Serum Lipid Serum Lipid AbnormalitiesAbnormalities

M Chadi Alraies, MDM Chadi Alraies, MDChief Medical ResidentChief Medical Resident

Case Western Reserve University / St. Vincent HospitalCase Western Reserve University / St. Vincent Hospital

Cleveland, OhioCleveland, Ohio

Saturday, December 20, 2007Saturday, December 20, 2007

A quick look at the A quick look at the differential differential

diagnosis of Heart diagnosis of Heart MurmursMurmurs

or or or or or or or

Intervention HOCM Aortic Stenosis Mitral Regurgitation

Valsalva IncreasedIncreased DecreasedDecreased Decreased Decreased or sameor same

Standing IncreasedIncreased IncreasedIncreased DecreasedDecreased

Handgrip or squatting

DecreasedDecreased DecreasedDecreased IncreasedIncreased

Supine position with legs elevated

DecreasedDecreased IncreasedIncreased No changeNo change

Exercise IncreasedIncreased IncreasedIncreased DecreasedDecreased

Amyl nitrite Markedly Markedly increasedincreased

IncreasedIncreased DecreasedDecreased

Iso-Proterenol

Markedly Markedly increasedincreased

IncreasedIncreased DecreasedDecreased

Lipid Lipid abnormalitiesabnormalities

TerminologyTerminology

Primary preventionPrimary prevention Secondary preventionSecondary prevention Lipoproteins.Lipoproteins. Apoproteins.Apoproteins.

General considerationGeneral consideration

The two main lipids in blood are The two main lipids in blood are cholesterol and triglyceride. cholesterol and triglyceride.

Why lipids are deposited into the Why lipids are deposited into the walls of large and medium-sized walls of large and medium-sized arteries is not known. arteries is not known.

LipoproteinsLipoproteins

Particles that have a hydrophobic Particles that have a hydrophobic core (TG/Cholesterol), core (TG/Cholesterol),

Surrounded by a hydrophilic Surrounded by a hydrophilic phospholipid outer layers which phospholipid outer layers which allows transport through the blood.allows transport through the blood.

LDL, VLDL, IDL, CHYLOMICRONS, LDL, VLDL, IDL, CHYLOMICRONS, HDLHDL

ApoproteinsApoproteins

Small proteins.Small proteins. Surrounding Lipoproteins.Surrounding Lipoproteins. Helps lipoproteins:Helps lipoproteins:

Binding to receptors.Binding to receptors. Activating enzymes.Activating enzymes.

LIPOPROTEINS & LIPOPROTEINS & ATHEROGENESISATHEROGENESIS

The higher the LDL, the greater the risk The higher the LDL, the greater the risk of CHD.of CHD.

The higher the HDL, the lower the risk The higher the HDL, the lower the risk of (CHD). of (CHD).

The mechanism of formation of The mechanism of formation of atherosclerotic plaques is not known. atherosclerotic plaques is not known.

Lipid Fractions Lipid Fractions

In fasting serum…In fasting serum…

Most triglyceride is found in VLDL Most triglyceride is found in VLDL particles, which contain five times as particles, which contain five times as much triglyceride by weight as much triglyceride by weight as cholesterol. cholesterol.

Lipid FractionsLipid Fractions

the LDL should always be estimated the LDL should always be estimated as the mean of at least two as the mean of at least two determinations…determinations…

Valid only if TG < 400 mg/dlValid only if TG < 400 mg/dl

LipoproteinsLipoproteins

Chylomicrons (I)Chylomicrons (I)

Large globules.Large globules. Apo (B48, CII, E)Apo (B48, CII, E) CII activates LPL (lipoprotein CII activates LPL (lipoprotein

lipase).lipase). LPL removes TG from chylomicrons.LPL removes TG from chylomicrons. Familial LPL deficiencyFamilial LPL deficiency Familial CII deficiency.Familial CII deficiency.

VLDL (IV)VLDL (IV)

Apo (B100, CII, E)Apo (B100, CII, E) Smaller than chylomicronsSmaller than chylomicrons Contain more cholesterol than Contain more cholesterol than

chylomicrons.chylomicrons. Metabolized by LPL by means of CII.Metabolized by LPL by means of CII. Familial LPL deficiencyFamilial LPL deficiency Familial CII deficiency.Familial CII deficiency. FCHLFCHL

IDL (III)IDL (III)

Apo B100, EApo B100, E VLDL remnant.VLDL remnant. ½ taken by liver. Strong affinity to ½ taken by liver. Strong affinity to

B100 & EB100 & E ½ stays in plasma and convert to ½ stays in plasma and convert to

LDL.LDL. Familial betadyslipoproteinemia.Familial betadyslipoproteinemia.

LDL (IIA)LDL (IIA)

Apo B100…ONLY!Apo B100…ONLY! Formed from IDLFormed from IDL 2/3 binds to receptors & 1/3 2/3 binds to receptors & 1/3

scavenged.scavenged. Liver receptors have a weak affinity Liver receptors have a weak affinity

to B100.to B100. Familial hypercholesterolemia.Familial hypercholesterolemia. FCHLFCHL

LDL receptors LDL receptors Down-regulated or decreased:Down-regulated or decreased:

High dietary cholesterol or saturated fat.High dietary cholesterol or saturated fat. AgeAge Familial hypercholesterolemia.Familial hypercholesterolemia.

Up-regulated or increased:Up-regulated or increased: Low dietary cholesterolLow dietary cholesterol EstrogenEstrogen ThyroxineThyroxine Acute illnessAcute illness Meds: statins and bile acid resins.Meds: statins and bile acid resins.

HDLHDL

Apo (A1, A2, C)Apo (A1, A2, C) Protein and phospholipids.Protein and phospholipids. Very little cholesterol and TG Very little cholesterol and TG Scavenges the unesterified Scavenges the unesterified

cholesterol.cholesterol. Low HDL Low HDL low apo C (including low apo C (including

CII)CII)

increased VLDL and Chylomicrons.increased VLDL and Chylomicrons.

Familial hyperlipidemia Familial hyperlipidemia syndromessyndromes

TypeType What is What is elevated?elevated?

DefectDefect NameName

II TGTG

(chylomicrons)(chylomicrons)LPL deficiencyLPL deficiency

CII deficiencyCII deficiencyFamilial LPL Familial LPL

deficiencydeficiency

Familial CII Familial CII deficiencydeficiency

IIAIIA CholesterolCholesterol

(LDL)(LDL)Decreased LDL receptorsDecreased LDL receptors

Apo B + VLDL overproductionApo B + VLDL overproductionFamilial Familial

hypercholesterolehypercholesterolemiamia

FCHLFCHL

IIBIIB TG + TG + CholesterolCholesterol

(LDL & VLDL)(LDL & VLDL)

Apo B + VLDL overproductionApo B + VLDL overproduction FCHLFCHL

IIIIII TG + TG + Cholesterol Cholesterol

(IDL)(IDL)

Abnormal apo E (E2/E2)Abnormal apo E (E2/E2) Familial Familial dysbetalipoproteidysbetalipoprotei

nemianemia

IVIV TGTG

(VLDL)(VLDL)LPL deficiencyLPL deficiency

CII deficiencyCII deficiency

Apo B + VLDL overproductionApo B + VLDL overproduction

Familial hyper TGFamilial hyper TG

FCHLFCHL

Familial CII Familial CII deficiencydeficiency

VV TG TG

Chylomicrons & Chylomicrons & VLDLVLDL

LPL deficiencyLPL deficiency

CII deficiencyCII deficiency

Apo B + VLDL overproductionApo B + VLDL overproduction

Familial LPL Familial LPL deficiencydeficiency

FCHLFCHL

Familial CII Familial CII deficiencydeficiency

I + IV = V have isolated I + IV = V have isolated hypertriglyceridemiahypertriglyceridemia

IIa = cholesterol aloneIIa = cholesterol alone IIb and III = both cholesterol and IIb and III = both cholesterol and

TG.TG.

Clinical findingsClinical findings

Tendinous xanthomas: Achilles Tendinous xanthomas: Achilles xanthomas xanthomas

Tendinous xanthomas: elbow Tendinous xanthomas: elbow xanthomas xanthomas

Tendinous xanthomas: knuckle Tendinous xanthomas: knuckle xanthomas xanthomas

Lipemia retinalisLipemia retinalis

CLINICAL CLINICAL PRESENTATIONSPRESENTATIONS

No specific symptoms or signs.No specific symptoms or signs. Triglyceride level (>1000 mg/dL)Triglyceride level (>1000 mg/dL)

eruptive xanthomaseruptive xanthomas High LDL concentrations High LDL concentrations

TTendinous xanthomasendinous xanthomas on tendons of on tendons of (Achilles, patella, back of the hand).(Achilles, patella, back of the hand).

Triglyceride levels (above 2000 Triglyceride levels (above 2000 mg/dL):mg/dL): Lipemia retinalis.Lipemia retinalis.

SECONDARY SECONDARY CONDITIONS CONDITIONS THAT AFFECT THAT AFFECT

LIPID LIPID METABOLISMMETABOLISM

CauseCause Associated Lipid AbnormalityAssociated Lipid Abnormality

Obesity Increased triglycerides, decreased HDL cholesterol

Sedentary lifestyle Decreased HDL cholesterol

Diabetes mellitus Increased triglycerides, increased total cholesterol

Alcohol use Increased triglycerides, increased HDL cholesterol

Hypothyroidism Increased total cholesterol

Hyperthyroidism Decreased total cholesterol

Nephrotic syndrome Increased total cholesterol

Chronic renal insufficiency Increased total cholesterol, increased triglycerides

Hepatic disease (cirrhosis) Decreased total cholesterol

Obstructive liver disease Increased total cholesterol

Malignancy Decreased total cholesterol

Cushing's disease (or corticosteroid use) Increased total cholesterol

Oral contraceptives Increased triglycerides, increased total cholesterol

Diuretics Increased total cholesterol, increased triglycerides

Beta Blockers Increased total cholesterol, decreased HDL

Therapeutic Effects of Lowering Therapeutic Effects of Lowering Cholesterol Cholesterol

Primary prevention is statistically Primary prevention is statistically significant and showed clinically significant and showed clinically important reductions in:important reductions in: Rates of myocardial infarctions, Rates of myocardial infarctions, New cases of angina, New cases of angina, Need for coronary artery bypass Need for coronary artery bypass

procedures. procedures. In general, decrease in In general, decrease in morbiditymorbidity..

Primary prevention Primary prevention Pravastatin: West of Scotland Study.Pravastatin: West of Scotland Study. Lovastatin: AFCAPS/TexCAPS study.Lovastatin: AFCAPS/TexCAPS study. Atorvastatin: (ASCOT) study.Atorvastatin: (ASCOT) study.

Secondary preventionSecondary prevention

1.1. Regression of atherosclerotic Regression of atherosclerotic plaques.plaques.

2.2. Reduces the progression of Reduces the progression of atherosclerosis in saphenous vein atherosclerosis in saphenous vein grafts.grafts.

3.3. Slow or reverse carotid artery Slow or reverse carotid artery atherosclerosis. atherosclerosis.

SECONDARY CONDITIONS THAT SECONDARY CONDITIONS THAT AFFECT LIPID METABOLISMAFFECT LIPID METABOLISM

These are important for two reasons:These are important for two reasons: Abnormal lipid levels may be the Abnormal lipid levels may be the

presenting sign of some of these presenting sign of some of these conditions.conditions.

correction of the underlying condition correction of the underlying condition may obviate the need to treat an may obviate the need to treat an apparent lipid disorder. apparent lipid disorder.

SCREENING FOR SCREENING FOR HIGH BLOOD HIGH BLOOD

CHOLESTEROLCHOLESTEROL

Who should be screened for Who should be screened for high lipids?high lipids?

CHDCHD CHD risk equivalents:CHD risk equivalents:

1.1. Peripheral Peripheral arteryartery disease. disease.

2.2. AAAAAA

3.3. SymptomaticSymptomatic carotid artery disease carotid artery disease

4.4. Diabetes mellitusDiabetes mellitus

5.5. Multiple risk factors that confer a Multiple risk factors that confer a greater than 20% 10-year risk for greater than 20% 10-year risk for developing CHD!developing CHD!

National Cholesterol Education National Cholesterol Education Program (NCEP):Program (NCEP): Screen all adults aged 20 years or older.Screen all adults aged 20 years or older.

USPSTF:USPSTF: Screen every 35 years in men and age 45 Screen every 35 years in men and age 45

years in women unless there are other years in women unless there are other risk factors for CHD.risk factors for CHD.

Risk factors of coronary artery Risk factors of coronary artery diseasedisease

Age and gender Age and gender Men aged 45 years or older.Men aged 45 years or older. Women aged 55 years or olderWomen aged 55 years or older

A family history of premature CHD:A family history of premature CHD:1.1. MI or sudden cardiac death MI or sudden cardiac death

1.1. <55 years in a 1<55 years in a 1stst degree degree malemale relative. relative.

2.2. <65 years in a 1<65 years in a 1stst degree female relative. degree female relative.

2.2. Hypertension (whether treated or not.)Hypertension (whether treated or not.)

3.3. Current cigarette smoking (10 or more Current cigarette smoking (10 or more cigarettes per day).cigarettes per day).

4.4. HDL cholesterol (< 40 mg/dL). HDL cholesterol (< 40 mg/dL).

10-year risk of developing CHD 10-year risk of developing CHD using Framingham projections using Framingham projections

of 10-year risk of 10-year risk Because risk factors alone are an Because risk factors alone are an

imprecise measure of CHD risk, imprecise measure of CHD risk, estimating the 10-year risk using estimating the 10-year risk using Framingham data is likely to be Framingham data is likely to be helpful even in patients with one or helpful even in patients with one or no risk factors. no risk factors.

Screening in WomenScreening in Women

Low HDL is more important risk factor Low HDL is more important risk factor than a high LDL cholesterol in women.than a high LDL cholesterol in women.

Using estimates of 10-year CHD risk Using estimates of 10-year CHD risk may be particularly helpful in women.may be particularly helpful in women.

Women are less likely to benefit from Women are less likely to benefit from therapy unless their LDL cholesterol is therapy unless their LDL cholesterol is extremely high (greater than 190 extremely high (greater than 190 mg/dL).mg/dL).

Screening in Older Screening in Older PatientsPatients

Patients age 75 years or older:Patients age 75 years or older: + CHD: LDL-lowering therapy can be + CHD: LDL-lowering therapy can be

continued. continued. No CHD: recommend screening and No CHD: recommend screening and

treatment.treatment. Decisions to discontinue therapy:Decisions to discontinue therapy:

Overall functional status.Overall functional status. Life expectancy.Life expectancy. Comorbidities.Comorbidities. Patient preference.Patient preference.

TreatmentTreatment

Goal of treatmentGoal of treatment

Risk Category LDL Goal (mg/dL) LDL Level at Which to Initiate Lifestyle Changes

(mg/dL)

LDL Level at Which to Consider

Drug Therapy (mg/dL)

High risk: CHD or CHD risk equivalents (10-year risk > 20%)

< 100 100 100

Moderately high risk: 2+ risk factors

(10-year risk 10% to 20%)

< 130 130 130

Moderate risk: 2+ risk factors

(10-year risk < 10%)

< 130 130 160

Low risk: 0–1 risk factors

< 160 160 190

Treatment of High LDL Treatment of High LDL Cholesterol Cholesterol

General measures:General measures: Quitting smoking: increase HDL & Quitting smoking: increase HDL &

lower LDL.lower LDL. Exercise (and weight loss) reduce the Exercise (and weight loss) reduce the

LDL increase the HDL. LDL increase the HDL. Modest alcohol use (1–2 ounces a day): Modest alcohol use (1–2 ounces a day):

raises HDL raises HDL

Diet Diet

Diet TherapyDiet Therapy 5–10% decrease in LDL cholesterol.5–10% decrease in LDL cholesterol. Should be assessed 4 weeks after initiation. Should be assessed 4 weeks after initiation. Reduce…Reduce…

Total daily fat to 25–30% Total daily fat to 25–30% Saturated fat to less than 7% of daily calories. Saturated fat to less than 7% of daily calories.

Dietary cholesterol less than 200 mg/d.Dietary cholesterol less than 200 mg/d. Polyunsaturated fats decrease LDL and Polyunsaturated fats decrease LDL and

HDLHDL Monounsaturated fats:Monounsaturated fats:

Decrease LDLDecrease LDL Increase HDL… GOOD!Increase HDL… GOOD!

Diet TherapyDiet Therapy

"Mediterranean diet“, "Mediterranean diet“, monounsaturated fat such as that monounsaturated fat such as that found in canola oil and in olives, found in canola oil and in olives, peanuts, avocados, and their oils. peanuts, avocados, and their oils.

Soluble fiber, reduce LDL cholesterol Soluble fiber, reduce LDL cholesterol by 5–10%.by 5–10%.

Garlic, soy protein, vitamin C, pecans, Garlic, soy protein, vitamin C, pecans, and plant sterols.and plant sterols.

Antioxidants, found primarily in fruits Antioxidants, found primarily in fruits and vegetables. and vegetables.

Pharmacologic Pharmacologic treatmenttreatment

General measuresGeneral measures Aspirin prophylaxis at a dose of 81 mg/d.Aspirin prophylaxis at a dose of 81 mg/d. The therapeutic goal is:The therapeutic goal is:

Approached slowlyApproached slowly Watching for side effects.Watching for side effects. Encouraging adherence to nonpharmacologic Encouraging adherence to nonpharmacologic

Rx. Rx. Achieve a 30–40% reduction in LDL.Achieve a 30–40% reduction in LDL. Combinations of drugs may be necessary.Combinations of drugs may be necessary. Monitor periodically (every 6–8 weeks) Monitor periodically (every 6–8 weeks)

after starting therapy.after starting therapy.

NIACIN (NICOTINIC NIACIN (NICOTINIC ACID)ACID)

Decrease the production of VLDL.Decrease the production of VLDL. Full-dose niacin therapy, 3–4.5 g/d Full-dose niacin therapy, 3–4.5 g/d 15–25% reduction in LDL cholesterol.15–25% reduction in LDL cholesterol. 25–35% increase in HDL cholesterol.25–35% increase in HDL cholesterol. Reduce triglycerides by half.Reduce triglycerides by half. Side effects:Side effects:

Flushing and pruritus. Less with aspirin 325 Flushing and pruritus. Less with aspirin 325 mg.mg.

Increase blood sugar.Increase blood sugar. Exacerbate gout and peptic ulcer disease.Exacerbate gout and peptic ulcer disease.

BILE ACID-BINDING BILE ACID-BINDING RESINSRESINS

Cholestyramine and Colestipol.Cholestyramine and Colestipol. Decrease plasma LDL levels 15–25%.Decrease plasma LDL levels 15–25%. Increase Triglyceride level.Increase Triglyceride level. Don’t affects HDL.Don’t affects HDL. Side effects:Side effects:

constipation and gasconstipation and gas Nausea and vomiting.Nausea and vomiting. Absorption of fat-soluble vitamins.Absorption of fat-soluble vitamins.

(HMG-COA) REDUCTASE (HMG-COA) REDUCTASE INHIBITORS (STATINS)INHIBITORS (STATINS)

atorvastatin, fluvastatin, lovastatin, atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin.pravastatin, rosuvastatin, and simvastatin.

Reduce MI and total mortality in secondary Reduce MI and total mortality in secondary prevention.prevention.

Significant reduction in risk of stroke.Significant reduction in risk of stroke. Decrease LDL level by up to 35%. Decrease LDL level by up to 35%. Increases HDL levels Increases HDL levels Decreases triglyceride levels. Decreases triglyceride levels. Myositis and hepatitis.Myositis and hepatitis. Monitor LFT’s Q 2-3 months then 2x/year if Monitor LFT’s Q 2-3 months then 2x/year if

stable.stable.

Fibric Acid Derivatives Fibric Acid Derivatives

Gemfibrozil, Fenofibrate and Clofibrate.Gemfibrozil, Fenofibrate and Clofibrate. Increase the activity of LPL on VLDL.Increase the activity of LPL on VLDL. Reduce triglyceride levels by about 40%Reduce triglyceride levels by about 40% Reduce LDL levels by about 10–15%.Reduce LDL levels by about 10–15%. Raise HDL levels by about 15–20%. Raise HDL levels by about 15–20%. Side effects (mainly Clofibrate):Side effects (mainly Clofibrate):

cholelithiasis, hepatitis and hepatic cancer cholelithiasis, hepatitis and hepatic cancer and myositis.and myositis.

EZETIMIBEEZETIMIBE

Inhibits the intestinal absorption of Inhibits the intestinal absorption of dietary and biliary cholesterol. dietary and biliary cholesterol.

Reduces LDL 15% - 20% when used Reduces LDL 15% - 20% when used as monotherapy.as monotherapy.

The usual dose of ezetimibe is 10 The usual dose of ezetimibe is 10 mg/d orally.mg/d orally.

HDLHDL

What increase What increase HDL?HDL?

HDL increasesHDL increases

Nicotinic acidNicotinic acid Statins.Statins. Moderate alcohol intakeModerate alcohol intake GemfibrozilGemfibrozil ExerciseExercise Stopping smokingStopping smoking Losing weight. Losing weight.

HDL decreases in …HDL decreases in …

Beta blockers (except Labetalol).Beta blockers (except Labetalol). SmokingSmoking High polyunsaturated diet.High polyunsaturated diet.

High Blood Triglycerides High Blood Triglycerides

Risk for pancreatitis.Risk for pancreatitis. Treat fasting levels above 500 Treat fasting levels above 500

mg/dL.mg/dL.

High Blood Triglycerides High Blood Triglycerides The primary therapy is dietary:The primary therapy is dietary:

Avoiding alcoholAvoiding alcohol Avoiding simple sugarsAvoiding simple sugars Avoiding refined starchesAvoiding refined starches Avoiding saturated trans fatty acids.Avoiding saturated trans fatty acids. Restricting total calories. Restricting total calories.

Medications: niacin, a fibric acid Medications: niacin, a fibric acid derivative, or an HMG-CoA reductase derivative, or an HMG-CoA reductase inhibitor.inhibitor.

Elevated TG increase CHD risk in men by Elevated TG increase CHD risk in men by 14% and in women by 37%.14% and in women by 37%.

Metabolic syndromeMetabolic syndrome

25% of Americans25% of Americans 3 or more of the following:3 or more of the following:

1.1. Waist circumference > 102 cm in men or Waist circumference > 102 cm in men or > 88 cm in women> 88 cm in women

2.2. Serum triglyceride level of at least 150 Serum triglyceride level of at least 150 mg/dLmg/dL

3.3. HDL level of < 40 mg/dL in men or < 50 HDL level of < 40 mg/dL in men or < 50 mg/dL in women.mg/dL in women.

4.4. Blood pressure of at least 130/85 mm HgBlood pressure of at least 130/85 mm Hg5.5. Serum glucose level of at least 110 Serum glucose level of at least 110

mg/dL. mg/dL.

NCEP ATP IIINCEP ATP III

1.1. TG (150–199 mg/dL): calorie TG (150–199 mg/dL): calorie restriction and exercise. restriction and exercise.

2.2. TG (> 200 mg/dL): Diet and TG (> 200 mg/dL): Diet and medications to make non-HDL medications to make non-HDL cholesterol 30 mg/dL higher than cholesterol 30 mg/dL higher than the LDL goal. the LDL goal.

Should be used for high risk Should be used for high risk patients. patients.

ReferencesReferences CMDT 2007.CMDT 2007. Harrison’s principles of internal medicine.Harrison’s principles of internal medicine. MedStudy 2007/2008.MedStudy 2007/2008. Executive Summary of the Third Report of The Executive Summary of the Third Report of The

National Cholesterol Education Program (NCEP) National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). (Adult Treatment Panel III). JAMA. 2001 May 16;285(19):2486–97.JAMA. 2001 May 16;285(19):2486–97. http://http://

www.nhlbi.nih.gov/guidelines/cholesterol/index.htmwww.nhlbi.nih.gov/guidelines/cholesterol/index.htm

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