The Usual Suspects: Cholesterol and Triglyceride
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Transcript of The Usual Suspects: Cholesterol and Triglyceride
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The Usual Suspects: Cholesterol and Triglyceride
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Lipid StructureCholesterol: Membranes
Bile AcidsSteroid HormonesProtein modification
Fatty Acids: Fuel, Prostanoids
Glycerol
Triglycerides: FA for Fuel, ProstanoidsProtein modification
Phospholipid: Lecithin Membranes2nd Messengers
HO
COOH
COOH
COOH
HO
HO
HO
+
COO
COO
COO
COO
COO
OPOON+
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Structure of a Typical Lipoprotein
Free cholesterol (surface and core)
Phospholipid (amphipath at surface only)
Triglyceride (core only)
Cholesteryl ester (core only)
Apolipoprotein (amphipath at surface only)
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Lipoprotein classes and sub-Classes
1.20
1.10
1.06
1.02
1.006
0.95
5 10 20 40 60 80 1000
ChylomicronRemnants
VLDL
LDL
HDL2
HDL3
Particle Size (nm)
Den
sity
(g/m
l)
Chylomicron
VLDLRemnants
Lp(a)
IDL
Directly atherogenic (found in plaque)
pre-β2 HDL
pre-β1 HDL
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Substrates for Triacylglycerol Synthesis
Glucose
Glc-6-Pase
PEP
Pyruvate
NEFA
Acyl-CoA SynthetaseCoA
MitochondriaCPT I
Acyl-CarnitineCPT II
Acyl-CoA
Acetyl-CoA
Pyruvate
Ketone BodiesHMG-CoA Synthase
Krebs Cycle
CO2
CPT = Carnitine palmitoyl transferase
Glucose-6-P
PEPCKPyruvate kinase
ATP Citrate Lyase
Acetyl-CoA
Acyl-CoA Carboxylase
Malonyl-CoA
Fatty Acid Synthase
Acyl-CoA
Triglycerides
Beta-oxidation
Hepatocyte
PEP = phosphoenolpyruvate PEPCK = PEP carboxylase
Citrate
Acyl-CoA
Citrate
Plasma
Multiple steps
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Structures of Fatty Acids
CHO
O
CHO
O
CHO
O
CHO
O
CHO
O
16:0 (palmitic)
cis-18:1 -6 (oleic)
trans-18:1 -6 (elaidic)
18:2 -6 (linoleic)
18:3 -3(alpha linolenic)
CHO
O 20:5 -3 (EPA)
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Liver
Lymphatic chylomicron
Muscle and adipose tissue
Lipoprotein lipase Lipoprotein Lipase
Plasma chylomicron
Fatty acids
Bloodstream
LDLreceptor
Hepatocyte
ChylomicronRemnant
Exogenous (dietary) lipid metabolism
Apo C-II enhances and apo C-III inhibits
LPL activity
Apo B and apo E are ligands for LDL
receptorLDL (apo B,E) receptor clears ChylomicronRemnants
Xenical blocks diatary fat digestion
INTESTINE
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Liver
VLDL
Muscle and adipose tissue
Lipoprotein lipase Lipoprotein LipaseAnd hepatic lipase
IDL
Fatty acids
Bloodstream
LDLreceptor
Hepatocyte
LDL
Endogenous (hepatic) lipid metabolism
Apo C-II enhances and apo C-III inhibits
LPL activity
Apo B and apo E are ligands for LDL
receptorLDL (apo B,E)
receptor clears VLDL, IDL & LDL
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Clinical Hypertriglyceridaemia
Condition Features
Secondary Relatively common (obesity, diabetes,renal impairment, liver disease, drugs)
Familial Overproduction of apo B lipoproteinsCombined H/L TG and TC vary with age and weight
Polygenic Accounts for the majority of cases
Familial HTG TG predominates. CVD risk variesPredisposes to massive HTG
Massive HTG Lipoprotein Lipase deficiency or saturation. Risk of pancreatitis
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Therapy for Hypertriglyceridaemia
Intervention Features
Diet, Exercise Relatively responsive
Fibrates Effective in high TG, low HDL
Alcohol restriction Often sufficient in heavy intake
Manage 2o causes Diabetes, renal
Statins Mild TG and HDL benefitFish oils (eg 6gm/d) Benefits TG rather than HDLNiacin Effective, but increases glu, urate.
Bile acid resins Contraindicated. Increase TGFuture DGAT 2 Inhibitors?
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400 mg/day
1,300 mg/day
NORMAL CHOLESTEROL ABSORPTION
Oil phase
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400 mg/day
1,300 mg/day
NORMAL CHOLESTEROL ABSORPTION
Plant sterols competewith cholesterol here
Oil phase
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400 mg/day
1,300 mg/day
17,400 mg/day
850 mg/day
NORMAL CHOLESTEROL ABSORPTION
Ezetimibe competeswith cholesterol here
Oil phase
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400 mg/day
1,300 mg/day
850 mg/day
NORMAL CHOLESTEROL ABSORPTION
Oil phase 17,400 mg/day
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Intracellular cholesterol sensing by SREBPs (Sterol Regulatory Element Binding Proteins)
WD Reg
WD
bHLH
bHLH bHLH
bHLH
Reg
S1P S2P
ZN++
Serine protease Metalloproteinase
Golgi Apparatus
Lumen
Sterols
Cytosol
SREBPSCAPNucleus
ERSRE
SCAP or SREBP activating protein
Membrane fluidity reflects intracellular cholesterol. Low levels allow cleavage to active form which binds nuclear receptor to control gene expression.• SREBP-2 controls
cholesterol synthesis and sterol metabolism
• SREBP-1c is the major isoform in liver and is a key regulator of fatty acid & triglyceride synthesis
Other nuclear receptors: FXR, LXR.
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LDL Receptor activity reflects intracellular cholesterol homeostasis
*[SREBP] = sterol regulatory element-binding protein. 1. Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438..
Cholesterol delivery via LDL-R alters intracellular membrane cholesterol and SREBP, whicha) Reduces synthesis via
HMGCoA Reductaseb) Reduces LDL-R synthesisc) Increases storage as esterd) Reduces counter-regulatory
PCSK9
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LCAT
Hepatic lipase, endothelial
lipase
ABCA1, ATP-binding cassette protein A1; CETP, cholesterol ester transfer protein; FC, free cholesterol; LCAT, lecithin:cholesterol acyltransferase; SR-A, scavenger receptor class A; SR-BI, scavenger receptor class B type I.
PL&UC
Bile
SR-BI
Macrophage
VLDL/LDL
CETP
Spheroidal HDL Pre-β HDL
SR-A
Oxidation
The Role of HDL inReverse Cholesterol Transport
LDLReceptor
LiverABCA1UC
ABCG1 &SR-B1
UC
Adapted with permission from Cuchel C et al. Arterioscler Thromb Vasc Biol. 2003;23:1710–1712
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Clinical Hypercholesterolaemia
Condition Features
Secondary Relatively uncommon, but potent (hypothyroidism, nephrotic syndrome,primary biliary cirrhosis)
Familial Overproduction of apo B lipoproteinsCombined H/L TG and TC vary with age and weight
Polygenic Accounts for the majority of cases
Familial Prevalent, Accelerates CVD.Hyperchol’aemia Due to defects in genes related to LDL-R
Increased HDL ?OK if LDL not raised?
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Therapy for Hypercholesterolaemia
Intervention Features
Diet Plant sterols, avoid sat & trans FAManage 2o causes Rarer, but potent: (Thyroid, liver,
renal.) Statins First line for LDL reductionEzetimibe 2nd line. Neutral for TG & HDL
Niacin Improves LDL, TG, HDL & Lp(a)Bile acid resins Colesevalam better tolerated
Future PCSK9 Inhibitors, MTP inhibitors?Apo B antisense oligonucleotides
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Triglyceride and Cholesterol:Why are they linked?
• Most lipoproteins have TG and/or CE in their core• Hepatic Triglyceride rich lipoproteins are precursors of
cholesterol-rich LDL• Cholesterol-ester transfer protein allows all
triglyceride-rich lipoproteins to modify the composition of cholesterol-rich HDL and LDL. As a result, hypertriglyceridaemia is associated with reduced HDL cholersterol as well as “small dense LDL”.
• The major gene regulators for lipid metabolism affect both TG and Chol
•
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Key Regulators of Genes in Fatty Acid and Triglyceride Metabolism
LXR
RXR
PPAR
FXR
HNF-4α
SREBP-1c
NEFAAcyl CoA
Apolipoproteins Pyruvate kinase
Glucose-6-phosphalase Transferin
Bile Acids
Unsaturated Saturated
Fatty acid metabolismTransport
Oxidation Fatty Acid Binding Protein
Ketogenesis
L-FABP
Acetyl CoA Carboxylase Fatty Acid Synthase
Spot 14
SHPBile Acids
Adapted from Pegorier JP et al. J Nutr 2004;134:2444S-9S
SHP = Short Heterodimer Partner
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Key Regulators of Genes in Lipid Metabolism
Cellular Cholesterol
Homeostasis
Hepatobiliary IntestineLiver X Receptor (LXR)
Sterol Regulatory Element Binding Protein (SREBP2)
Farnesoid X Receptor (FXR)
Peroxisome proliferated activator receptors PPARsSynthesis Delivery
Acquisition
Excretion
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Link to mixed HL cases
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Patient is a 43 year-old male with a strong family history of premature CVD who presents for initial evaluation.
He has a 10 year history of dyslipidaemia and hypertension, for which he has received beta blockers in the past. More recently he has been on an ARB/diuretic combination. Three months prior to this visit a fasting lipid profile showed:
Total Cholesterol: 5.7 mmol/L Triglyceride: 2.8 mmol/L HDL-C: 0.7 mmol/L LDL-C: 3.6 mmol/L
He has managed to lose 3 kg and today results include:
Case MC
Total Cholesterol: 6.9 mmol/L Triglyceride: 1.8 mmol/L HDL-C: 0.8 mmol/L LDL-C: 5.2 mmol/L
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Questions concerning Mr M.C.
• 1) Is ethnicity an independent risk factor for CVD? Yes / No?
• 2) In the absence of any symptoms or signs of hypothyroidism, would you perform thyroid function tests? Yes / No?
• 3) His brother’s lipids include LDL = 5.4 mmol/l, TG = 1.9 mmol/l, HDL = 0.9 mmol/l . What is the most likely cause of MC’s lipid abnormality?
• A) Dyslipidaemia secondary to Insulin resistance and the Metabolic Syndrome• B) Polygenc dyslipidamia• C) Familial Combined Hyperlipidaemia• D) Familial Hypercholesterolaemia• E) Lipids aren’t really an issue in this patient
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• 1) Is ethnicity an independent risk factor for CVD? Yes / No?• 2) In the absence of any symptoms or signs of hypothyroidism,
would you perform thyroid function tests? Yes / No?• 3) His brother’s lipids include
LDL = 5.4 mmol/l, TG = 1.9 mmol/l, HDL = 0.9 mmol/l . What is the most likely cause of MC’s lipid abnormality?
• A) Dyslipidaemia secondary to Insulin resistance and the Metabolic Syndrome• B) Polygenc dyslipidamia• C) Familial Combined Hyperlipidaemia• D) Familial Hypercholesterolaemia• E) Lipids aren’t really an issue in this patient
Patient is a 43 year-old male with a strong family history of premature CVD who presents for initial evaluation. He has a 10 year history of dyslipidaemia. Hypertension, for which he has received beta blockers in the past. More recently he has been on an ARB/diuretic combination. Three months prior to this visit a fasting lipid profile showed:
TC: 5.7 Triglyceride: 2.8 mmol/L HDL-C: 0.7 mmol/L LDL-C: 3.6 mmol/LHe has managed to lose 3 kg and today results include: TC: 6.9 Triglyceride:1.8 mmol/L HDL-C: 0.8 mmol/L LDL-C: 5.2 mmol/L
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Is ethnicity an independent risk factor for CVD? Yes / No?
• YES:
• NO:
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Is ethnicity an independent risk factor for CVD? Case for a qualified “Yes”.
Same risk factors, different pattern
INTERHEART, Joshi et al 2007
INTERHEART, Karthikeyan et al 2009,
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2) In the absence of any symptoms or signs of hypothyroidism, would you perform thyroid
function tests? Yes / No?
• Yes:
• No:
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2) In the absence of any symptoms or signs of hypothyroidism, would you perform thyroid
function tests? The case for “Yes”
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What is the most likely cause of MC’s lipid abnormality?
• A) Dyslipidaemia secondary to Insulin resistance
and the Metabolic Syndrome
• B) Polygenc dyslipidamia
• C) Familial Combined Hyperlipidaemia
• D) Familial Hypercholesterolaemia
• E) Lipids aren’t really an issue in this patient
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What is the most likely cause of MC’s lipid abnormality? The case for “C”, maybe “A” or “B”
Condition Features
Secondary Relatively uncommon, but potent (hypothyroidism, nephrotic syndrome,primary biliary cirrhosis)
Familial Overproduction of apo B lipoproteinsCombined H/L TG and TC vary with age and weight
Polygenic Accounts for the majority of cases
Familial Prevalent, Accelerates CVD.Hyperchol’aemia Due to defects in genes related to LDL-R
Increased HDL ?OK if LDL not raised?
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Mr MC started statin, therapy, Atorvastatin 20 mg/ day, but unfortunately he had and inferior AMI still 4 months later. His discuharge medication include:
Atorvastatin 20mg, Metoprolol 20 mg, Aspirin 100mg, and his previous ARB/diuretic. Follow-up 2 months later reveals: 2 kg weight loss, BP 118 / 78, Fasting tests:
• Glu 5.3 mmol/l, TC 4.4 mmol/l TG 4.2 mmol/l, • HDL 0.7 mmol/l, LDL 1.8 mmol/l
Case MC (continued)
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Case MC: Further questions:• Should you stop his beta blocker? Yes / No?
• Do you trust the LDL-C result? Yes / No?
• Is it practical to try to manage Mr M.C’s lipid profile to target levels? Yes / No?
• What is the next lipid-lowering drug that you would add to his therapy?
a) Ezetimibe b) Niacinc) I would increase Atorvastatin to 80 mg but I wouldn’t
give anything other than a statind) Fenofibratee) Fish Oil
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• Should you stop his beta blocker? Yes / No?• Do you trust the LDL-C result? Yes / No?• Is it practical to try to manage Mr M.C’s lipid profile to target
levels? Yes / No?• What is the next lipid-lowering drug that you would add to his
therapy?a) Ezetimibe b) Niacin c) Increase Atorvastatin to 80 mg but
don’t give anything other than a statind) Fenofibrate e) Fish Oil
Mr MC started statin, therapy, Atorvastatin 20 mg/ day, but unfortunately he had and inferior AMI still 4 months later. His discuharge medication include:
Atorvastatin 20mg, Metoprolol 20 mg, Aspirin 100mg, and his previous ARB/diuretic. Follow-up 2 months later reveals:2 kg weight loss, BP 118 / 78, Fasting tests:
• Glu 5.3 mmol/l, TC 4.4 mmol/l TG 4.2 mmol/l, • HDL 0.7 mmol/l, LDL 1.8 mmol/l
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Should you stop his beta blocker?
• Yes
• No
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Should you stop his beta blocker? The case for “no”
Some β-blockers decrease HDL and increase triglycerides.25 In spite of this, BHAT data showed that propranolol improves survival after MI.26 Low-dose metoprolol CR/XL alone or in combination with a statin resulted in significant slowing of the progression of carotid artery’s intima-media thickness over a 3-year period.27
M Gheorghiade et al Circulation.2002; 106: 394-398
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Do you trust the LDL-C result?
• Yes
• No
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Do you trust the LDL-C result?The case for “No”
Discussion of the effect of Cholesterol ester transfer protein willExplain why LDL-C underestimates risk when TG is elevated
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Is it practical to try to manage Mr M.C’s lipid profile to target levels?
• Yes
• No
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Is it practical to try to manage Mr M.C’s lipid profile to target levels? The case for “Yes”
Combination therapy is safe and effective, but yet to be supported by clinical endpoint data.
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What is the next lipid-lowering drug that you would add to his therapy?
a) Ezetimibe
b) Niacin
c) I would increase Atorvastatin to 80 mg but I wouldn’t give anything other than a statin
d) Fenofibrate
e) Fish Oil
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What is the next lipid-lowering drug that you would add to his therapy?
The case for “d” or “b”, possibly “c” or “e”anticipate “residual risk” module
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Patient is a 47 year-old female who has been gaining weight for several years.
She has a 10 year history of mildly elevated triglyceride. She received therapeutic lifestyle counseling but she has been largely non-compliant. Three months prior to this visit, a fasting lipid profile showed: Total Cholesterol: 5.5mmol/L Triglyceride: 2.4mmol/L HDL-C: 1.0mmol/L
LDL-C:3.6 mmol/L
Now she has symptoms of hyperglycaemia and repeat fasting glucose confirms Type 2 diabetes
Case GS
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Review of Symptoms: Thirst, polyuria, folliculitis, Weight unchanged (increased 2kg, then lost when
polyuria commenced BP 118/72 Pulse 72 Wt 85kg Ht 175cm Waist 93
cm BMI 27.8: Physical examination unremarkable
Current fasting lipid results surprise you:Total Cholesterol: 8.5mmol/LTriglyceride: 7.4mmol/LHDL-C: 1.0mmol/LLDL-C: unable to be calculated
Case GS
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Questions:How could you obtain an LDL-C result?a) Friedewald equationb) Abusive phonecall to labc) “Direct method” involving detergentsd) Ultracentifugatione) Subtract HDL-C from Total cholesterol
Which class or classes of lipoproteins would you expect to be increased?
f) Chylomicrons and LDLg) VLDL and LDLh) VLDL and HDLi) IDL and chylmicron “remnants” j) Why bother? It doesn’t matter
Which combination of extra tests would be most useful?a) LDL size+HDL subfractions b) Lipid EPG+ApoE phenotype c) LDL subfractions HDL size d) Lp(a)+ homocysteinee) Routine fasting lipids are the only lipid tests that are ever required
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• How could you obtain an LDL-C result?• Which class or classes of lipoproteins would you expect
to be increased?• Which combination of extra tests would be most useful?
She has a 10 year history of mildly elevated triglyceride. She received therapeutic lifestyle counseling but she has been largely non-compliant. Three months prior to this visit, a fasting lipid profile showed: Total Cholesterol: 5.5mmol/L Triglyceride: 2.4mmol/L HDL-C: 1.0mmol/L LDL-C:3.6 mmol/L Now she has symptoms of hyperglycaemia and repeat fasting glucose confirms Type 2 diabetes. Symptoms: Thirst, polyuria, folliculitis, Weight increased 2kg, then lost when polyuria commenced
BP 118/72 Pulse 72 Wt 85kg Ht 175cm Waist 93 cm BMI 27.8: Physical examination unremarkable
Current fasting lipid results surprise you: TC: 8.5mmol/L TG: 7.4mmol/L HDL-C: 1.0mmol/L LDL-C: unable to be calculated
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How could you obtain an LDL-C result?a) Friedewald equationb) Abusive phonecall to lab
c) “Direct method” involving detergentsd) Ultracentifugation
e) Subtract HDL-C from Total cholesterol
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How could you obtain an LDL-C result?The case for “d”, but “c” is misleading
Lab Tests Online:“Direct LDL-C is ordered whenever calculation of LDL cholesterol will not be accurate because the person's triglyceridesare significantly elevated. It may be ordered by a doctor when prior test results have indicated high triglycerides. In some laboratories, this direct LDL test will automatically be performed when the triglyceride levels are too high to calculate LDL-C. This saves the doctor time by not needing to order another test, saves the patient time by not needing to have a second blood sample drawn, and speeds up the time to provide the test result.”
Ultracentrifuge gives absolute result. Detergent methods assume LDL
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Which class or classes of lipoproteins would you expect to be increased?
a) Chylomicrons and LDL
b) VLDL and LDLc) VLDL and HDL
d) IDL and chylmicron “remnants”
e) Why bother? It doesn’t matter
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Which class or classes of lipoproteins would you expect to be increased? The case for “b”(orange) or “d” (green)
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Which combination of extra tests would be most useful?
• a) LDL size+HDL subfractions
• b) Lipid EPG+ApoE genotype/phenotype
• c) LDL subfractions HDL size
• d) Lp(a)+ homocysteine
• e) Routine fasting lipids are the only lipid tests that are ever required
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Which combination of extra tests would be most useful?
The case for “b”
CM β preβ α
ApoE isoforms
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The patient subsequently complied with diet and started on Simvastatin 40 mg daily and other treatment, which she tolerates without difficulty. Current Medications:
1. Metformin 850 mg bid 2. Enalapril 10 mg q day
3. ASA 81 mg q day 4. Simvastatin 40 mg q day
Subsequent results include: LEPG – Broad beta pattern presentApo E Genotype: Apo E2:E2
Case GS (continued)
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This implies the accumulation of which lipoprotein class(es)?a) VLDL + LDL b) IDL and Chylomicron “remnants”
Which lipid-lowering drug is the ideal treatment for this situation?a) Simvastatin b) Nicotinic Acid c) Questran d) Fibrate e) Fish oil f) Ezetimibe
Which lipid-lowering therapy is strongly CONTRAindicated? a) Simvastatin b) Nicotinic Acid c) Questran d) Fibrate
e) Fish oil f) Ezetimibe
Would you stop his statin therapy? Yes / No
Do you agree with the use of low-dose aspirin in this patient? Yes / No
Questions
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This implies the accumulation of which lipoprotein class(es)?Which lipid-lowering drug is the ideal treatment for this situation?Which lipid-lowering therapy is strongly CONTRAindicated?Would you stop his statin therapy?Do you agree with the use of low-dose aspirin in this patient?The patient asks you about his risk of Alzheimers’ Disease. Is it increased?
The patient subsequently complied with diet and started on Simvastatin 40 mg daily and other treatment, which she tolerates without difficulty. Current Medications:
1. Metformin 850 mg bid 2. Enalapril 10 mg q day
3. ASA 81 mg q day 4. Simvastatin 40 mg q day
Subsequent results include: LEPG – Broad beta pattern presentApo E Genotype: Apo E2:E2
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a) VLDL + LDL
b) IDL and Chylomicron “remnants”
This implies the accumulation of which lipoprotein class(es)?
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This implies the accumulation of which lipoprotein class(es)? The case for “b”
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a) Simvastatin
b) Nicotinic Acid
c) Questran
d) Fibrate
e) Fish oil
f) Ezetimibe
Which lipid-lowering drug is the ideal treatment for this situation?
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Which lipid-lowering drug is the ideal treatment for this situation? The case for “d”
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a) Simvastatin
b) Nicotinic Acid
c) Questran
d) Fibrate
e) Fish oil
f) Ezetimibe
Which lipid-lowering therapy is strongly CONTRAindicated?
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Which lipid-lowering therapy is strongly CONTRAindicated? The case for “c”
Hepatocyte
Bile Duct
Acetyl CoA
SREPB-1c
FA, TG
VLDL (TG levels)
MDRP2/3
Heterodimerization with RXR
Phospholipids
FXR
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Do you agree with the aspirin dose? Comment on the role of aspirin in this patient.
• Yes• No
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Do you agree with the aspirin dose? Comment on the role of aspirin in this patient.Evidence and opinion tending towards “no”?