Dyslipidemia Harper CHO

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Dyslipidemia

Rene J. Harper, M.D.

Georgia Health Sciences University

October 21, 2012

Dyslipidemia

Definition

Classification

Signs and symptoms

Primary causes

Secondary causes Evaluation

Treatment


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Dyslipidemia

Elevation of plasma cholesterol and/ortryglycerides or a low HDL level thatcontributes to the development ofatherosclerosis.

Causes may be primary (genetic) orsecondary (most common).

Diagnosis is by measuring plasma levels oftotal cholesterol, TGs, and individuallipoproteins.

Treatment is dietary changes, exercise, andlipid-lowering drugs.

Dyslipidemia

There is no natural cutoff between normal andabnormal lipid levels because lipid measurementsare continuous

A linear relation probably exists between lipid levelsand cardiovascular risk, so many people with

normal cholesterol levels benefit from achievingstill lower levels

Consequently, there are no numeric definitions of

dyslipidemia; the term is applied to lipid levels forwhich treatment has proven beneficial Proof of benefit is strongest for lowering elevated

LDL levels; it is less strong for lowering elevated TGand increasing low HDL levels, in part becauseelevated TG and low HDL levels are more predictiveof cardiovascular risk in women than in men


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Dyslipidemia

Dyslipidemias have been traditionallyclassified by patterns of elevation inlipids and lipoproteins (Fredricksonphenotype)

Fredrickson Classification

Lipoprotein Patterns (Fredrickson Phenotypes)

Phenotype Elevated Lipoprotein(s) Elevated LipidsI Chylomicrons TGsIIa LDL CholesterolIIb LDL and VLDL TGs and

cholesterolIII VLDL and chylomicron remnants TGs and

cholesterolIV VLDL TGs

V Chylomicrons and VLDL TGs andcholesterol


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Classification of

dyslipidemiasA more practical system classifies

dyslipidemias as primary or secondaryand characterizes these by: increases in cholesterol only (pure or

isolated hypercholesterolemia)

increases in TGs only (pure or isolatedhypertriglyceridemia)

increases in both cholesterol and TGs(mixed or combined hyperlipidemias)

Signs and symptoms

Dyslipidemias are usually asymptomatic but oftenlead to atherosclerotic vascular disease

High levels of LDL can cause eyelid xanthelasmaand xanthomas found at the Achilles, elbow, andknee tendons and over metacarpophalangeal joints(tendinous) or pressure areas (tuberous)

Patients with the homozygous form of familial

hypercholesterolemia may have the above findingsand additionally planar or cutaneous xanthomas

Patients with hypertriglyceridemia may havexanthelasma and eruptive or planar xanthomas


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Signs and symptoms

Patients with the rare dysbetalipoproteinemia mayhave palmar and tuberous xanthomas andinvolvement of palmar creases

Patients with severe elevations of TGs can haveeruptive xanthomas over the trunk, back, elbows,buttocks, knees, hands, and feet

Severe hypertriglyceridemia (> 2000 mg/dL) maygive retinal arteries and veins a creamy whiteappearance (lipemia retinalis)

Extremely high lipid levels also give a lactescent

(milky) appearance to blood plasma. High TGs (> 1000 mg/dL) may cause acute

pancreatitis

Planar xanthoma


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Tendinous xanthoma

Tendinous xanthoma


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Eruptive xanthoma

Eruptive xanthoma


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Tuberous xanthoma

Palmar xanthoma


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Tuberous xanthoma

Xanthelasma


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Xanthelasma

Lipemia retinalis


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Lipemia retinalis

Arcus corneae


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Lipoprotein

Size and BuoyancyCharacteristics ofLipoproteins


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Primary (genetic) causes

Single or multiple genetic mutations that result ineither overproduction or defective clearance of TGand LDL cholesterol, or in underproduction orexcessive clearance of HDL.

Primary lipid disorders are suspected when apatient has physical signs of dyslipidemia, onset ofpremature atherosclerotic disease (< 60 yr), afamily history of atherosclerotic disease, or serumcholesterol > 240 mg/dL (> 6.2 mmol/L).

Primary disorders are the most common cause of

dyslipidemia in children, but dont cause a largepercentage of cases in adults.


Familial hypercholesterolemia (FH) Defect in LDL receptor that leads to diminished

LDL clearance Autosomal dominant inheritance Heterozygotes: 1/500; 5% of AMIs < 60 yr

Tendon xanthomas, xanthelasma, arcus corneaeand premature CAD (ages 3050)

TC 250500 mg/dL, normal TGL Homozygotes: 1/1 million Tendon xanthomas, xanthelasma, planar

xanthomas, and premature CAD (< age 18) TC > 500 mg/dL, normal TGL


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Familial defective apo B-100 Defect in Apo B (LDL receptor-binding

region) that leads to diminished LDLclearance

Autosomal dominant inheritance

1/700

Xanthomas, xanthelasma, and premature

CAD (milder manifestations than FH) TC 250500 mg/dL


Polygenic hypercholesterolemia

Unknown genetic defect; likely multipledefects and mechanisms

Variable inheritance

Common

Premature CAD

TC 250350 mg/dL


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LPL deficiency (chylomicronemia) Defect in endothelial LPL that leads to

diminished chylomicron clearance

Recessive inheritance

Rare

Failure to thrive (infants), eruptivexanthomas, lipemia retinalis,

hepatosplenomegaly, and pancreatitis TG > 750 mg/dL


Apo C-II deficiency Defect in Apo C-II (activating cofactor for

LPL) leading to functional LPL deficiency

Recessive inheritance

Very rare, frequency < 1/1 million

Pancreatitis in children and young adults,may be associated with metabolicsyndrome

TG > 750 mg/dL


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Familial hypertriglyceridemia Unknown defect, possibly multiple defects and

mechanisms Autosomal dominant 1/100 (affects 1/2 of first-degree relatives) Usually no symptoms or findings; obesity and

insulin resistance; occasional eruptivexanthomas or pancreatitis; low HDL,hyperuricemia

TG 200500 mg/dL; levels increased by dietaryfactors, estrogens, hypothyroidism and alcohol


Familial combined hyperlipidemia Unknown defect

Autosomal dominant

1/50 to 1/100

Premature CAD, 15% of AMIs < 60 yr; obesityand insulin resistance; low HDL, hyperuricemia

Small, dense LDL; apo B elevated

TC 250500 mg/dL

TG 250750 mg/dL


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Familial dysbetalipoproteinemia Defect in Apo E (usually e2/e2 homozygotes);

diminished chylomicron and VLDL clearance

Recessive (more common) or dominant (lesscommon)

1/5000

Xanthomas (especially palmar), yellow palmarcreases, premature CAD

TC 250500 mg/dL TG 250500 mg/dL

Secondary causes

Most cases of dyslipidemia in adults The most important secondary cause in developed

countries is a sedentary lifestyle with excessivedietary intake of saturated fat, cholesterol, andtrans fatty acids (TFAs)

Other common secondary causes: diabetes mellitus alcohol abuse

chronic renal insufficiency, nephrotic syndrome hypothyroidism primary biliary cirrhosis and other cholestatic liver

diseases, Drugs: thiazides, -blockers, retinoids, highly-active

antiretroviral agents, estrogen and progestins, andglucocorticoids


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Diabetic dyslipidemia

Diabetic patients, in particular DM-2, tend to have anatherogenic combination of high TGs, high small/denseLDL and low HDL.

This profile may be a consequence of obesity and/orpoor control of diabetes, which increases circulatingFFAs, leading to increased hepatic VLDL production.

TG-rich VLDL then transfers TG and cholesterol to LDLand HDL, promoting formation of TG-rich, small, denseLDL and clearance of TG-rich HDL.

Diabetic dyslipidemia is often exacerbated by theincreased caloric intake and physical inactivity that

characterize the lifestyles of some patients with DM-2. Diabetic women may be at special risk for cardiac

disease.


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Diagnosis and Screening

Measure serum lipids (lipid profile)

TC, TG, and HDL are measureddirectly

LDL is calculated or measured directly

TC and TG values reflect cholesteroland TG in all circulating lipoproteins,including chylomicrons, VLDL, IDL,LDL, and HDL.


LDL values are often calculated as the amount ofcholesterol not contained in HDL and VLDL, where

VLDL is estimated by TG 5: LDL = TC [HDL +(TG 5)] (Friedewald formula); valid only when TGare < 400 mg/dL and patients are fasting

The calculated LDL value incorporates measures ofall non-HDL, nonchylomicron cholesterol, includingthat in IDL and Lp(a)

LDL can be measured directly using plasmaultracentrifugation or by immunoassay Direct measurement may be useful in patients with

elevated TG to determine if LDL levels are elevated


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TC values may vary by 10% and TG by upto 25% even in the absence of disease

Testing should be postponed until afterresolution of acute illness, because TGincrease and cholesterol levels decrease ininflammatory states

Lipid profiles are generally reliable within

the first 24 h after an AMI but then changeafterwards


A fasting lipid profile (TC, TG, HDL, and calculatedLDL) should be obtained in all adults 20 yr andshould be repeated q 5 yr

Assessment of other cardiovascular risk factors atthe time of initial screening:

DM

Smoking

HTN FH of premature CAD - 1st-degree relative

male before age 55

female before age 65


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Indications for screening patients < 20yr Atherosclerotic risk factors

DM

HTN

Smoking

Obesity

Premature CAD in a parent, grandparent, orsibling

Cholesterol level > 240 mg/dL or knowndyslipidemia in a parent

Additional testing

Blood tests for secondary causes ofdyslipidemia should be obtained inpatients with recently diagnoseddyslipidemia, or when a component ofthe lipid profile has changed for the

worse: FBG, liver enzymes, creatinine, TSH,

urinary protein


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Evaluation

1. Measure fasting lipoproteins2. Identify CAD or CAD equivalents

Other atherosclerotic disease: peripheral arterial disease,abdominal aortic aneurysm, symptomatic carotid arterydisease

Diabetes mellitus

3. Identify major CAD risk factors Cigarette smoking Hypertension (BP 140/90 oron antihypertensive drug) Low HDL (40 mg/dL

Family history of premature CAD - 1st-degree relativemale < 55 yrfemale < 65 yr

Age (men 45 yr, women 55 yr)

Evaluation

If 2 major risk factors are presentwithout CAD or CAD equivalent, assess10-yr risk of MI or CAD death usingFramingham risk tables or electroniccalculation tool


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Estimation of CHD risk*

*Use internet Framingham 10-year risk calculator

Online calculation tools

http://hp2010.nhlbihin.net/atpiii/calculator.asp

http://www.mdcalc.com/framingham-coronary-heart-disease-risk-score-si-units/

http://www.medcalc.com/heartrisk.html http://reference.medscape.com/calculato

r/framingham-coronary-risk-ldl


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Lipid profile references

TC (mg/dL)

< 200 Desirable

200239 Borderline high

240 High

LDL (mg/dL)

< 100 Optimal

100129 Near optimal/above optimal


160189 High190 Very high

Lipid profile references

HDL (mg/dL)

< 40 Low

60 High

TG (mg/dL)

< 150 Desirable


200499 High500 Very high


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Comparison of LDL Cholesterol andNon-HDL Cholesterol Goals for

Three Risk Categories

LDL-C Goal

(mg/dL)Risk CategoryNon-HDL-C

Goal (mg/dL)

20%)


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ATP III update

The treatment goal for high-riskpatients is an LDL < 100 mg/dL

Update: There is a therapeutic optionto set the goal at an LDL


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Drug therapy

Drug treatment options depend on the specific lipidabnormality, although different lipid abnormalitiesoften coexist.

In some patients, a single abnormality may requireseveral drug therapies

In others, a single drug treatment may be adequatefor several abnormalities.

Treatment should always include treatment ofhypertension and diabetes, smoking cessation, andin those with a 10-yr risk of MI or death from CAD

of 10% (as determined from the Framinghamtables) low-dose daily aspirin.

Drug therapy - statins

Statins are the treatment of choice for LDLreduction and demonstrably reducecardiovascular mortality

Statins inhibit hydroxymethylglutaryl CoAreductase, a key enzyme in cholesterolsynthesis, leading to up-regulation of LDL

receptors and increased LDL clearance They reduce LDL by up to 60% and produce

small increases in HDL and modestdecreases in TGs


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Statins also appear to decrease intra-arterialand/or systemic inflammation by stimulatingproduction of endothelial nitric oxide

They may also decrease LDL deposition inendothelial macrophages and decreasecholesterol in inflammatory cell membranes

This anti-inflammatory effect is

antiatherogenic even in the absence ofelevated lipid levels


Adverse effects are uncommon but include liverenzyme elevations, and myositis or rhabdomyolysis

Muscle toxicity without enzyme elevation has alsobeen reported

Adverse effects are more common in older patients,those with multiple diseases, and those on multipledrugs; changing from one statin to another orlowering the dose may relieve the problem

Muscle toxicity seems to be most common whensome of the statins are used with drugs that inhibitcytochrome P3A4 (eg, macrolide antibiotics, azoleantifungals, cyclosporine) and with fibrates(especially gemfibrozil)


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Drug therapy - fibrates

Activate PPAR (peroxisomeproliferator-activated receptors)especially PPAR

Stimulate endothelial LPL, leading toincreased fatty acid oxidation in the

liver and muscle and decreasedhepatic VLDL synthesis

Structurally and pharmacologicallyrelated to the thiazolidinediones (TZD)


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Drug therapy - fibrates

Reduce TGs by up to 50%

Increase HDLs by up to 20%

May cause GI adverse effects,including dyspepsia and abdominalpain; rarely cause cholelithiasis

Potentiate muscle toxicity when usedwith statins and potentiate the effectsof warfarin

PPAR -alpha and -gamma pathways.


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Drug therapy - bile acid

sequestrants Block intestinal bile acid reabsorption,

forcing up-regulation of hepatic LDLreceptors to recruit circulatingcholesterol for bile synthesis.

Proven to reduce cardiovascularmortality.

Usually used with statins or withnicotinic acid to augment LDLreduction

Drug therapy - bile acidsequestrants

Drugs of choice for children andwomen who are or are planning tobecome pregnant

Safe, but their use is limited byadverse effects of bloating, nausea,

cramping, and constipation

They may also increase TGs, so theiruse is contraindicated in patients withhypertriglyceridemia.


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Drug therapy - bile acid

sequestrants Cholestyramine and colestipol, but not

colesevelam, interfere with absorptionof other drugsnotably thiazides, -blockers, warfarin, digoxin, andthyroxinean effect that can beminimized by administration 4 h

before or 1 h after other drugs Lower LDL 15-25%

Drug therapy - niacin

Most effective drug for increasing HDLs

Mechanism of action is unknown, but itappears to both increase HDL productionand inhibit HDL clearance; it may alsomobilize cholesterol from macrophages.

Also decreases TGs and, in doses of 1500 to

2000 mg/day, reduces LDLs Lower LDL 15-30%, lower TGs 30-40% amd

raise HDL 15-25%


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Drug therapy - niacin

Produces flushing, pruritus, and nausea;premedication with low-dose aspirin mayprevent these adverse effects; slow-releasepreparations cause these side effects less often

May cause liver enzyme elevations andoccasionally liver failure, insulin resistance, andhyperuricemia and gout.

In patients with average LDL and below-

average HDL levels, niacin combined with statintreatment may be effective in preventingcardiovascular disease

Drug therapy - ezetimibe

Inhibits intestinal absorption of cholesteroland phytosterol

Usually lowers LDL by 15-20% and causessmall increases in HDL and a mild decreasein TGs

Can be used as monotherapy in patientsintolerant to statins or added to statins for

patients on maximum doses with persistentLDL elevation

Adverse effects are infrequent


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Drug therapy omega-3

fatty acids Omega-3 fatty acids in high doses (1 to 6 g/day

of eicosapentaenoic acid [EPA] anddocosahexaenoic acid [DHA]) can be effectivein reducing TGs

The -3 fatty acids EPA and DHA are the activeingredients in fish oil or -3 capsules

Adverse effects include eructation and diarrhea;these may be decreased by giving the fish oil

capsules with meals in divided doses (eg, bid ortid)

Omega-3 fatty acids can be a useful adjunct toother therapies

Treatment of diabeticdyslipidemia

Treatment of diabetic dyslipidemia shouldalways involve lifestyle changes, with statinsto reduce LDLs and/or fibrates to decreaseTGs

Metformin lowers TGs, which may be areason to choose it over other oralantihyperglycemic drugs when treating

diabetics with dyslipidemia


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Treatment of diabetic

dyslipidemia Thiazolidinediones (TZDs) may increase

both HDLs and LDLs (probably the lessatherogenic large, buoyant type of LDLs)

TZDs may decrease TGs; however, theseagents should not be chosen over lipid-lowering drugs to treat lipid abnormalities indiabetic patients but may be useful adjuncts

Patients with very high TG levels and lessthan optimally controlled diabetes may havebetter response to insulin than to oralantihyperglycemic drugs

Targets for dyslipidemiain diabetic patients

LDL


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Dyslipidemia Harper CHO