Post on 16-Dec-2015
Chylomicrons VLDL LDL HDL
COMPOSITION OF PLASMA LIPOPROTEINS
Densityg/ml
0.93 0.93-1.006 1.019-1.063 1.063-1.25
Size (nM) 75-1200 30-60 18-25 9-12
Cholesterol/cholesteryl estersProteinTriglyceridePhospholipid
Bilheimer. Textbook of Internal Medicine. 1989:2139-44
Chylomicrons VLDL LDL HDL
86 55 6
5
57
50
196
1822
2240
33
22
2
Apo E Apo E
Exogenous Pathway (Chylomicron metabolism)Exogenous Pathway (Chylomicron metabolism)
B48CE
Chylomicron Remnant Liver
Intestines
CEB48
CETG
LPL
C-II
Fatty acids
TG
Remnant Receptor
Endogenous Pathway (VLDL metabolism)
Apo E Apo E
B100
CE
VLDL Remnant LDL (VLDL/IDL)
Liver
CEB100
CETG
RemnantReceptor LPL
C-II
Fatty acids
TG
B100
CE
Basic Pathways in LDL Regulation
apo B-100
apo C
apo E
VLDL
VLDLRemnant
LDL
Liver
VLDLPRODUCTION
LDL CLEARANCE
LIPOLYSIS
CONVERSION
Other sites
SHUNT PATHWAY
Familial Hypercholesterolemia
• Autosomal Dominant Inheritance
• LDL Receptor Deficiency:
- Heterozygous (1/500)
- Homozygous (1/1,000,000)
• LDL Cholesterol Increased
- Heterozygous 2 times (>250 mg/dl)
- Homozygous 4-6 times elevated
• Familial Defective apoB is an exact phenocopy
(note this is NOT Familial Combined HLD)
Familial Hypercholesterolemia
Apo E Apo E
apoBCE
ChyloVLDL Remnants LDL
Liver
CEapoB
CETG
LPL
C-II
Fatty acids
TG
B100LDL-R
Familial Hypercholesterolemia: Clinical Manifestations
• Severe Hypercholesterolemia (LDL>250 mg/dl)
- Atherosclerotic vascular disease
• Premature CHD
• Xanthelasma/ Corneal Arcus as young adults
• Tendon Xanthomas
• Arthritic type pains in joints
• Family History of premature CHD
Familial Hypercholesterolemia: Ligand Defective ApoB
B100LDL-R
Apo E Apo E
apoBCE
ChyloVLDL Remnants LDL
Liver
CEapoB
CETG
LPL
C-II
Fatty acids
TG
Familial Combined HyperlipidemiaFamilial Combined Hyperlipidemia
Common (1/100)Common (1/100)
Autosomal dominant pattern of inheritanceAutosomal dominant pattern of inheritance
Variable lipoprotein pattern in individual and familyVariable lipoprotein pattern in individual and family
Multiple Phenotypes (IIa, IIb, IV, V)Multiple Phenotypes (IIa, IIb, IV, V)
Pathophysiology: overproduction of apoB-100 Pathophysiology: overproduction of apoB-100
particlesparticles
CHD risk is increasedCHD risk is increased
Familial Combined Hyperlipidemia (HyperapoB)
Liver
CE
Apo E
B100CETG
LPL
C-II
Fatty acids
Apo E
B100CE
TG
B100
VLDL Remnant LDL (VLDL/IDL)
LDL-RCE
Familial (Type I) Hyperlipoproteinemia/Chylomicronemia
• Rare (1/1,000,000)
• Recessive inheritance
• Triglycerides > 1000 mg/dl with usual diet
• Presents in childhood, especially puberty in girls
• Pathophysiology: absence of lipoprotein lipase or
apo C-II
• Complications: pancreatitis, xanthomatosis,
hepatosplenomegaly
Familial (Type I) Hyperlipoproteinemia/Chylomicronemia
Apo E Apo E
apoB
Chylo/VLDL Remnants LDL (VLDL/IDL)
Liver
CEapoB
CE
TG
LPL
C-II
Fatty acids
CE
TG
B100LDL-RCE
Remnant Removal Disease
• Synonyms: Familial Dysbetalipoproteinemia, Type III hyperlipoproteinemia, Broad beta disease
• Uncommon: 1/1000 – 1/5000
• Requires apo E2/E2 (1/100) + second defect for clinical expression
• Pathophysiology: impaired clearance of apoB/E remnant particles by the remnant receptor
• Chylomicron and VLDL (-VLDL) remnants accumulate
• Diagnosis: VLDL-C/TG >0.3; broad -band on EP
• CHD and peripheral vascular disease
• Palmar and tuberoeruptive xanthomata
_
Remnant Removal Disease (Type III Hyperlipidemia)
B100LDL-R
Apo E Apo E2/E2
apoBCE
ChyloVLDL Remnants LDL
Liver
CEapoB
CETG
LPL
C-II
Fatty acids
TG
Primary Hypercholesterolemia: Clinical Classification
• Elevated LDL cholesterol (>160 mg/dl; 1/4 of all
American Adults)
- Familial Hypercholesterolemia (1/500)
- Familial Combined Hyperlipidemia (1/100)
- Polygenic Hypercholesterolemia (1/4)
Dietary HyperlipidemiaDietary Hyperlipidemia
VLDL
LDL
Apo E
Apo C
apoB-100
LDL
VLDLremnants
Increased conversionto LDL
XX
Overproduction ofVLDL TG
Other sites
Reduced activityof LDL receptors
( Saturated fat and cholesterol In the diet)
Caloric intake
Reverse cholesterol transportReverse cholesterol transport
A-I
Liver
CECE
FCLCAT
FC
Bile
A-I
ABCA1
Macrophage
Mature HDL
Nascent HDL
FCCE
Reverse cholesterol transport : Reverse cholesterol transport : Role of CETP in HDL MetabolismRole of CETP in HDL Metabolism
CETP = cholesteryl ester transfer protein
A-I
Liver
CECE
FCFCLCAT
FC
Bile
SR-BI
A-I
ABCA1
Macrophage
CE B
LDLR
VLDL/LDL
CETP
Mature HDL
Nascent HDL
CE
SRA
OxidationCETG
Secondary Causes of Low HDL-CSecondary Causes of Low HDL-CSmokingSmoking
Obesity (visceral fat)Obesity (visceral fat)
Sedentary LifestyleSedentary Lifestyle
High carbohydrate or very-low-fat dietHigh carbohydrate or very-low-fat diet
Hypertriglyceridemia (from any cause)Hypertriglyceridemia (from any cause)
DrugsDrugs– Beta-blockers Beta-blockers – Androgenic steroidsAndrogenic steroids– Androgenic progestinsAndrogenic progestins
Cholesterol disorders associated with premature CAD
Familial Hypercholesterolemia Low HDLNephrotic SyndromeLp(a) [ not ApoA].
Triglyceride Disorders associated with premature CAD
(+) premature CAD (-) premature CAD
Familial Combined HLD Familial HTGRemnant Removal Dz Familial ChylomicronemiaCentral Obesity (metabolic syndrome) EstrogenDiabetes AlcoholNephrotic syndrome/Uremia/dialysis Bile Acid ResinsHypothyroidism High Carbohydrate dietCushing’s syndrome
New Concepts in Atherosclerosis New Concepts in Atherosclerosis Risk: Risk:
Triglycerides, Small Dense LDL Triglycerides, Small Dense LDL and the Metabolic Syndromeand the Metabolic Syndrome
Atherosclerosis
HDL VLDL IDL
TG
LDL
CigaretteSmoking
HypertensionDiabetes
Pro CoagulantState
Thrombosis
CHD
HYPERTRIGLYCERIDEMIA
Small, dense LDL
HDL IDL
VLDLremnants
Chylomicronremnants
Metabolic Consequences of Hypertriglyceridemia
Insulin Resistance and Insulin Resistance and DyslipidemiaDyslipidemia
(lipoprotein or
hepatic lipase)
Fat Cells
Insulin
IR
FFA
Liver
(CETP)
CE
TG Apo A-I(CETP)CE TG
VLDL HDL
SDLDLLDL
TGApo BVLDL
Kidney
v
Feingold KR et al. Arterioscler Thromb. 1992;12:1496-1502.Lamarche B et al. Circulation. 1997;95:69-75.
Significance of Small, Dense LDLSignificance of Small, Dense LDL
Low cholesterol content of LDL particlesLow cholesterol content of LDL particles particle number for given LDL-C levelparticle number for given LDL-C level
Associated with Associated with levels of TG variable LDL-C, and levels of TG variable LDL-C, and levels of HDL levels of HDL22
Marker for common genetic trait associated with Marker for common genetic trait associated with risk of coronary disease (LDL subclass pattern B) risk of coronary disease (LDL subclass pattern B)
Possible mechanisms of Possible mechanisms of atherogenicity atherogenicity– greater arterial uptakegreater arterial uptake uptake by macrophagesuptake by macrophages oxidation susceptibilityoxidation susceptibility
Atherogenic CholesterolAtherogenic Cholesterol
VLDL + IDL + LDL
= Total Cholesterol - HDL
= non HDL cholesterol
Calculating LDL CholesterolCalculating LDL Cholesterol
• LDL-C = TC – HDLC – TG/5
• Invalid when TG > 400 mg/dl
• Underestimates “atherogenic cholesterol”
when TG >200 mg/dl
• nonHDL-C = TC - HDLC
Non-HDL CholesterolNon-HDL Cholesterol
Predictive of CV Events Rates in ProspectivePredictive of CV Events Rates in Prospective
Clinical TrialsClinical Trials
Useful when triglycerides > 200 mg/dlUseful when triglycerides > 200 mg/dl
Allows use of NCEP LDL guidelines Allows use of NCEP LDL guidelines
(+ 30 mg/dl)(+ 30 mg/dl)
Flexible - Allows use of non fasting samplesFlexible - Allows use of non fasting samples
to assess lipid treatment goalsto assess lipid treatment goals
ATP III: The Metabolic Syndrome*ATP III: The Metabolic Syndrome*
*Diagnosis is established when 3 of these risk factors are present.†Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡Some men develop metabolic risk factors when circumference is only marginally increased.
Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
Risk Factor Defining LevelAbdominal obesity† (Waist circumference‡)MenWomen
>102 cm (>40 in)>88 cm (>35 in)
TG 150 mg/dLHDL-C
MenWomen
<40 mg/dL<50 mg/dL
Blood pressure 130/85 mm HgFasting glucose 110 mg/dL
ATP III: New Features of Guidelines—ATP III: New Features of Guidelines—Focus on Multiple Risk FactorsFocus on Multiple Risk Factors
Persons with diabetes without CHD raised to level of Persons with diabetes without CHD raised to level of CHD risk equivalentCHD risk equivalent
Framingham 10-year absolute CHD risk projections Framingham 10-year absolute CHD risk projections used to identify certain patients with used to identify certain patients with 2 risk factors for 2 risk factors for more intensive treatmentmore intensive treatment
Persons with multiple metabolic risk factors (the Persons with multiple metabolic risk factors (the metabolic syndrome) identified as candidates for metabolic syndrome) identified as candidates for intensified therapeutic lifestyle changes (TLC)intensified therapeutic lifestyle changes (TLC)
Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.