺发育异常中的极罕见类型。目前该病的具体发病机制尚未完全阐明。本文旨在综述ADP的发病胚胎学基础、遗传学基础、临床表现及诊断与治疗方法等。

1 发病基础

胚胎发育第7周时，内胚层的肝憩室向外突出形成腹胰芽，其对侧上皮形成背胰芽，它们分别发育出树突状管状系统^[2-3]。腹胰芽随胆管向十二指肠降部左侧后方迁移，形成钩突尾部和胰头，即腹胰；背胰芽延伸到肠系膜背侧并形成胰头的头端、颈部、胰体和胰尾，即背胰^[4-5]（图1）。这种时空精确的发育程序受到多层级基因调控网络的严格把控，任何关键基因的表达异常或信号通路的失调均可导致包括ADP在内的多种胰腺先天性畸形^[6]。如背胰芽未发育出胰尾，称为背侧胰腺部分发育不全；若仅存在胰头而胰体缺失，则称为ADP^[7]。

人类胰腺胚胎发育过程中呈现出复杂的细胞异质性和时空特异性调控特征。单细胞转录组研究揭示了胰腺发育过程中关键细胞群体的分子特征，特别是多能祖细胞（multipotent progenitor cells，MP）在腹侧和背侧原基中表现出显著的转录组差异。腹侧MP主要参与核糖体生物发生和成肌细胞分化过程，这种分子特征可能与其主要分化为导管细胞和内分泌前体细胞的命运相关；背侧MP显著激活Wnt信号通路，同时高表达细胞连接组装和突触组织相关基因，主要分化为外分泌系的尖端细胞和腺泡细胞^[8]，这种差异可能源于发育过程中腹背侧MP接收到不同的微环境信号，从而激活了不同的分子程序，最终导致其分化为不同的细胞类型^[9]。

2 遗传学基础

发育是一个多阶段协调的过程，可分为胚胎期形态发生和出生后功能完善两个主要阶段。在胚胎发育早期，前肠末端腹背侧及对侧上皮增厚形成腹芽和背芽，其中腹芽与十二指肠原基相连，背芽则向脾脏方向延伸^[10]。此阶段关键转录因子，如胰腺和十二指肠同源框1（pancreas duodenum homeobox 1，PDX1）和胰腺特异性转录因子1α（pancreas transcription factor 1α，PTF1α）通过协同作用维持MP的增殖潜能，这些细胞具有分化为导管、腺泡和内分泌细胞的能力^[11-12]。中期发育的特征是肠道旋转引发的腹背芽融合及分支形态发生。随着前体细胞的增殖和上皮重塑，形成“顶端－躯干”结构：顶端区细胞分化为腺泡谱系，而躯干区细胞则通过Notch信号维持前体状态并分化为导管和内分泌细胞^[13]。此阶段伴随胰腺特异性基因PTF1α、GATA结合蛋白4（GATA binding protein 4，GATA4）的上调，外分泌腺泡和导管系统开始构建，同时内分泌前体细胞脱离上皮向间充质迁移^[14]。晚期主要涉及组织成熟：腺泡细胞获得酶原颗粒，导管系统完成与十二指肠的连接，而迁移的内分泌细胞聚集成胰岛^[14]。出生后阶段则依赖PDX1、GATA6等因子调控胰腺功能成熟。值得注意的是，背腹芽的独立发育模式及“顶端-躯干”区的时空动态平衡对胰腺正常形态建成具有决定性作用^[12]。

2.1 运动神经元和胰腺同源盒1（motor neuron and pancreas homeobox 1，MNX1）

MNX1（又称HLXB9）是位于7号染色体q36.3区域的关键转录因子，在胰腺发育中起重要作用，在胚胎8 d左右出现于脊索和原肠内胚层，尤其参与胰芽外翻和β细胞分化两个阶段。HLXB9基因负责调控胰腺发育相关重要基因（如PDX1、胰岛素基因增强蛋白）的表达。研究表明，HLXB9基因失活会导致胰腺背侧上皮内信号通路缺陷，引起PDX1和胰岛素基因增强蛋白表达缺失，进而阻碍上皮外翻及多种胰腺细胞分化，最终导致小鼠胰腺背侧发育受损^[15]。值得注意的是，HLXB9失活仅影响胰腺背侧上皮发育，而腹侧胰腺上皮与背侧胰腺间质的发育未受明显影响。然而，残留胰腺中胰岛结构紊乱且产胰岛素β细胞数量减少，说明HLXB9是维持正常胰腺发育与功能的关键因子^[16]。有趣的是，人类HLXB9基因突变或缺失可引起Currarino综合征，但该综合征通常不伴随胰腺发育不良，提示HLXB9功能异常的影响具有广泛性^[17]。

2.2 肝细胞核因子1B（hepatic nuclear factor 1 homeobox B，HNF1B）

HNF1B是位于17号染色体q12区域的重要转录因子，主要表达于肝脏、胰腺等器官，在正常胰腺形态发生及β细胞终末分化中起关键作用^[18]。在胰腺发育早期，HNF1B通过激活成纤维细胞生长因子通路和调节Notch通路，对于胰腺祖细胞增殖进行调控，另外HLXB9主要通过直接作用于Ngn3 调控胰岛内分泌细胞前体细胞发育^[19]。尽管ADP在儿童与成人中均为散发病例，但研究表明ADP可能与HNF1B基因的常染色体显性缺失、错配及突变相关^[20-21]，诱发青年发病的成年型糖尿病（maturity-onset diabetes of the young 5，MODY5）^[22]。通过Sanger测序检测HNF1B基因全部编码区及外显子/内含子边界序列，证实ADP患者存在HNF1B杂合性全基因缺失^[23]。日本一项针对33例HNF1B基因变异或缺失的研究^[24]发现，7例患者存在胰腺发育不全。另有报道^[25]显示，1例无显著病史及家族史的女性在孕30周终止妊娠时发现胎儿无胰腺发育，经基因组测序发现其HNF1B转录因子TCF2外显子4存在杂合性移码突变，从而导致胰腺发育不良；另1例孕22周胎儿检查证实胰腺发育不良，因其父患慢性肾衰合并胰腺囊肿，经TCF2突变筛查发现外显子5-9杂合性缺失，提示该突变遗传自父亲。

2.3 PDX1和PTF1α

PDX1与PTF1α是胰腺发育的两大核心转录因子，在胰芽形成初期即参与复杂调控，随背、腹侧胰芽形成开始表达^[26-28]。PDX1尤其对促进胰腺发育及前肠内胚层生长起关键作用，同时是胰岛素基因表达的核心调控因子^[29]。研究发现，在胰腺上皮和小管结构形成后，若通过基因干预阻断PDX1的表达，小鼠胰腺的发育将出现显著缺陷。此时，胰腺组织仅保留导管结构，而无法正常形成腺泡或胰岛细胞。这一结果表明，PDX1在胰腺外分泌（腺泡）和内分泌（胰岛）谱系的分化过程中发挥关键作用，其缺失会导致胰腺发育停滞在导管主导的未成熟状态^[30]。PDX1敲除猪表现为严重糖尿病、胰腺发育不良、胰岛结构异常及胆管外分泌细胞功能或形态改变^[31]；同样，研究表明，PTF1α对胰腺细胞谱系定向及腺泡细胞分化状态的维持具有决定性作用。谱系追踪实验证实，胰腺外分泌部的全部细胞（包括腺泡和导管细胞）以及大部分内分泌细胞均起源于PTF1α阳性祖细胞^[32]。进一步研究显示，PTF1α的表达水平与胰腺发育密切相关：在斑马鱼模型中，内外分泌腺的形成呈现明显的PTF1α剂量依赖性，提示该因子通过浓度梯度调控胰腺细胞的命运^[33]；PTF1α缺陷小鼠则表现为腹侧胰腺发育不全且背侧胰腺体积显著缩小，导致胰腺形成严重受损^[34-35]。此外，N-钙黏蛋白缺陷小鼠与视黄醛脱氢酶2缺陷小鼠同样可引发ADP，其机制均与PTF1α或PDX1表达降低间接相关^[36-37]。

在人类，PDX1或PTF1α突变亦可导致胰腺发育不良：PDX1杂合性变异可引起新生儿背侧胰腺发育不全^[38]；PTF1α基因缺失及增强子突变可导致孤立性胰腺发育不良^[39]。PTF1α通过与PDX1的增强子结合增加其表达水平^[19]。这些均表明二者在胰腺生长中具有重要功能^[40-42]。

2.4 GATA4和GATA结合蛋白6（GATA binding protein 6，GATA6）

GATA4与GATA6是锌指结构转录因子，在胰腺与心脏胚胎发育中起主要作用^[43]。在胰腺中，GATA4与GATA6均在内胚层过表达，但逐渐分区域表达：GATA4局限于外分泌区，而GATA6主要表达于内分泌区^[44]。对小鼠胰芽转录组分析表明，GATA4与GATA6基因缺失会导致胰腺祖细胞减少，进而引起胰腺发育受损^[45]。在小鼠胰腺发育研究中发现GATA4与GATA6的间接作用：与杂合胚胎相比，GATA4与GATA6双敲除小鼠胚胎腹侧前肠中表达PDX1的细胞更少，说明GATA4缺失主要影响腹侧胰腺发育障碍^[46]；GATA6在人类内胚层表达，参与胰腺分化及葡萄糖反应性β样细胞发育^[47]；研究表明，GATA6功能缺失突变会通过抑制维A酸信号通路，引发多重胰腺发育异常：胰腺整体结构发生显著变形和胰岛β细胞数量急剧减少，临床表现胚胎期表现为胰腺发育不全和新生儿期永久性糖尿病^[48-49]。另有研究^[43]显示，过表达GATA6阻遏物嵌合蛋白可抑制胰腺发育。在人类胰腺发育遗传病例报道中，少数患者由GATA4功能不全引起，而多数胰腺发育病例由GATA6功能不全导致^[43,50]。在24例合并GATA6突变的ADP患者中，21例存在胰腺发育不良；而39例胰腺发育不良患者中，21例携带GATA6突变^[51]。通过CRISPR/Cas9技术构建的GATA6敲除斑马鱼模型，能够高度重现人类GATA6突变患者的多种发育缺陷：心脏流出道发育缺陷、胰腺发育不全、胆管畸形和肝内胆汁淤积等。分子水平分析显示，这些表型缺陷可能与GATA6调控的内胚层谱系分化障碍密切相关^[52]。

3 临床表现

3.1 腹痛

ADP患者临床表现差异较大，可无症状或出现腹痛、烦渴等症状。部分儿童期患者可能表现为糖尿病样症状或其他多系统发育异常，应高度怀疑ADP并完善基因检测^[53-54]。腹痛是最常见的临床症状。其发生机制与多种因素相关，包括Oddi括约肌功能障碍、慢性胰腺炎、糖尿病性自主神经病变、胰管高压、胰管结石以及分泌酶代偿性增加等^[1]。约30%的患者可并发急性胰腺炎、复发性胰腺炎或慢性胰腺炎^[1,55]，部分病例甚至出现胰腺外分泌功能不全的典型表现^[56]。研究显示，ADP继发胰腺炎的病理机制主要涉及Oddi括约肌功能障碍导致的胰液排泄受阻，以及残留腹侧胰腺代偿性肥大引发的胰管内压升高^[57]。Mahey团队^[58]曾报告1例ADP合并慢性胰腺炎病例，患者以腹痛和糖尿病为主要表现，经胰岛素治疗、脂肪酶补充及饮食调整后症状显著改善；Jeong等^[59]报道的青年ADP患者则因糖尿病酮症酸中毒合并急性胰腺炎入院，经禁食、补液及胰岛素治疗后病情缓解。对于顽固性胰腺炎相关疼痛，De Paep等^[60]实施的胰腺全切联合胰岛细胞自体移植术可使临床症状完全缓解。

3.2 糖尿病

近半数ADP患者存在血糖代谢异常，且发病起始时间存在差异^[57]。胰岛细胞主要分布于胰腺尾部，胰体尾缺如导致胰岛素分泌不足是糖尿病发生的重要机制^[61-62]。Fukuoka等^[63]通过ADP病例研究发现，胰头组织中散在的胰岛细胞也可能伴随结构破坏。值得注意的是，在非糖尿病ADP家族中，患者肝脏糖原代谢存在显著缺陷，可能与胰岛β细胞数量减少引发的糖耐量异常相关，这种代谢紊乱最终可进展为糖尿病^[64]。Lalchandani等^[65]报道的1例中年ADP合并糖尿病患者，接受中效胰岛素后症状改善。

3.3 胰腺肿瘤

目前关于ADP相关胰腺肿瘤的文献报道非常有限，已发现的肿瘤类型包括实性乳头状肿瘤、实性假乳头状肿瘤、胰管内乳头状黏液性肿瘤（IPMN）及胰腺癌等。2009年Sakpal团队^[66]首次报道ADP合并恶性IPMN病例，并成功实施胰腺全切联合十二指肠切除、Roux-en-Y式胃肠吻合、肝管空肠吻合及胆囊切除术。此后Sannappa等^[67]相继报道多例ADP合并IPMN的治疗经验。2019年Julianov等^[68]首次报道ADP合并胰腺癌病例，行胰十二指肠切除术。Rittenhouse等^[61]也陆续报告ADP并发胰腺癌的多个案例。Shyr等^[69]则创新性地采用保留胰头的胰腺切除术治疗ADP合并实性假乳头状肿瘤。现有证据表明，胰腺肿瘤与背侧胰腺发育不良的直接关联性较低，但ADP继发的慢性胰腺炎可能是肿瘤形成的危险因素。由于此类患者多需行胰腺全切术，术后需终身接受胰岛素和胰酶替代治疗，因此ADP患者的胰腺肿瘤早期筛查具有重要临床意义。

3.4 先天合并症

ADP虽多为独立发生的先天性畸形，但常合并多种发育异常，包括多脾综合征、异位脾、肠旋转不良、左位胆囊、胆总管囊肿、环状胰腺、胰腺钙化、阴道闭锁及先天性心脏病或血管畸形等^[66,70-71]。研究^[72]发现，ADP家族中母子两代均存在背侧胰腺发育不良，这为ADP的遗传学发病机制提供了直接证据。

4 诊断方法

4.1 超声检查

超声是评估ADP最常用的影像学手段^[72]，典型表现为球形增大的胰头伴胰体尾缺如^[56]。然而，受患者体型及胃肠道气体干扰等因素限制，超声对胰腺组织的检出存在一定局限性^[73]。当CT与磁共振胰胆管造影（magnetic resonance cholangio-pancreatography，MRCP）难以鉴别胰腺肿瘤与ADP时，超声内镜（EUS）可发挥重要鉴别诊断价值：其特征性表现为腹侧胰腺代偿性增大、主胰管内径正常，同时显示背侧胰腺及副胰管缺如。若合并胰腺肿瘤，超声内镜引导下细针穿刺活检可提供病理诊断依据^[56,74]。

4.2 CT检查

CT影像特征包括胰头体积增大、实质密度均匀，胰体尾部结构缺失，脾静脉前方脂肪组织密度均匀且无纤维条索及渗出性病变。但CT对胰管系统的评估存在局限性^[75]。

4.3 MRCP检查

MRCP可清晰显示肝内胆管及胆总管中上段扩张、胆总管中下段局限性狭窄、胰管短缩及胰体尾部结构缺如等特征性改变^[75]。该技术能精确描绘胰管形态学特征^[76]，且无辐射暴露风险，可作为ADP患者的首选无创性检查手段^[73]。

4.4 内镜逆行胰胆管造影（endoscopic retrograde cholangio-pancreatography，ERCP）

ERCP通过显示背侧胰管及副乳头缺如即可诊断为ADP，同时可鉴别胰腺发育不良与胰腺肿瘤^[77]。但该技术为侵入性操作，存在依赖性操作者及并发症发生风险^[76,78]。

综上，不同影像学方法在ADP诊断中各具优势与局限，需根据患者的具体情况综合选择（表1）。

5 治疗现状

根据胰腺发育缺陷程度，ADP可分为完全型背侧胰腺发育不全（球形胰腺）、体尾部发育不全（短胰腺）及尾部发育不全三种类型^[7,56]。无伴随疾病的ADP患者无需特殊治疗。当出现腹痛、腹胀、多饮、多食等临床症状时需及时就诊。目前ADP与肿瘤发生的关联机制尚未明确，其合并胰腺肿瘤的手术治疗原则与正常胰腺患者基本一致。但因胰尾部缺如，胰头切除术后需长期使用外源性胰岛素替代治疗胰腺外分泌功能不全^[74,79]，尽管目前干细胞工程尚无法完全模拟人类β细胞的所有功能特性，但研究显示，由人MP定向分化产生的胰岛样细胞在移植入糖尿病模型小鼠体内后，能够显著改善糖代谢紊乱，部分甚至可完全逆转高血糖状态。这一突破性进展为ADP引起糖尿病治疗提供了新的希望^[80]。此外，ADP常合并其他器官畸形，全面细致的系统检查有助于早期干预合并症^[71,81]。

6 研究展望

胰腺发育的基因调控呈现严格的时序性和层级性特征。目前ADP的分子机制尚未完全阐明。基于动物模型的研究表明，由HLXB9、HNF1B、PDX1、PTF1A、GATA4及GATA6等关键基因构成的级联调控网络在胰腺形态发生过程中发挥核心作用。这些基因在胰腺腹背侧原基中的差异性时空表达模式，可能是导致ADP发生的重要基础。值得注意的是，临床观察发现ADP既呈现家族聚集性，又存在散发病例，这一特征提示其遗传模式可能符合常染色体显性遗传^[82]。

综上，ADP作为罕见的胰腺发育不全性疾病，其诊断主要依赖超声、CT、MRCP、ERCP等影像学检查。诊断ADP主要依据是副胰管和胰尾缺失，但需要与继发于慢性胰腺炎的胰腺分裂和自体消化、胰腺肿瘤相鉴别^[7,83]。在医生诊断困难时，考虑到ADP常合并其他器官畸形，同时可行基因检测进行区分。对于出现间歇性腹痛或胰腺功能不全症状者，需规范进行胰岛素及胰酶替代治疗。同时该疾病可伴随一些其他先天疾患，在没有症状的情况下，不需要特殊的治疗，对于出现并发症时仔细评估及治疗。

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基金资助

浙江省嘉兴市重点学科—外科医学（肝胆胰）基金资助项目(2023-ZC-005)

浙江省嘉兴市省市共建学科—普通外科（微创）基金资助项目(2023-PYXK-001)

浙江省医药卫生科技基金资助项目(2024KY434)