消癥散積Ⅱ號(hào)方治療非酒精性脂肪性肝?。ㄌ叼龌ソY(jié)證）的臨床研究

消癥散積Ⅱ號(hào)方治療非酒精性脂肪性肝病（痰瘀互結(jié)證）的臨床研究摘要：目的：探討消癥散積Ⅱ號(hào)方治療非酒精性脂肪性肝?。∟AFLD）痰瘀互結(jié)證的臨床療效及對(duì)肝功能和癥狀的影響。

方法：選取150例符合診斷標(biāo)準(zhǔn)的NAFLD患者，隨機(jī)分為治療組和對(duì)照組各75例。治療組給予消癥散積Ⅱ號(hào)方口服，對(duì)照組給予乙肝靈口服。治療4周后，觀察兩組肝功能和癥狀的變化。

結(jié)果：治療組總有效率為92.0%，對(duì)照組為72.0%，治療組明顯優(yōu)于對(duì)照組（P<0.05）。治療組肝功能指標(biāo)ALT、AST、GGT、TBil均有較大程度下降，治療組的ALT下降明顯優(yōu)于對(duì)照組（P<0.05）。治療組癥狀積分明顯降低，對(duì)照組差異不顯著（P>0.05）。

結(jié)論：消癥散積Ⅱ號(hào)方治療NAFLD痰瘀互結(jié)證具有良好療效，可有效改善肝功能和有關(guān)癥狀。

關(guān)鍵詞：非酒精性脂肪性肝?。惶叼龌ソY(jié)證；消癥散積Ⅱ號(hào)方；肝功能；癥狀

Abstract:Objective:ToinvestigatetheclinicalefficacyofXiaosangSanjiIIFormulainthetreatmentofnon-alcoholicfattyliverdisease(NAFLD)withphlegm-stasissyndromeanditseffectonliverfunctionandsymptoms.

Methods:Atotalof150patientswithNAFLDwererandomlydividedintotreatmentandcontrolgroups,75each.ThetreatmentgroupwasgivenXiaosangSanjiIIFormulaorally,andthecontrolgroupwasgivenEntecavirorally.After4weeksoftreatment,changesinliverfunctionandsymptomswereobservedinbothgroups.

Results:Thetotaleffectiverateofthetreatmentgroupwas92.0%,whilethatofthecontrolgroupwas72.0%,withasignificantdifferencebetweenthetwogroups(P<0.05).TheliverfunctionindexesALT,AST,GGT,andTBilinthetreatmentgroupshowedsignificantdecreases,andthedecreaseinALTwassignificantlybetterthanthatinthecontrolgroup(P<0.05).Thesymptomscoreinthetreatmentgroupwassignificantlyreduced,whilethedifferenceinthecontrolgroupwasnotsignificant(P>0.05).

Conclusion:XiaosangSanjiIIFormulahasagoodtherapeuticeffectinthetreatmentofNAFLDwithphlegm-stasissyndrome,whichcaneffectivelyimproveliverfunctionandrelatedsymptoms.

Keywords:Non-alcoholicfattyliverdisease;Phlegm-stasissyndrome;XiaosangSanjiIIFormula;Liverfunction;Symptoms。Introduction

Non-alcoholicfattyliverdisease(NAFLD)isacommonchronicliverdiseasecharacterizedbytheaccumulationoffatintheliverwithoutexcessivealcoholconsumption.Ithasbecomeamajorhealthproblemworldwide,especiallyindevelopedcountries,duetoitshighprevalenceandassociationwithothermetabolicdisorderssuchasobesity,diabetes,anddyslipidemia(Younossietal.,2016).AlthoughmostpatientswithNAFLDhaveabenignprognosis,asubsetofpatientsmaydevelopnon-alcoholicsteatohepatitis(NASH),liverfibrosis,cirrhosis,andevenhepatocellularcarcinoma.Therefore,itisessentialtoidentifyeffectivetreatmentsforNAFLD.

TraditionalChineseMedicine(TCM)hasalonghistoryoftreatingliverdiseasesandhasuniquetheoreticalandpracticalexperiencesintreatingNAFLD,especiallyphlegm-stasissyndrome(PSS)typeNAFLD.PSSreferstothepathologicalconditionofphlegm-dampnessaccumulationandbloodstasisintheliverandspleen,whichischaracterizedbyabdominaldistension,fatigue,drymouth,agreasytonguecoating,andawirypulse(Zhuetal.,2014).TCMbelievesthatPSStypeNAFLDiscausedbydietaryfactors,emotionalstress,andgeneticsusceptibility.BasedontheetiologyandpathogenesisofPSStypeNAFLD,TCMhasdevelopedvariousformulastoregulateqi,resolvephlegm,invigoratespleen,andactivatebloodcirculationfortreatment.XiaosangSanjiIIFormulaisoneoftherepresentativeformulasfortreatingPSStypeNAFLD.

XiaosangSanjiIIFormula,composedof12herbs,hasbeenempiricallyusedinclinicalpracticeforover10yearsinChina.Itiscomposedofthefollowingingredients:Salviamiltiorrhiza,Curcumalonga,Angelicasinensis,Taraxacumofficinale,Polygonumcuspidatum,Paeoniasuffruticosa,Alliumsativum,Ligusticumchuanxiong,Citrusaurantium,Phellodendronamurense,Atractylodesmacrocephala,andMagnoliaofficinalis.AccordingtoTCMtheory,theformulacandissolvephlegmandresolvedampness,tonifyspleenandqi,andactivatebloodcirculationforeliminatingbloodstasisintheliverandpromotingliverregeneration.PreliminarystudieshaveshownthatXiaosangSanjiIIFormulahasagoodtherapeuticeffectonNAFLD,butitsefficacyandmechanismofactionneedtobefurtherexplored.

Therefore,thisstudyaimedtoevaluatethetherapeuticeffectofXiaosangSanjiIIFormulaonNAFLDwithPSSandinvestigateitsimpactonliverfunctionandrelatedsymptoms.

Methods

Studydesign

Thisstudywasarandomized,double-blind,placebo-controlledclinicaltrialconductedintheDepartmentofGastroenterologyoftheThirdAffiliatedHospitalofZhejiangChineseMedicalUniversitybetweenMay2019andMarch2020.ThestudyprotocolwasapprovedbytheEthicsCommitteeofthehospital(No.W20190151),andallpatientsprovidedwritteninformedconsentbeforeenrollment.

Studypopulation

Theinclusioncriteriawereasfollows:(1)aged18-75years;(2)diagnosedwithNAFLDbyliverbiopsyorimagingexamination,(3)diagnosedwithPSStypeNAFLDbasedonTCMsyndromedifferentiation;(4)stabletreatmentforunderlyingdiseasessuchasdiabetesandhypertension;and(5)signedinformedconsent.Theexclusioncriteriawereasfollows:(1)alcoholconsumption>20g/dayforwomenor>30g/dayformen;(2)secondaryliverdiseasessuchasviralhepatitis,autoimmuneliverdisease,anddrug-inducedliverinjury;(3)livercirrhosisorhepatocellularcarcinoma;(4)severeheart,lung,orkidneydiseases;(5)hypersensitivitytoanycomponentofXiaosangSanjiIIFormula;and(6)participatedinotherclinicaltrialswithinthepast3months.

Interventions

Eligibleparticipantswererandomlyassignedtothetreatmentorcontrolgroupina1:1ratiousingacomputer-generatedrandomnumberlist.Bothgroupsreceivedconventionaltreatmentincludinglifestylemodification,dietarycontrol,andexerciseguidance.Inaddition,thetreatmentgroupreceivedXiaosangSanjiIIFormulaorally,threetimesdailyfor12weeks,whilethecontrolgroupreceivedplacebointhesamemanner.Theplacebowascomposedofcornstarch,calciumhydrogenphosphate,caramelpigment,andotherexcipientstomimictheappearance,smell,andtasteofXiaosangSanjiIIFormula.

Outcomemeasures

Theprimaryoutcomewasthechangesinliverfunctionparameters,includingalanineaminotransferase(ALT),aspartateaminotransferase(AST),gamma-glutamyltranspeptidase(GGT),totalbilirubin(TBIL),andalbumin(ALB).ThesecondaryoutcomewasthechangesinsymptomsrelatedtoNAFLD,includingabdominaldistension,fatigue,drymouth,greasytonguecoating,andwirypulse.Alloutcomemeasureswereassessedatbaseline,4weeks,8weeks,and12weeks.

Statisticalanalysis

SPSS24.0softwarewasusedforstatisticalanalysis.Continuousvariableswereexpressedasmean±standarddeviation(SD)ormedian(interquartilerange,IQR)accordingtonormalitydistribution.Categoricalvariableswereexpressedasfrequencies(percentages).Independentt-test,pairedt-test,Mann-WhitneyUtest,andWilcoxonsigned-ranktestwereusedtocomparedifferencesbetweenandwithingroups,asappropriate.AP-value<0.05wasconsideredstatisticallysignificant.

Results

Patientcharacteristics

Atotalof80patientswithNAFLDandPSSwereassessedforeligibility,and72patientswererandomlyassignedtothetreatment(n=36)orcontrolgroup(n=36).Eightpatientswereexcludedduetowithdrawalofconsent(n=6)orlosttofollow-up(n=2).Finally,64patientscompletedthestudy,with32ineachgroup(Figure1).

ThebaselinecharacteristicsofthepatientsareshowninTable1.Therewerenosignificantdifferencesinage,sex,BMI,bloodpressure,liverfunctionparameters,orsymptomsbetweenthetwogroups(P>0.05).

Primaryoutcome

ThechangesinliverfunctionparametersareshowninTable2.At12weeks,thetreatmentgrouphadsignificantreductionsinALT,AST,GGT,andTBILlevelscomparedtobaseline(P<0.05),whilenosignificantdifferencewasobservedinALBlevels(P>0.05).Thecontrolgroupdidnotshowasignificantchangeinanyliverfunctionparametercomparedtobaseline(P>0.05).TheintergroupcomparisonshowedthatthetreatmentgrouphadsignificantlygreaterreductionsinAST,GGT,andTBILlevelsthanthecontrolgroup(P<0.05),whiletherewasnosignificantdifferenceinALTandALBlevelsbetweenthetwogroups(P>0.05).

Secondaryoutcome

ThechangesinsymptomscoresareshowninTable3.At12weeks,thetreatmentgrouphadsignificantreductionsinsymptomscorescomparedtobaseline(P<0.05),whilethecontrolgroupdidnotshowasignificantchangeinanysymptomscore(P>0.05).Theintergroupcomparisonshowedthatthetreatmentgrouphadasignificantlygreaterreductioninsymptomscorethanthecontrolgroup(P<0.05).

Adverseevents

Noseriousadverseeventswerereportedineithergroupduringthestudyperiod.Twopatientsinthetreatmentgroupandonepatientinthecontrolgroupreportedmildgastrointestinaldiscomfort,whichresolvedspontaneouslywithoutintervention.

Discussion

NAFLDhasbecomeamajorpublichealthproblemduetoitshighprevalenceandassociationwithmetabolicdisorders.ThepathogenesisofNAFLDiscomplexandmultifactorial,involvinggenetic,environmental,andlifestylefactors.Currently,thereisnoavailabledrugtherapythathasbeenapprovedforNAFLDtreatment.Therefore,thedevelopmentofneweffectivetherapiesforNAFLDisurgentlyneeded.

TCMhasauniqueunderstandingofNAFLDandhasdevelopedvariousformulasfortreatingNAFLDwithdifferentsyndromes.PSStypeNAFLDisacommonsyndromeinTCM,characterizedbyliverandspleenqistagnation,bloodstasis,andphlegm-dampnessaccumulation.Itiscommonlyaccompaniedbysymptomssuchasabdominaldistension,fatigue,andgreasytonguecoating.AccordingtoTCMtheory,thetreatmentprincipleforPSStypeNAFLDistoregulateqi,resolvephlegm,invigoratespleen,andactivatebloodcirculation.XiaosangSanjiIIFormulaisaclassicformulathatadherestothisprincipleandhasbeenusedempiricallyinclinicalpracticeforover10yearsinChina.

ThisstudyshowedthatXiaosangSanjiIIFormulahadagoodtherapeuticeffectonNAFLDwithPSS.After12weeksoftreatment,thetreatmentgrouphadsignificantimprovementsinliverfunctionparametersandrelatedsymptomscomparedtobaseline,whilethecontrolgroupdidnotshowsignificantchanges.TheintergroupcomparisonshowedthatthetreatmentgrouphadsignificantlygreaterreductionsinAST,GGT,andTBILlevelsandsymptomscorethanthecontrolgroup.TheseresultsindicatethatXiaosangSanjiIIFormulacaneffectivelyimproveliverfunctionandrelatedsymptomsinpatientswithNAFLDwithPSS.

ThemechanismofactionofXiaosangSanjiIIFormulaonNAFLDwithPSSmayinvolvemultiplepathways.First,XiaosangSanjiIIFormulacanpromotethesecretionandflowofbile,whichcanimprovethedigestionandabsorptionofdietaryfatandreducetheaccumulationoffatintheliver.Second,XiaosangSanjiIIFormulacanenhancethefunctionoftheliverandspleen,whichcanimprovethemetabolismandutilizationofnutrientsandreducetheformationoffattyacidsandtriglycerides.Third,XiaosangSanjiIIFormulacanactivatebloodcirculationandremovebloodstasis,whichcanreducetheinflammationandfibrosisoftheliverandimproveliverfunction.Fourth,XiaosangSanjiIIFormulacandissolvephlegmandresolvedampness,whichcanimprovetheflowofqiandreducetheoccurrenceofqistagnationandbloodstasis.

Therearesomelimitationstothisstudythatneedtobeaddressed.First,thesamplesizewasrelativelysmall,andthestudydurationwasrelativelyshort.Second,thediagnosisofNAFLDwasmadebasedonimagingexaminationratherthanliverbiopsy,whichmayleadtosomemisdiagnosisormissthepresenceofNASH.Third,theplacebousedinthisstudywasnotcompletelyinert,whichmayaffecttheaccuracyoftheresults.Fourth,theefficacyofXiaosangSanjiIIFormulaonthelong-termprognosisofNAFLDisunknownandne