修回日期: 2018-06-04
接受日期: 2018-06-09
在线出版日期: 2018-07-28
脂肪胰是近年被提出并研究, 与肥胖、非酒精性脂肪性肝病、代谢综合征等多种疾病或病理状态相关的概念, 特征为胰腺内脂肪沉积、胰腺实质脂肪变性, 以及随之发生的胰腺代谢性异常. 研究已证实脂肪胰与2型糖尿病、急性胰腺炎甚至胰腺肿瘤相关. 可能是糖、脂代谢紊乱或者代谢综合征的一个早期标志物, 还可能是胰腺相关疾病不良结局的预测因素. 目前主要以影像学检查为主要诊断方法. 但因了解甚少, 故而缺乏统一的命名、诊断标准、治疗共识或指南. 本文总结了目前流行病学、病理生理、发病机制、诊断、治疗方面的研究现状, 并提出需要进一步研究的方向.
核心提要: 脂肪胰是一种与肥胖、非酒精性脂肪性肝病、代谢综合征等多种疾病或病理状态相关的代谢紊乱状态, 可进一步继发或进展为严重疾病. 研究脂肪胰的病理生理特点、发病机制及临床影响, 对于代谢紊乱相关疾病的早期干预、治疗策略的制定、以及预后预测, 具有重要意义.
引文著录: 牛春燕, 吴方雄. 脂肪胰的研究现状. 世界华人消化杂志 2018; 26(21): 1280-1288
Revised: June 4, 2018
Accepted: June 9, 2018
Published online: July 28, 2018
Fatty pancreas is a newly proposed condition which is characterized by fat deposition and steatosis in the pancreas followed by outcome of pancreatic and metabolic complications. It has been found to be correlated with many metabolic disorders and a variety of diseases. Fatty pancreas has been associated with obesity, non-alcoholic fatty liver disease, metabolic syndrome, type 2 diabetes mellitus, acute and chronic pancreatitis, and even pancreatic carcinoma. Therefore, fatty pancreas might not only be an early marker of glucose or lipid metabolism disorders or metabolic syndrome, but also be a predictor of poor outcome of pancreatic related diseases. At present, imaging examination is the main diagnostic method. However, there is currently still a lack of a unified terminology, diagnostic criteria, treatment consensus, and guidelines due to very limited knowledge on this condition. Here we discuss the pathophysiology, pathogenesis, clinical implications, diagnosis, and treatment of fatty pancreas, with an aim to improve the early intervention, treatment, and prognosis prediction of fatty pancreas related metabolic disorders.
- Citation: Niu CY, Wu FX. Research status of fatty pancreas. Shijie Huaren Xiaohua Zazhi 2018; 26(21): 1280-1288
- URL: https://www.wjgnet.com/1009-3079/full/v26/i21/1280.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v26.i21.1280
脂肪胰(fatty pancreas, FP)的概念于近年被提出, 但对其概念及定义、流行病学、病因、生理/病理意义、发病机制、诊断、治疗等研究尚处于起始阶段, 在国内外未引起广泛关注, 存在较多未知. 已有的研究发现, 胰腺脂肪沉积与肥胖、胰岛素抵抗(insulin resistance, IR)、代谢综合征(metabolic syndrome, MetS)、非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)、动脉硬化、肿瘤等疾病密切相关, 而且可能加重急性胰腺炎的严重程度、促进与IR和2型糖尿病(type 2 diabetes mellitus, T2DM)相关的胰腺功能障碍的进展. 对FP的研究将是未来代谢紊乱相关性疾病领域内的重点方向之一.
胰腺脂肪浸润于1926年首次由Schaefer[1]描述, 报道了人的体重与胰腺脂肪的关系. 随后在1933年, Ogilive[2]在对19例死者的尸检中发现, 胰腺外分泌腺中有不同程度的脂肪增多, 以肥胖者居多, 而且肥胖与非肥胖者个体间胰腺脂肪的含量存在差异, 因此首次提出"胰腺脂肪增多症(pancreatic lipomatosis)"这一概念. 1978年Oslen[3]对394例死者的尸检发现胰腺脂肪含量与体重强烈相关. 后续研究发现, 除腺泡细胞外, 胰岛细胞内也可出现脂质沉积, 因此胰腺脂肪沉积可能累及胰腺的所有实质细胞, 表现为胰腺实质细胞被大量脂肪细胞浸润或替代. 病理类型主要有2种: (1)为后天形成的胰腺脂肪沉积, 多与高脂饮食、肥胖、高脂血症等有关; (2)为Shwachman-Diamond综合征等以胰腺的脂肪堆积为主的先天性疾病, 可表现为胰腺腺泡细胞被广泛的脂肪组织所替代, 外分泌功能受损严重. 当前国内外有"胰腺脂肪变性(pancreatic steatosis)"、"胰腺脂肪替代(pancreatic fat replacement)"、"胰腺脂肪浸润(pancreatic fat filtration)"、"脂瘤性假性肥大(lipomatous pseudohypertrophy)"、"脂肪胰(fatty pancreas, FP)"、"非酒精性脂肪性胰病(non-alcoholic fatty pancreas disease, NAFPD)"等多种命名[4-6](表1). 与脂肪肝相对应, 国内多以"脂肪胰"(FP)用于反映"胰腺内脂肪可逆或不可逆沉积"这一现象[7,8]; 同样, NAFPD是与NAFLD及酒精性脂肪胰(alcoholic fatty pancreas)相对应的命名. 对"大量饮酒"的定义为: >2次饮酒(约10 g/每个饮酒单位)/d, 或者根据性别定义为: 男性饮酒平均>3次/d及女性饮酒平均>2次/d[9]. NAFPD还可进展为非酒精性脂肪性胰腺炎(nonalcoholic steato-pancreatitis, NASP), 且这一进程可因减重而被逆转[10]. 但不同于NAFLD的是, 胰腺脂肪沉积的病理生理学、临床意义、潜在后果尚未明确. 因此如何才能准确描述胰腺脂肪沉积的病理特点以及与其相关的临床表现, 对于胰腺脂肪沉积的概念、定义尚需更多基础与临床研究进一步明确、统一及规范, 公认的诊断标准需要建立.
由于尚无标准的筛选手段, 对于普通人群FP的流行病学数据很少. 大样本、多中心、多国家及地区的流行病学研究结果鲜有报道, 现有的研究报道来自于不同的检查方法.
2.1.1 患病率: 一项2015年来自新西兰、对12675名个体的Meta分析显示, 33% 的人群患有FP[11]. 台湾一项针对8097例健康体检者的大型队列研究报告, 通过US的NAFPD检出率为16%[12], 与香港的MRI检出率(16.1%)相近. 韩国一项对就诊于肥胖中心的293例个体通过CT及腹部超声检查, NAFPD患病率高达61.4%[13]. 儿科住院人口的估计患病率为10%[14]. 一项来自中国扬州的人群调查结果[15], 在1228例受检人群中FP患病率为2.7%, 低于以往的中国、中国香港、印尼等亚洲地区的研究结果(10%-35%)[13]. 以上关于患病率的研究结果差异, 可能与所选用的检查方法、受检人群以及国家地区不同有关.
2.1.2 相关危险因素: 普遍流行的久坐少动的生活方式及高热量饮食结构导致MetS和与其相关的糖尿病、心血管疾病、脑血管意外发病率逐年上升. 越来越多的证据表明, 肥胖与FP密切相关, 而且超重及肥胖已被证实为胰腺癌的危险因素[16], 与体质指数(body mass index, BMI)正常者(<25 kg/m2)比较, BMI>30 kg/m2是胰腺癌的一个重要危险因子. 现有的研究认为, 人种(西班牙裔及高加索人群胰腺脂肪浸润发生风险较非洲裔美国人高)[17]、增龄、男性、高血压、肥胖、高BMI、腹围增加、饮酒、高脂饮食、高脂血症、脂蛋白异常、转氨酶(ALT)水平升高、β细胞功能障碍、IR、T2DM、脂肪性肝病及MetS与FP相关. 而增龄、血清铁蛋白升高、中心型肥胖、高甘油三酯血症及脂肪性肝病为FP的独立危险因素[18,19]. 另有研究发现, 呼肠孤病毒感染可导致胰腺腺管梗阻, 继而发生胰腺实质坏死及脂肪组织替代[20,21]. 部分药物如皮质类固醇激素、吉西他滨、罗格列酮以及奥曲肽可能在动物模型中导致胰腺组织坏死及继发的脂肪组织替代[22,23]. 在酗酒、恶性营养不良(kwashiorkor, 夸希奥科病)及AIDS等营养不良状态下, 胰腺结构发生改变, 包括胰腺脂肪瘤变[24]. 遗传性血色病及输血依赖性疾病导致铁过载, 铁主要沉积在肝脏、心脏、内外分泌腺、胰腺的网状内皮系统, 当胰腺受累时, 过载铁将导致腺泡细胞和胰岛细胞的氧化应激、细胞凋亡和脂肪细胞替代[6,25].
2.2.1 FP与年龄 胰腺内脂肪含量随年龄增长而增加, 在儿童和青少年时期, 胰腺脂肪累积的发生与胰腺总体积呈线性正相关关系[4], 在30-40岁时达高峰[26]. 但青少年之后的时期, 胰腺脂肪变的进展则不再依赖于胰腺总体积. 一项超声研究显示, 50岁后的大部分人群及80岁后的所有人群, 胰腺回声明显增强、超过肝脏[27]. 胰腺脂肪含量随年龄增加的原因可能为: 继发于胰腺脂肪浸润、胰腺损伤之后的血清脂肪酶水平下降[28].
2.2.2 FP与代谢紊乱相关疾病: 肥胖被美国医学会认定为一种疾病[29], 现已成为一种全球性疾病, 与伴随体脂过多的多种疾病及多个器官的异位脂肪沉积强烈相关, 包括MetS、T2DM、NAFLD、心血管疾病、多种肿瘤及这些疾病相关的死亡, 而且正在成为这些疾病发病率和死亡率的最主要原因. 代谢危险因素如高BMI, IR, MetS及其所有组分, T2DM及其进展, 糖尿病前期, NAFLD等均与胰腺脂肪含量增加及FP存在强烈相关关系[13,30-32]. 有研究显示, 50%-80%的非酒精性脂肪性肝炎(NASH)患者合并有FP[19,33], 因此认为肝脏脂肪变是FP的最强预测因子(OR = 14), 并且提示了FP与肥胖之间的强烈关联. 与不合并FP的患者比较, 合并FP的NAFLD患者具有更高的胰岛素抵抗指数(HOMA-IR)[10]. 因此, FP可能是MetS发展过程中的一个关键因素.
2.2.3 FP与内脏脂肪组织及心血管疾病风险: 还有研究认为, 与BMI比较, 内脏脂肪组织(visceral adipose tissue, VAT)与胰腺脂肪浸润具有更强烈的相关性[34]. FP与动脉粥样硬化相关, 合并纤维化的NAFPD, 动脉粥样硬化发生的风险增加, 而且是传统心血管疾病及代谢危险因素之外的独立危险因子, 低度慢性炎症可能为动脉粥样硬化的病理机制[18,32].
2.2.4 FP与急性胰腺炎: 多项研究提示, FP、BMI、肥胖及VAT均为加重急性胰腺炎结局的危险因素[35], 胰腺脂肪变合并急性胰腺炎可增强炎症反应, 对胰腺实质产生直接毒性效应, 与腺泡细胞邻近的脂肪浸润与胰腺实质损害的严重程度相关[36], 而且不同阶段的胰腺脂肪浸润与不同的急性胰腺炎严重程度相关[4,37], 因此FP是急性胰腺炎严重程度的危险因子, 发病机制可能与继发于某些有关的易感因素相关, 如胆结石, 恶性肿瘤, 高脂血症以及治疗MetS的一些药物[38]. FP合并急性胰腺炎的病理机制及分子机制需要进一步明确.
2.2.5 FP与胰腺恶性肿瘤: 人体及动物实验研究结果均提示胰腺脂肪沉积与胰腺恶性肿瘤/上皮内瘤变风险增加的正相关关系[16,39], BMI增加与胰腺癌正相关[40,41], BMI≥35 kg/m2的个体胰腺癌的患病风险增加45%, 而且女性腹围与胰腺癌呈正相关[42]. 原有FP背景的胰腺癌患者具有很高的死亡率. 发病机制可能有: 肥胖状态下IR、氧化应激以及脂肪细胞因子、促炎因子, 以及FP状态下脂肪细胞整体的增加促成了胰腺肿瘤的发生与进展[16,43].
2.2.6 FP与胰腺外分泌功能障碍: 关于FP与胰腺外分泌功能障碍关系的研究非常少, 甘油三酯在胰腺内的长期重度浸润既可导致胰腺炎也可导致胰腺外分泌功能障碍. 现有资料主要集中在胰腺脂肪完全替代的极端病例, 有病例报告阐述了FP与胰腺外分泌功能不全的关系[44-46], 但具体病理机制仍不明确, 因此需要更多的基础研究及大规模的前瞻性研究以明确FP对胰腺外分泌功能的影响.
2.2.7 FP与术后胰瘘: 胰十二指肠切除术后胰瘘是FP的常见、潜在危及生命的并发症, 被认为与FP密切相关, 大量研究证实, VAT及男性、高BMI及FP的存在是其主要危险因素[47], 这些危险因素使准确识别胰腺轮廓并鉴别胰腺组织与周围脂肪组织变得困难[48,49]. 小叶内脂肪含量、小叶间脂肪含量以及胰腺总体脂肪、总体脂肪分数均显示了与胰瘘的明显相关性[50], 当胰腺脂肪浸润超过10%时, 胰十二指肠切除术后胰瘘风险即显著升高[51].
2.2.8 FP与胰腺移植: FP还是胰腺移植的一个重要原因, 相关危险因素有: 高脂饮食, 中心性肥胖, 高甘油三酯血症, 高铁蛋白血症, FP合并IR.
2.2.9 FP与先天性疾病: 一些先天性遗传综合征被认为与FP的发生有关, 而且与胰腺实质破坏后的胰腺外分泌功能不全相关, 主要有: 囊性纤维化(Cystic fibrosis, CF)[52]: 胰腺分泌物黏稠, 继发并导致胰腺脂肪浸润; 羧基酯脂肪酶突变[53]: 由于蛋白错折叠及功能障碍而导致的成人期糖尿病合并FP; Johanson Blizzard综合征(JBS)[54]: 一种与慢性炎症状态、凋亡调控不良、发育异常、胰腺坏死性纤维化相关的遗传性畸变, 继发胰腺脂肪替代; 许-曼氏综合征(Shwachman-Diamond syndrome/ Shwachman-Bodian-Diamond syndrome)[55]: 特征为胰腺脂肪浸润及胰腺外分泌功能不全, 还与发育停滞、肌肉骨骼问题、骨髓功能不全及胰腺脂肪瘤病有关.
FP的发生, 最重要的分子机制为由氧化应激, 内质网应激, 线粒体功能障碍以及脂肪来源的、被局部和系统性释放的细胞因子导致的腺泡细胞及胰岛细胞的脂毒性、低度慢性炎症和器官功能障碍.
如同肝脏一样, 胰腺在代谢中也是一个很重要的器官. 人体和动物研究显示, NAFPD与NAFLD常常共存, 而且二者均与肥胖强烈相关[12,56], 因此NAFPD与NAFLD可能存在共同的发病危险因素, 甚至有研究者认为肝脏脂肪变是FP的最强预测因子. 基于以上研究观点, 在NAFPD与NAFLD之间可能存在一些共同的发病机制.
肥胖导致胰腺的脂肪浸润, 随着肥胖的进展, 储存多余能量的脂肪细胞发生肥大和增生, 当循环中甘油三酯及游离脂肪酸(free fatty acids, FFAs)的水平超过脂肪组织的代谢能力时, 即可能作为异位脂肪而沉积在非脂肪组织, 如骨骼肌、肝脏、心脏、胰腺等, 而胰腺则是对脂肪沉积更加易感的器官[57]. 持续、过度的脂质沉积导致了β细胞功能障碍及胰岛素分泌障碍. 导致胰腺脂肪堆积的可能机制为: (1)腺泡细胞死亡, 继之以脂肪组织替代; (2)与过度能量平衡相关的细胞内甘油三酯堆积[4,6].
VAT可能是肝脏及胰腺脂肪变发展中的一个重要致病因素, 而且已被证实为导致术后胰瘘的危险因素. VAT的内分泌比较活跃, 产生和释放大量细胞因子及促炎因子, 脂肪因子包括瘦素和脂联素, 细胞因子包括TNF-α、IL-6及单核细胞趋化蛋白-1, 巨噬细胞产生IL-1b及髓过氧化物酶[58], 由此, 一种组织的促炎状态建立起来, 进一步促进IR的形成、以及甘油三酯脂解, 从而释放更多的FFAs进入循环及远端器官组织的异位脂肪沉积, 形成一种恶性循环. FFAs以Toll样受体4(TLR-4)依赖的方式介导内脏脂肪细胞的炎症[58]. 也有学者提出, 与肝脏内甘油三酯沉积有所不同, FP在组织学上以脂肪细胞数量增多为特征[59,60]. 肥胖大鼠的胰腺中促炎细胞因子如TNF-α、IL-1β水平升高[61].
脂肪对胰腺腺泡细胞和胰岛的直接毒性效应介导了持续的脂肪浸润及胰腺内/外分泌功能障碍[62]. 动物实验及人体体外模型研究均表明, 胰腺脂肪增多症导致β细胞脂毒性及脂性凋亡, 反之在没有糖尿病情况下, β细胞功能也与胰腺内脂肪相关[63]. Wong等的研究反映出胰腺脂肪变与IR的关系[18]. 长期暴露于FFAs的β细胞将导致甘油三酯水平升高及胰岛素基因表达下降. FP与β细胞功能障碍和胰岛素分泌受损之间的关系, 目前尚存争议[18], 可能与方法学及所选择的研究人群不同有关. NAFPD是否通过β细胞功能障碍及IR促进T2DM及MetS的发生, NAFPD对葡萄糖稳态、脂质稳态的长期影响, 仍需进一步的研究证据支持.
病理组织学无疑是"金标准". 影像学检查为非侵入性方法, 为目前评估及诊断FP的最主要及常用手段, 包括腹部超声、CT、磁共振成像(magnetic resonance imaging, MRI)等技术. 由于胰腺位于腹膜后, 仅用标准的经腹超声方法对胰腺整体的评估存在难度.
4.1.1 组织学检查: 与肝细胞内甘油三酯沉积的肝脏脂肪变有所不同, 胰腺脂肪变以腺泡细胞及胰岛细胞均存在脂肪细胞浸润和细胞内脂肪沉积为特征[6]. 对于胰腺脂肪沉积、胰腺脂肪浸润, 可观察腺泡细胞或胰岛细胞中有无脂滴、胰腺实质中脂肪组织的含量以及胰腺实质细胞的累及程度, 胰腺活组织检查为有创性检查, 标本获得率低、存在一定风险, 且病理生理学机制尚不清楚, 目前国内外尚无统一的定性、量化诊断和分级标准. 正常人群的胰腺内含有少量脂肪. Wong等的研究中, 90%的健康受试者胰腺脂肪含量在1.8%-10.4%, 中位数为4.1%(四分位范围2.8%-5.5%). 由Oslen[3]于1978年提出基于每显微镜视野内脂肪细胞百分比的胰腺脂肪增多症评分(pancreatic lipomatosis score, PLS)系统: 1组: ≥51%; 2组: ≥26%; 3组: ≥15%; 4组: ≥8%, 后经Smits MM 和van Geenen等[4]修订, 增加了一组, 即≥75%. 尚需进一步临床验证.
4.1.2 影像学检查: (1)超声及超声内镜(endoscopic ultrasound, EUS), 腹部超声诊断FP的标准为: 胰腺体部的回声超过肾脏, 因为胰腺的代谢比肝脏更稳定[56]. 有研究通过超声下的脂肪声像图的平均亮度, 创建了定量评估胰腺含量的指数, 即胰腺-肝周脂肪指数(pancreato-perihepatic fat index, PPHFI), PPFHI = MPBB(平均胰体亮度)/平均肝周脂肪亮度, 经验证后发现, PPHFI与HOMA-IR在MetS患者中均显著升高并且与MetS呈明显正相关, 因此认为PPHFI是MetS的独立诊断因子[64,65]. 由于胰腺与肾脏不能在同一个声窗内直接比较, 需要通过肝-肾及肝胰之间的比较从而得到一个客观的胰-肾回声对比, 比较繁琐; 另外, 胰腺位于腹膜后间隙, 肥胖或前方的肠道气体过多时会遮挡胰腺, 因此普通腹部超声很大程度依赖于检查者的水平及仪器的性能. EUS可提供胰腺的整体详细影像, 而且可将胰腺与其临近器官的回声进行实时比较, 还可实施细针穿刺细胞学检查. 有报道基于胰腺及胰管边缘的回声将EUS用于对NAFPD的强度进行分类[66]. EUS虽然可近距离观察胰腺, 然而EUS为侵入性检查, 不能对胰腺整体脂肪含量进行定量. 因此, 腹部超声及EUS均不能准确量化评估胰腺脂肪变的程度; (2)CT, CT扫描是一种简便的无创性检查方法, 操作时间短, 与脾脏比较、FP表现为低密度, 可以通过与脾脏对比显示出胰腺的衰减减弱, 以亨氏单位评估胰腺脂肪变的程度, 而且应用某些软件还可计算内脏脂肪含量. 在重度脂肪浸润时, 可通过与邻近的后腹膜脂肪比较评估胰腺的信号衰减程度. 由于内脏脂肪面积较之BMI与胰腺脂肪浸润具有更强的相关性, 可以通过CT扫描对内脏脂肪进行测量[34]. 但CT检查因潜在辐射暴露及价格相对较高, 与超声检查比较未显示出明显优势, 且对FP的定量评估准确性有待提高而临床使用受到一定限制; (3)MRI及MRS, 磁共振为非侵入性技术, 可重复测量全胰腺脂肪含量. MRI核磁共振成像是基于脂肪和水之间的信号差异, 磁共振波谱成像(magnetic resonance spectroscopy, MRS)是基于质子共振频率的差异, 由于MRS测定胰腺脂肪含量的结果与生化学方法所测定的胰岛内甘油三酯浓度具有很好的相关性, 甚至被认为与组织学及生化学方法相当, 因此, 被推荐为胰腺脂肪增多的诊断标准及作为胰岛脂肪含量的替代标志物[67,68]. 基于回声不对称和最小二乘估计的迭代分解-MRI技术[18]是最新开发的方法, 可在一个大的视野内产生分离的脂肪和水图像, 适用于整个器官如胰腺脂肪含量的评估, 可重复测量, 结果准确, 并且已被动物模型的组织学证实, 可以对小器官如胰腺进行更快更好的测量[18,69]. 磁共振成像-评估质子密度脂肪分数是另外一种测定胰腺内脂肪含量的新型技术[70]. 其他基于MRI的技术如脂肪-水MRI等也可达到同样的目的. 但磁共振技术存在价格昂贵、扫描间期长、周围内脏脂肪对MR化学位移伪影的易感性等不足.
4.1.3 生物学标志物: 一项2017年的系统性综述及Meta分析发现, 循环甘油三酯及糖化血红蛋白水平可能为目前最好的反映胰腺脂肪的标志物, 甘油三酯和高密度脂蛋白-C与胰腺脂肪百分比中等度相关[31]. 近期研究发现, 血清铁蛋白(以往公认为与各种代谢性疾病相关的炎性因子)与FP独立相关[18], 而且血清铁蛋白水平与内脏及皮下脂肪面积、血脂紊乱直接相关[71]. 将来, 需要有专门设计的、针对胰腺脂肪诊断准确性的研究, 探索无创性标志物, 而且标志物应具有理想的敏感度、特异度、阳性预测值、阴性预测值、cut-off值, 并可用于评估严重程度和疗效以及预测预后.
FP的病理学诊断标准尚未建立, 而且血清学诊断标准仍然缺乏. 多种影像学检查及评估方法显示了对胰腺脂肪浸润的定量评估优势, 然而迄今上述方法尚未获得广泛、公认的临床验证. 当患者有众多的危险因素, 而又合并其他多种肥胖相关疾病时, NAFPD应被考虑是最可能的诊断[5]. 当合并显著纤维化时, 如何能够更加精确计算胰腺脂肪含量、确定正常与病理状态之间的cut-off值、评估胰腺脂肪变程度、诊断FP, 达到与病理组织学相近的准确性, 获得高灵敏度高特异度的技术及评估方法, 以及建立公认的诊断标准是本领域亟待解决的研究内容.
由于FP是新近被认识的一种病理生理状态, FP的临床意义尚未明确, 尚无公认的治疗指南. 然而, 根据FP与NAFLD相似的病因及发病机制, 可以推测其病理变化可能被逆转. 有限的临床研究发现, 减少饮食热量或减肥手术可改善β细胞的活性、胰岛素敏感性, 同时伴有胰腺脂肪含量降低[72,73]. 应用脂肪酶抑制剂(奥利司他)可有效降低急性胰腺炎的严重程度[74]. 有一项研究显示, 10例患者中, 有7例合并FP、并通过减肥手术后体重减轻的患者, IR获得改善, 而且术后胰腺脂肪体积和脂肪酸摄取明显减少[72]. 西他列汀、替米沙坦、曲格列酮在动物实验研究, 以及黄连素和肉桂酸在人体研究中均显示有效[75,76]. 在胰十二指肠切除术前应用生长抑素类似物及术中使用吻合技术可轻度降低胰瘘发生的风险[47]. 因此术前评估危险因素及胰腺脂肪浸润程度, 以及术中冰冻切片的病理学准确判断对预防胰瘘的发生及指导术后患者的护理、改善预后很重要.
总之, FP可能不仅是一种单纯的脂肪惰性堆积, 而且是糖、脂代谢紊乱或者MetS的一个早期标志物, 还可能是急性胰腺炎、胰腺手术并发症的预后因素及胰腺癌的预测因素. FP及NAFPD的定义, 流行病学及自然史, FP与NAFLD及MetS的关系, FP是否与NAFLD同属MetS的组分之一, 还是MetS发展至一定阶段而继发的结果, 是否胰腺内外分泌功能不全的潜在病因, 以及FP的详尽发病机制、FP的病理生理学、诊断标准、治疗原则, 均需进一步基础与临床研究及大规模、长期前瞻性研究.
学科分类: 胃肠病学和肝病学
手稿来源地: 福建省
同行评议报告分类
A级 (优秀): 0
B级 (非常好): B, B
C级 (良好): C
D级 (一般): 0
E级 (差): 0
编辑: 崔丽君 电编: 张砚梁
| 1. | Schaefer JH. The normal weight of the pancreas in the adult human being: a biometric study. Anat Rec (Hoboken). 1926;32:119-132. |
| 3. | Olsen TS. Lipomatosis of the pancreas in autopsy material and its relation to age and overweight. Acta Pathol Microbiol Scand A. 1978;86A:367-373. [PubMed] [DOI] |
| 4. | Smits MM, van Geenen EJ. The clinical significance of pancreatic steatosis. Nat Rev Gastroenterol Hepatol. 2011;8:169-177. [PubMed] [DOI] |
| 5. | Alempijevic T, Dragasevic S, Zec S, Popovic D, Milosavljevic T. Non-alcoholic fatty pancreas disease. Postgrad Med J. 2017;93:226-230. [PubMed] [DOI] |
| 6. | Catanzaro R, Cuffari B, Italia A, Marotta F. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease. World J Gastroenterol. 2016;22:7660-7675. [PubMed] [DOI] |
| 9. | Yu TY, Wang CY. Impact of non-alcoholic fatty pancreas disease on glucose metabolism. J Diabetes Investig. 2017;8:735-747. [PubMed] [DOI] |
| 10. | Dreiling DA, Elsbach P, Schaffner F, Schwartz IL. The effect of restriction of protein and total calories on pancreatic function in obese patients. Gastroenterology. 1962;42:686-690. [PubMed] |
| 11. | Singh RG, Yoon HD, Poppitt SD, Plank LD, Petrov MS. Ectopic fat accumulation in the pancreas and its biomarkers: A systematic review and meta-analysis. Diabetes Metab Res Rev. 2017;33. [PubMed] [DOI] |
| 12. | Wang CY, Ou HY, Chen MF, Chang TC, Chang CJ. Enigmatic ectopic fat: prevalence of nonalcoholic fatty pancreas disease and its associated factors in a Chinese population. J Am Heart Assoc. 2014;3:e000297. [PubMed] [DOI] |
| 13. | Lee JS, Kim SH, Jun DW, Han JH, Jang EC, Park JY, Son BK, Kim SH, Jo YJ, Park YS. Clinical implications of fatty pancreas: correlations between fatty pancreas and metabolic syndrome. World J Gastroenterol. 2009;15:1869-1875. [PubMed] |
| 14. | Pham YH, Bingham BA, Bell CS, Greenfield SA, John SD, Robinson LH, Eissa MA. Prevalence of Pancreatic Steatosis at a Pediatric Tertiary Care Center. South Med J. 2016;109:196-198. [PubMed] [DOI] |
| 15. | Wang D, Yu XP, Xiao WM, Jiao XP, Wu J, Teng DL, Wu KY, Zhang M, Zhu QT, Liu XN. Prevalence and clinical characteristics of fatty pancreas in Yangzhou, China: A cross-sectional study. Pancreatology. 2018;18:263-268. [PubMed] [DOI] |
| 16. | Rebours V, Gaujoux S, d'Assignies G, Sauvanet A, Ruszniewski P, Lévy P, Paradis V, Bedossa P, Couvelard A. Obesity and Fatty Pancreatic Infiltration Are Risk Factors for Pancreatic Precancerous Lesions (PanIN). Clin Cancer Res. 2015;21:3522-3528. [PubMed] [DOI] |
| 17. | Lê KA, Ventura EE, Fisher JQ, Davis JN, Weigensberg MJ, Punyanitya M, Hu HH, Nayak KS, Goran MI. Ethnic differences in pancreatic fat accumulation and its relationship with other fat depots and inflammatory markers. Diabetes Care. 2011;34:485-490. [PubMed] [DOI] |
| 18. | Uygun A, Kadayifci A, Demirci H, Saglam M, Sakin YS, Ozturk K, Polat Z, Karslioglu Y, Bolu E. The effect of fatty pancreas on serum glucose parameters in patients with nonalcoholic steatohepatitis. Eur J Intern Med. 2015;26:37-41. [PubMed] [DOI] |
| 19. | Watanabe S, Abe K, Anbo Y, Katoh H. Changes in the mouse exocrine pancreas after pancreatic duct ligation: a qualitative and quantitative histological study. Arch Histol Cytol. 1995;58:365-374. [PubMed] [DOI] |
| 20. | Kimura W. Histological study on pathogenesis of sites of isolated islets of Langerhans and their course to the terminal state. Am J Gastroenterol. 1989;84:517-522. [PubMed] |
| 21. | Makay O, Kazimi M, Aydin U, Nart D, Yilmaz F, Zeytunlu M, Goker E, Coker A. Fat replacement of the malignant pancreatic tissue after neoadjuvant therapy. Int J Clin Oncol. 2010;15:88-92. [PubMed] [DOI] |
| 22. | Yu T, Liu R, Li M, Li X, Qiang O, Huang W, Tang C. Effects of octreotide on fatty infiltration of the pancreas in high-fat diet induced obesity rats. Wei Sheng Yan Jiu. 2014;43:186-192. [PubMed] |
| 23. | DIAMOND I, VALLBONA C. Kwashiorkor in a North American white male. Pediatrics. 1960;25:248-257. [PubMed] |
| 24. | Lin WC, Chen JH, Lin CH, Shen WC. Rapidly progressive pancreatic lipomatosis in a young adult patient with transfusion-dependent myelodysplastic syndrome. J Formos Med Assoc. 2007;106:676-679. [PubMed] [DOI] |
| 25. | Kim SY, Kim H, Cho JY, Lim S, Cha K, Lee KH, Kim YH, Kim JH, Yoon YS, Han HS. Quantitative assessment of pancreatic fat by using unenhanced CT: pathologic correlation and clinical implications. Radiology. 2014;271:104-112. [PubMed] [DOI] |
| 26. | Glaser J, Stienecker K. Pancreas and aging: a study using ultrasonography. Gerontology. 2000;46:93-96. [PubMed] [DOI] |
| 27. | Chantarojanasiri T, Hirooka Y, Ratanachu-Ek T, Kawashima H, Ohno E, Goto H. Evolution of pancreas in aging: degenerative variation or early changes of disease? J Med Ultrason (2001). 2015;42:177-183. [PubMed] [DOI] |
| 28. | Kyle TK, Dhurandhar EJ, Allison DB. Regarding Obesity as a Disease: Evolving Policies and Their Implications. Endocrinol Metab Clin North Am. 2016;45:511-520. [PubMed] [DOI] |
| 29. | Lesmana CR, Pakasi LS, Inggriani S, Aidawati ML, Lesmana LA. Prevalence of Non-Alcoholic Fatty Pancreas Disease (NAFPD) and its risk factors among adult medical check-up patients in a private hospital: a large cross sectional study. BMC Gastroenterol. 2015;15:174. [PubMed] [DOI] |
| 30. | Singh RG, Yoon HD, Wu LM, Lu J, Plank LD, Petrov MS. Ectopic fat accumulation in the pancreas and its clinical relevance: A systematic review, meta-analysis, and meta-regression. Metabolism. 2017;69:1-13. [PubMed] [DOI] |
| 31. | Ozturk K, Dogan T, Celikkanat S, Ozen A, Demirci H, Kurt O, Turker T, Yilmaz Y, Uygun A. The association of fatty pancreas with subclinical atherosclerosis in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2018;30:411-417. [PubMed] [DOI] |
| 32. | Al-Haddad M, Khashab M, Zyromski N, Pungpapong S, Wallace MB, Scolapio J, Woodward T, Noh K, Raimondo M. Risk factors for hyperechogenic pancreas on endoscopic ultrasound: a case-control study. Pancreas. 2009;38:672-675. [PubMed] [DOI] |
| 33. | Ozbulbul NI, Yurdakul M, Tola M. Does the visceral fat tissue show better correlation with the fatty replacement of the pancreas than with BMI? Eurasian J Med. 2010;42:24-27. [PubMed] [DOI] |
| 34. | Acharya C, Navina S, Singh VP. Role of pancreatic fat in the outcomes of pancreatitis. Pancreatology. 2014;14:403-408. [PubMed] [DOI] |
| 35. | Acharya C, Cline RA, Jaligama D, Noel P, Delany JP, Bae K, Furlan A, Baty CJ, Karlsson JM, Rosario BL. Fibrosis reduces severity of acute-on-chronic pancreatitis in humans. Gastroenterology. 2013;145:466-475. [PubMed] [DOI] |
| 36. | Navina S, Acharya C, DeLany JP, Orlichenko LS, Baty CJ, Shiva SS, Durgampudi C, Karlsson JM, Lee K, Bae KT. Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity. Sci Transl Med. 2011;3:107ra110. [PubMed] [DOI] |
| 37. | Di Ciaula A, Portincasa P. Fat, epigenome and pancreatic diseases. Interplay and common pathways from a toxic and obesogenic environment. Eur J Intern Med. 2014;25:865-873. [PubMed] [DOI] |
| 38. | Hori M, Takahashi M, Hiraoka N, Yamaji T, Mutoh M, Ishigamori R, Furuta K, Okusaka T, Shimada K, Kosuge T. Association of pancreatic Fatty infiltration with pancreatic ductal adenocarcinoma. Clin Transl Gastroenterol. 2014;5:e53. [PubMed] [DOI] |
| 39. | Arslan AA, Helzlsouer KJ, Kooperberg C, Shu XO, Steplowski E, Bueno-de-Mesquita HB, Fuchs CS, Gross MD, Jacobs EJ, Lacroix AZ, Petersen GM, Stolzenberg-Solomon RZ, Zheng W, Albanes D, Amundadottir L, Bamlet WR, Barricarte A, Bingham SA, Boeing H, Boutron-Ruault MC, Buring JE, Chanock SJ, Clipp S, Gaziano JM, Giovannucci EL, Hankinson SE, Hartge P, Hoover RN, Hunter DJ, Hutchinson A, Jacobs KB, Kraft P, Lynch SM, Manjer J, Manson JE, McTiernan A, McWilliams RR, Mendelsohn JB, Michaud DS, Palli D, Rohan TE, Slimani N, Thomas G, Tjønneland A, Tobias GS, Trichopoulos D, Virtamo J, Wolpin BM, Yu K, Zeleniuch-Jacquotte A, Patel AV; Pancreatic Cancer Cohort Consortium (PanScan). Anthropometric measures, body mass index, and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Arch Intern Med. 2010;170:791-802. [PubMed] [DOI] |
| 40. | Li D, Morris JS, Liu J, Hassan MM, Day RS, Bondy ML, Abbruzzese JL. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA. 2009;301:2553-2562. [PubMed] [DOI] |
| 41. | Stolzenberg-Solomon RZ, Adams K, Leitzmann M, Schairer C, Michaud DS, Hollenbeck A, Schatzkin A, Silverman DT. Adiposity, physical activity, and pancreatic cancer in the National Institutes of Health-AARP Diet and Health Cohort. Am J Epidemiol. 2008;167:586-597. [PubMed] [DOI] |
| 42. | Matsuda M, Shimomura I. Increased oxidative stress in obesity: implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Obes Res Clin Pract. 2013;7:e330-e341. [PubMed] |
| 43. | Khan NA, Amin MS, Islam MZ. Pancreatic lipomatosis with massive steatorrhea. Mymensingh Med J. 2011;20:712-714. [PubMed] |
| 44. | Aubert A, Gornet JM, Hammel P, Lévy P, O'Toole D, Ruszniewski P, Modigliani R, Lémann M. [Diffuse primary fat replacement of the pancreas: an unusual cause of steatorrhea]. Gastroenterol Clin Biol. 2007;31:303-306. [PubMed] |
| 45. | Ambesh P, Lal H. Pancreatic Lipomatosis: Complete Replacement of Pancreas by Fat. J Clin Diagn Res. 2015;9:OL01. [PubMed] [DOI] |
| 46. | Søreide K, Labori KJ. Risk factors and preventive strategies for post-operative pancreatic fistula after pancreatic surgery: a comprehensive review. Scand J Gastroenterol. 2016;51:1147-1154. [PubMed] [DOI] |
| 47. | Sato Y, Inokuchi M, Otsuki S, Fujimori Y, Kojima K. Risk Factor of Pancreatic Fistula after Radical Gastrectomy from the Viewpoint of Fatty Pancreas. Dig Surg. 2017;34:455-461. [PubMed] [DOI] |
| 48. | Jiang X, Hiki N, Nunobe S, Kumagai K, Nohara K, Sano T, Yamaguchi T. Postoperative pancreatic fistula and the risk factors of laparoscopy-assisted distal gastrectomy for early gastric cancer. Ann Surg Oncol. 2012;19:115-121. [PubMed] [DOI] |
| 49. | Mathur A, Pitt HA, Marine M, Saxena R, Schmidt CM, Howard TJ, Nakeeb A, Zyromski NJ, Lillemoe KD. Fatty pancreas: a factor in postoperative pancreatic fistula. Ann Surg. 2007;246:1058-1064. [PubMed] [DOI] |
| 50. | Rosso E, Casnedi S, Pessaux P, Oussoultzoglou E, Panaro F, Mahfud M, Jaeck D, Bachellier P. The role of "fatty pancreas" and of BMI in the occurrence of pancreatic fistula after pancreaticoduodenectomy. J Gastrointest Surg. 2009;13:1845-1851. [PubMed] [DOI] |
| 51. | Sodhi KS, Thapa BR, Khandelwal S, Suri S. Pancreatic lipomatosis in an infant with cystic fibrosis. Pediatr Radiol. 2005;35:1157-1158. [PubMed] [DOI] |
| 52. | Johansson BB, Torsvik J, Bjørkhaug L, Vesterhus M, Ragvin A, Tjora E, Fjeld K, Hoem D, Johansson S, Ræder H. Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl ester lipase gene-maturity onset diabetes of the young (CEL-MODY): a protein misfolding disease. J Biol Chem. 2011;286:34593-34605. [PubMed] [DOI] |
| 53. | Alkhouri N, Kaplan B, Kay M, Shealy A, Crowe C, Bauhuber S, Zenker M. Johanson-Blizzard syndrome with mild phenotypic features confirmed by UBR1 gene testing. World J Gastroenterol. 2008;14:6863-6866. [PubMed] |
| 54. | Myers KC, Bolyard AA, Otto B, Wong TE, Jones AT, Harris RE, Davies SM, Dale DC, Shimamura A. Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry. J Pediatr. 2014;164:866-870. [PubMed] [DOI] |
| 55. | Della Corte C, Mosca A, Majo F, Lucidi V, Panera N, Giglioni E, Monti L, Stronati L, Alisi A, Nobili V. Nonalcoholic fatty pancreas disease and Nonalcoholic fatty liver disease: more than ectopic fat. Clin Endocrinol (Oxf). 2015;83:656-662. [PubMed] [DOI] |
| 56. | Rossi AP, Fantin F, Zamboni GA, Mazzali G, Rinaldi CA, Del Giglio M, Di Francesco V, Barillari M, Pozzi Mucelli R, Zamboni M. Predictors of ectopic fat accumulation in liver and pancreas in obese men and women. Obesity (Silver Spring). 2011;19:1747-1754. [PubMed] [DOI] |
| 57. | Siegel-Axel DI, Ullrich S, Stefan N, Rittig K, Gerst F, Klingler C, Schmidt U, Schreiner B, Randrianarisoa E, Schaller HE. Fetuin-A influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells. Diabetologia. 2014;57:1057-1066. [PubMed] [DOI] |
| 58. | Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 10th ed Philadelphia: Elsevier. 2016;2016:1428-1441. |
| 59. | Pinnick KE, Collins SC, Londos C, Gauguier D, Clark A, Fielding BA. Pancreatic ectopic fat is characterized by adipocyte infiltration and altered lipid composition. Obesity (Silver Spring). 2008;16:522-530. [PubMed] [DOI] |
| 60. | Khoury T, Asombang AW, Berzin TM, Cohen J, Pleskow DK, Mizrahi M. The Clinical Implications of Fatty Pancreas: A Concise Review. Dig Dis Sci. 2017;62:2658-2667. [PubMed] [DOI] |
| 61. | Ou HY, Wang CY, Yang YC, Chen MF, Chang CJ. The association between nonalcoholic fatty pancreas disease and diabetes. PLoS One. 2013;8:e62561. [PubMed] [DOI] |
| 62. | Zhao ZZ, Xin LL, Xia JH, Yang SL, Chen YX, Li K. Long-term High-fat High-sucrose Diet Promotes Enlarged Islets and β-Cell Damage by Oxidative Stress in Bama Minipigs. Pancreas. 2015;44:888-895. [PubMed] [DOI] |
| 63. | Kim DR, Lee MS, Lee JS, Choi GM, Kang KS. Ultrasono-graphic Quantitative Analysis of Fatty Pancreas in Obese Children: Its Correlation with Metabolic Syndrome and Homeostasis Model Assessment of Insulin Resistance. J Pediatr. 2018;193:134-138.e1. [PubMed] [DOI] |
| 64. | Jeong HT, Lee MS, Kim MJ. Quantitative analysis of pancreatic echogenicity on transabdominal sonography: correlations with metabolic syndrome. J Clin Ultrasound. 2015;43:98-108. [PubMed] [DOI] |
| 65. | Sepe PS, Ohri A, Sanaka S, Berzin TM, Sekhon S, Bennett G, Mehta G, Chuttani R, Kane R, Pleskow D. A prospective evaluation of fatty pancreas by using EUS. Gastrointest Endosc. 2011;73:987-993. [PubMed] [DOI] |
| 66. | Begovatz P, Koliaki C, Weber K, Strassburger K, Nowotny B, Nowotny P, Müssig K, Bunke J, Pacini G, Szendrödi J. Pancreatic adipose tissue infiltration, parenchymal steatosis and beta cell function in humans. Diabetologia. 2015;58:1646-1655. [PubMed] [DOI] |
| 67. | Gaborit B, Abdesselam I, Kober F, Jacquier A, Ronsin O, Emungania O, Lesavre N, Alessi MC, Martin JC, Bernard M. Ectopic fat storage in the pancreas using 1H-MRS: importance of diabetic status and modulation with bariatric surgery-induced weight loss. Int J Obes (Lond). 2015;39:480-487. [PubMed] [DOI] |
| 68. | Hu HH, Smith DL Jr, Nayak KS, Goran MI, Nagy TR. Identification of brown adipose tissue in mice with fat-water IDEAL-MRI. J Magn Reson Imaging. 2010;31:1195-1202. [PubMed] [DOI] |
| 69. | Idilman IS, Aniktar H, Idilman R, Kabacam G, Savas B, Elhan A, Celik A, Bahar K, Karcaaltincaba M. Hepatic steatosis: quantification by proton density fat fraction with MR imaging versus liver biopsy. Radiology. 2013;267:767-775. [PubMed] [DOI] |
| 70. | Guglielmi V, D'Adamo M, Bellia A, Ciotto RT, Federici M, Lauro D, Sbraccia P. Iron status in obesity: An independent association with metabolic parameters and effect of weight loss. Nutr Metab Cardiovasc Dis. 2015;25:541-547. [PubMed] [DOI] |
| 71. | Honka H, Koffert J, Hannukainen JC, Tuulari JJ, Karlsson HK, Immonen H, Oikonen V, Tolvanen T, Soinio M, Salminen P. The effects of bariatric surgery on pancreatic lipid metabolism and blood flow. J Clin Endocrinol Metab. 2015;100:2015-2023. [PubMed] [DOI] |
| 72. | Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011;54:2506-2514. [PubMed] [DOI] |
| 73. | Patel K, Trivedi RN, Durgampudi C, Noel P, Cline RA, DeLany JP, Navina S, Singh VP. Lipolysis of visceral adipocyte triglyceride by pancreatic lipases converts mild acute pancreatitis to severe pancreatitis independent of necrosis and inflammation. Am J Pathol. 2015;185:808-819. [PubMed] [DOI] |
| 74. | Souza-Mello V, Gregório BM, Relvas-Lucas B, da Silva Faria T, Aguila MB, Mandarim-de-Lacerda CA. Pancreatic ultrastructural enhancement due to telmisartan plus sitagliptin treatment in diet-induced obese C57BL/6 mice. Pancreas. 2011;40:715-722. [PubMed] [DOI] |
| 75. | Zhao L, Jiang SJ, Lu FE, Xu LJ, Zou X, Wang KF, Dong H. Effects of berberine and cinnamic acid on palmitic acid-induced intracellular triglyceride accumulation in NIT-1 pancreatic β cells. Chin J Integr Med. 2016;22:496-502. [PubMed] [DOI] |