楊 琦，李樹鈞，吳開春

第四軍醫(yī)大學(xué)附屬西京醫(yī)院消化病醫(yī)院，陜西 西安 710032

急性胰腺炎合并肝損傷的研究進(jìn)展

楊 琦，李樹鈞，吳開春

第四軍醫(yī)大學(xué)附屬西京醫(yī)院消化病醫(yī)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(nèi)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(yán)重的臨床癥狀而有較多的研究。合并肝損傷常未出現(xiàn)明顯的臨床癥狀，但近年研究發(fā)現(xiàn)其在AP全身多系統(tǒng)炎癥反應(yīng)中有著不可忽視的作用，對加速AP病情進(jìn)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(yīng)，是系統(tǒng)性地合并其他多器官或組織損傷，起病急，死亡率高。根據(jù)合并其他功能臟器損傷衰竭或系統(tǒng)綜合征出現(xiàn)的程度將其分為輕度、中度和重度[1]。20%的患者可發(fā)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(huán)衰竭、腸道衰竭分別是最常出現(xiàn)的衰竭，在SOFA器官損傷分級(SOFA organ damage grading)中，還將肝臟、凝血系統(tǒng)和中樞神經(jīng)系統(tǒng)加入其中[3]。肝損傷由于在胰腺炎炎癥反應(yīng)中的重要作用，越來越多的研究發(fā)現(xiàn)AP合并肝損傷不僅對AP的病情有影響，對其他遠(yuǎn)隔器官如肺和腎的損傷衰竭起到促進(jìn)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(tǒng)與胰腺共同開口于十二指腸，膽石堵塞成為AP發(fā)病的主要因素，而由于肝臟和胰腺的特殊解剖關(guān)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(zhì)引起的脂毒性通過改變細(xì)胞因子基因表達(dá)等加重炎癥反應(yīng)，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(chǎn)生氧化與非氧化代謝物對肝臟和胰腺損傷，在AP發(fā)病后，產(chǎn)生炎癥因子進(jìn)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(jīng)門靜脈入肝，瀑布式的鏈?zhǔn)窖装Y反應(yīng)在肝臟內(nèi)通過Kupffer細(xì)胞等作用進(jìn)一步發(fā)展，導(dǎo)致肝臟組織和其余遠(yuǎn)隔器官的損傷[9]。有研究證實AP時的肝損傷和AP的嚴(yán)重程度呈正相關(guān)，在AP病情發(fā)展過程中肝損傷一直存在[4]。在AP發(fā)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(jìn)一步加重AP的發(fā)生發(fā)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(jī)制

AP發(fā)生的分子學(xué)機(jī)制主要與Ca+的超載、高濃度的游離脂肪酸、炎癥反應(yīng)、內(nèi)質(zhì)網(wǎng)的應(yīng)激、自身酶原的活化、細(xì)胞凋亡、內(nèi)毒素血癥等相關(guān)[10]。合并肝損傷的分子學(xué)機(jī)制主要與肝內(nèi)巨嗜細(xì)胞的應(yīng)激、壞死組織炎癥反應(yīng)及其他保護(hù)機(jī)制相關(guān)。

1.1 肝內(nèi)Kupffer細(xì)胞 Kupffer細(xì)胞在肝損傷炎癥反應(yīng)中起重要作用。胰腺釋放的炎癥因子進(jìn)入肝臟后，在肝臟內(nèi)活化Kupffer細(xì)胞，使Kupffer 細(xì)胞釋放一系列免疫調(diào)節(jié)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?zhǔn)窖装Y反應(yīng)，巨嗜細(xì)胞的活化還可促進(jìn)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(huán)造成肺內(nèi)皮細(xì)胞損傷水腫滲出[11]。彈性蛋白酶主要通過激活Kupffer細(xì)胞，產(chǎn)生系列炎癥因子，還可誘導(dǎo)其他遠(yuǎn)隔器官巨嗜細(xì)胞內(nèi)TNF引起臟器損傷，調(diào)控TNF、IL-1、PAF、NO等中性粒細(xì)胞相關(guān)炎癥因子調(diào)節(jié)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(xì)胞的炎性分子，作用于NF-κB轉(zhuǎn)錄因子的磷酸化，NF-κB的活化可促進(jìn)IL-1、IL-6、TGF-β、Interferon-γ、TNF-α等多種炎癥分子的產(chǎn)生[13]。

1.2 炎癥反應(yīng) 炎癥反應(yīng)對肝臟的損傷由TNF-α、IL-1β、NO等主要的炎癥因子介導(dǎo)，TNF-α、IL-1β、NO均被認(rèn)為起源于巨嗜細(xì)胞。TNF家族的激活釋放可引起組織壞死，組織壞死進(jìn)一步促進(jìn)炎癥反應(yīng)的進(jìn)行，組織壞死和炎癥反應(yīng)循環(huán)式的反應(yīng)引起肝臟的進(jìn)一步損傷[14-15]。Toll樣受體家族在炎癥反應(yīng)中作用同樣重要，Toll-4樣受體在自身免疫和巨嗜細(xì)胞活化有關(guān)鍵作用，與肝損傷時Kupffer細(xì)胞關(guān)系密切。Toll-4受體可上調(diào)炎癥細(xì)胞因子的轉(zhuǎn)錄，激活胞外的XBP-1蛋白，使胞內(nèi)DNA從受損的細(xì)胞中釋放。Toll-4還可通過與PKC-ζ的偶聯(lián)來調(diào)控NF-κB，引起肝損傷和肝細(xì)胞的凋亡[16]。

1.3 基因調(diào)控 Fasl基因主要是調(diào)控細(xì)胞凋亡，肝臟中的Fasl基因調(diào)控其下游P38-MAPK和Caspase-3激活肝內(nèi)Kupffer細(xì)胞產(chǎn)生鏈?zhǔn)窖装Y反應(yīng)。除Fasl基因外，細(xì)胞因子基因的改變也可引起肝損傷[17]。有研究[7]發(fā)現(xiàn)，肥胖可改變細(xì)胞因子基因的表達(dá)引起肝損傷，主要通過介導(dǎo)TNF-α、IL-6、IL-10等炎癥相關(guān)分子信使RNA的表達(dá)來促進(jìn)肝損傷的發(fā)生。

1.4 氧化應(yīng)激 AP造成肝細(xì)胞線粒體的損傷，其相關(guān)細(xì)胞色素c等釋放入血，線粒體的電子轉(zhuǎn)移途徑被破壞，細(xì)胞色素氧化酶等濃度減少[18]。受損的線粒體調(diào)節(jié)線粒體一氧化氮合成酶，產(chǎn)生NO等炎癥因子與線粒體基因相互作用，啟動氧化還原調(diào)控機(jī)制與炎癥因子進(jìn)一步作用加重炎癥反應(yīng)[19]。氧化呼吸鏈還可通過控制線粒體反應(yīng)性氧代謝產(chǎn)物的形成，進(jìn)一步加速細(xì)胞的凋亡、壞死[20]。

1.5 保護(hù)因素

1.5.1 抗氧化劑保護(hù)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(xì)胞清除氧自由基和細(xì)胞因子酶的合成。作用于胰腺減少腺細(xì)胞內(nèi)NF-κB的活性，Ca+的聚集和各種損傷性細(xì)胞因子的活性。作用于肝損傷，減少TNF-α活性和NF-κB的表達(dá)，減輕肝損傷[21]?？箟难岷屯屎谒氐绕渌寡趸瘎┮簿哂蓄愃频谋Ｗo(hù)功能[22]。

1.5.2 其他保護(hù)作用：血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)是一種促進(jìn)血管上皮生長、增加血管上皮細(xì)胞活性和促進(jìn)血管滲透性的糖蛋白，由于其可促進(jìn)受損血管生長，抑制間充質(zhì)細(xì)胞凋亡壞死，被認(rèn)為對AP的壞死組織和遠(yuǎn)隔器官包括肝臟組織有保護(hù)作用[23]。生長抑素也可通過抑制NF-κB保護(hù)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(nèi)基質(zhì)金屬蛋白酶(matrix metallopriteinase,MMP)表達(dá)保護(hù)肝損傷，減輕AP時的炎癥反應(yīng)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(hù)肝臟[26]。

2 診斷

AP合并肝損傷的診斷除了常用的影像學(xué)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(chǎn)生腹水，改變肝細(xì)胞生長微環(huán)境及產(chǎn)生各種細(xì)胞毒性因子促使肝細(xì)胞壞死凋亡，腹水中的正鐵血紅素被認(rèn)為是損害性細(xì)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(jiān)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(nèi)營養(yǎng)對AP的治療很關(guān)鍵，對減輕肝損傷也有一定的作用，可加速肝臟細(xì)胞能量代謝緩解細(xì)胞損傷[30]。有研究指出通過硬膜外鎮(zhèn)痛抑制神經(jīng)遞質(zhì)的分泌可緩解AP導(dǎo)致的應(yīng)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(yán)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(nèi)毒素引起的內(nèi)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(yīng)用大黃附子湯肝損傷明顯好轉(zhuǎn)[33]。同從中藥中提取的雷公藤內(nèi)酯，由于其對炎癥因子的調(diào)節(jié)作用，對肝損傷有一定保護(hù)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(hù)肝臟，還可減輕AP合并肺損傷[35]。以往認(rèn)為對肝臟有保護(hù)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(fā)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(jìn)行相互影響，AP及肝損傷的病情發(fā)展與其他器官衰竭之間的關(guān)系復(fù)雜，作用的分子機(jī)制等還值得進(jìn)一步研究。

[1]Otsuki M,Takeda K,Matsuno S,et al. Criteria for the diagnosis and severity stratification of acute pancreatitis [J]. World J Gastroenterol,2013,19(35): 5798-5805.

[2]Johnson CD,Besselink MG,Carter R. Acute pancreatitis [J]. BMJ,2014,349: g4859.

[3]Das SL,Papachristou GI,De Campos T,et al. Individual patient data meta-analysis of organ failure in acute pancreatitis: protocol of the PANCREA II study [J]. JOP,2013,14(5): 475-483.

[4]Wang Y,Liu W,Liu X,et al. Role of liver in modulating the release of inflammatory cytokines involved in lung and multiple organ dysfunction in severe acute pancreatitis [J]. Cell Biochem Biophys,2015,71(2): 765-776.

[5]Whitcomb DC. Clinical practice. Acute pancreatitis [J]. N Engl J Med,2006,354(20): 2142-2150.

[6]Mateescu G,Com?nescu M,Mehedinti R,et al. Immunohistochemical expression of growth factors in the exocrine pancreas of patients with chronic liver diseases [J]. Rom J Morphol Embryol,2010,51(2): 303-307.

[7]Segersv?rd R,Tsai JA,Herrington MK,et al. Obesity alters cytokine gene expression and promotes liver injury in rats with acute pancreatitis [J]. Obesity (Silver Spring),2008,16(1): 23-28.

[8]Bhopale KK,Wu H,Boor PJ,et al. Metabolic basis of ethanol-induced hepatic and pancreatic injury in hepatic alcohol dehydrogenase deficient deer mice [J]. Alcohol,2006,39(3): 179-188.

[9]Miyahara S,Isaji S. Liver injury in acute pancreatitis and mitigation by continuous arterial infusion of an antibiotic via the superior mesenteric artery [J]. Pancreas,2001,23(2): 204-211.

[10]Thrower E,Husain S,Gorelick F. Molecular basis for pancreatitis [J]. Curr Opin Gastroenterol,2008,24(5): 580-585.

[11]Gloor B,Blinman TA,Rigberg DA,et al. Kupffer cell blockade reduces hepatic and systemic cytokine levels and lung injury in hemorrhagic pancreatitis in rats [J]. Pancreas,2000,21(4): 414-420.

[12]Murr MM,Yang J,Fier A,et al. Pancreatic elastase induces liver injury by activating cytokine production within Kupffer cells via nuclear factor-Kappa B [J]. J Gastrointest Surg,2002,6(3): 474-480.

[13]Wei S,Huang Q,Li J,et al. Taurine attenuates liver injury by downregulating phosphorylated p38 MAPK of Kupffer cells in rats with severe acute pancreatitis [J]. Inflammation,2012,35(2): 690-701.

[14]Pasparakis M,Vandenabeele P. Necroptosis and its role in inflammation [J]. Nature,2015,517(7534): 311-320.

[15]Kearney CJ,Cullen SP,Tynan GA,et al. Necroptosis suppresses inflammation via termination of TNF-or LPS-induced cytokine and chemokine production [J]. Cell Death Differ,2015,22(8): 1313-1327.

[16]Hoque R,Farooq A,Ghani A,et al. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity [J]. Gastroenterology,2014,146(7): 1763-1774.

[17]Moniaux N,Song H,Darnaud M,et al. Human hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein cures fas-induced acute liver failure in mice by attenuating free-radical damage in injured livers [J]. Hepatology,2011,53(2): 618-627.

[18]Sha H,Ma Q,Jha RK,et al. Resveratrol ameliorates hepatic injury via the mitochondrial pathway in rats with severe acute pancreatitis [J]. Eur J Pharmacol,2008,601(1-3): 136-142.

[19]Yang LJ,Wan R,Shen JQ,et al. Effect of L-cysteine on remote organ injury in rats with severe acute pancreatitis induced by bile-pancreatic duct obstruction [J]. Hepatobiliary Pancreat Dis Int,2013,12(4): 428-435.

[20]Maccarrone M,Brüne B. Redox regulation in acute and chronic inflammation [J]. Cell Death Differ,2009,16(8): 1184-1186.

[21]Chen F,Zhou YJ. Hepatic effect of NAC on sevear acute pancreatitis of rats [J]. Asian Pac J Trop Med,2014,7(2): 141-143.

[22]Mauriz JL,Collado PS,Veneroso C,et al. A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives [J]. J Pineal Res,2013,54(1): 1-14.

[23]Ueda T,Takeyama Y,Yasuda T,et al. Vascular endothelial growth factor increases in serum and protects against the organ injuries in severe acute pancreatitis [J]. J Surg Res,2006,134(2): 223-230.

[24]Zhou X,Xue C. Ghrelin inhibits the development of acute pancreatitis and nuclear factor kappaB activation in pancreas and liver [J]. Pancreas,2009,38(7): 752-757.

[25]Rios EC,Moretti AI,de Souza HP,et al. Hypertonic saline reduces metalloproteinase expression in liver during pancreatitis [J]. Clin Exp Pharmacol Physiol,2010,37(1): 35-39.

[26]Luan ZG,Zhang H,Ma XC,et al. Therapeutic treatment with ethyl pyruvate attenuates the severity of liver injury in rats with severe acute pancreatitis [J]. Pancreas,2012,41(5): 729-737.

[27]Tutcu S,Serter S,Kaya Y,et al. Hepatic perfusion changes in an experimental model of acute pancreatitis: evaluation by perfusion CT [J]. Eur J Radiol,2010,75(2): 203-206.

[28]Ueda T,Takeyama Y,Takase K,et al. Hematin is one of the cytotoxic factors in pancreatitis-associated ascitic fluid that causes hepatocellular injury [J]. Surgery,2002,131(1): 66-74.

[29]Jin HT,L?ms? T,Nordback PH,et al. Association between remote organ injury and tissue polyamine homeostasis in acute experimental pancreatitis-treatment with a polyamine analogue bismethylspermine [J]. Pharmacol Rep,2011,63(4): 999-1008.

[30]Moran RA,Hernaez R,Singh VK. Early versus on-demand tube feeding in pancreatitis [J]. N Engl J Med,2015,372(7): 684.

[31]Freise H,Lauer S,Konietzny E,et al. Hepatic effects of thoracic epidural analgesia in experimental severe acute pancreatitis [J]. Anesthesiology,2009,111(6): 1249-1256.

[32]Ridgway D,Manas D,Shaw J,et al. Preservation of the donor pancreas for whole pancreas and islet transplantation [J]. Clin Transplant,2010,24(1): 1-19.

[33]Wu L,Li H,Zheng SZ,et al. Da-Huang-Fu-Zi-Tang attenuates liver injury in rats with severe acute pancreatitis [J]. J Ethnopharmacol,2013,150(3): 960-966.

[34]Zhao YF,Zhai WL,Zhang SJ,et al. Protection effect of triptolide to liver injury in rats with severe acute pancreatitis [J]. Hepatobiliary Pancreat Dis Int,2005,4(4): 604-608.

[35]Mota R,Sánchez-Bueno F,Berenguer-Pina JJ,et al. Therapeutic treatment with poly (ADP-ribose) polymerase inhibitors attenuates the severity of acute pancreatitis and associated liver and lung injury [J]. Br J Pharmacol,2007,151(7): 998-1005.

[36]Durval A,Zamidei L,Bettocchi D,et al. Hyperlipidemic acute pancreatitis: a possible role of antiretroviral therapy with entecavir [J]. Minerva Anestesiol,2011,77(10): 1018-1021.

[37]Alhan E,Usta A,Türkyllmaz S,et al. Effects of glutamine alone on the acute necrotizing pancreatitis in rats [J]. J Surg Res,2015,193(1): 161-167.

(責(zé)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(fā)攻關(guān)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