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        肝性腦病中醫(yī)/壯醫(yī)“濁毒致病”理論及防治策略的構(gòu)建與實踐

        2025-03-20 00:00:00吳智鵬張鈺琴姚春王明剛王娜彭夢如磨寧芳鄭婭晴張榮臻毛德文
        臨床肝膽病雜志 2025年2期

        摘要:肝性腦病為肝病領(lǐng)域的疑難危重疾病,進展迅速、治療手段有限、發(fā)病機制亟待突破。選擇合適的防治策略,對于延緩疾病進展、降低發(fā)病率和病死率起到重要作用。本文就中醫(yī)/壯醫(yī)肝性腦病“濁毒致病”理論及防治策略進行述評,提出肝性腦病中醫(yī)/壯醫(yī)“濁毒致病”新學(xué)說,解析“濁”“毒”及“濁毒致病”理論的科學(xué)內(nèi)涵,構(gòu)建肝性腦病“四步曲”防治策略,并以此為基礎(chǔ)延伸出以“四方兩技法”為代表的肝性腦病臨床防治新方案,繼而闡明核心方藥與技法防治肝性腦病的效應(yīng)機制與生物學(xué)基礎(chǔ),以期為肝性腦病的防治提供參考。

        關(guān)鍵詞:肝性腦??;濁毒致??;治療學(xué)

        基金項目:國家自然科學(xué)基金(82160881,82260899);廣西重點研發(fā)計劃項目(桂科AB22035076);廣西中醫(yī)藥大學(xué)“岐黃工程”高層次人才團隊培育項目(202409);廣西中醫(yī)藥大學(xué)桂派中醫(yī)藥傳承創(chuàng)新團隊項目(2022A001);廣西中醫(yī)藥大學(xué)第一附屬醫(yī)院青年拔尖人才培養(yǎng)對象資助項目(院黨字〔2022〕46號)

        Construction and practice of the theory of“turbid toxin pathogenesis”and related prevention and treatment strategies for hepatic encephalopathy in traditional Chinese medicine/Zhuang medicine

        WU Zhipeng1,ZHANG Yuqin2,YAO Chun1,WANG Minggang1,WANG Na1,PENG Mengru1,MO Ningfang1,ZHENG Yaqing3,ZHANG Rongzhen1,MAO Dewen1

        1.First Ward of Hepatology,The First Affiliated Hospital of Guangxi University of Chinese Medicine,Nanning 530023,China;2.School of Pre-clinical Medicine,Guangxi Medical University,Nanning 530021,China;3.Department of Acupuncture and Moxibustion,Guang’anmen Hospital,China Academy of Chinese Medical Sciences,Beijing 100053,China

        Corresponding authors:ZHANG Rongzhen,zhangrongzhen2007@163.com(ORCID:0000-0003-2243-665X);MAO Dewen,mdwboshi2005@163.com(ORCID:0000-0001-9438-9325)

        Abstract:Hepatic encephalopathy is a difficult and critical disease with rapid progression and limited treatment methods in the field of liver disease,and it is urgently needed to make breakthroughs in its pathogenesis.Selection of appropriate prevention and treatment strategies is of great importance in delaying disease progression and reducing the incidence and mortality rates.This article reviews the theory of“turbid toxin pathogenesis”and related prevention and treatment strategies for hepatic encephalopathy in traditional Chinese medicine/Zhuang medicine,proposes a new theory of“turbid toxin pathogenesis”,analyzes the scientific connotations of“turbid”,“toxin”,and the theory of“turbid toxin pathogenesis”,and constructs the“four-step”prevention and treatment strategies for hepatic encephalopathy,thereby establishing the new clinical prevention and treatment regimen for hepatic encephalopathy represented by“four prescriptions and two techniques”and clarifying the effect mechanism and biological basis of core prescriptions and techniques in the prevention and treatment of hepatic encephalopathy,in order to provide a reference for the prevention and treatment of hepatic encephalopathy.

        Key words:Hepatic Encephalopathy;Turbid Toxin Pathogenic;Therapeutics

        Research funding:National Natural Science Foundation of China(82160881,82260899);Guangxi Key Research and Development Plan Project(Guike AB22035076);Guangxi University of Chinese Medicine‘Qihuang Project’High-Level Talent Team Training Project(202409);Guangxi University of Chinese Medicine Inheritance Innovation Team Project(2022A001);The First Affiliated Hospital of Guangxi University of Chinese Medicine Youth Top-Notch Talent Training Object Funding Project(yuandangzi[2022]46)

        肝性腦病是嚴重肝病引起的,以代謝紊亂為基礎(chǔ)、中樞神經(jīng)系統(tǒng)功能失調(diào)為主的臨床綜合征,是重癥肝病常見致死性并發(fā)癥[1]。在我國,肝衰竭并發(fā)肝性腦病的臨床救治最為棘手,有研究顯示肝性腦病發(fā)病3年后存活率僅為23%,降氨、抗炎、醒腦等綜合治療手段尚未能將肝衰竭并發(fā)肝性腦病治療有效率提升至50%以上[2]。近年來,肝性腦病綜合治療手段得到了長足的發(fā)展,但現(xiàn)代醫(yī)學(xué)治療肝性腦病的方法尚存在作用范圍有限、不良反應(yīng)較多、經(jīng)濟負擔偏重等不足[3]。傳統(tǒng)中醫(yī)/壯醫(yī)具有一定的療效與經(jīng)濟優(yōu)勢,但也存在著對病因病機及病位的認識尚未清晰、理論創(chuàng)新不足、操作流程欠規(guī)范、療效機制待明確等問題,以致成為阻礙中醫(yī)/壯醫(yī)在肝性腦病防治方面發(fā)揮優(yōu)勢的關(guān)鍵技術(shù)閂鎖。有鑒于此,本課題組歷時近20年潛心攻關(guān),在以中醫(yī)藥為主線的基礎(chǔ)上充分融合廣西壯醫(yī)藥特色優(yōu)勢,形成了肝性腦病的中醫(yī)/壯醫(yī)防治策略。

        1肝性腦病中醫(yī)/壯醫(yī)“濁毒致病”新學(xué)說

        肝性腦病歸屬于中醫(yī)學(xué)“黃疸”“肝厥”等范疇。從古至今,諸多醫(yī)家對肝性腦病中醫(yī)病因病機的認識多受限于“痰蒙神竅”的傳統(tǒng)思維之中[4-5]。壯醫(yī)學(xué)則提出肝性腦病核心致病機制為“毒”邪盤踞,阻滯“三道兩路”致使?jié)岫厩忠u“巧塢”(腦),發(fā)為本?。?]。課題組經(jīng)過長期臨床實踐與大量前期研究,并結(jié)合廣西地域壯醫(yī)藥優(yōu)勢,突破“痰蒙神竅”“毒邪致病”的桎梏,創(chuàng)新性提出完整的肝性腦病“濁毒致病”新學(xué)說,初步厘清“濁”“毒”既是肝性腦病致病之因,又是病理產(chǎn)物,“濁”→“毒”→“濁毒”,由微至極,共同介導(dǎo)了肝性腦病的發(fā)生及發(fā)展[7]。具體來說,肝性腦病基礎(chǔ)疾病在疾病進程中可產(chǎn)生“濕”“熱”“痰”“瘀”等病邪,“濁”是在“濕”“熱”“痰”“瘀”等病邪的基礎(chǔ)上兼夾伴生的病理產(chǎn)物,這些病理產(chǎn)物在體內(nèi)形成后若化解不及時,則可進一步積聚成濁,成濁后進一步阻礙氣機、阻滯血脈及蒙蔽神竅,濁盛而成“毒”,“濁毒”致使肝性腦病典型發(fā)作[5,7]。

        2肝性腦病“濁”“毒”及“濁毒致病”理論的科學(xué)內(nèi)涵

        肝性腦病的發(fā)病機制有待完善,氨中毒學(xué)說、腸道菌群失調(diào)是當前現(xiàn)代醫(yī)學(xué)主流的發(fā)病機制假說[8]。本課題組前期研究即發(fā)現(xiàn)肝性腦病患者氨代謝異常,腸道菌群紊亂及腸道微環(huán)境改變與肝性腦病的發(fā)生密切相關(guān)[9-10]?,F(xiàn)代醫(yī)學(xué)中血氨、腸道菌群與中醫(yī)“濁”的概念不謀而合,內(nèi)毒素與中醫(yī)“毒”的概念異曲同工[11]。目前認為,肝性腦病主要源于紊亂腸道菌群和持續(xù)受損的腸道功能障礙,導(dǎo)致血氨、內(nèi)毒素等產(chǎn)生、吸收增多,加之肝功能衰竭,其解毒能力下降,毒素在體內(nèi)高度富集,損害腦神經(jīng)系統(tǒng)而發(fā)?。?]。同時,內(nèi)毒素又可通過刺激單核巨噬細胞產(chǎn)生IL-18、IL-6等細胞炎癥因子,間接引發(fā)炎癥“二次打擊”效應(yīng),導(dǎo)致病情進一步惡化,內(nèi)毒素血癥發(fā)展為炎癥“二次打擊”效應(yīng)介導(dǎo)了肝性腦病的發(fā)病或者病情加重的過程,可視為由“濁”→“毒”→“濁毒”嬗變的過程[11]。從免疫應(yīng)激損傷、血氨累積、腸道菌群紊亂等層面闡明肝性腦病“濁”“毒”及“濁毒致病”理論的科學(xué)內(nèi)涵,為肝性腦病臨床治療提供了新思路。

        3肝性腦病“四步曲”防治策略(圖1)

        3.1第一步曲:“濁邪”未成,使邪有出路,防諸邪日久生濁(潛伏期)該階段“濁邪”未成,尚未見“濁邪”上擾神明、蒙蔽清竅之癥,以處理肝臟基礎(chǔ)疾?。ǜ斡不⒏伟?、肝衰竭)所生“濕”“痰”“瘀”諸邪為主,兼顧患者久病體虛為輔。運用“祛濕”“化痰”“化瘀”“補虛”等法從源頭上干預(yù),既有迎頭抗邪之功,又有防芽遏萌之妙。方選三仁分消飲,方中酌用杏仁、白蔻仁、陳皮、石菖蒲、薏苡仁祛濕化痰,郁金、赤芍、丹參活血化瘀,紅景天、白術(shù)、茯神兼能補虛,根據(jù)諸邪側(cè)重,辨證施藥,祛原發(fā)疾病之邪,避免日久產(chǎn)生濁邪[12]。

        3.2第二步曲:“濁邪”初成,宣暢三焦、降氣化濁,遏邪于萌芽(前驅(qū)期)該階段諸邪日久初生“濁邪”,易擾心神、蒙蔽腦竅,臨床癥見夜寐不安,欣快激動或淡漠少言。此時“濁邪”尚輕,尚易化解,但有邪勢漸升之虞,故治當宣暢三焦,降氣化濁,可予六味醒神顆粒治之。方中膽南星、石菖蒲豁痰開竅,清三焦流竄濁邪;法半夏、枇杷葉燥濕化痰,清上焦肺氣以降濁邪;白術(shù)、茯神健脾化濕化中焦?jié)嵝埃?3]。

        3.3第三步曲:“濁毒”俱蕃,清熱解毒、化濁開竅,驅(qū)濁毒之邪盡出(發(fā)作期)該階段“濁毒”俱蕃,流竄心腦,狂、躁、昏俱備?;颊叱霈F(xiàn)神志改變拒絕服藥,首當解毒化濁、通腑開竅,驅(qū)濁毒之邪盡出,運用大黃煎劑保留灌腸,使?jié)岫局皬南露?,并?lián)合運用壯醫(yī)針刺療法針刺雙側(cè)貓爪尖穴(十指指尖)解毒化濁、開竅醒神,先解“拒藥”之慮。內(nèi)服方藥可予解毒化瘀方,方中大黃、茵陳、白花蛇舌草、赤芍清熱解毒化濁,郁金、石菖蒲解毒化濁開竅[14]。該階段內(nèi)服與外治聯(lián)合多管齊下療效倍加。

        3.4第四步曲:“濁毒”已散,扶正兼顧祛邪,防邪留戀(恢復(fù)期)該階段“濁毒”已散,但邪散正虛,正虛之時,“濁毒”仍可再聚為患。治以扶正補虛、調(diào)節(jié)陰陽為主,兼顧解毒化濁,以防“濁毒”復(fù)聚,可予溫陽化瘀退黃方,方中附片、白術(shù)、薏苡仁補火助陽健脾祛濕以化濁,茵陳、虎杖、赤芍、丹參、郁金清熱涼血活血化瘀以解毒[15]。同時,合用六味醒神顆粒,諸藥共會“扶正兼顧祛邪,防邪留戀”之意。

        4以“四方兩技法”為代表的肝性腦病臨床防治新方案

        肝性腦病臨床癥狀極其復(fù)雜、變化迅速,尤其晚期患者更是諸臟俱損,諸癥并存,虛實夾雜,寒熱錯雜,導(dǎo)致臨床中醫(yī)師難以進行準確的辨證論治,往往是藥到證已改,嚴重影響治療效果穩(wěn)定性。有鑒于此,課題組根據(jù)肝性腦病中醫(yī)/壯醫(yī)病機理論新認識及“四步曲”防治策略,經(jīng)過反復(fù)臨床實踐與優(yōu)化,形成了針對肝性腦病4期病癥辨病論治的系列方藥及治法,具體方藥如下:(1)潛伏期(“濁邪”未成):基本病機為久病體虛,痰、濕、瘀三氣膠結(jié),治療原則為祛痰化濕、扶正化瘀,核心方藥為三仁分消飲;(2)前驅(qū)期(“濁邪”初成):基本病機為濁邪上逆,流竄三焦,治療原則為宣暢三焦、降氣化濁,核心方藥為六味醒神顆粒;(3)發(fā)作期(“濁毒”俱蕃):基本病機為熱毒熾盛、濁邪閉阻清竅,治療原則為清熱解毒,化濁開竅,核心方藥為解毒化瘀方,核心技法為大黃煎劑保留灌腸、壯醫(yī)針刺療法;(4)恢復(fù)期(“濁毒”已散):基本病機為正氣虧虛、恢復(fù)陰陽平衡,治療原則為扶正補虛、調(diào)節(jié)陰陽為主,兼顧解毒化濁,核心方藥為溫陽化瘀退黃方合用六味醒神顆粒。

        5核心方藥及技法防治肝性腦病的效應(yīng)機制與生物學(xué)基礎(chǔ)

        5.1六味醒神顆粒六味醒神顆粒治療肝性腦病可見總有效率從76.0%提高至92.3%,其機制在于降低肝性腦病患者血氨、內(nèi)毒素、細胞炎癥因子水平,通過降低血腦屏障通透性、調(diào)節(jié)腸道菌群代謝,減少內(nèi)毒素血癥的發(fā)生,進而改善患者神經(jīng)生理功能[16]。此外,六味醒神顆??捎行Ц纳聘涡阅X病患者中醫(yī)證候積分、數(shù)字連接試驗-A分值和數(shù)碼符號試驗分值(Plt;0.05),短期療效與乳果糖基本相當[17]。實驗研究與網(wǎng)絡(luò)藥理學(xué)分子對接研究亦發(fā)現(xiàn)六味醒神顆粒能調(diào)控血腦屏障通透性、影響腸道菌群結(jié)構(gòu)及功能代謝,改善肝性腦病患者認知功能障礙[18-19]。

        5.2大黃煎劑保留灌腸多中心、隨機、平行對照臨床研究發(fā)現(xiàn)大黃煎劑保留灌腸治療肝性腦病患者的總有效率由60.83%提高到86.00%,并將患者的蘇醒時間縮短至(7.4±1.5)h以內(nèi),同時降低人均住院費用,整體臨床療效優(yōu)于西藥和傳統(tǒng)中醫(yī)治療方法[20-21]。有研究通過正交實驗方法,對該技術(shù)中的藥液溫度、插管深度、保留時間、灌腸后體位等影響療效的關(guān)鍵性因素的具體參數(shù)進行優(yōu)化研究,形成規(guī)范的臨床操作和護理規(guī)程,可提升臨床療效[22-24]。實驗研究揭示大黃煎劑保留灌腸拮抗肝性腦病的作用機制與調(diào)控PI3K/AKT/mTOR信號通路,改善輕微型肝性腦病大鼠認知功能及腦組織炎癥損傷有關(guān)[25]。基于16S rDNA基因測序和膽汁酸代謝組學(xué)的研究顯示大黃煎劑保留灌腸顯著改善肝性腦病大鼠的肝功能,降低血氨水平,減輕腦水腫并恢復(fù)認知功能,還能逆轉(zhuǎn)腸道菌群紊亂并調(diào)節(jié)膽汁酸代謝[26-27]。

        5.3解毒化瘀方臨床研究表明解毒化瘀方能改善肝性腦病患者智力水平和神經(jīng)電生理學(xué)檢查指標,進而提高患者認知功能與神經(jīng)生理功能,臨床療效優(yōu)于單用乳果糖[28-29]。實驗研究表明解毒化瘀方通過降低血氨水平,促進血氨的代謝及通過保護腦線粒體的結(jié)構(gòu),恢復(fù)腦神經(jīng)元功能以治療肝性腦病[30]。同樣,一項隨機平行對照研究亦表明解毒化瘀方能改善肝性腦病大鼠血漿內(nèi)毒素、血氨、肝臟病理等指標[14]。

        6總結(jié)與展望

        肝性腦病發(fā)病迅速、病情兇險、病死率高。由于肝性腦病的發(fā)病機制尚不完全明確,目前尚無特異性治療方法,因而找到肝性腦病治療的最佳途徑是肝病學(xué)界科研攻關(guān)的熱點與難題,同樣也是需要重點關(guān)注和亟待解決的重大社會公共衛(wèi)生問題。本課題組毛德文教授在前人認識基礎(chǔ)上結(jié)合廣西地域壯醫(yī)藥優(yōu)勢,提出了肝性腦病“濁毒致病”新學(xué)說。在該理論的指導(dǎo)下采用中醫(yī)/壯醫(yī)對肝性腦病進行按疾病分期、分階段辨證次第治療,有望成為肝性腦病防治的新策略。本文為課題組20年間的截斷面研究成果總結(jié),部分方藥與技法的后續(xù)研究還在跟進,今后的研究將繼續(xù)完善核心方藥與技法防治肝性腦病的效應(yīng)機制與生物學(xué)基礎(chǔ);同時,在現(xiàn)有應(yīng)用基礎(chǔ)上,加強核心方藥的轉(zhuǎn)化力度,打造新藥產(chǎn)業(yè)化鏈條,助推疑難重癥疾病中醫(yī)藥治療的新發(fā)展。

        利益沖突聲明:本文不存在任何利益沖突。

        作者貢獻聲明:吳智鵬、張鈺琴負責(zé)撰寫論文;彭夢如、磨寧芳、鄭婭晴參與修改論文;姚春、王明剛、王娜負責(zé)擬定寫作思路;毛德文、張榮臻指導(dǎo)撰寫文章并最后定稿。

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        收稿日期:2024-05-29;錄用日期:2024-06-24

        本文編輯:劉曉紅

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