Dyslipidemia

Dyslipidemia Dyslipidemia

Prof Talaat Abdel AttiInternal Medicine Department

Unit of Diabetes and MetabolismUnit of Diabetes and Metabolism

Alexandria Faculty of Medicine

2009 - 2010

AgendaAgenda Lipids (types and function). Digestion and absorption of lipids. Lipoproteins. Dyslipidemia.

Definition. Classification. Diagnosis. Management.

Lipids (types and function). Digestion and absorption of lipids. Lipoproteins. Dyslipidemia.

Definition. Classification. Diagnosis. Management.

LipidsLipids• Lipids are a family of non-polarnon-polar organic

compounds that are characterized by their insolubility in water insolubility in water but dissolve in organic solvents.

• Lipids includes triglyceridestriglycerides, phospholipidsphospholipids, sterolssterols and fat soluble vitamins.

TriglyceridesTriglycerides

• What we refer to as fats and oils.• T.G make up 95% 95% of lipids found in foods.• T.G make up 99% 99% of lipids stored in the body.• Triglyceride = glycerol + 3 fatty acids3 fatty acids

Types of Fatty Acids

I- Saturated fatty acids:• No double bonds between carbon atoms.• Includes

Animal fatPalm oil ( النخيل (زيتCoconut oil ( الهند جوز (زيت

II- Mono-unsaturated F.A

H O

H C C C C OH

H H H

• Only oneone double bond between carbon atoms.

• Includes olive oil and canola oil ( زيت ال. (الحار

III- Poly-unsaturated FA

H H H H O

H C C C C C C OH

H• More than ONE double bond

between carbon atoms.• E.g: Corn oil and sunflower oil.

Essential fatty acids Omega 3 & 6

• The body can make all but two of the fatty acids it needs (Omega-3 and Omega-6)(Omega-3 and Omega-6).

• Because they must be supplied by the diet they are called essential fatty acidsessential fatty acids.

• Foods that help supply these two essential fatty acids are vegetable oils, seeds, nuts, fish, and other meats.

Fats versus oilsFats versus oils• Fats are lipids that are solid at room

temperature.• Oils are lipids that are liquid at room

temperature.

Hydrogenation and Trans-fatHydrogenation and Trans-fat

• Chemical process of adding hydrogen atoms to mono- and polyunsaturated fatty acids creates trans fatstrans fats.

• Adding Hydrogen alters the oils & changes them to more solid /plastic fats.

• Adding H = more saturated = more solid fat.• Why Hydrogenate:

– to prevent RANCIDITY and increases shelf life.

Results of Hydrogenation:Results of Hydrogenation:

• Hydrogenated fats react the same way saturated fats do.

• Trans fats formed during hydrogenation process have been linked to adverse effects on Blood Cholesterol and higher risk of coronary heart disease.

• Food examples of trans-fat includes cakes , biscuits, potato crisps and fast food

PhospholipidsPhospholipids• Compound similar to triglyceride but having a

phosphate group in place of one of fatty acids.• Not an essential nutrient as liver produces lecithin.• Importance of phospholipids:o Constituent of cell membranes.o Facilitate movement of lipids across membranes.o Enable fat soluble vitamins and hormones to pass in

and out of cells.

SterolsSterols• Present in animal foods (cholesterol) and

plant foods (phytosterols).

• Most common sterol is cholesterol.

• Only animal products contain cholesterol.

• Our livers make about 800-1500 mg of cholesterol per day from fragments of carbohydrates, proteins and fat

Two Sources of Cholesterol: Hepatic Synthesis and Absorption from deit

Two Sources of Cholesterol: Hepatic Synthesis and Absorption from deit

Fecal bile acids and neutral sterols (~700 mg/day)

Extrahepatictissues

BiliaryBiliarycholesterolcholesterol

(~1000 mg/day(~1000 mg/day))

Absorption(~700 mg/day)

LiverLiverSynthesis*Synthesis*

Intestine

DietaryDietarycholesterolcholesterol

(~300–700 mg/day)(~300–700 mg/day)

SterolsSterols• Roles of sterols:

– Bile acids (which help to digest fats)– Sex hormones– Adrenal hormones– Vitamin D

• Cholesterol is a major component of nerve & brain tissue.

Functions of Lipids Functions of Lipids • Most concentrated source of energy 1g 9 Kcals.• Fuel reserve.• Carries fat-soluble vitamins in the body. (D,E,K, A) • InsulatesInsulates the body against cold and injury.• Provides longer satietysatiety (satisfaction of hunger).• Carries fat-soluble flavorsflavors.• Nerve transmission Nerve transmission speeds up due to lipids around

nerves (mylin)

Fat Content of Some Dietary FatsFat Content of Some Dietary Fats

Ghee………………………….….100%

Margarines (Synthetic butter)…81%

Butter………………………………81%

Oils…………….………………....100%

Cream……………..…………...20-30%

Lipid DigestionLipid Digestionand Absorptionand Absorption

Lipids Digestion• Stomach:Stomach:

– Little digestion takes place in stomach• Small intestineSmall intestine

– Primary site of fat digestion

– Bile and emulsification.

– Pancreatic and intestinal lipases break T.G → glycerol + fatty acids.

– 95% of fat consumed is absorbed.

I- I- EmulsificationEmulsification:1.Breaking down Large fats to smaller fats.2.Coating small fat globules with bile salts. 3.After emulsification fats are smaller and more exposed to the action of lipases.

II- II- Fat hydrolysisFat hydrolysis:1.Emulsification droplets are acted upon by lipases.2.Lipases break T.G → glycerol + fatty acids.

III- III- Lipid uptake by micellesLipid uptake by micelles:1.Micelles in bile pick up products of fat digestion.2.Micelles are a phospholipid bi-layer which can be taken by the intestinal brush border.

http://en.wikibooks.org/wiki/File:Micelle_bile_acid.png

Fat Digestion: Formation of MicellesFat Digestion: Formation of Micelles

TriglyceridesTriglyceridesTriglyceridesTriglyceridesDietaryDietaryCholesterolCholesterol

DietaryDietaryCholesterolCholesterol

Fatty Acids +Fatty Acids +Mono-glyceridesMono-glycerides

Fatty Acids +Fatty Acids +Mono-glyceridesMono-glycerides

1. Intestinal cells absorb lipids from micelles.2. Intestinal cells re-synthesize triglycerides.3. Intestinal cells package T.G, cholesterol and

phospholipids into protein coated chylomicron.4. Chylomicron are secreted into lacteals and then

carried via lymph to the veins

Fat Absorption

Cholesterol Absorption Cholesterol Absorption

IntestinalIntestinalcellcell

FFAFFA

MicellesMicelles

Bile acidsBile acids

LiverLiver

CholesterolCholesterol

FFAFFA

ChylomicronsChylomicrons

Digest foodDigest food Cholesteryl esterCholesteryl ester CholesterolCholesterol

FFAFFA

Free Free cholesterolcholesterol

BloodBlood

LymphaticLymphaticchannelschannels

Lipoproteins: Introduction

Triglycerides, long chain FA, phospholipids, cholesterol are insoluble in water.

Their transport in blood from the site of absorption or synthesis to sites of utilization or elimination requires a special mechanism.

This is accomplished when the lipids combine with water soluble proteins.

VLDLVLDL

sd-HDLsd-HDL

FFAFFA

abdominal obesityabdominal obesity+ insulin resistance+ insulin resistance

dysfunctionaldysfunctionaladipose tissueadipose tissue CETPCETP CECE

TG

TGTG

CETPCETP

sd-LDLsd-LDL

TG

lipaseslipases

ApoA-1ApoA-1

TGTGCECE

renalrenalclearanceclearance

TG

lipaseslipaseslipaseslipases

fatty liverfatty liver

TGTG

TG rich, CE poorTG rich, CE poor

TG rich, CE poorTG rich, CE poor

adapted from:adapted from:Bays H. Combination Lipid-Altering Drug Therapy with Statins: An Update, 1999, lipidsonline.orgBays H. Combination Lipid-Altering Drug Therapy with Statins: An Update, 1999, lipidsonline.orgGinsberg H. Diabetic Dyslipidemia and Atherosclerosis, 1999, lipidsonline.org CETP cholesteryl ester transfer proteinGinsberg H. Diabetic Dyslipidemia and Atherosclerosis, 1999, lipidsonline.org CETP cholesteryl ester transfer proteinCE Cholesteral EsterCE Cholesteral Ester

Abnormal Lipid Metabolism

HDL HDL

Clusters of lipids associated with proteins that serve as transporttransport vehicles for lipids in lymph and blood.

Lipoproteins: Definition

ECTG

Apoprotein boat

Structure of Lipoproteins

Rye KA, et al. Atherosclerosis. 1999;145:227-238.

Hydrophobic Core Hydrophobic Core TriglycerideTriglycerideCholesterylCholesteryl

EstersEsters

Surface CoatSurface CoatMonolayer of Monolayer of Phospholipids Phospholipids

and Free and Free CholesterolCholesterol

Apo lipoproteins Apo lipoproteins

Anatomy of a Lipoprotein

Lipoproteins Metabolism

Lipoproteins: Classification

Transport Endogenous

lipids

Transport Exogenous

lipids

Chylomicrons

Intestine to the liver through

lymph

Liver tissuesVLDL-CLDL-C

Tissues LiverHDL-C

Classification ofLipoproteins

Triglyceride rich Cholesterol rich

HDLLDL

Chylomicrons

VLDL

Classes of lipoprotein

Class Source Function

Chylomicrons Intestine Transport dietary TG

VLDLLiver Transport

endogenous TG

LDL circulation by partial

breakdown of IDL.

Delivers cholesterol to

peripheral tissues

HDL Liver. Removes cholesterol from tissues and takes

it to liver.

Chylomicrons

LargestLargest lipoprotein.

LowestLowest density.

Made up primarily of triglycerides triglycerides (85%)

Transporting dietarydietary triglycerides

NotNot found in 12 – 14 hr fasting blood samples.

VLDL Structure

Rich in triglycerides (65%).

More dense than chylomicrons

Contains ApoB-100.

Major carrier of endogenous (liver synthesized) triglyceride.

Delivers triglyceride to the periphery.

The precursor for IDL and LDL.

It is formed after triglyceride in VLDL is hydrolyzed by lipoprotein lipase.

The core is 50% triglyceride and 50% cholesteryl ester.

IDL contains Apo-B-100.

IDL: Structure

LDL-Cholesterol

Core is rich in cholesteryl ester.

Most cholesterol rich lipoprotein.

LDL contains apo B-100.

LDL-Cholesterol

Synthesized from IDL.

Accounts for majority of cholesterol circulating in blood.

LDL plays a major role in development of atherosclerosis.atherosclerosis.

The cholesterol in LDL is often called “bad cholesterol”“bad cholesterol”.

LDL size seems to be an important predictor of cardiovascular events and progression of coronary artery disease.

Predominance of small, dense LDL has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III.

LDL – Does Size Matter?

HDL Cholesterol

Smallest lipoproteins.

The major structural protein is apo A-I.

Core is predominantly cholesteryl ester.

Carries 20-35% of plasma cholesterol.

HDL: Reverse Cholesterol Transport

BloodBloodBloodBloodPeripheralPeripheralTissuesTissues

PeripheralPeripheralTissuesTissues

LiverLiverLiverLiver

BileBile

ExcessExcessCholesterolCholesterol

HDL- Cholesterol

Removes excess cholesterol from body cells and transports it to the liver for elimination.

known as "good "good cholesterol" cholesterol" as it prevents accumulation of cholesterol in blood vessels and is associated with a reduced risk of coronary artery disease.

Anti-Atherogenic Properties of HDLAnti-Atherogenic Properties of HDL::

Reverse Cholesterol TransportReverse Cholesterol Transport..

Anti-Oxidant PropertiesAnti-Oxidant Properties..

Anti-Inflammatory PropertiesAnti-Inflammatory Properties::

Vasodilator.Vasodilator.

Anti-Thrombotic.Anti-Thrombotic.

Endothelial ProtectionEndothelial Protection..

Causes of Low HDL-CCauses of Low HDL-C Smoking Obesity (visceral fat) Very-low-fat diet Hypertriglyceridemia Drugs

– Beta-blockers – Androgenic steroids– Androgenic progestins

Smoking Obesity (visceral fat) Very-low-fat diet Hypertriglyceridemia Drugs

– Beta-blockers – Androgenic steroids– Androgenic progestins

Tangier DiseaseTangier Disease

Autosomal codominant disorder due to mutations in both alleles of ABC1 gene

Extremely marked reduction in HDL-C and apoA-I

Markedly accelerated catabolism of apoA-I and apoA-II

Cholesterol accumulation:– Enlarged orange tonsils– Hepatosplenomegaly– Peripheral neuropathy

Autosomal codominant disorder due to mutations in both alleles of ABC1 gene

Extremely marked reduction in HDL-C and apoA-I

Markedly accelerated catabolism of apoA-I and apoA-II

Cholesterol accumulation:– Enlarged orange tonsils– Hepatosplenomegaly– Peripheral neuropathy

To increase the level of HDL life style modification Exesise Stop smoking Drugs Fibrate And Nicin

To increase the level of HDL life style modification Exesise Stop smoking Drugs Fibrate And Nicin

Dyslipidemia Dyslipidemia

DyslipidemiaDyslipidemia is a range of disorders is a range of disorders that include both abnormally high that include both abnormally high and low lipoprotein levels, as well as and low lipoprotein levels, as well as disorders in the composition of these disorders in the composition of these particlesparticles..

Dyslipidemia: Classification During the 1960's; based on

the composition of serum lipoproteins, Fredrickson suggested 5 different phenotypes of hyper-lipoproteinemia.

This classification became commonly used for distinguishing hyper-lipidemic conditions. Donald S.

Fredrickson

Fredrickson Classification Fredrickson Classification of the Hyperlipidemiasof the Hyperlipidemias

PhenotypePhenotypeLipoprotein(s) Lipoprotein(s)

elevatedelevated

Plasma Plasma cholesterol cholesterol

levellevel

Plasma Plasma triglyceride triglyceride

levellevelAthero-Athero-genicitygenicity

Relative Relative frequency frequency

in USin US

II ChylomicronChylomicronss

Normal to Normal to

–– <<1%1%

IIaIIa LDLLDL NormalNormal ++++++ 10%10%

IIbIIb LDL and LDL and VLDLVLDL

++++++ 40%40%

IIIIII IDLIDL ++++++ <<1%1%

IVIV VLDLVLDL Normal to Normal to

++ 45%45%

VV VLDL and VLDL and chylomicronchylomicron

ss

to to ++ 5%5%

Classification of DyslipidemiaClassification of Dyslipidemia

• Etiologic classification: Etiologic classification:

I.I. Primary dyslipidemia:Primary dyslipidemia:o Polygenic hypercholestermia.Polygenic hypercholestermia.o Familial hypercholestermia.Familial hypercholestermia.o Familial hyper-triglycerdemia.Familial hyper-triglycerdemia.o Chylomicronemia.Chylomicronemia.o Familial combined dyslipidemia.Familial combined dyslipidemia.


• Polygenic hypercholestermia:Polygenic hypercholestermia:o ↑↑ ↑↑ LDL.LDL.o Multiple gene defects.Multiple gene defects.o Increased cardiovascular risk.Increased cardiovascular risk.


• Familial hypercholestermia:Familial hypercholestermia:o ↑↑↑ ↑↑↑ LDL.LDL.o ↓ ↓ LDL receptor activity.LDL receptor activity.o Markedly ncreased cardiovascular risk.Markedly ncreased cardiovascular risk.


• Familial hypertriglycerdemia:Familial hypertriglycerdemia:o ↑↑↑ ↑↑↑ TG.TG.o ↓ ↓ Lipoprotein lipase activity.Lipoprotein lipase activity.o No increase in cardiovascular risk.No increase in cardiovascular risk.


• Chylomicronemia:Chylomicronemia:o ↑↑↑ ↑↑↑ TG.TG.o ↓ ↓ Lipoprotein lipase activity or apo C-II Lipoprotein lipase activity or apo C-II

deficiency.deficiency.o No increase in cardiovascular risk.No increase in cardiovascular risk.o Pancreatitis.Pancreatitis.


• Chylomicronemia:Chylomicronemia:o Retinal lipemia.Retinal lipemia.o Milky serum.Milky serum.


• Chylomicronemia:Chylomicronemia:o Eruptive xanthoma.Eruptive xanthoma.


• Chylomicronemia:Chylomicronemia:o Eruptive xanthoma.Eruptive xanthoma.


• Familial combined dyslipidemia:Familial combined dyslipidemia:

o ↑↑↑ ↑↑↑ TG.TG.

o ↑↑↑ ↑↑↑ LDL.LDL.

o Apo B overproductionApo B overproduction

o Increased cardiovascular risk.Increased cardiovascular risk.



II. Secondary dyslipidemia:II. Secondary dyslipidemia:o Diabetic dyslipidemia.Diabetic dyslipidemia.o Obesity, insulin resistance or metabolic Obesity, insulin resistance or metabolic

syndrome.syndrome.o Hypothyroidism.Hypothyroidism.o Nephrotic syndrome.Nephrotic syndrome.



II. Secondary dyslipidemia:II. Secondary dyslipidemia:o Cholestatic liver disease.Cholestatic liver disease.o Steroids, non selective beta blockers, Steroids, non selective beta blockers,

diuretics, esterogen and ciclosporin.diuretics, esterogen and ciclosporin.


• Diabetic dyslipidemia:Diabetic dyslipidemia:

o ↑ ↑ TG.TG.

o ↓ ↓ HDL.HDL.

o ↑↑Small dense LDL.Small dense LDL.

o Due to VLDL overproduction.Due to VLDL overproduction.

o Increased cardiovascular risk.Increased cardiovascular risk.

Causes of secondary dyslipidemiaDiabetes mellitus

Alcohol abuse

Therapeutic i.e. iatrogenic (Diuretics, oral contraceptives, retinoids, corticosteroids, anabolic steroids, etc…)

Hypothyroidism

Chronic Renal failure

Nephrotic syndrome

Cholestasis

Bulimia and Anorexia nervosa

Pregnancy

Classification of Classification of HypertriglyceridemiaHypertriglyceridemia

TG (mg/dL)TG (mg/dL) Primary concernPrimary concern

<<150150 NormalNormal

150150––199199 Borderline Borderline highhigh

Metabolic Metabolic syndromesyndrome

200200––499499 HighHigh CHD riskCHD risk

500500 Very highVery high PancreatitisPancreatitis

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-

2497.

Agenda

Introduction. Definition of dyslipidemia. Classification of dyslipidemia. Diagnostic steps:i. History.ii. Examination.iii.Investigations.iv.NCEP-ATP III Guidelines.

Diagnosis of DyslipidemiaDiagnosis of Dyslipidemia

• Diagnostic goals:Diagnostic goals:

o Detect / classify lipoprotein abnormalities.Detect / classify lipoprotein abnormalities.

o Assess cardiovascular risk:Assess cardiovascular risk:

Screen for other cardiovascular risk factors.Screen for other cardiovascular risk factors.

Detect already existing atherosclerotic disease.Detect already existing atherosclerotic disease.

Traditional Risk FactorsTraditional Risk Factors

Non modifiable

Age – middle to late.

Sex – Males.

Family history.

Potentially Modifiable

Dyslipidemia.

Hypertension.

Smoking.

Diabetes

Life style.

Emerging Risk FactorsEmerging Risk Factors

Lipid risk factors:

Lipoprotein (a) .

Lipoprotein remnants .

Small dense LDL particles .

↑ Apolipoprotein B.

↓Apolipoprotein A-I.

Non-lipid risk factors:

Homocysteine .

Inflammatory markers CRP .

Fibrinogen & PAI-1.


• History taking:History taking:o Signs & symptoms of coronary heart disease, Signs & symptoms of coronary heart disease,

cerebrovascular disease and peripheral cerebrovascular disease and peripheral arterial disease.arterial disease.

o History of other cardiovascular risk factors.History of other cardiovascular risk factors.o History of disease causing secondary History of disease causing secondary

dyslipidemia.dyslipidemia.o Dietary habits.Dietary habits.


• History taking:History taking:o Medications.Medications.o Family history of:Family history of:Cardio-vascular disease.Cardio-vascular disease.Diabetes.Diabetes.Hypertension.Hypertension.Dyslipidemia.Dyslipidemia.


• Clinical examination:Clinical examination:o Xanthomatas.Xanthomatas.o Arcus lipoides.Arcus lipoides.o Blood pressure.Blood pressure.o Ankle brachial index (A.B.I).Ankle brachial index (A.B.I).o Waist circumference.Waist circumference.


• Clinical examination:Clinical examination:o Xanthomatas:Xanthomatas:Xanthelasma:Xanthelasma:


• Clinical examination:Clinical examination:o Xanthomatas:Xanthomatas:Xanthelasma:Xanthelasma:


• Clinical examination:Clinical examination:o Xanthomatas:Xanthomatas:Xanthelasma:Xanthelasma: Cholesterol depostion in the epidermal layer Cholesterol depostion in the epidermal layer

of the orbita.of the orbita. LDL-hypercholestermia.LDL-hypercholestermia.


• Clinical examination:Clinical examination:o Xanthomatas:Xanthomatas:Planer xanthomata:Planer xanthomata:


• Clinical examination:Clinical examination:o Xanthomatas:Xanthomatas:Planer xanthomata:Planer xanthomata: Yellow orange deposit in the skin of inter-Yellow orange deposit in the skin of inter-

digital area or buttocks.digital area or buttocks. Familial hypercholestermia. Familial hypercholestermia.


• Clinical examination:Clinical examination:o Xanthomatas:Xanthomatas:Tendon xanthoma:Tendon xanthoma:








• Clinical examination:Clinical examination:o Xanthomatas:Xanthomatas:Tendon xanthoma:Tendon xanthoma: Cholesterol deposits in tendons of extensor Cholesterol deposits in tendons of extensor

muscles (hand, achilles tendon or elbow).muscles (hand, achilles tendon or elbow). Severe LDL-hypercholestermia.Severe LDL-hypercholestermia.


• Clinical examination:Clinical examination:o Xanthomatas:Xanthomatas:Tuberous xanthoma:Tuberous xanthoma:


• Clinical examination:Clinical examination:o Xanthomatas:Xanthomatas:Tuberous xanthoma:Tuberous xanthoma:


• Clinical examination:Clinical examination:o Xanthomatas:Xanthomatas:Tuberous xanthoma:Tuberous xanthoma: Elevated xanthomata at pressure areas.Elevated xanthomata at pressure areas. Dys-lipoproteinemia.Dys-lipoproteinemia.

Eruptive XanthomaEruptive XanthomaEruptive XanthomaEruptive Xanthoma


• Clinical examination:Clinical examination:o Arcus lipoides:Arcus lipoides:


• Clinical examination:Clinical examination:o Blood pressure:Blood pressure: Patient seated.Patient seated. Adequate size of blood pressure cuff.Adequate size of blood pressure cuff.


• Clinical examination:Clinical examination:o Waist cirumfernce:Waist cirumfernce: Correlates with cardio-vascular risk.Correlates with cardio-vascular risk. > 94 cm in men.> 94 cm in men. > 80 cm in women.> 80 cm in women.

Measurement of WaistMeasurement of Waist

Normal Visceral Adiposity

Visceral Fat DistributionVisceral Fat Distribution


• Investigations:Investigations:o Fasting lipid profile.Fasting lipid profile.o Lipoprotein electrophoresis.Lipoprotein electrophoresis.o Lipoprotein ultracentrifugation.Lipoprotein ultracentrifugation.o Lipoprotein (a).Lipoprotein (a).o Apo-lipoproteins measurement.Apo-lipoproteins measurement.o Determination of enzymatic activity.Determination of enzymatic activity.o Small dense LDL.Small dense LDL.

Tendinous XanthomaTendinous XanthomaTendinous XanthomaTendinous Xanthoma

Management ofManagement of

DyslipidemiaDyslipidemia

Diagnostic approach for dyslipidemia (A case of

Xanthoma)

Diagnostic approach for dyslipidemia (A case of

Xanthoma)1. To prove dyslipidemia.

– Fasting lipid profile (TC, T.G, HDL.C, LDL.C).2. To prove the cause of

dyslipidemia. - Complete history taking (especially drug

history) and physical examination– Thyroid function.– Glycemic profile.– Kidney functions.– Assessment for obstructive jaundice.

3. To determine the target.

1. To prove dyslipidemia.– Fasting lipid profile (TC, T.G, HDL.C, LDL.C).

2. To prove the cause of dyslipidemia.

- Complete history taking (especially drug history) and physical examination

– Thyroid function.– Glycemic profile.– Kidney functions.– Assessment for obstructive jaundice.

3. To determine the target.

Step 2: Identify presence of clinical Step 2: Identify presence of clinical CHDCHD or or CHD Risk EquivalentsCHD Risk Equivalents..

Step 3: Determine the presence of major Step 3: Determine the presence of major Risk FactorsRisk Factors..

Step 4: If 2 + risk factors (other than CHD) are present without Step 4: If 2 + risk factors (other than CHD) are present without CHD or CHD risk equivalent, assess 10-y CHD risk.CHD or CHD risk equivalent, assess 10-y CHD risk.

Step 5: Determine risk category to establish Step 5: Determine risk category to establish LDL-C GoalLDL-C Goal, need for , need for TLC & drug therapy. TLC & drug therapy.

Step 8: Treat decreased Step 8: Treat decreased HDL-CHDL-C..

Step 7: Treat elevated Step 7: Treat elevated TrigyceridesTrigycerides..

Step 6: Identify Metabolic Syndrome and treat.Step 6: Identify Metabolic Syndrome and treat.

Step 9: How to estimate (Framingham Risk-Scores) 10-y riskStep 9: How to estimate (Framingham Risk-Scores) 10-y risk

Step 1: Determine Lipoprotein Step 1: Determine Lipoprotein LevelsLevels. .

Management of DyslipidemiaManagement of DyslipidemiaAccording to NCEP-ATP III Guidelines According to NCEP-ATP III Guidelines

What is Framingham Risk Score?What is Framingham Risk Score?

The new Canadian Cardiovascular Society position statement – Recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease

– Recommended for the initial assessment of the majority of patients in the primary prevention category

– The Framingham risk estimate tables adjust for certain risk factors such as TC and smoking status for age, and correct for the effects of treatment on blood pressure measurement

– Provides an estimate of the 10-year risk estimate of hard cardiac end points

The new Canadian Cardiovascular Society position statement – Recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease

– Recommended for the initial assessment of the majority of patients in the primary prevention category

– The Framingham risk estimate tables adjust for certain risk factors such as TC and smoking status for age, and correct for the effects of treatment on blood pressure measurement

– Provides an estimate of the 10-year risk estimate of hard cardiac end points

Can J Cardiol 2006;22(11):913-27.

Framingham Score Card – Framingham Score Card – Female 10-year risk of CVDFemale 10-year risk of CVD

Age

Age Risk Points

20-34 -7

35-39 -3

40-44 0

45-49 3

50-54 6

55-59 8

60-64 10

65-69 12

70-74 14

75-79 16

Risk Factor Risk Points

Smoker

Age Group, Yr

20-39 40-49 50-59 60-69 70-79

No 0 0 0 0 0

Yes 9 7 4 2 1

Total Risk Points

10-Year Risk (%)

<9 1

9-12 1

13-14 2

15 3

16 4

17 5

18 6

19 8

20 11

21 14

22 17

23 22

24 27

<25 <30

HDL-C Level (mmol/L)

Systolic Blood Pressure (mm Hg)

Untreated Treated

<1.55 -1 <120 0 0

1.30-1.54 0 120-129 1 3

1.04-1.29 1 130-139 2 4

<1.04 2140-159 3 5

<160 4 6

Total Cholesterol Level (mmol/L)

Age

20-39 40-49 50-59 60-69 70-79

4.14 0 0 0 0 0

4.15-5.19 4 3 2 1 1

5.20-6.19 8 6 4 2 1

6.20-7.20 11 8 5 3 2

<7.21 13 11 7 4 2

CHD Risk EquivalentsCHD Risk Equivalents

Diabetes.

Peripheral Arterial Disease (PAD).

Abdominal Aortic Aneurysm.

Carotid Artery Disease

Diabetes.

Peripheral Arterial Disease (PAD).

Abdominal Aortic Aneurysm.

Carotid Artery Disease

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Assessing CHD Risk in MenAssessing CHD Risk in MenStep 1: Age

YearsPoints

20-34 -935-39 -440-44 045-49 350-54 655-59 860-64 1065-69 1170-74 1275-79 13

Step 2: Total Cholesterol

TC Points at Points at Points at Points atPoints at(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69

Age 70-79 <160 0 0 0 0

0160-199 4 3 2 1

0200-239 7 5 3 1

0240-279 9 6 4 2

1280 11 8 5 3

1

HDL-C(mg/dL) Points

60 -1

50-59 0

40-49 1

<40 2

Step 3: HDL-Cholesterol

Systolic BP PointsPoints

(mm Hg) if Untreated if Treated

<120 0 0120-129 0 1130-139 1 2140-159 1 2

160 2 3

Step 4: Systolic Blood Pressure

Step 5: Smoking Status

Points at Points at Points at Points atPoints at

Age 20-39 Age 40-49 Age 50-59 Age 60-69Age 70-79

Nonsmoker 0 0 0 00

Smoker 8 5 3 11

Age

Total cholesterol

HDL-cholesterol

Systolic blood pressure

Smoking status

Point total

Step 6: Adding Up the Points

Point Total 10-Year Risk Point Total 10-Year Risk

<0 <1% 118%

0 1% 1210%

1 1% 1312%

2 1% 1416%

3 1% 1520%

4 1% 1625%

5 2% 1730%

6 2%7 3%8 4%9 5%10 6%

Step 7: CHD Risk

ATP III Framingham Risk Scoring

© 2001, Professional Postgraduate Services®

www.lipidhealth.org

Men

YearsPoints20-34 -935-39 -440-44045-49350-54655-59860-641065-691170-741275-7913

Step 1: AgeStep 1: Age

Expert Panel on Detection, Evaluation, and Treatment of High BloodCholesterol in Adults. JAMA. 2001;285:2486-2497.

Women

YearsPoints20-34 -735-39 -340-44045-49350-54655-59860-641065-691270-741475-7916



www.lipidhealth.org

Step 2: Total CholesterolStep 2: Total Cholesterol

Note: TC and HDL-C values should be the average of at least two fasting lipoprotein measurements.


MenTC Points at Points at Points at Points at

Points at(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age

70-79 <160 0 0 0 0

0160-199 4 3 2 1

0200-239 7 5 3 1

0240-279 9 6 4 2

1280 11 8 5 3

1

WomenTC Points at Points at Points at Points at

Points at(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age

70-79 <160 0 0 0 0

0160-199 4 3 2 1

1200-239 8 6 4 2

1240-279 11 8 5 3

2280 13 10 7 4

2



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Step 3: HDL-CholesterolStep 3: HDL-Cholesterol

Note: HDL-C and TC values should be the average of at least two fasting lipoprotein measurements.


Men

HDL-C(mg/dL)

Points60 -1

50-59 0

40-49 1

<40 2

Women

HDL-C(mg/dL)

Points60 -1

50-59 0

40-49 1

<40 2



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Step 4: Systolic Blood PressureStep 4: Systolic Blood PressureMen

Systolic BP Points Points(mm Hg) if Untreated if Treated

<120 0 0120-129 0 1130-139 1 2140-159 1 2

160 2 3

Note: The average of several BP measurements is needed for an accuratemeasurement of baseline BP. If an individual is on antihypertensive treatment,extra points are added.


WomenSystolic BP PointsPoints

(mm Hg) if Untreated if Treated

<120 0 0120-129 1 3130-139 2 4140-159 3 5

160 4 6



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Step 5: Smoking StatusStep 5: Smoking Status

Note: Any cigarette smoking in the past month.


Men Points at Points at Points at Points at

Points at Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age

70-79 Nonsmoker 0 0 0 00Smoker 8 5 3 11

Women Points at Points at Points at Points at

Points at Age 20-39 Age 40-49 Age 50-59 Age 60-69

Age 70-79 Nonsmoker 0 0 0 00Smoker 9 7 4 21



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Step 6: Adding Up the Points(Sum From Steps 1–5)

Step 6: Adding Up the Points(Sum From Steps 1–5)


AgeTotal cholesterolHDL-cholesterolSystolic blood pressureSmoking statusPoint total



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Step 7: CHD Risk for MenStep 7: CHD Risk for Men

Note: Determine the 10-year absolute risk for hard CHD (MI and coronary death) from point total.


Point Total10-Year Risk Point Total 10-Year Risk

<0 <1% 118%

0 1% 1210%

1 1% 1312%

2 1% 1416%

3 1% 1520%

4 1% 1625%

5 2% 1730%

6 2%7 3%8 4%9 5%

10 6%



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Major CHD Risk Factorsthat Modify LDL Goals

Major CHD Risk Factorsthat Modify LDL Goals

† HDL cholesterol ³60 mg/dL counts as a “negative” risk factor; its presence removes one risk factor from the

(1)(1) AgeAge (>45 years in Men & >55years in Women).(>45 years in Men & >55years in Women).

(2) (2) Family HistoryFamily History of Premature CHD of Premature CHD (<55 years in Male & <65 years in Female).(<55 years in Male & <65 years in Female).

(3) (3) HypertensionHypertension(BP>140/90 mmHg or Antihypertensive medication).(BP>140/90 mmHg or Antihypertensive medication).

(4) Cigarette (4) Cigarette SmokinSmokingg..

(5) Low (5) Low HDL-CHDL-C (<40 mg/dl). (<40 mg/dl).

(1)(1) AgeAge (>45 years in Men & >55years in Women).(>45 years in Men & >55years in Women).

(2) (2) Family HistoryFamily History of Premature CHD of Premature CHD (<55 years in Male & <65 years in Female).(<55 years in Male & <65 years in Female).

(3) (3) HypertensionHypertension(BP>140/90 mmHg or Antihypertensive medication).(BP>140/90 mmHg or Antihypertensive medication).

(4) Cigarette (4) Cigarette SmokinSmokingg..

(5) Low (5) Low HDL-CHDL-C (<40 mg/dl). (<40 mg/dl).

NCEP ATP III LDL-C GoalsNCEP ATP III LDL-C Goals

Risk CategoryRisk Category LDL-C GoalLDL-C Goal(mg/dl)(mg/dl)

CHD or CHD Risk Equivalents <100

2+ Risk Factors <130

0–1 Risk Factor <160

NCEP ATP= National Cholesterol Education Program Adult Treatment Panel.

LDL-C = low-density lipoprotein cholesterol.


Non-HDL CholesterolNon-HDL Cholesterol

Non-HDL Cholesterol = TC – HDL Cholesterol1

Secondary target of therapy when serum TG

200 mg/dL1

New non-HDL-C goal for patients with elevated

TG is LDL-C goal + 30 mg/dL1

Non-HDL-C includes all atherogenic lipoprotein particles including LDL-C, Lp(a), IDL-C, and

VLDL-C2

Non-HDL Cholesterol = TC – HDL Cholesterol1

Secondary target of therapy when serum TG

200 mg/dL1

New non-HDL-C goal for patients with elevated

TG is LDL-C goal + 30 mg/dL1

Non-HDL-C includes all atherogenic lipoprotein particles including LDL-C, Lp(a), IDL-C, and

VLDL-C21. NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497. 2. Cui Y, et al. Arch Intern Med. 2001;161:1413-1419.

Therapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle Change

Dietary Management of Dyslipidemia

(ATP III Recommendations)

Dietary Management of Dyslipidemia

(ATP III Recommendations)NutrientNutrient Recommended IntakeRecommended Intake

CarbohydratesCarbohydrates 50-60%50-60% of total caloriesof total calories

Fiber Fiber 20-30 g/day20-30 g/day

Protein Protein 15% of total calories15% of total calories

Total fat Total fat 25-35% of total calories25-35% of total calories

Polyunsaturated Fat Polyunsaturated Fat Up to 10% of total caloriesUp to 10% of total calories

Monounsaturated Fat Monounsaturated Fat Up to 20% of total caloriesUp to 20% of total calories

Saturated FatSaturated Fat < 7% of total calories< 7% of total calories

Total calories Total calories (energy)(energy)

Balance energy intake and Balance energy intake and expenditure to maintain desirable expenditure to maintain desirable body weight .body weight .

† Carbohydrate should be derived predominantly from foods rich in complex carbohydrates including grains, especially whole grains, fruits, and vegetables.

Drugs Used in the Treatment Drugs Used in the Treatment of Dyslipidemiaof Dyslipidemia

Drugs Used in the Treatment Drugs Used in the Treatment of Dyslipidemiaof Dyslipidemia

Primary treatment goal Primary treatment goal


High LDL-CHigh LDL-CHigh LDL-CHigh LDL-C


Drug TherapyDrug TherapyDrug TherapyDrug Therapy

Therapy of Choice: Therapy of Choice: StatinStatinTherapy of Choice: Therapy of Choice: StatinStatin

Alternative:Ezetimibe ,Alternative:Ezetimibe ,Resin or niacinResin or niacin

Treatment of Mixed HyperlipidemiaTreatment of Mixed Hyperlipidemia


High LDL-C and TGsHigh LDL-C and TGsHigh LDL-C and TGsHigh LDL-C and TGs


Drug TherapyDrug TherapyDrug TherapyDrug Therapy

Achieve the LDL-C goalAchieve the LDL-C goal11STEPSTEP

Achieve the non-HDL-C goalAchieve the non-HDL-C goalIncrease LDL-C lowering orIncrease LDL-C lowering orAdd a fibrate, niacin or fish oilsAdd a fibrate, niacin or fish oils22STEPSTEP

StatinsStatins

Inhibit synthesis of cholesterol by cells

Inhibition HMG-CoA reductase enzyme which is the key enzyme of Cholesterol synthesis.

Lower LDL cholesterol

Statins are considered the primary pharmacological modality for LDL-C lowering.

Inhibit synthesis of cholesterol by cells

Inhibition HMG-CoA reductase enzyme which is the key enzyme of Cholesterol synthesis.

Lower LDL cholesterol

Statins are considered the primary pharmacological modality for LDL-C lowering.

Statin Adverse EventsStatin Adverse Events Common side effects

– Headache – Myalgia – Fatigue– GI intolerance – Flu-like symptoms

Increase in liver enzymes

– Occurs in 0.5 to 2.5% of cases in dose-dependent manner

– Serious liver problems are exceedingly rare Myopathy

– Occurs in 0.2 to 0.4% of patients– Rare cases of rhabdomyolysis– Presence of muscle toxicity requires the

discontinuation of the statin

Common side effects

– Headache – Myalgia – Fatigue– GI intolerance – Flu-like symptoms

Increase in liver enzymes

– Occurs in 0.5 to 2.5% of cases in dose-dependent manner

– Serious liver problems are exceedingly rare Myopathy

– Occurs in 0.2 to 0.4% of patients– Rare cases of rhabdomyolysis– Presence of muscle toxicity requires the

discontinuation of the statin

FibratesFibrates

Indications:Indications: HypertriglyceridemiaHypertriglyceridemia

Combined DyslipidemiaCombined Dyslipidemia

Mechanism of Mechanism of Action:Action:

Decrease Decrease hepatichepatic TG productionTG production

Efficacy:Efficacy: Decrease Decrease TGTG 20–50% 20–50%LDL-CLDL-C decreases slightly 5-20% decreases slightly 5-20%Increase Increase HDL-C HDL-C 10–20%10–20%

Side Effects:Side Effects: GI upsetGI upset (8%), (8%), cholelithiasischolelithiasis, , myositismyositis, , abn abn LFTsLFTs

Contraindications:Contraindications: HepaticHepatic or or renalrenal dysfunction dysfunctionPre-existing Pre-existing GB diseaseGB disease

Net Effect: Net Effect: LDL-C LDL-CNet Effect: Net Effect: LDL-C LDL-C

Gall Gall BladderBladder

LDL ReceptorsLDL Receptors

VLDL and LDL VLDL and LDL removalremoval

Cholesterol 7-Cholesterol 7- hydroxylasehydroxylase Conversion of cholesterol Conversion of cholesterol to BAto BA BA SecretionBA Secretion

LiverLiver

BA ExcretionBA Excretion

Terminal Terminal IleumIleum

Bile AcidBile Acid

Enterohepatic Enterohepatic

RecirculationRecirculation

Reabsorption Reabsorption of of

bile acidsbile acids

Cholesterol Absorption Inhibitors Bile Acid Resins:

Cholesterol Absorption Inhibitors Bile Acid Resins:

Adverse effectsAdverse effects

– GI intolerance: constipation, bloating, abdominal pain, GI intolerance: constipation, bloating, abdominal pain, flatulenceflatulence

– Lack systemic toxicityLack systemic toxicity

Drug interactionsDrug interactions (colestipol and cholestyramine) (colestipol and cholestyramine)

– Bind other negatively charged drugsBind other negatively charged drugs

– Impede the absorption of drugs and/or fat-soluble Impede the absorption of drugs and/or fat-soluble vitaminsvitamins

– Must give other drugs 1 hour before or 4–6 hours after Must give other drugs 1 hour before or 4–6 hours after BARsBARs

Mechanism of Action of Niacin Mechanism of Action of Niacin

LiverLiver CirculationCirculationHDLHDL

Serum VLDL Serum VLDL results in results in reduced reduced lipolysis to lipolysis to LDL LDL Serum Serum LDLLDL

VLDL

Decreases hepatic production of VLDLDecreases hepatic production of VLDL

VLDL VLDL

secretiosecretio

nn

Apo BApo B

HepatocyeHepatocye Systemic CirculationSystemic Circulation

Mobilization of Mobilization of FFAFFA

TG TG

synthesissynthesis

VLDL

LDL

Nicotinic AcidNicotinic Acid Products available (daily dose)Products available (daily dose)

– Immediate-releaseImmediate-release, 2–4 g/d, 2–4 g/d– Extended-releaseExtended-release (Niaspan (Niaspan®®), 1–2 g/d), 1–2 g/d

Best agent to raise Best agent to raise HDL-CHDL-C Adverse effectsAdverse effects

– FlushingFlushing, itching, , itching, headacheheadache, , hepatotoxicityhepatotoxicity. . – Activation of Activation of peptic ulcerpeptic ulcer– HyperglycemiaHyperglycemia..

ContraindicationsContraindications– Active Active liver liver disease or unexplained LFT disease or unexplained LFT

elevationselevations– Peptic ulcer diseasePeptic ulcer disease

DuodenumDuodenumDuodenumDuodenum

JejunumJejunumJejunumJejunum

IleumIleumIleumIleum

CMapoB48

Liver

CM RemnantapoB48

VLDLapoB100

EzetimibeXX

LDLapoB100

ColonColonColonColon

Indications: Adjunctive therapy to dietHypertriglyceridemia With statins or other LDL-C–lowering drugs in mixed hyperlipidemia

Efficacy: Decrease TG 30–40%LDL-C remains the same or increasesNo change in HDL-C

Side Effects:

GI upset and a “fish burp”

LDL - HYPERCHOLEST

TARGETACHIEVED AND

TOLERATED

STATIN

NOT TOLERATED

EZETEMIBE

BILE ACIDBINDING RESIN

FIBRATE/NIACIN

TARGET VALUES NOTACHIEVED

COMBINATION WITHEZETIMIBE

ADDITITIONALBILE ACID BINDING

LDL-APHERESISCAD

HYPERTRIGLICEREDEMIA

LIFE STYLE MODIFICATION SECONDARY CAUSES; ALCOHOL,DIABETES,OBESITY

TARGET VALUES

ACHIEVEDAND WELL TOLERATED

FIBRATE

NOT TOLERATED

STATIN

NIACIN

TARGET VALUES NOT ACHIEVED

CONSIDER COMBINATIONWITH NIACIN

COMBINED HYPERLIPOPROT

LIFE STYLE MODIFICATION

STATIN

TARGET NOT ACHIEVED

FIBRATE

POSIBLE COMBINATION

STATIN WITH NICOTINIC

FIBRATE WITHG NICOTINIC

FIBRATE WITH EZETIMIBEAND

STATIN WITH FIBRATE

Thank YouThank You

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Dyslipidemia

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