修回日期: 2023-10-27
接受日期: 2023-11-01
在线出版日期: 2023-11-08
随着生活水平的提高, 高甘油三酯血症(hypertriglyceridemia, HTG)已经成为中国急性胰腺炎(acute pancrea-titis, AP)的第二大病因. 高甘油三酯血症性急性胰腺炎(hypertriglyceridemia-induced acute pancreatitis, HTG-AP)相较于其他原因所致AP有其独特的特点. 首先, 血淀粉酶、脂肪酶升高不明显; 其次, 病情严重程度与血甘油三酯(triglyceride, TG)水平成正相关. 治疗HTG-AP的关键是迅速降低血脂, 常用的方法包括饮食调整、降脂药物、低分子肝素联合胰岛素、血液净化以及中西医结合治疗等. 本文就国内外HTG-AP降脂方法的进展作一综述.
核心提要: 治疗高甘油三酯血症性急性胰腺炎的关键是迅速降低血脂, 但一些降脂方法目前仍存有争议. 本文着重回顾文献并总结高甘油三酯血症性急性胰腺炎不同降脂方法之间的疗效和安全性的差异, 以指导临床实践.
引文著录: 陈慧敏, 苏东帅, 李宏宇, 郭晓钟, 祁兴顺. 高甘油三酯血症性急性胰腺炎的降脂治疗进展. 世界华人消化杂志 2023; 31(21): 882-888
Revised: October 27, 2023
Accepted: November 1, 2023
Published online: November 8, 2023
With the improvement of the living standard, hypertriglyceridemia (HTG) has become the second major cause of acute pancreatitis (AP) in China. Hypertriglyceridemia-induced acute pancreatitis (HTG-AP) has its own unique characteristics. First, the elevation of blood amylase and lipase levels is not significant. Second, the severity of the disease positively correlates with blood triglyceride (TG) level. The goal of treatment of HTG-AP is to lower blood lipids rapidly. Common lipid-lowering methods include dietary modification, lipid-lowering drugs, low-molecular heparin combined with insulin, blood purification, and combined Chinese and Western medicine. This article reviews the recent advances on lipid-lowering approaches used in HTG-AP patients.
- Citation: Chen HM, Su DS, Li HY, Guo XZ, Qi XS. Lipid-lowering therapy for hypertriglyceridemia-induced acute pancreatitis: Recent advances. Shijie Huaren Xiaohua Zazhi 2023; 31(21): 882-888
- URL: https://www.wjgnet.com/1009-3079/full/v31/i21/882.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v31.i21.882
急性胰腺炎(acute pancreatitis, AP)指各种原因引起胰酶异常激活, 并作用于胰腺自身及周围器官, 引起胰腺炎性反应, 导致多器官功能障碍的急腹症[1]. AP的常见病因包括胆石症、酗酒和高甘油三酯血症(hypertriglyceridemia, HTG)等. 近些年, 饮食结构的改变使HTG成为我国AP的第二大病因[2]. 满足AP的诊断, 且血甘油三酯(triglyceride, TG)≥11.3 mmol/L, 或血TG在5.65-11.3 mmol/L之间同时伴有乳糜样血, 排除其他原因引起的AP后, 即可诊断为高甘油三酯血症性急性胰腺炎(hypertriglyceridemia-induced acute pancreatitis, HTG-AP)[3]. HTG-AP的发病与血TG浓度密切相关, 血TG水平越高, 患HTG-AP的风险越高, 发展为重症急性胰腺炎(severe acute pancreatitis, SAP)的风险越大, 普遍认为血TG≥11.3 mmol/L是HTG-AP的高危因素[4,5]. 2021年《高甘油三酯血症性急性胰腺炎诊治急诊专家共识》[3]指出, 治疗HTG-AP的关键是将血清TG水平快速降至5.65 mmol/L. 以下本文总结了HTG-AP的常见降脂治疗方法的临床疗效, 包括饮食调整、降脂药物、低分子肝素联合胰岛素、血液净化和中西医结合等, 旨在帮助临床医生了解各种方法的优缺点, 以选择合适的治疗方法.
HTG-AP的常见高危因素有高脂饮食、肥胖、糖尿病、酗酒等[6]. 其发病机制尚不明确,目前现有4种常见的假说: (1)游离脂肪酸学说[7]: 血TG分解产生的游离脂肪酸可促进胰淀粉酶释放, 在高浓度下可损伤胰腺血管内皮细胞和腺泡细胞; (2)炎性反应[8]: 游离脂肪酸引起胰腺损伤, 激活炎性因子后产生瀑布式的级联反应, 导致促炎因子与抗炎因子失衡, 进而加重胰腺自身损伤和微循环障碍; (3)钙超载[9]: 细胞外或细胞质内钙离子浓度升高可导致空泡形成和酶原活化, 进而引起腺泡细胞损伤; (4)微循环障碍[10,11]: HTG-AP患者血液黏度增加, 血流速度减慢, 易引起组织缺血缺氧, 小血管内微血栓形成, 胰腺微循环障碍, 可能是胰腺坏死进展的原因之一.
除了腹痛、腹胀、恶心、呕吐等AP的常见临床表现外, HTG-AP还具有其自身特点: (1)血脂紊乱, 血TG升高, 血可呈乳糜状[12]; (2)血、尿淀粉酶升高不明显[13]; (3)平均发病年龄约38-44岁, 男性占比约65%-80%[14,15]; (4)并发症多, 局部并发症包括急性胰周液体聚集、急性坏死物聚集、胰腺假性囊肿和包裹性坏死, 发生率分别可达58%-88.9%[16,17]、26%-66.7%[17,18]、2%-44.9%[17,18]和16%-39.4%[17,18]; 全身并发症包括全身炎症反应综合征、脓毒症和腹内高压, 发生率分别可达51%-60.9%[16,19]、0.8%-6.1%[17,20]和85.4%[17]; (5)复发率高, 可达22%-57%[14,21]; (6)预后差, SAP、胰腺坏死、器官衰竭和死亡率分别可达23.3%-62.6%[14,17]、28.3%-40%[15,22]、35.8%-88%[17,22]和7%-18%[15,18].
禁食是HTG-AP的早期治疗之一[1,6]. 在禁食状态下, 血液中富含TG的乳糜微粒迅速减少, 同时, 低热量的静脉输液可切断肝脏内极低密度脂蛋白的输出, 使血TG水平进一步下降[6]. Dominguez-Muñoz等[23]发现, 血脂异常的AP患者在禁食72 h后, 血TG显著下降, 但在15 d后, 大多数患者血TG水平有轻微升高. 李艳梅等[24]观察到, HTG-AP患者在入院后即使未接受任何降脂药物或血液透析治疗, 常规禁食24 h后, 血TG水平下降了一半, 3 d-4 d后可降至5.65 mmol/L以下; 但难以降至正常, 多在2 mmol/L-4 mmol/L波动. 2020年《欧洲临床营养和代谢学会急慢性胰腺炎临床营养指南》[25]提出, HTG-AP患者先禁食24 h-48 h, 此后可低脂、柔软食物, 但SAP和伴有胸腔积液的患者经口进食耐受性差. 对于此类患者, 可使用经鼻空肠管的肠内营养或全肠外营养, 从而减轻炎症、减少感染、纠正负氮平衡, 改善预后[6,25,26].
3.2.1 他汀类药物和贝特类药物: 他汀类药物, 即3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂, 可通过上调低密度脂蛋白受体、减少载脂蛋白B-100的肝脏合成, 从而减少富含TG的脂蛋白的合成和分泌, 可降低血TG水平7.3%-32.19%[27-29]. 其常见不良反应是肝毒性、肌痛、横纹肌溶解等[30]. 有研究发现[31], 他汀类药物可降低餐后脂蛋白水平, 用药4 wk后空腹血TG可下降约30%, 且在停药4 wk后仍然维持在较低水平. 贝特类药物通过刺激过氧化物酶体增殖物激活受体-α, 增加脂蛋白脂解和脂肪酸摄取, 进而减少TG合成[32]. 贝特类药物可降低血TG水平约30%-50%, 常见不良反应为胃肠道症状和头痛, 严重不良反应为肌肉毒性和横纹肌溶解[33-35]. 一项前瞻性、多中心、双盲研究发现[36], 对于单用他汀类药物不能有效控制血TG水平的患者, 联合非诺贝特治疗4 wk后可降低血TG水平32.49%, 8 wk后可降低44.47%; 仅4.6%的患者发生了药物不良反应. Zhao等[37]发现, 对于血脂异常伴高心血管风险的患者, 在原有的他汀类药物治疗基础上联合非诺贝特(200 mg/d)治疗8 wk后, 血TG水平下降了38.1%, 未发生严重肌肉损伤事件(肌酸激酶升高超过5倍正常值上限或横纹肌溶解), 且与单用他汀类药物或非诺贝特治疗相比, 在血谷丙转氨酶和谷草转氨酶的上升情况方面无差异, 表明他汀类药物联合非诺贝特治疗血脂异常患者并未额外增加肝毒性. 因此, 他汀类药物联合非诺贝特治疗HTG是一种安全、有效的降脂方法, 尤其是在他汀类药物降脂效果不佳的情况下.
3.2.2 烟酸: 烟酸可抑制肝脏合成TG的关键酶二酰基甘油酰基转移酶-2、调节脂肪组织中TG的脂解, 从而降低血TG[38]. 但其不良反应较多, 包括潮红、瘙痒、黏膜刺激、肝脏毒性和胃肠紊乱等[39]. 有研究显示[40], 烟酸使血脂异常患者的血TG水平下降了48%, 但其不良反应发生率显著高于非诺贝特(54% vs 11%, P<0.001). 因此, 使用烟酸作为降脂药物时, 需注意其副作用.
3.2.3 ω-3脂肪酸: ω-3脂肪酸降低血TG的机制与抑制胃肠道脂质吸收和增加脂肪酸氧化有关, 可使血TG水平下降25%-50%[41,42], 且其耐受性好, 无严重不良事件发生[43]. ω-3脂肪酸联合他汀类药物可有效降低血TG、低密度脂蛋白和胆固醇水平[44]. 有研究显示[45], 对于单用他汀类药物治疗HTG效果不佳的患者, 加用ω-3脂肪酸(4 g/d)治疗8 wk后, 血TG水平下降了26.3%, 不良事件发生率与单用瑞舒伐他汀相比无差异(15.5% vs 17.3%, P = 0.732), 仅1.9%的患者发生严重不良事件(1例卵巢癌、1例帕金森症), 但认为与该药物无关. 因此, 对其他降脂药物耐受性差的患者可考虑使用ω-3脂肪酸.
总体来说, 以上降脂药物疗效的相关数据主要是来源于它们在血脂异常患者应用的研究. 临床上HTG-AP多采用联合降脂方案, 鲜有研究讨论单一降脂药物对HTG-AP患者的效果.
Hahn[46]于1943年在一项动物实验中首次发现静脉输注肝素可降低血脂. 然而, 有研究认为[47], 参与TG分解的脂蛋白脂肪酶在长期使用肝素后可被耗尽, 进而使血TG水平升高, 因此单用肝素降脂的方法存在争议. 王玉柱等[48]发现, 对平均血TG为24.87 mmol/L的重症HTG-AP患者, 静脉输注胰岛素不仅可控制血糖, 还可迅速降低血TG, 治疗3 d-4 d后, 血TG可降至5.65 mmol/L以下且腹痛消失, 8 d-9 d后, 肠功能恢复, 但无法缩短住院天数及改善预后. 刘丽娜等[49]采用皮下注射低分子肝素联合静脉输注胰岛素方案治疗HTG-AP患者; 在24 h-36 h内, 平均血TG水平由43.7 mmol/L降至11.3 mmol/L以下; 治疗4 d后, 降至5.65 mmol/L以下. 杨宇龙等[50]在一般治疗的基础上加入了具有降脂功效的中药: 丹参和大黄; 与一般对症支持治疗相比, 低分子肝素联合胰岛素的患者仅需3 d-4 d即可将血TG降至5.65 mmol/L以下, 其所需时间减少了近一倍. 有研究表明[51-53], 与单用胰岛素降低血TG相比, 低分子肝素联合胰岛素治疗HTG-AP患者, 降低血TG的效果更明显, 腹痛及腹胀缓解所需时间及住院时间均明显缩短, 死亡率更低. 陈俞兵等[54]比较了常规治疗、常规加胰岛素、常规加低分子肝素和常规加低分子肝素联合胰岛素治疗重症HTG-AP患者的疗效差异; 治疗6 d后, 低分子肝素联合胰岛素组的血TG及CRP水平明显低于其他组, 且总有效率最高. 梁政等[55]推荐使用低分子肝素联合胰岛素泵治疗HTG-AP, 因为胰岛素泵可减少血糖波动, 减少低血糖等不良事件的发生. 戴伟等[56]在常规治疗的基础上添加了口服降脂药物, 比较了低分子肝素联合胰岛素与双重血浆置换(plasmapheresis, PE)对重症HTG-AP的疗效差异; 虽然双重PE在清除炎性因子和早期脏器功能保护方面更有优势, 但在降低血TG水平、缩短住院时间、改善胰腺功能以及病死率方面上两者无差异. 综上, 低分子肝素联合胰岛素降脂效果确切, 可作为缺少PE条件下的安全、有效的替代方法.
血液净化可快速降低HTG-AP患者的血脂水平, 包括PE、血液灌流、血液滤过和血液透析滤过等方式. 其中, PE最常用, 但也最具争议.
3.4.1 PE: PE可在体外将血中有毒、有害物质分离出去, 同时将新鲜血浆、白蛋白溶液或平衡液等血浆替代品回输体内[57]. 一项研究发现[58], 对于接受HTG-AP标准药物治疗的血TG>45.2 mmol/L的HTG-AP患者, 首次行PE后血TG水平下降了74.7%; 但在随后的几天内, PE组与药物治疗组在血TG水平上的差异逐渐缩小, 4 d后该差异无统计学意义. 因此, PE可在短时间内迅速降低HTG-AP患者的血TG水平55.6%-74.7%[58-60]. 一项研究报道了1例因脂蛋白脂肪酶基因突变引起乳糜微粒血症综合征且反复发作HTG-AP的患者[61], 在禁食和最大药物剂量治疗下, 血TG仍处于45.2-56.5 mmol/L, 遂接受长期PE治疗, 血浆和血清白蛋白分别作为置换液在降脂作用方面上并无差异; 因此, 建议选择副作用较少和费用较低的血清白蛋白作为血浆替代品; 值得注意的是, 该患者在接受PE治疗后未再复发AP. AP早期死亡的主要原因是全身炎症反应综合征导致的多脏器功能衰竭, 晚期死亡原因为不可控制的感染, 因此单纯降低血TG水平而早期应用PE是不必要的, 而肥胖、止痛剂加量、氧合下降、烦躁不安和重症患者则应早期行PE治疗[62]. 另外, PE存在导管相关感染、气胸和局部出血等不良事件, 甚至出现危及生命的严重过敏反应和低血压[63]. 故PE应严格按照指征用于临床.
3.4.2 其他: 与PE不同, 其他血液净化方法治疗HTG-AP的研究较少, 包括血液灌流、血液滤过、血液透析滤过. 血液灌流是通过固体吸附剂对溶质进行吸附, 以达到血液净化的目的[64]. 血液滤过可通过吸附和/或过筛的方法去除血液循环中的炎性介质[65]. 血液透析滤过结合了血液透析的高效弥散清除小分子和血液滤过的对流移除大分子的优点[66]. Sun等[67]发现, 在口服降脂药物、胰岛素和/或肝素治疗的基础上, 使用血液灌流联合高容量血液滤过的方法治疗HTG-AP患者; 2 h后, 血TG降至10.62 mmol/L, 48 h后, 降至2.92 mmol/L, 且与常规治疗组相比, 白介素和肿瘤坏死因子-α明显下降, 48 h可降至接近正常值水平, ICU时间明显缩短. He等[68]和Lv等[69]的研究中, 患者均接受了常规治疗; 前者对比了早期高容量血液滤过和低分子肝素联合胰岛素对HTG-AP患者降脂疗效的差异, 高容量血液滤过组治疗约9 h即可将血TG降至5.65 mmol/L以下, 而低分子肝素联合胰岛素组需要48 h; 然而, 高容量血液滤过组的器官衰竭发生率及费用较高(P<0.05), 两组在局部并发症发生率、手术率、死亡率和住院时间方面均无差异; 后者使用血浆透析滤过治疗HTG-AP, 一次治疗后, 血TG水平下降了79.06%. Li等[70]的研究发现, 在丹参降脂的基础上, 血液灌流联合血液透析滤过治疗HTG-AP的24 h、48 h和72 h后, 血TG水平分别下降了49.02%、62.81%和69.57%; 随着血TG水平的下降, 患者呼吸和循环也逐渐恢复正常. 综上, 血液净化虽可快速、大幅度地降低HTG-AP患者的血TG水平, 但改善预后的效果仍不确切且成本高昂, 主要推荐用于重症HTG-AP患者的快速降脂.
中西医结合治疗HTG-AP有着较好的疗效. 郭秀红等[71]发现,清胰降脂汤联合西医常规治疗可有效改善HTG-AP患者的临床症状、促进胃肠功能恢复、降低血TG水平及改善胰腺影像学表现. 马林等[72]发现, 降脂清肠汤联合奥曲肽治疗不仅可降低HTG-AP患者的血脂, 还可降低血液黏滞度. 杨成宁等[73]比较了清解化攻方联合西医常规治疗与单用西医常规治疗对瘀毒互结型HTG-AP的临床疗效; 联合治疗组的总有效率显著高于西医常规治疗组(90.6% vs 69.7%, P<0.05), 联合治疗7 d后血TG水平下降了77.1%, 且并发症发生率更低. 因此, 中西医结合治疗HTG-AP疗效较好, 且副作用少; 但不同中医之间差距较大, 且中药需个体化治疗, 目前仍缺少多中心大样本的研究, 难以确定统一的用药规范.
指南[1]建议轻症AP至少随访6 mo, 中重症AP和SAP至少随访18 mo, 每6 mo评估胰腺功能, 并注意高脂血症等病因是否去除. 高TG是HTG-AP复发的危险因素, TG≥11.7 mmol/L的患者的复发率显著高于TG<11.7 mmol/L的患者[74]. Ding等[14]发现, TG≥5.65 mmol/L的患者的复发率是TG<5.65 mmol/L的患者的两倍; 出院后继续服用降脂药物>1年的患者与用药<1 mo的患者相比, HTG-AP复发率下降了75%. 因此, 出院后有必要持续控制血脂.
HTG-AP的发病与血TG水平成正相关, 且血TG水平越高, 患者病情越严重. 快速降低血TG是治疗HTG-AP的关键. 降脂方法多样, 最基础的饮食调整不应忽视; 药物降脂的方法简便, 但起效相对慢; PE是降脂最快的方法, 但成本高昂; 低分子肝素联合胰岛素可显著降低血TG, 但在减轻炎症方面上不如PE; 中西医结合治疗降脂效果稳定, 但仍需更多前瞻性研究证实其疗效, 出院后仍需控制血脂以减少复发. 目前仍需进一步明确HTG-AP的发病机制, 并建立治疗HTG-AP及预防复发的有效方法.
学科分类: 胃肠病学和肝病学
手稿来源地: 辽宁省
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科学编辑:张砚梁 制作编辑:张砚梁
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