急性胰腺炎合并肝損傷的研究進展

楊 琦，李樹鈞，吳開春

第四軍醫大學附屬西京醫院消化病醫院，陜西 西安 710032

急性胰腺炎合并肝損傷的研究進展

楊 琦，李樹鈞，吳開春

第四軍醫大學附屬西京醫院消化病醫院，陜西 西安 710032

急性胰腺炎(acute pancreatitis，AP)起病急，死亡率高，是常見的內科急腹癥。合并多器官臟器功能衰竭是其死亡率高的原因之一。肺、腎、心臟是最常損傷的器官，由于合并嚴重的臨床癥狀而有較多的研究。合并肝損傷常未出現明顯的臨床癥狀，但近年研究發現其在AP全身多系統炎癥反應中有著不可忽視的作用，對加速AP病情進展，加重其他器官損傷衰竭也有重要影響。

急性胰腺炎；肝損傷；多器官功能衰竭

急性胰腺炎(acute pancreatitis，AP)是一種胰腺急性炎癥反應，是系統性地合并其他多器官或組織損傷，起病急，死亡率高。根據合并其他功能臟器損傷衰竭或系統綜合征出現的程度將其分為輕度、中度和重度[1]。20%的患者可發展至重癥急性胰腺炎(severe acute pancreatitis，SAP)，死亡率15%～20%[2]。2013亞特蘭大分級(2013 Atlanta Classification)中，呼吸衰竭、腎臟衰竭、循環衰竭、腸道衰竭分別是最常出現的衰竭，在SOFA器官損傷分級(SOFA organ damage grading)中，還將肝臟、凝血系統和中樞神經系統加入其中[3]。肝損傷由于在胰腺炎炎癥反應中的重要作用，越來越多的研究發現AP合并肝損傷不僅對AP的病情有影響，對其他遠隔器官如肺和腎的損傷衰竭起到促進作用[4]。膽源性、酒精性、高脂血癥性分別是AP最常見的類型[5]。膽源性胰腺炎中，膽道系統與胰腺共同開口于十二指腸，膽石堵塞成為AP發病的主要因素，而由于肝臟和胰腺的特殊解剖關系，肝損傷可能是由于膽汁或胰液反流引起的[6]。高脂血癥性胰腺炎中，過量脂質引起的脂毒性通過改變細胞因子基因表達等加重炎癥反應，引起其他多器官功能損害，對于肝臟的損害也是明確的[7]。酒精性胰腺炎中，酒精代謝分別通過產生氧化與非氧化代謝物對肝臟和胰腺損傷，在AP發病后，產生炎癥因子進一步損害肝臟[8]。而在其他類型的AP中，可能是由于炎癥因子經門靜脈入肝，瀑布式的鏈式炎癥反應在肝臟內通過Kupffer細胞等作用進一步發展，導致肝臟組織和其余遠隔器官的損傷[9]。有研究證實AP時的肝損傷和AP的嚴重程度呈正相關，在AP病情發展過程中肝損傷一直存在[4]。在AP發病后可引起原有肝臟疾病，如脂肪肝、肝損傷或肝臟功能不全等惡化，進一步加重AP的發生發展，這部分肝臟功能受到影響是否可逆目前尚不清楚。

1 分子機制

AP發生的分子學機制主要與Ca+的超載、高濃度的游離脂肪酸、炎癥反應、內質網的應激、自身酶原的活化、細胞凋亡、內毒素血癥等相關[10]。合并肝損傷的分子學機制主要與肝內巨嗜細胞的應激、壞死組織炎癥反應及其他保護機制相關。

1.1 肝內Kupffer細胞 Kupffer細胞在肝損傷炎癥反應中起重要作用。胰腺釋放的炎癥因子進入肝臟后，在肝臟內活化Kupffer細胞，使Kupffer 細胞釋放一系列免疫調節和炎癥因子，包括IL-1、IL-6、TGF-β、interferon-γ、TNF-α等，使炎癥因子迅速增多，繼而引起鏈式炎癥反應，巨嗜細胞的活化還可促進TNF-α和IL-1β的mRNA增多、增加血清中ALT等造成肝損傷，還可通過血液循環造成肺內皮細胞損傷水腫滲出[11]。彈性蛋白酶主要通過激活Kupffer細胞，產生系列炎癥因子，還可誘導其他遠隔器官巨嗜細胞內TNF引起臟器損傷，調控TNF、IL-1、PAF、NO等中性粒細胞相關炎癥因子調節終末期器官損傷[12]。磷酸化的肝酶P38-MAPK也是一種可以活化巨嗜細胞的炎性分子，作用于NF-κB轉錄因子的磷酸化，NF-κB的活化可促進IL-1、IL-6、TGF-β、Interferon-γ、TNF-α等多種炎癥分子的產生[13]。

1.2 炎癥反應 炎癥反應對肝臟的損傷由TNF-α、IL-1β、NO等主要的炎癥因子介導，TNF-α、IL-1β、NO均被認為起源于巨嗜細胞。TNF家族的激活釋放可引起組織壞死，組織壞死進一步促進炎癥反應的進行，組織壞死和炎癥反應循環式的反應引起肝臟的進一步損傷[14-15]。Toll樣受體家族在炎癥反應中作用同樣重要，Toll-4樣受體在自身免疫和巨嗜細胞活化有關鍵作用，與肝損傷時Kupffer細胞關系密切。Toll-4受體可上調炎癥細胞因子的轉錄，激活胞外的XBP-1蛋白，使胞內DNA從受損的細胞中釋放。Toll-4還可通過與PKC-ζ的偶聯來調控NF-κB，引起肝損傷和肝細胞的凋亡[16]。

1.3 基因調控 Fasl基因主要是調控細胞凋亡，肝臟中的Fasl基因調控其下游P38-MAPK和Caspase-3激活肝內Kupffer細胞產生鏈式炎癥反應。除Fasl基因外，細胞因子基因的改變也可引起肝損傷[17]。有研究[7]發現，肥胖可改變細胞因子基因的表達引起肝損傷，主要通過介導TNF-α、IL-6、IL-10等炎癥相關分子信使RNA的表達來促進肝損傷的發生。

1.4 氧化應激 AP造成肝細胞線粒體的損傷，其相關細胞色素c等釋放入血，線粒體的電子轉移途徑被破壞，細胞色素氧化酶等濃度減少[18]。受損的線粒體調節線粒體一氧化氮合成酶，產生NO等炎癥因子與線粒體基因相互作用，啟動氧化還原調控機制與炎癥因子進一步作用加重炎癥反應[19]。氧化呼吸鏈還可通過控制線粒體反應性氧代謝產物的形成，進一步加速細胞的凋亡、壞死[20]。

1.5 保護因素

1.5.1 抗氧化劑保護作用：NAC(N-乙酰半胱氨酸)作為一種常用的抗氧化劑，減少谷胱甘肽前體細胞清除氧自由基和細胞因子酶的合成。作用于胰腺減少腺細胞內NF-κB的活性，Ca+的聚集和各種損傷性細胞因子的活性。作用于肝損傷，減少TNF-α活性和NF-κB的表達，減輕肝損傷[21]。抗壞血酸和褪黑素等其他抗氧化劑也具有類似的保護功能[22]。

1.5.2 其他保護作用：血管內皮生長因子(vascular endothelial growth factor,VEGF)是一種促進血管上皮生長、增加血管上皮細胞活性和促進血管滲透性的糖蛋白，由于其可促進受損血管生長，抑制間充質細胞凋亡壞死，被認為對AP的壞死組織和遠隔器官包括肝臟組織有保護作用[23]。生長抑素也可通過抑制NF-κB保護受損的胰腺和肝臟[24]。新的研究顯示，高張力鹽通過減少肝臟內基質金屬蛋白酶(matrix metallopriteinase,MMP)表達保護肝損傷，減輕AP時的炎癥反應和死亡率[25]，丙酮酸乙酯(ethyl pyruvate,EP)通過減少炎癥因子TNF-α、IL-1β、IL-6的作用保護肝臟[26]。

2 診斷

AP合并肝損傷的診斷除了常用的影像學方法外，CT灌注成像(CT perfusion imaging，PCT)是一種診斷胰腺炎合并肝臟衰竭靈敏性與特異性均較高的方法[27]。AP時組織壞死滲出產生腹水，改變肝細胞生長微環境及產生各種細胞毒性因子促使肝細胞壞死凋亡，腹水中的正鐵血紅素被認為是損害性細胞毒性因子，含量變化可用于肝損傷程度的診斷[28]。除對腹水檢測外，由于多元胺的水平會隨肝損傷的加重而增多，對血、尿、組織中多元胺的監測可作為一種新的診斷方法[29]。

3 治療

3.1 一般治療 早期腸內營養對AP的治療很關鍵，對減輕肝損傷也有一定的作用，可加速肝臟細胞能量代謝緩解細胞損傷[30]。有研究指出通過硬膜外鎮痛抑制神經遞質的分泌可緩解AP導致的應激引起的肝損傷[31]。器官移植是一個熱門的研究，胰腺壞死嚴重的患者可以選擇，移植后對多臟器損傷包括肝損傷有一定療效[32]。

3.2 藥物治療 在藥物方面，改變腸道內毒素引起的內毒素紊亂也可減輕肝損傷，合并大黃素的EAEEN比起單純EEN療效較好，有研究證實AP時應用大黃附子湯肝損傷明顯好轉[33]。同從中藥中提取的雷公藤內酯，由于其對炎癥因子的調節作用，對肝損傷有一定保護作用[34]。激素地塞米松通過抑制腫瘤壞死因子通路同時抑制炎癥因子通路對肝損傷療效作用明確，生長抑素及類似的多酶抑制劑等藥物抑制胰酶的同時保護肝臟，還可減輕AP合并肺損傷[35]。以往認為對肝臟有保護作用的藥物如谷氨酰胺和恩替卡維對AP有一定療效，但對AP合并肝損傷的作用目前還不清楚[36-37]。

AP合并肝損傷是AP發展過程中一個重要的部分，通過解剖位置、血流灌注、炎癥因子等各個方面進行相互影響，AP及肝損傷的病情發展與其他器官衰竭之間的關系復雜，作用的分子機制等還值得進一步研究。

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(責任編輯：馬 軍)

Research progress of the acute pancreatitis and liver damage

YANG Qi,LI Shujun,WU Kaichun

The Fourth Military Medical University Affiliated Hospital of Xijing Digestive Diseases Hospital,Xi’an 710032,China

Acute pancreatitis (AP) is a common urgent disease,an acute abdominal pain with high mortality. Multiple organ failure is one of the reasons for its high mortality rate. Due to the merger of severe clinical symptoms,there are more researches on it. Lung,kidney and heart are the most common incidence injury organs. Liver damage is often without obvious clinical symptoms,but recent studies find that the body in AP with the system plays a noticeable important role in inflammatory reaction. It also plays an important role in the progression of AP and other organ damage.

Acute pancreatitis; Liver damage; Multiple organ dysfunction syndrome

陜西省社發攻關基金(2014SF2-11)

楊琦，碩士，研究方向：胰腺炎。E-mail：358090799@qq.com

李樹鈞，博士，副教授，研究方向：胰腺炎。E-mail：lishujun@fmmu.edu.cn

10.3969/j.issn.1006-5709.2016.04.032

R576

A

1006-5709(2016)04-0476-03

2015-05-27