Mbs127 Slide Dislipidemia

7/28/2019 Mbs127 Slide Dislipidemia

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IntroductionIntroductionDyslipidemiaDyslipidemia is a general term associated withis a general term associated withhigh cholesterol and/or high triglyceride (TG)high cholesterol and/or high triglyceride (TG)levels in plasma.levels in plasma.

Combined DyslipidemiasCombined Dyslipidemias is bothis both cholesterolcholesterol..

Cholesterol and triglycerides are normallyCholesterol and triglycerides are normallypresent in the body and needed forpresent in the body and needed for normal cellnormal cellfunction.function. (steroids, digestion, cell membranes)(steroids, digestion, cell membranes)

Two major clinical sequlae of hyperlipidemia areTwo major clinical sequlae of hyperlipidemia areacute pancreatitisacute pancreatitis andand atherosclerosisatherosclerosis..


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Lipoprotein Subclasses

1.02

1.006

0.95

ty(g/ml)

Ch lomicron

VLDL

IDL

Chylo-

microns

5 10 20 40 60 80 1000

Diameter (nm)

1.20

1.10

1.06

Densi

HDL2

HDL3

Remnants

Lp(a)

LDL


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Functions of the PlasmaLipoproteins

ChylomicronTransport of dietary triglyceride VLDL Transport of endogenous triglyceride

IDL -LDL precursor

HDL Reverse cholesterol transport (GOOD)


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Released into lymph, and reach circulation through thoracic duct


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Apolipoproteins ApoA-I, which is synthesized in the liver and intestine, is

found on virtually all HDL1 particles. ApoA-II is the second most abundant HDL apolipoprotein.

ApoB is the major structural protein of chylomicrons,VLDL2, IDL3, and LDL4; apoB-48 (chylomicrons) or

apoB-100 (VLDL, IDL, or LDL), ApoE is present in multiple copies on chylomicrons,

VLDL, and IDL and plays a critical role in the metabolismand clearance of triglyceride-rich particles.

ApoC-series (apoC-I, -II, and -III) also participate in themetabolism of triglyceride-rich lipoproteins.


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AtherosclerosisAtherosclerosisAtherosclerosis is theAtherosclerosis is the deposit of plaquesdeposit of plaques containing cholesterolcontaining cholesteroland lipids on the innermost layer of the walls of arteries.and lipids on the innermost layer of the walls of arteries.

AtherosclerosisAtherosclerosis is theis the leading cause of deathleading cause of death for both sexesfor both sexesin the US. (in the US. (MI, hypertension,, brain infarct, deathMI, hypertension,, brain infarct, death))

ey r s ac orey r s ac or n t e eve opment on t e eve opment o a erosc eros sa erosc eros s sshigh bloodhigh blood cholesterol.cholesterol.

AmongAmong nonnon--Hispanic whitesHispanic whites age 20 and older, the ageage 20 and older, the age--adjustedadjusted prevalence ofprevalence oftotal blood cholesterol levelstotal blood cholesterol levels overover 200200mg/dLmg/dL isis 48.9 percent of men and 52.1 percent of women.48.9 percent of men and 52.1 percent of women. **

* National Health and Nutrition Examination Survey (NHANES), 1999* National Health and Nutrition Examination Survey (NHANES), 1999--2002, Centers for Disease2002, Centers for DiseaseControl/National Center for Health Statistics.Control/National Center for Health Statistics.


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Pathogenesis of Atherosclerotic PlaquesPathogenesis of Atherosclerotic Plaques

Protective response results in production ofcellular adhesion molecules (ICAM)

Protective response results in production ofcellular adhesion molecules (ICAM)

Monocytes and T lymphocytes attach toMonocytes and T lymphocytes attach to

Endothelial damageEndothelial damage

sticky surface of endothelial cells

sticky surface of endothelial cells

Migrate through arterial wall to subendothelial spaceMigrate through arterial wall to subendothelial space

Lipid-rich foam cellsLipid-rich foam cells

Macrophages take up oxidised LDL-CMacrophages take up oxidised LDL-C

Fatty streak and plaqueFatty streak and plaque


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The inflammatory atherosclerotic processThe inflammatory atherosclerotic process

sdLDL

sdLDL

monocyte

Complex

Lumen of

blood vessel

endothelium

Inflamm

Inflamm

markers,

CRP

MMP-9

MCP-1

PLAQUE

RUPTURE

ox-LDL

chemotaxis

m

O2

foam cell

differentiation

(vu nera e)

plaqueArterywall

IL-6, TNF

ROS-

Smooth muscle

cells

ICAM-1

NFB


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Lipid Levels in ATP III


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Disorder Lipoprotein metabolisme

1. Hypertriglyceride

Primary Hypertriglyceridemia

Secondary Hypertriglyceridemia

2. Primary Familial Hypercholesterolemia

am a yperc o es ero em a Familial combined Hyperlipidemia

Lp (a) hyperlipoproteinemia

3. Secundary Hypercholesterolemia

Obesity, Diabetes, Hypothyroid, Cushing disease, renaldisease


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I. Primary TriglyceridemiasI. Primary Triglyceridemias

HighHigh triglyceride (TG) levelstriglyceride (TG) levels have been epidemiologicallyhave been epidemiologically

linked withlinked with increased risk of coronary diseaseincreased risk of coronary disease..

Often linked withOften linked with elevated VLDL and chylomicronelevated VLDL and chylomicron levels.levels.

TGTG clearanceclearance is dependent onis dependent on lipoprotein lipaselipoprotein lipase..

WhenWhen plasma levels of TGsplasma levels of TGs reach levels reachreach levels reach 800mg/dl800mg/dl

or higher, lipoprotein lipase becomes saturated,or higher, lipoprotein lipase becomes saturated,individuals above that level must be treated to preventindividuals above that level must be treated to preventacute pancreatitisacute pancreatitis..

Niacin and fibric acid derivativesNiacin and fibric acid derivatives areare effectiveeffective treatments.treatments.


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II.II. Familial HypercholesterolemiaFamilial Hypercholesterolemia

Is anIs an autosomal dominantautosomal dominant trait, a defect in thetrait, a defect in the highhighaffinity LDL receptoraffinity LDL receptor..

Homozygous individuals can have serum cholesterolHomozygous individuals can have serum cholesterol

levels as high as 1000mg/dl, leading to childhoodlevels as high as 1000mg/dl, leading to childhooddevelopment of coronary disease.development of coronary disease.

Niacin and Atorvastatin are beneficial, butNiacin and Atorvastatin are beneficial, but bindingbindingresinsresins have fromhave from little to no effect in this disorder,little to no effect in this disorder,

depending on LDL receptor activity.depending on LDL receptor activity.


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III.III. Familial LigandFamilial Ligand--Defective Apolipoprotein BDefective Apolipoprotein B

Defect in ligand region of apo B100 region of LDLDefect in ligand region of apo B100 region of LDL

Impairs the endocytosis of LDL, leading toImpairs the endocytosis of LDL, leading to moderatelymoderately

severe hypercholesterolemiassevere hypercholesterolemias..StatinsStatins havehave variable effectsvariable effects, since even with, since even withupregulation of LDL receptors, defective LDL still cantupregulation of LDL receptors, defective LDL still canttaken up by cells.taken up by cells.

NiacinNiacin producesproduces beneficialbeneficial effects by reducing vLDLeffects by reducing vLDLplasma levels.plasma levels.


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IV. Familial Combined Hyperlipidemia

(The Phenotypic Classification of the Hyperlipoproteinemias basedupon serum electrophoresis are: Types I, IIA, IIB, III, IV and V)

Type I Hyperlipidemia

chylomicrons (triglycerides) results LPL or apo C-II,

LDL.

Type IIB Hyperlipidemia :

of both LDL cholesterol and triglycerides.

Type III Hyperlipidemia

defect in VLDL remnant clearance


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Type IV Hyperlipidemia

- Hypertriglyceridemia 250 and 500 mg/dl.

Type V Hyperlipidemia- chylomicrons and VLDL.

Coronary event, Eruptive xanthomas and pancreatitis


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Symptoms of Hyper Cholesterolemia

High cholesterol rarely causes symptoms.

It is usually detected during a regular blood test

The first symptom of coronary artery disease (CAD) is oftenchest pain (angina).

Unless the person has a transient ischemic attack (TIA), itis rare to have any warning signs of an oncoming stroke.

Some people with lipid disorders or familiallhypercholesterolemia symptoms such as deposits of

excess cholesterol in the skin or eye tissue, nodules intendons in the hands or feet or rarely yellow streaks in thehands.


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Eye signs in HyperlipidaemiaEye signs in Hyperlipidaemia

CORNEAL ARCUS XANTHELASMATA


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Secundary Hypercholesterolemia

Diabetes Mellitus

(1) LPL catabolism of chylomicrons, VLDL.

(2) release of FFA from the adipose tissue(3) FFA synthesis in the liver,(4) hepatic VLDL production.

Hypothyroid

- hepatic LDL receptor function and clearance of LDL.

Cushing Syndrome

- VLDL synthesis and hypertriglyceridemia.

Regular alcohol consumption

- oxidation FFA hepatic syntesis VLDL


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CHD Risk FactorsCHD Risk Factors SmokingSmoking

HTN >140/90 or on HTN MedsHTN >140/90 or on HTN Meds

HDL < 40 mg/dlHDL < 40 mg/dl Family Hx of Premature CHDFamily Hx of Premature CHD

11stst degree Male < 45 yodegree Male < 45 yo

AgeAge

Men > 45 yoMen > 45 yo

Women > 55 yoWomen > 55 yo

DMDM

HDLHDL 60 mg/dl counts as negative Risk Factor60 mg/dl counts as negative Risk Factor


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Risk EquivalentsRisk Equivalents CHDCHD

MIMI AnginaAngina

An io lastAn io last

Bypass SurgeryBypass Surgery

NonNon--coronary Atherosclerotic Diseasecoronary Atherosclerotic Disease

Peripheral Artery DiseasePeripheral Artery Disease

Carotid Artery DiseaseCarotid Artery Disease

DMDM


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TREATMENT OPTIONS FOR

DYSLIPIDEMIA

Lifestyle Changes include:

-reduce CAD risk include smoking cessation,-dietary changes,-weight loss,- .

Dietary changes include:- reducing the intake of saturated fats to less than7% of the diet,

- reducing cholesterol to


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Treatment ParadigmTreatment Paradigm


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Lipid Lowering DrugsLipid Lowering Drugs


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Lipoprotein Effects of Lipid-

modifying TherapyStatins Nicotinic

acidFibrates

LDL 18%-55% 5%-25% 5%-20%

HDL 5%-15% 15%-35% 10%-20%

Triglycerides 7%-30% 20%-50% 20%-50%

Small, dense

LDL

No effect Decrease Decrease

Effect oninsulinresistance

None May increase May increase


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AntiAnti--hyperlipidemic Drugshyperlipidemic Drugs

A. Niacin (Nicotinic Acid)A. Niacin (Nicotinic Acid)

TreatsTreats combined dyslipidemiascombined dyslipidemias

Decreases LDL levels and vLDL levelsDecreases LDL levels and vLDL levels..

PharmacokineticsPharmacokinetics

Rapid absorption, Plasma TRapid absorption, Plasma T1/21/2

-- (20(20--40min)40min)

Water soluble Vitamin BWater soluble Vitamin B33 which is converted in the body intowhich is converted in the body intonicotinamide adenine dinucleotide (NAD).nicotinamide adenine dinucleotide (NAD).

Excreted unchanged as well as a number of metabolites.Excreted unchanged as well as a number of metabolites.

Mechanism primarily involves the inhibition of vLDLMechanism primarily involves the inhibition of vLDLsecretion therebysecretion thereby reducingreducing LDL levels!!LDL levels!!. Also. Alsolowerslowers bothboth triglycerides and Lp(a) levelstriglycerides and Lp(a) levels..


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Niacin (cont)Niacin (cont)Side Effects:Side Effects:

FlushingFlushing, tachycardia, atrial arrhythmias, dry skin, nausea,, tachycardia, atrial arrhythmias, dry skin, nausea,hyperuricemia,hyperuricemia, diarrhea, peptic ulcer disease,diarrhea, peptic ulcer disease, glucoseglucoseintolerance, hepatic dysfunction.intolerance, hepatic dysfunction.

ContraindicationsContraindicationsPeptics ulcers, cardiac arrhythmias,Peptics ulcers, cardiac arrhythmias, liver diseaseliver disease,, goutgout andanddiabetes mellitusdiabetes mellitus

Drug InteractionsDrug InteractionsWorks synergistically with ganglionic blockers leading toWorks synergistically with ganglionic blockers leading toorthostatic hypotensionorthostatic hypotension..


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B. Fibric Acid DerivativesB. Fibric Acid DerivativesGemfibrozil and FenofibrateGemfibrozil and Fenofibrate

Reduces vLDL levelsReduces vLDL levels andand increasesincreases thethe activityactivity ofoflipoprotein lipase!!!lipoprotein lipase!!!..Typically used to treatTypically used to treat hypertriglyceridemiashypertriglyceridemias in which vLDLin which vLDLpredominate and inpredominate and in dysbetalipoproteinemia.dysbetalipoproteinemia.

Lowers triglycerides and raises HDL.Lowers triglycerides and raises HDL.

PharmacokineticsPharmacokinetics

absorbed from the GI tract & undergoes enterohepaticabsorbed from the GI tract & undergoes enterohepaticcirculation. Most (70%) is eliminated unchanged through thecirculation. Most (70%) is eliminated unchanged through thekidneys. Half life is 1.5 hrs.kidneys. Half life is 1.5 hrs.


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Fibric Acid Derivatives (cont)Fibric Acid Derivatives (cont)Side Effects:Side Effects:

rare cases of rash, GI symptoms,rare cases of rash, GI symptoms, myopathy,myopathy,arrhythmias,arrhythmias, hypokalemia & highhypokalemia & high aminotransferase oraminotransferase oralkalinealkaline phosphatase levelsphosphatase levels, risk of, risk of cholesterolcholesterolgallstones.gallstones.

Major drug interactions:Major drug interactions:fibric acid derivativesfibric acid derivatives increase the anticoagulantincrease the anticoagulant effecteffectof coumarin & indanediones.of coumarin & indanediones.

ContraindicationsContraindicationspatients withpatients with hepatic or renal dysfunctionhepatic or renal dysfunction, patients with, patients withbiliary tract diseasebiliary tract disease


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C. Bile Acid Binding ResinsC. Bile Acid Binding Resins

Colestipol and CholestyramineColestipol and CholestyramineDecrease LDL levels, increase HDL and TGsDecrease LDL levels, increase HDL and TGs

Mechanism of Action:Mechanism of Action:

ColestipolColestipol binds bile acidsbinds bile acids in thein the intestineintestine forming aforming acomplex that is excreted in the feces.complex that is excreted in the feces.

This nonsystemic action results in a partial removal of theThis nonsystemic action results in a partial removal of thebile acids from the enterohepatic circulation,bile acids from the enterohepatic circulation, preventingpreventingtheir reabsorption.their reabsorption.

The increased fecal loss of bile acids due to colestipolThe increased fecal loss of bile acids due to colestipolhydrochloride administration leads to anhydrochloride administration leads to an increasedincreased

oxidation of cholesterol to bile acidsoxidation of cholesterol to bile acids..

****** This results in anThis results in an increaseincrease in the number ofin the number of lowlow--densitydensity lipoprotein (LDL) receptorslipoprotein (LDL) receptors,, therebytherebydecreasing serum LDL levelsdecreasing serum LDL levels


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Bile Acid Binding Resins (cont)Bile Acid Binding Resins (cont)

Pharmacokinetics:Pharmacokinetics:Not absorbed!!!Not absorbed!!!

Side EffectsSide EffectsConstipationConstipation,, may cause an increase in vLDLmay cause an increase in vLDLnecessitating the addition of a 2necessitating the addition of a 2ndnd agent such as niacin.agent such as niacin.Bad tastingBad tasting may lead to compliance issues.may lead to compliance issues.ne ect vene ect ve nn omozygous am a c o esterem aomozygous am a c o esterem a due todue to

lack of LDL receptor.lack of LDL receptor.

Drug interactions:Drug interactions:may delay or reduce the absorption of other concomitant oralmay delay or reduce the absorption of other concomitant oral

medicationsmedications

Because these resins bind bile acids theyBecause these resins bind bile acids they may interfere withmay interfere withnormal fat digestion and absorptionnormal fat digestion and absorption and thus may preventand thus may preventabsorption of fat soluble vitamins such asabsorption of fat soluble vitamins such as A, D, E, and K.A, D, E, and K.


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D. HMGD. HMG--CoA Reductase InhibitorsCoA Reductase Inhibitors

StatinsStatinsThey are structural analogues ofThey are structural analogues of hydroxyhydroxy--methylmethyl--glutarylglutaryl

coenzyme Acoenzyme A (HMG(HMG--CoA) and areCoA) and are competitivecompetitive

inhibitorsinhibitors ofof HMGHMG--CoA reductase!!CoA reductase!!..

Used primarily for theUsed primarily for the reduction of LDLreduction of LDL levels. Seems tolevels. Seems toalso have an effect onalso have an effect on CC--reactive proteinreactive protein (CRP) levels as(CRP) levels as

..

MechanismMechanism

HMGHMG--CoA reductase mediates the first committed step inCoA reductase mediates the first committed step insterol biosynthesis.sterol biosynthesis.

******This leads to anThis leads to an inductioninduction of high affinityof high affinity LDL receptorsLDL receptors,,thusthus lowering serum LDL levels.lowering serum LDL levels.

Increasing LDL receptors is the impt. part of mechanism!Increasing LDL receptors is the impt. part of mechanism!

Due to the highDue to the high first pass metabolismfirst pass metabolism, the main effect of, the main effect ofthese drugs is on the liver.these drugs is on the liver.


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Statins (cont)Statins (cont)PharmacokineticsPharmacokinetics

Lovastatin (Mevacor) and simvastatin (Zocor*Lovastatin (Mevacor) and simvastatin (Zocor*)) areareinactiveinactive prodrugsprodrugs and are activated in the GI tract,and are activated in the GI tract,all others are active drug.all others are active drug.

Absorption varies betweenAbsorption varies between 4040--7575%, with%, with fluvastatinfluvastatin(Lescol*)(Lescol*) being nearly completely absorbed.being nearly completely absorbed.

HighHigh first pass metabolismfirst pass metabolism by Cytochrome P450by Cytochrome P450((CYP 3A4 or CYP2C9CYP 3A4 or CYP2C9) (grapefruit juice)) (grapefruit juice)

Mainly excreted in the bile with 5Mainly excreted in the bile with 5--20% excreted in20% excreted in

urine.urine.

TT1/21/2 ranges fromranges from 1 to 3 hours1 to 3 hours,, exceptexcept atorvastatinatorvastatin((Lipitor*)Lipitor*) TT1/21/2=14 hrs.=14 hrs.


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Statins (cont)Statins (cont)

Side EffectsSide EffectsElevations ofElevations of serum aminotransferaseserum aminotransferase activity up toactivity up to 3x3xcommonly occur andcommonly occur and generally do not result ingenerally do not result in

hepatotoxicityhepatotoxicity..

InIn ~2%~2% of patients (some of whom haveof patients (some of whom have underlying liverunderlying liversease or a co o a usesease or a co o a use may avemay ave >> nn

aminotransferase levels, may indicate severeaminotransferase levels, may indicate severehepatotoxicityhepatotoxicity,, statinstatin treatment shouldtreatment shoulddiscontinue immediately.discontinue immediately.

RareRare side effect includeside effect include myositismyositis (muscle pain), marked by(muscle pain), marked byelevated creatine kinase activity. If the drug is notelevated creatine kinase activity. If the drug is not

discontinued,discontinued, rhabdomyolysisrhabdomyolysis may occur producingmay occur producingmyoglobinemiamyoglobinemia that may lead tothat may lead to acute renal failureacute renal failure..


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Statins (cont)Statins (cont)Major drug interactions:Major drug interactions:

Drugs that inhibit or compete forDrugs that inhibit or compete for CYP 3A4CYP 3A4 ororCYP2C9CYP2C9 will increase the plasma concentrationswill increase the plasma concentrationsof statins.of statins.

levels (see below).levels (see below).Concomitant use of amiodarone or verapamilConcomitant use of amiodarone or verapamilcauses an increased risk of myopathy.causes an increased risk of myopathy.

ContraindicationsContraindicationsPregnancyPregnancy due todue to potential teratogenicitypotential teratogenicity


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E. EZETIMIBE (E. EZETIMIBE (Zetia*)Zetia*)

ProdrugProdrug(liver(liverglucuronide)glucuronide)DecreasesDecreases GI Uptake of cholesterolGI Uptake of cholesterol

BothBoth dietary and biliarydietary and biliary secreted cholesterolsecreted cholesterolReduces tightly regulated cholesterol pool in liverReduces tightly regulated cholesterol pool in liverresulting in increased synthesis of high affinity LDLresulting in increased synthesis of high affinity LDL

LOWERSLOWERS SERUM LDLSERUM LDL andand TRIGLYCERIDES!!TRIGLYCERIDES!!

INDICATIONS:INDICATIONS: hypercholesterolemiahypercholesterolemiaTOXICITY: Well tolerated, but may increase hepaticTOXICITY: Well tolerated, but may increase hepatictoxicity withtoxicity with HMG CoA reductase inhibitorsHMG CoA reductase inhibitors

Dyslipidemia Treatment Guideline


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Visit 1 Rule out secondary dyslipidemia* Assess CHD risk

Identify CHD risk equivalents(DM, AAA, ASPVD, symptomatic carotid disease)

Calculate 10-year risk -- see Framingham Risk ScoringIdentify major risk factors (RF) (see reverse)

If TG 400 treat to < 400$

Set LDL goal$ (Consider ordering labs for next visit now) Determine initial treatment plan$

TG < 200

y pThis algorithm is useful once a confirmatory 9-12 hour fasting lipoproteinprofile is available and secondary dyslipidemia has been ruled out.

NCEP ATP III JAMA. 2001;285:2486-2497

HDL 40

HDL < 40and CHD orequivalent

Isolated low-HDLTLC and Rx HDL(see reverse)

Meet LDL goal consider secondary

treatment goals

Visit 3 (6 weeks later) Check LDL response Intensify TLC Consider drug therapy(Go to VISIT 2, TLC & Rx)

Visit 2 TLC ONLY

(6 weeks later)

Check LDL response Intensify TLC Consider ordering labs for next visit

Follow up Visit(q 4-6 mos.) Monitor treatment

response Maintain TLC Monitor for drug

side effects

Begin Therapeutic Lifestyle Changes (TLC) if LDL > goal

TG 200-499

Primary Treatment Goals (mg/dL)

When TG 400, lab cant calculate LDLTreat: TG-specific TLC + Niacin/FibrateWhen TG < 400; set LDL goalsFramingham LDL Goal Consider10-yr Risk (TLC if LDL above goal) Add Meds< 10% (0-1 RF) < 160 160< 10% (2+ RF) < 130 160

10-20% < 130 130> 20% < 100 130

Visit 2 TLC AND Rx

(6 weeks later)

Check LDL response Intensify TLC Initiate LDL drug therapy if LDLexceeds levels shown below. Consider ordering labs for next visit

Visit 3 (6 weeks later) Check LDL response Maintain/Intensify TLC Intensify current med

or initiate combinationtherapy as needed

*Secondary Dyslipidemia Diabetes Hypothyroidism Obstructive liver disease Chronic renal failure Drugs that LDL

Progestins

Anabolic steroidsCorticosteroids

Metabolic Syndrome 3 of 5Waist CircumferenceMen > 40Women > 35

Triglycerides 150 HDL

Men < 40Women < 50

Fasting glucose 110 Blood Pressure 130 / 85

Secondary Treatment Goals

If TG 200 mg/dL non-HDL is 2 targetUsually seen with metabolic syndromeLDL + VLDL = non-HDL-C = Total cholesterol HDLNormal VLDL = 30 mg/dL, therefore

10-yr Risk LDL Goal non-HDL Goal< 10% (0-1 RF) < 160 < 190< 10% (2+ RF) < 130 < 160

10-20% < 130 < 160> 20% < 100 < 130


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Slide 41


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JCF4 Should these be sub-bullets, or the same level as the insulin resistance one?Maj Jill C Feig; 11/24/2003


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Primary Prevention with Lipoprotein AnalysisPrimary Prevention with Lipoprotein Analysis

2004, 2002 Elsevier Inc. All rights reserved.

(From National Cholesterol Education Program: Second Report of the Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults (Adult Treatment Panel II). National Institutes of Health, NIH Publication No. 93-3095. Bethesda,MD: National Heart, Lung, and Blood Institute, 1993.)


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Reference- 1. Basic and Clinical Endocrinology 7th Edition- 2. 16th Edition HARRISONS PRINCIPLES OF Internal Medicine

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Mbs127 Slide Dislipidemia