慢性间歇性缺氧与非酒精性脂肪性肝病研究进展

赵钰鑫, 琚 坚,叶江锋

昆明医科大学第二附属医院特需病房科, 云南 昆明650101

慢性间歇性缺氧与非酒精性脂肪性肝病研究进展

赵钰鑫, 琚 坚,叶江锋

昆明医科大学第二附属医院特需病房科, 云南 昆明650101

非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)是一组除外酒精和其他明确肝损伤因素所致的以肝细胞内脂肪过度沉积的临床病理综合征。阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea syndrome,OSAS)是睡眠期间反复发生的以部分或完全上气道阻塞为特征的呼吸紊乱，常伴有胸内负压增加、片段睡眠及间歇性低氧血症。而间歇性缺氧是其主要的病理生理。目前已有研究认为慢性间歇性缺氧(chronic intermittent hypoxia,CIH)与NAFLD整个疾病谱密切相关。本文将通过国内外研究对CIH与NAFLD相关性作一概述。

慢性间歇性缺氧;阻塞性呼吸睡眠暂停综合征; 非酒精脂肪性肝病

非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是一组除外酒精和其他明确的肝损伤因素所致的以肝细胞内脂肪过度沉积的临床病理综合征。NAFLD增加了肝相关并发症，如肝细胞肿瘤、终末期肝疾病及心血管疾病、慢性肾脏疾病、糖尿病[1]，并推测它可能是2020年肝移植的主要原因[2]。目前关于NAFLD发病机制尚不完全明确，胰岛素抵抗(insulin resistance,IR)被广为接受。

阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea syndrome, OSAS)是睡眠期间反复发生的以部分或完全性上气道阻塞为特征的呼吸紊乱，肥胖是OSAS关键致病因素。目前大量动物及临床研究表明OSAA与多脏器如心、脑、肺、肾等多脏器损伤及内分泌系统紊乱有关，是高血压、冠心病、糖尿病、脑卒中及代谢综合征等疾病的独立危险因素[3-5]。近年来相关动物及临床研究已证实OSA同时与NAFLD密切相关[6]，且OSAS所致的慢性间歇性缺氧(chronic intermittent hypoxia, CIH)是导致NAFLD及其他相关疾病的主要发病因素。相关实验研究表明，CIH与非酒精性肝病整个疾病谱相关[7]。

1 CIH与NAFlD

1.1 CIH与非酒精性脂肪肝(non-alcoholic fatty liver,NAFL)目前对于NAFL的的发病机制尚未明确， IR被广为接受。IR是指机体组织或靶器官对内源性或外源性胰岛素的敏感性和(或)反应性降低，正常量的胰岛素产生低于正常量的生理效应，或需要超常量的胰岛素才能达到正常的生理效应。目前认为IR会使脂肪细胞数量和激素敏感性脂肪酶活性增加，肝脏摄取游离脂肪酸作用增强，同时减弱胰岛素对脂解作用的抑制，增加游离脂肪酸浓度，最终导致肝细胞脂肪变性。早在2002年，Ip等[8]证实了OSAS 与IR密切相关，该研究通过对270例OSAS患者研究发现，OSAS患者的空腹胰岛素及稳态胰岛素评价指数(HOMA-IR)水平较正常组升高。用多元回归分析方法证实了空腹胰岛素、HOMA-IR与呼吸暂停低通气指数、最低氧饱和度呈显著相关性。Louis等[9]通过对13名健康志愿者研究表明OSAS致间歇性缺氧(intermittent hypoxia, IH)进而导致胰岛素敏感性下降。Drager等[10]在对小鼠的实验中也证实了IH增加空腹血糖及糖耐量耐受、IR抗加剧。最近Fu等[11]动物实验研究也证实了CIH导致IR及糖耐量受损。

IH除参与IR外，同时参与脂质代谢紊乱。相关研究[12]证明，CIH阻碍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]随机对照临床实验表明持续正压通气后的患者餐后甘油三酯及总胆固醇得到改善。Shpirer等[14]通过对47例中-重度OSAS并脂肪性肝病患者持续正压通气治疗后肝脂肪变性得到改善，有研究[15]认为IH干预脂质代谢是通过上调胆固醇调节元件结合蛋白-1c (SREBP-1c)及SREBP-1c调节酶、硬脂酰辅酶A脱氢酶1(SCD-1)，SREBP-1c是肝脂质合成的关键转录因子，是代谢综合征中重要的基因调控连结点[16]，SCD-1能将饱和脂肪酸转化为单不饱和脂肪酸。多余的单不饱和脂肪酸能加速胆固醇酯及甘油三酯的合成，从而增加极低密度脂蛋白合成[17]。Drager等[18]通过大量的临床及动物实验研究综述了IH可能通过过多脂解脂肪组织及游离脂肪酸进入肝，增加了甘油三酯及脂蛋白合成，抑制脂蛋白清除导致脂质紊乱，最终导致脂肪肝形成。CIH还能使交感神经兴奋性增强，释放过多儿茶酚胺，从而使激素敏感性TG酯酶生物学活性明显增强,促进脂肪分解为游离脂肪酸及甘油，后两者在肝脏中重新合成极低密度脂蛋白，促使脂代谢异常进一步加剧[19]。

1.2 CIH与非酒精性肝炎(non-alcoholic steatohepatitis,NASH)对于NASH发病机制，近十多年来最广为接受的是“二次打击”学说，一次打击是甘油三酯积聚导致NAFL，二次打击为细胞因子及炎症介质释放产生自由基致NASH产生。NASH能增加肝纤维化及肝相关并发症发生的风险[1],近期美国肝病协会(AASLD)、美国胃肠病学会(ACG)和美国胃肠病协会(AGA)联合推荐指南提出早期诊断及治疗NASH有助于减缓肝病进展。有研究[20]认为OSAS是NAFLD单纯性脂肪肝向NASH转化的一个危险因素，国内李亚勇等[21]通过动物实验也证实了CIH致NASH的发生，并与Fractalkine 趋化因子相关，而Fractalkine是被认为肝损伤的重要参与者[22]。对于CIH 所致的NASH可能与以下机制相关：(1)缺氧本身就能上调脂肪合成基因及下调脂质代谢基因的表达，同时能通过某些细胞通路如NF-κB、未折叠蛋白反应等促进甘油三脂积聚、坏死性炎症及肝纤维化产生[23]。(2)在Savransky[24]等的研究中， CIH导致血清和肝脏脂质过氧化明显增加，表明CIH增加肝脏活性氧(reactwe oxygen species,ROS)的产生，同时CIH使肝脏过氧化物酶(myeloperoxidase, MPO)增加，表明CIH通过氧化应激参与 NASH发生。(3)CIH可以激活缺氧诱导因子-1α(HIF-1α) 和缺氧诱导因子-2α(HIF-2α)，HIF是缺氧条件下机体的一种氧依赖转录因子 ,可以减少肝脏脂肪代谢 ,增加肝脏脂肪合成,上调肝脏炎症反应[24]而HIF-1α和HIF-2α两种关键转录调节因子参与肝细胞脂肪从头合成和脂肪酸氧化和巨噬细胞、肝星状细胞活化基因的表达，从而促进肝细胞坏死性炎症、肝纤维化[25]。(4)最近研究[26]表明 OSAS所致NASH 与肠肝轴损伤相关，OSAS破坏肝-肠轴稳态，增加内毒血症易感性，这表明肠道微环境的改变是 OSAS介导 NASH机制之一。由此推断不可否认可能参与肝-肠轴的破坏。

2 CIH与肝纤维化

Agrawal等[25]通过对100例NAFLD患者研究得出 NAFLD伴有OSAS患者肝纤维化程度明显重于单纯NAFLD患者，且在多变量分析中只有自身免疫性肝炎(autoimmune hepatitis,AIH)是肝纤维化独立预测因子。另外，AIH与睡眠缺氧时间百分比及Fibroscan 值相关，由此推断OSAS IH参与非酒精性肝病肝纤维化。国内阚海峰等[27]也得出相似结论，该研究通过肥胖合并OSAS 27例，正常体质量OSAS 23例及单纯性肥胖、正常体质量各30例正常者对照研究表明OSAS患者血浆透明质酸、3型前胶原、4型胶原和层黏连蛋白与呼吸暂停低通气指数(AHI)和体质量指数(BMI)呈正相关，由此推断OSAS可能导致肝纤维化。Nobili等[26]通过对81例NAFL儿童的研究得出：排外肥胖、代谢综合征、IR等因素，OSAS与NASH及肝纤维化有关，且睡眠呼吸暂停及夜间缺氧的严重程度与NAS评分及纤维化程度呈正相关[2]。Feng等[28]通过CIH对小鼠肝损伤研究表明：暴露于间歇性缺氧9周的高脂肪饲养小鼠较单纯高脂肪饲养小鼠相比出现明显的细胞肿胀、炎症细胞浸润、局部坏死、门静脉及窦周出现纤维化，由此证明CIH参与了肝纤维化的进展，在该研究中暴露于间歇性缺氧9周的高脂肪饲养小鼠髓MPO明显升高，说明CIH通过氧化应激参与肝细胞炎症及肝纤维化发展。

3 讨论

综上所述，CIH参与了NAFLD整个疾病谱的发展，在Aron-Wisnewsky等[29]研究中同样证实了该结论，Zheng等[30]通过对大量研究进行Meta分析得出HIF-1α可预测肝细胞肿瘤预后，由此推断CIH可能与肝细胞肿瘤预后相关。总之对于CIH与NAFLD之间的相关性，近年来越来越多的研究得已证实，对其机制也有了一定认识，但对于CIH在分子基础上如何导致 NAFLD的发生、发展，目前尚未清楚，如CIH如何诱导 IR具体机制、通过激活什么靶点而导致促炎因子产生及参与肝-肠轴紊乱具体机制等问题有待进一步解决。且关于CIH与 NAFLD 相关研究目前大多是以动物实验为主，临床研究较少且研究范围局限。尽管CIH对 NAFLD发生机制不完全清楚，但对NAFLD 的治疗又提供了一条新思路。对于OSAS伴有NAFLD患者改善缺氧环境也许是最佳治疗方案。

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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

赵钰鑫，在读硕士研究生，研究方向：消化系统疾病。E-mail:260840308@qq.com

琚坚，教授，主任医师，研究方向：消化系统疾病。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