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1、Related problems on clinical application of plasma lipids assayn nProfessor Professor zhouzhou xinxin n nDepartment of Laboratory Medicine,Department of Laboratory Medicine,n nZhongnan Zhongnan hospital of hospital of wuhanwuhan university.university.n nDr.Dr.ShengSheng-kaikai YanYan,PhD,PhDn nDepar
2、tment of Laboratory Medicine,Department of Laboratory Medicine,n nPeking Union Medical College HospitalPeking Union Medical College HospitalAll kinds of lipids in plasma were called blood lipidsAll kinds of lipids in plasma were called blood lipids Total cholesterol Total cholesterol，TC TC free chol
3、esterolfree cholesterolcholesterolcholesterol ester ester Neutral fatty Neutral fattytriglyceridetriglyceride，(TG)TG)non non esterifiedesterified fatty acid fatty acid（free fatty acid free fatty acid，FFAFFA）phospholipid phospholipid ,glucolipidglucolipid Lipids were insoluble in water Lipids were in
4、soluble in water,they were transported in the form of,they were transported in the form of lipoproteinlipoproteinPlasmalipidsPlasmalipoproteinLDLLp(a)VLDLIDLHDLstructure of lipoproteinClinicalitemsforlipidsdetectionn ntotal cholesteroltotal cholesterol，TCTCn ntriglyceridetriglyceride，TGTGn nhigh den
5、sity lipoprotein cholesterolhigh density lipoprotein cholesterol，HDL-CHDL-Cn nlow density lipoprotein cholesterollow density lipoprotein cholesterol，LDL-CLDL-Cn napolipoproteinapolipoprotein A1 A1，ApoA1ApoA1 apolipoproteinapolipoprotein B B，ApoBApoBn nlipoprotein(a)lipoprotein(a)n nThe first four it
6、ems were routine test,and The first four items were routine test,and should be carried out in healthy examinations should be carried out in healthy examinations Cinicalitemsforlipidsanalysis(2)nFFAnCerebroside esterceramidenSphingenine SphingomyelinnGalactode-cerebrosideGenotype nApoEgenotypeApoCIII
7、genotypenApoCIIgenotypeApo(a)genotypenLDLRgenotypeVLDLRgenotypenHMGCoARgenotypeSRgenotypeCinicalitemsforlipidsanalysis(3)Preanalytical Factors Affecting Lipid Test ResultsThe following factors may cause preanalytical variationsn nBiological factors Individualbiologicalvariations,gender,age,andrace,e
8、tc.n nLife-style factorsdiet,obesity,smoking,stress,alcohol,andcoffeeintake,andexercise,etc.Behaviourfactors(1)Dietn nTheThe foodfood containingcontaining abundantabundant unsaturated fattyacidcancandecreasedecreasethethelevellevelofofTC,TC,LDL-C,LDL-C,apoBapoB andTG.andTG.n nTheThefoodfoodcontainin
9、gcontainingabundantabundantsaturatedfattyacidcanelevateTC,LDL-C.canelevateTC,LDL-C.n nTheThefoodfoodcontainingcontainingabundantabundantfiberfibercancanreducereducethethelevallevalofTC.ofTC.n nTheThe levelslevels ofof LDL-CLDL-C andand LpLp(a)(a)inin vegetariansvegetarianswerewere lowerlower(37(37,3
10、535 respectively)respectively)thanthan non-non-vegetarians,vegetarians,whilewhileHDL-CHDL-Cwerewerehigherhigherthanthanthatthatofof 1212.Behaviourfactors(2)ObesityTG，TCandLDL-CHDL-CLostweightTG（40）TC（10）LDL-C（10）HDL-C（10）Smoking TG,LDL-CandLp(a)apoAandHDL-CHDL-CBehaviourfactors(3)Behaviourfactors(4)
11、AlcoholAlcohol abuse abusenHDL-C,apoA,apoA（1.2oz/dor34g/d）nPrimry hypertriglyceridemia with mild drinkingcanleadtothelevelofTGincreasedfurther.nAlcoholhasdifferenteffectsonLp(a)fromotherlipids.atthebeginLp(a)33%sixweekslaterLp(a)backtoinitiallevelnProperdrinkingredwinecandecreasethelevelofLp(a).Beha
12、viourfactors(5)nCoffee TCandLDL-CapoA,apoA,apoBandHDL-Cseemednotbeaffected.nTensionTCHospitalizationHDL-CandapoA(10)Behaviourfactors(6)ExerciseTG、LDL-CandapoBHDL-CandapoAThedegreewasrelatedtothekindsofsportsandintensity.IntenseexercisescanincreasethelevelofHDL-Cobviously.Moderateregularexerciseswasa
13、idealwaytodecreasethelevelofbloodlipid.Normalexerciseshavenoinfluencesonthelevelof Lp(a)，while intense physical activitycanincreasethelevelofLp(a)by1015.Clinical factorstherapeuticdrugs(1)Antihypertensive Antihypertensive agentsagentsnforexamplethiagine（diuresisdrug）canincreasethelevelofTC,LDL-C,TGa
14、ndapoBby12%、20%,7%,20%respectively,decreasethelevalofapoAIandHDL-Cby6%and16%.nBeta-neg（receptorblocker）canincreasethelevelofTGanddecreasethelevalofHDL-C.EstrogenEstrogennOraltakingcontraceptivewithprogesteronecanincreasethelevalofTCandLDL-C,anddecreasethelevalofHDL-C.nEstrintreatmentcandecreasethele
15、valofLp(a)by50%.nImmunosuppressive agentsCodelcortoneCodelcortonecanincreasethelevelofTC,LDL-C,canincreasethelevelofTC,LDL-C,HDL-C,HDL-C,TG,TG,apoAapoAandandapoBapoB.CiclosporinCiclosporincanincreasethelevelofTC,LDL-C,canincreasethelevelofTC,LDL-C,apoBapoB，anddecreasethelevelofanddecreasethelevelofL
16、pLp(a).(a).TacrolimusTacrolimusFK506candecreasethelevelofTC.FK506candecreasethelevelofTC.Clinical factorstherapeuticdrugs(2)The division of abnormal lipids level ThelipidlevelwasdiverseindifferentnationandThelipidlevelwasdiverseindifferentnationandarea.Ithasbeensuggestedthatthelevelwhicharea.Ithasbe
17、ensuggestedthatthelevelwhichcanincreasetheriskofCHDobviouslyshouldcanincreasetheriskofCHDobviouslyshouldserveasthedivisionstandardforabnormallevelserveasthedivisionstandardforabnormalleveloflipid,meanwhileweclaimtoformulatetheoflipid,meanwhileweclaimtoformulatethetherapeuticsdestinationandintervenet
18、hetherapeuticsdestinationandintervenetheprocedureaccordingtothelevel.procedureaccordingtothelevel.suggestionssuggestionsn nAdoptthestandardsofAdoptthestandardsofsuggestions on suggestions on prevention and cure lipid abnormality in chinaprevention and cure lipid abnormality in china.RiskrateTCandCHD
19、PlasmaTC Medical decision level for lipid assay mmol/L(mg/dl)n nindexindex chinachina（19971997）NCEP-ATPNCEP-ATP n nSerum TCSerum TCn nSuitbleSuitble levalleval5.20(200)5.20(200)5.20(200)5.20(200)n nmarginemargineincrease5.23-5.69(201-219)5.20-6.21(200-239)increase5.23-5.69(201-219)5.20-6.21(200-239)
20、n nIncreseIncrese5.72(220)6.24(240)5.72(220)6.24(240)n nSerum LDL-CSerum LDL-Cn nSuitbleSuitble levalleval3.12(120)3.12(120)3.38(130)3.38(130)n nmarginemargineincrease3.15-3.61(121-139)3.38-4.13(130-159)increase3.15-3.61(121-139)3.38-4.13(130-159)n nIncreseIncrese3.64(140)4.16(160)3.64(140)4.16(160)
21、n nserum HDL-Cserum HDL-Cn nSuitbleSuitble levalleval 1.04(40)1.56(60)Isa1.04(40)1.56(60)Isan nnegativeriskfactorofCHDnegativeriskfactorofCHDn nDecreseDecrese 0.91(35)0.91(35)0.91(35)Isa0.91(35)Isan nriskfactorofCHDriskfactorofCHDn nSerum TGSerum TGn nSuitbleSuitble levalleval1.70(150)1.70(150)2.26(
22、200)2.26(200)n nmarginemargineincrease2.26-4.52(200-400)increase2.26-4.52(200-400)n nIncreseIncrese 1.70(150)1.70(150)4.52(400)4.52(400)The classification of lipid level in ATP-III of the American National choleterol education project,mmol/L(mg/dl)n nLDL-CTCHDL-CTGLDL-CTCHDL-CTGlevallevaljudgementju
23、dgement 2.59(100)5.20(200)1.70(150)2.59(100)5.20(200)6.24(240)1.56(60)2.265.64(200499)high4.164.89(160189)6.24(240)1.56(60)2.265.64(200499)highn n 4.92(190)4.92(190)5.65(500)very5.65(500)veryhighhighn n1.04(40)low(a)300300mg/Lwasabnormal(recommend)mg/Lwasabnormal(recommend)LpLp(a)isanindependentrisk
24、factorof(a)isanindependentriskfactorofatherosclerosisatherosclerosisn nLpLp(a)increased(a)increasedAcutephasereactionAcutephasereaction:AMI,operation,acutewoundAMI,operation,acutewound、acuteinflammation,laststageofacuteinflammation,laststageofnephrosisnephrosis，nephroticsyndrome，maglinantmaglinanttu
25、morexceptforlivercancertumorexceptforlivercancer，pregnancyandsoon.Cinical significance of lipid assay(6)n nThe risk of AS was higher in low HDL-Canemia.n nThelowerthelevelofHDL-C,thehighertheriskofAS.n nWhentheHDL-Cdecreasedby1%,theriskofCHDmightincreaseby2%.Cinical significance of lipid assay(7)Pro
26、gressionRegression?HDLLDLVLDLIDLLp(a)RLPImgoodIftreatable,werenotthatbad!TheGoodTheGoodTheBadTheBadTheUgly?TheUgly?Plasma HDL-C level was affected by following diseasessecondary secondary：acutedisease:acutedisease:AMIAMI、operation,operation,adustumadustum、acuteacuteinflamationinflamationdietwithlowf
27、atandhighsugardietwithlowfatandhighsugarsmoking,obesitysmoking,obesityhypomotilityhypomotility hormonedecreasehormonedecreasedrug:drug:receptorblockingreceptorblockingphamaconphamaconsecondarysecondary ：alcohol abuse alcohol abuse primary biliary cirhosisprimary biliary cirhosisCETP activity increas
28、e CETP activity increase HTGL activity decreaseHTGL activity decrease drug-induced drug-induced：ACHACH、insulininsulin、estrogenestrogen、Micotinamide and its inductor Micotinamide and its inductor、HMG-CoA reductase blockerHMG-CoA reductase blocker、chlorinated hydrocarbonschlorinated hydrocarbons prima
29、ryprimary：Tanger deseaseTanger desease LCAT deficiency LCAT deficiency apoA apoAsbnormalitysbnormality familial hypercholesterolemia familial hypercholesterolemia famililial compated hyperlipidemia famililial compated hyperlipidemiaprimaryprimary：CETP deficiencyCETP deficiency HTGL hypoactivityHTGL
30、hypoactivity（macula opacitymacula opacity）apoA1 synthesis accentonapoA1 synthesis accenton HDL receptor abnormalityHDL receptor abnormalityHDL-C decreasedHDL-C decreasedHDL-C inceasedHDL-C inceasedhereditaryLipidmetabolicdisorderlipoproteingenedeficiencylipoproteinreceptorgenedeficiencylipidmetaboli
31、cenzymegenedeficiencycytolysosomelipidmetabolismenzymegenedeficiencyCinical significance of lipid assay(8)forinstance:Lysosomalhydrolasehereditarydefect,phospholipidmetabolismdisorderwereverycommon.Gene analysis of lysosomal storage disease The Structure and Function of LysosomeLysosomewassuchakindo
32、forganellelikeafilminthecell,withacystiformstructure,anditcontainedmanykindsofhydrolase,itworkedsothatitcanbreakdownmanykindsofendogenousandexogenoussubstance,soitwasalsoconsideredasapepticinthecell.Phospholipid could be divided into glycerophospholipideandsphingolipid;thelattercouldbedividedintosph
33、ingomyelinandglycosylsphingolipid.Thelysosomecontainedabout50kindsofhydrolase,suchasprotease,nuclease,glycosidase,lipase,phosphatase,phosphonolipidaseandsulfatidaseetc.鞘脂代谢Sphingolipid metabolismLysosomal lipids storage disordersdiseaseEnzymendefectEnzymendefectStoredlipidStoredlipidClinicalsymptom(
34、Fucosidosis)(Fucosidase)genelocus:1p34Cer-Glc-Gal-GalNAc-Gal-FucH-alloantigen(H-lsoantigen)cerebrumdegenerate，Convulsivetic，(Generalizedgangliosidosis)(GM1-galactosidase)genelocus:3pter-p21Cer-Glc-Gal(NeuAc)-GalNA-Gal(GM1Ganglioside)mentalaphrenia，skeletondeformhepatauxe，(Tay-Sachsdisease)(Hexosamin
35、idaseA)genelocus:15q13.1Cer-Glc-Gal(NeuAc)-GalNAc(GM2Ganglioside)mentalaphrenia，acroisaamyastheniaMetachromaticleukodystrophy,MLD)(ArysulfataseA)genelocus:10q21.1Cer-Gal-OSO3(3-suffogalactosyl-ceramide)mentalaphrenia，mentalretardateinadult，demyelination(Krabbesdisease)(-Galactosidase)genelocus:14q31
36、Cer-Gal(Galactosylceramide)mentalaphrenia:nearlynomyelin(Gaucherdisease,GD)(-Glucosidase,-glu)genelocus:1q21.1Cer-Glc(Glucosylceramidsplenohepatomegalia，Bone causticize，mental retardate inyougechild(Niemann-Pickdisease)(Sphingomyelinase,ASM)genelocus:11p15.1-p15.4Cer-_P-(Sphingomyelin)splenohepatome
37、galmentalretardateDieinyougechild(Farberdisease,)(Ceramidase)Acyl-(Ceramide)Acyl-(Ceramide)NeuAc,(N-acetylneuraminic acid)；Cer，(ceramide)；Glc，(glucose)；Gal,(galactose)；Fuc，(fucose)；-enzyme action site pletephysicalexamination2.cytologicalexaminationofmarrowandperipheralbloodcellsmainlyfindingthelarg
38、efoamcells.3.determinationofroutinebiochemicalindicatorespeciallythelipidlevelandfunctionalexaminationofliverandkidney.Laboratory diagnosis of hereditary lysosomal lipids storage diseaseGauchercellNiemann-Pickcell？4.lysosomal enzyme activity assayvChitotriosidase,CT ToidentifydiagnosisofLipidsStorag
39、eDiseaseGaucherdiseaseincreasedlightlyNiemann-Pickdiseasemorethan100timesvSphingomyelinase To confirm the diagnosis of Niemann-Pickdisease.vGlucocerebrosidase ToConfirmthediagnosisofGaucherdisease.5.High performance liquid chromatogram,HPLCTo analyze the composition of lipids To detect the enzymes a
40、ctivity 6.Physical examination To check up the pathological changes of liver,spleen,skeleton and brain.7.Gene analysis If the basic mutations resulted in the substitution of amio acids or the nucleotide depletions and/or insertions were identified,you can get a final diagnosis.Thelipiddetectionwhile
41、thelevelofTCwasnormalSerum:TC=VLDL-C+LDL-C+HDL-CSerum:TC=VLDL-C+LDL-C+HDL-Cfor instancefor instance：A and B were two person taken healthy examinationA and B were two person taken healthy examinationn n TC=VLDL-C+LDL-C+HDL-CTC=VLDL-C+LDL-C+HDL-C A.TC=0.5 +2.9 +1.7 =5.1 A.TC=0.5 +2.9 +1.7 =5.1 B.TC=0.
42、6 +3.7 +0.8 =5.1 B.TC=0.6 +3.7 +0.8 =5.1 A.TC is normal HDL-C 0.9mmol/L LDL-C0.9mmol/L LDL-C3.12 B.TC is normal HDL-C0.9 B.TC is normal HDL-C3.12/L LDL-C3.12n nSo B have a higher risk of AS than A.So B have a higher risk of AS than A.LipoproteinswhichresultedinAS n CM and VLDL remnantsn Modified LDL
43、n Small dense LDL n Lp(a)LiverArteryTransportationofTCPhysiologicalfunctionsofHDLandLDLTransportationofTC Non-HDL-C n nInATPInATP,non-HDL-Cwasrecommendtoregard,non-HDL-CwasrecommendtoregardasasecondtreatmenttargetforhighTGpatient.asasecondtreatmenttargetforhighTGpatient.n nWhenthechieftreatmenttarge
44、tarrived,whiletheWhenthechieftreatmenttargetarrived,whilethelevelofTGwasstilllevelofTGwasstillhigh(TGhigh(TG 2.262.26mmolmmol/L),/L),non-HDL-Cshouldbeassistedinnon-HDL-Cshouldbeassistedinminitoringminitoring therapeuticefficiencytherapeuticefficiencyn nInATPInATP,Patient,TGwasinmarginal,Patient,TGwa
45、sinmarginal(1.702.25mmol/L),wassuggestedtochangelife(1.702.25mmol/L),wassuggestedtochangelifestyle,andneednttocalculatenon-HDL-C.style,andneednttocalculatenon-HDL-C.The standard value and target value for hyperlipidimia received treatment (China 1997)AS(-)TC TC 5.72 5.72 mmol/Lmmol/LOther risk （220.
46、0mg/dl 220.0mg/dl）factor(-)Ldl-c Ldl-c 3 3.6.64 4 mmol/Lmmol/L （140.0mg/dl 140.0mg/dl）AS(-)TC TC 5.2 5.2 mmol/L mmol/L Other risk Other risk （200.0mg/dl 200.0mg/dl）factor(+)Ldl-c Ldl-c 3 3.1212 mmol/Lmmol/L （120.0mg/dl 120.0mg/dl）AS(+)TC TC 4.68 mmol/L 4.68 mmol/L （180.0mg/dl 180.0mg/dl）Ldl-c Ldl-c
47、3 3.6.64 4 mmol/Lmmol/L （100.0mg/dl 100.0mg/dl）Drug therapyDrug therapyDietDietTarget valueTarget valueTC TC 6.24 6.24 mmol/Lmmol/L（240.0mg/dl 240.0mg/dl）Ldl-c Ldl-c 4 4.1 16 6 mmol/L mmol/L （160.0mg/dl 160.0mg/dl）TC TC 5.72 5.72 mmol/Lmmol/L（220.0mg/dl 220.0mg/dl）Ldl-c Ldl-c 3 3.6.64 4 mmol/L mmol/
48、L （140.0mg/dl 140.0mg/dl）TC TC 5.20 5.20 mmol/Lmmol/L（200.0mg/dl 200.0mg/dl）Ldl-c Ldl-c 3 3.1212 mmol/L mmol/L （120.0mg/dl 120.0mg/dl）TC TC 5.725.72 mmol/Lmmol/L（220.0mg/dl 220.0mg/dl）Ldl-c Ldl-c 3 3.6.64 4 mmol/L mmol/L （140.0mg/dl 140.0mg/dl）TC TC 5.25.2 0mmol/L0mmol/L（200.0mg/dl 200.0mg/dl）Ldl-c
49、Ldl-c 3 3.1212 mmol/L mmol/L （140.0mg/dl 140.0mg/dl）TC TC 4.684.68 mmol/Lmmol/L（180.0mg/dl 180.0mg/dl）Ldl-c Ldl-c 2 2.6.60 0 mmol/L mmol/L （100.0mg/dl 100.0mg/dl）The target value of TLC and drug therapy in different kind of CHD (ATP 2001)RiskclassificationLDL-CLDL-CLDL-CtargetvalueonsetofTLCconsider
50、ingdrugtreatmentCHDorotherdangersign20%）100mg/dl100.0mg/dl100.0mg/dl）2.592.59.3 3.36mmol/L36mmol/Lconsideringifdrugtreatmentneeded2riskfactor3,363,36mmolmmol/L/L3,363,36mmolmmol/L/L10years-risk10%-20%(3,363,36mmolmmol/L)/L)10years-risk20%130mg/dl130mg/dl10years-risk10%(4,144,14mmolmmol/L)/L)01riskfa