慢性間歇性缺氧與非酒精性脂肪性肝病研究進展

趙鈺鑫, 琚 堅,葉江鋒

昆明醫(yī)科大學第二附屬醫(yī)院特需病房科, 云南 昆明650101

慢性間歇性缺氧與非酒精性脂肪性肝病研究進展

趙鈺鑫, 琚 堅,葉江鋒

昆明醫(yī)科大學第二附屬醫(yī)院特需病房科, 云南 昆明650101

非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)是一組除外酒精和其他明確肝損傷因素所致的以肝細胞內(nèi)脂肪過度沉積的臨床病理綜合征。阻塞性睡眠呼吸暫停綜合征(obstructive sleep apnea syndrome,OSAS)是睡眠期間反復發(fā)生的以部分或完全上氣道阻塞為特征的呼吸紊亂，常伴有胸內(nèi)負壓增加、片段睡眠及間歇性低氧血癥。而間歇性缺氧是其主要的病理生理。目前已有研究認為慢性間歇性缺氧(chronic intermittent hypoxia,CIH)與NAFLD整個疾病譜密切相關(guān)。本文將通過國內(nèi)外研究對CIH與NAFLD相關(guān)性作一概述。

慢性間歇性缺氧;阻塞性呼吸睡眠暫停綜合征; 非酒精脂肪性肝病

非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是一組除外酒精和其他明確的肝損傷因素所致的以肝細胞內(nèi)脂肪過度沉積的臨床病理綜合征。NAFLD增加了肝相關(guān)并發(fā)癥，如肝細胞腫瘤、終末期肝疾病及心血管疾病、慢性腎臟疾病、糖尿病[1]，并推測它可能是2020年肝移植的主要原因[2]。目前關(guān)于NAFLD發(fā)病機制尚不完全明確，胰島素抵抗(insulin resistance,IR)被廣為接受。

阻塞性睡眠呼吸暫停綜合征(obstructive sleep apnea syndrome, OSAS)是睡眠期間反復發(fā)生的以部分或完全性上氣道阻塞為特征的呼吸紊亂，肥胖是OSAS關(guān)鍵致病因素。目前大量動物及臨床研究表明OSAA與多臟器如心、腦、肺、腎等多臟器損傷及內(nèi)分泌系統(tǒng)紊亂有關(guān)，是高血壓、冠心病、糖尿病、腦卒中及代謝綜合征等疾病的獨立危險因素[3-5]。近年來相關(guān)動物及臨床研究已證實OSA同時與NAFLD密切相關(guān)[6]，且OSAS所致的慢性間歇性缺氧(chronic intermittent hypoxia, CIH)是導致NAFLD及其他相關(guān)疾病的主要發(fā)病因素。相關(guān)實驗研究表明，CIH與非酒精性肝病整個疾病譜相關(guān)[7]。

1 CIH與NAFlD

1.1 CIH與非酒精性脂肪肝(non-alcoholic fatty liver,NAFL)目前對于NAFL的的發(fā)病機制尚未明確， IR被廣為接受。IR是指機體組織或靶器官對內(nèi)源性或外源性胰島素的敏感性和(或)反應性降低，正常量的胰島素產(chǎn)生低于正常量的生理效應，或需要超常量的胰島素才能達到正常的生理效應。目前認為IR會使脂肪細胞數(shù)量和激素敏感性脂肪酶活性增加，肝臟攝取游離脂肪酸作用增強，同時減弱胰島素對脂解作用的抑制，增加游離脂肪酸濃度，最終導致肝細胞脂肪變性。早在2002年，Ip等[8]證實了OSAS 與IR密切相關(guān)，該研究通過對270例OSAS患者研究發(fā)現(xiàn)，OSAS患者的空腹胰島素及穩(wěn)態(tài)胰島素評價指數(shù)(HOMA-IR)水平較正常組升高。用多元回歸分析方法證實了空腹胰島素、HOMA-IR與呼吸暫停低通氣指數(shù)、最低氧飽和度呈顯著相關(guān)性。Louis等[9]通過對13名健康志愿者研究表明OSAS致間歇性缺氧(intermittent hypoxia, IH)進而導致胰島素敏感性下降。Drager等[10]在對小鼠的實驗中也證實了IH增加空腹血糖及糖耐量耐受、IR抗加劇。最近Fu等[11]動物實驗研究也證實了CIH導致IR及糖耐量受損。

IH除參與IR外，同時參與脂質(zhì)代謝紊亂。相關(guān)研究[12]證明，CIH阻礙多余甘油三酯的脂蛋白清除，并能使脂肪蛋白酶失活。在Phillips等[13]隨機對照臨床實驗表明持續(xù)正壓通氣后的患者餐后甘油三酯及總膽固醇得到改善。Shpirer等[14]通過對47例中-重度OSAS并脂肪性肝病患者持續(xù)正壓通氣治療后肝脂肪變性得到改善，有研究[15]認為IH干預脂質(zhì)代謝是通過上調(diào)膽固醇調(diào)節(jié)元件結(jié)合蛋白-1c (SREBP-1c)及SREBP-1c調(diào)節(jié)酶、硬脂酰輔酶A脫氫酶1(SCD-1)，SREBP-1c是肝脂質(zhì)合成的關(guān)鍵轉(zhuǎn)錄因子，是代謝綜合征中重要的基因調(diào)控連結(jié)點[16]，SCD-1能將飽和脂肪酸轉(zhuǎn)化為單不飽和脂肪酸。多余的單不飽和脂肪酸能加速膽固醇酯及甘油三酯的合成，從而增加極低密度脂蛋白合成[17]。Drager等[18]通過大量的臨床及動物實驗研究綜述了IH可能通過過多脂解脂肪組織及游離脂肪酸進入肝，增加了甘油三酯及脂蛋白合成，抑制脂蛋白清除導致脂質(zhì)紊亂，最終導致脂肪肝形成。CIH還能使交感神經(jīng)興奮性增強，釋放過多兒茶酚胺，從而使激素敏感性TG酯酶生物學活性明顯增強,促進脂肪分解為游離脂肪酸及甘油，后兩者在肝臟中重新合成極低密度脂蛋白，促使脂代謝異常進一步加劇[19]。

1.2 CIH與非酒精性肝炎(non-alcoholic steatohepatitis,NASH)對于NASH發(fā)病機制，近十多年來最廣為接受的是“二次打擊”學說，一次打擊是甘油三酯積聚導致NAFL，二次打擊為細胞因子及炎癥介質(zhì)釋放產(chǎn)生自由基致NASH產(chǎn)生。NASH能增加肝纖維化及肝相關(guān)并發(fā)癥發(fā)生的風險[1],近期美國肝病協(xié)會(AASLD)、美國胃腸病學會(ACG)和美國胃腸病協(xié)會(AGA)聯(lián)合推薦指南提出早期診斷及治療NASH有助于減緩肝病進展。有研究[20]認為OSAS是NAFLD單純性脂肪肝向NASH轉(zhuǎn)化的一個危險因素，國內(nèi)李亞勇等[21]通過動物實驗也證實了CIH致NASH的發(fā)生，并與Fractalkine 趨化因子相關(guān)，而Fractalkine是被認為肝損傷的重要參與者[22]。對于CIH 所致的NASH可能與以下機制相關(guān)：(1)缺氧本身就能上調(diào)脂肪合成基因及下調(diào)脂質(zhì)代謝基因的表達，同時能通過某些細胞通路如NF-κB、未折疊蛋白反應等促進甘油三脂積聚、壞死性炎癥及肝纖維化產(chǎn)生[23]。(2)在Savransky[24]等的研究中， CIH導致血清和肝臟脂質(zhì)過氧化明顯增加，表明CIH增加肝臟活性氧(reactwe oxygen species,ROS)的產(chǎn)生，同時CIH使肝臟過氧化物酶(myeloperoxidase, MPO)增加，表明CIH通過氧化應激參與 NASH發(fā)生。(3)CIH可以激活缺氧誘導因子-1α(HIF-1α) 和缺氧誘導因子-2α(HIF-2α)，HIF是缺氧條件下機體的一種氧依賴轉(zhuǎn)錄因子 ,可以減少肝臟脂肪代謝 ,增加肝臟脂肪合成,上調(diào)肝臟炎癥反應[24]而HIF-1α和HIF-2α兩種關(guān)鍵轉(zhuǎn)錄調(diào)節(jié)因子參與肝細胞脂肪從頭合成和脂肪酸氧化和巨噬細胞、肝星狀細胞活化基因的表達，從而促進肝細胞壞死性炎癥、肝纖維化[25]。(4)最近研究[26]表明 OSAS所致NASH 與腸肝軸損傷相關(guān)，OSAS破壞肝-腸軸穩(wěn)態(tài)，增加內(nèi)毒血癥易感性，這表明腸道微環(huán)境的改變是 OSAS介導 NASH機制之一。由此推斷不可否認可能參與肝-腸軸的破壞。

2 CIH與肝纖維化

Agrawal等[25]通過對100例NAFLD患者研究得出 NAFLD伴有OSAS患者肝纖維化程度明顯重于單純NAFLD患者，且在多變量分析中只有自身免疫性肝炎(autoimmune hepatitis,AIH)是肝纖維化獨立預測因子。另外，AIH與睡眠缺氧時間百分比及Fibroscan 值相關(guān)，由此推斷OSAS IH參與非酒精性肝病肝纖維化。國內(nèi)闞海峰等[27]也得出相似結(jié)論，該研究通過肥胖合并OSAS 27例，正常體質(zhì)量OSAS 23例及單純性肥胖、正常體質(zhì)量各30例正常者對照研究表明OSAS患者血漿透明質(zhì)酸、3型前膠原、4型膠原和層黏連蛋白與呼吸暫停低通氣指數(shù)(AHI)和體質(zhì)量指數(shù)(BMI)呈正相關(guān)，由此推斷OSAS可能導致肝纖維化。Nobili等[26]通過對81例NAFL兒童的研究得出：排外肥胖、代謝綜合征、IR等因素，OSAS與NASH及肝纖維化有關(guān)，且睡眠呼吸暫停及夜間缺氧的嚴重程度與NAS評分及纖維化程度呈正相關(guān)[2]。Feng等[28]通過CIH對小鼠肝損傷研究表明：暴露于間歇性缺氧9周的高脂肪飼養(yǎng)小鼠較單純高脂肪飼養(yǎng)小鼠相比出現(xiàn)明顯的細胞腫脹、炎癥細胞浸潤、局部壞死、門靜脈及竇周出現(xiàn)纖維化，由此證明CIH參與了肝纖維化的進展，在該研究中暴露于間歇性缺氧9周的高脂肪飼養(yǎng)小鼠髓MPO明顯升高，說明CIH通過氧化應激參與肝細胞炎癥及肝纖維化發(fā)展。

3 討論

綜上所述，CIH參與了NAFLD整個疾病譜的發(fā)展，在Aron-Wisnewsky等[29]研究中同樣證實了該結(jié)論，Zheng等[30]通過對大量研究進行Meta分析得出HIF-1α可預測肝細胞腫瘤預后，由此推斷CIH可能與肝細胞腫瘤預后相關(guān)?？傊畬τ贑IH與NAFLD之間的相關(guān)性，近年來越來越多的研究得已證實，對其機制也有了一定認識，但對于CIH在分子基礎(chǔ)上如何導致 NAFLD的發(fā)生、發(fā)展，目前尚未清楚，如CIH如何誘導 IR具體機制、通過激活什么靶點而導致促炎因子產(chǎn)生及參與肝-腸軸紊亂具體機制等問題有待進一步解決。且關(guān)于CIH與 NAFLD 相關(guān)研究目前大多是以動物實驗為主，臨床研究較少且研究范圍局限。盡管CIH對 NAFLD發(fā)生機制不完全清楚，但對NAFLD 的治療又提供了一條新思路。對于OSAS伴有NAFLD患者改善缺氧環(huán)境也許是最佳治療方案。

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(責任編輯：王全楚)

Progress of chronic intermittent hypoxia and non-alcoholic fatty liver disease

ZHAO Yuxin, JU Jian, YE Jiangfeng

Department of Special Wards Section, the Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China

Non-alcoholic fatty liver disease (NAFLD) is a group of clinic pathological syndrome of excessive fat deposition in hepatocyte which is caused by other definite hepatic impairment factors except alcohol. Obstructive sleep apnea syndrome (OSAS) is a kind breathing disorder which is featured of partial or complete upper airway obstruction and happens in sleeping period repeatedly. It normally accompanies with intrapleural negative pressure increasing, fragment sleep and intermittent hypoxemia. The chronic intermittent hypoxemia (CIH) is its main pathophysiology. Existed studies believe that CIH has close relation with the disease spectrum of NAFLD. This paper summarized the CIH and NAFLD through the studies in China and abroad.

Chronic intermittent hypoxia; Obstructive sleep apnea syndrome; Non-alcoholic fatty liver disease

趙鈺鑫，在讀碩士研究生，研究方向：消化系統(tǒng)疾病。E-mail:260840308@qq.com

琚堅，教授，主任醫(yī)師，研究方向：消化系統(tǒng)疾病。E-mail:jujianyn@163.cm

10.3969/j.issn.1006-5709.2017.01.031

R575.5

A

1006-5709(2017)01-0107-03

2015-00-00