Lec 2: Dyslipidemia Flashcards
UNIT conversions:
1 TC, LDL-C,HDL-C
mg/dl -> mmol/L
2 TG mg/dl -> mmol/L
3 Glucose mg/dl -> mmol/L
1 x 0.02586 = mmol/L
2 x 0.01129 = mmol/L
3 x 0.05551 = mmol/L
Lipoprotein Metabolism - - - - \: * check out SLIDE 4* for visual
- Free fatty acids can move freely
- free cholesterol & phospholipids on surface of lipoprotein particles
- triglycerides & cholesterol esters inside
- cholesterol esters = cholesterol + long chain FA
: Lipoprotiens are composed of proteins, lipids in middle [TG/ cholesterol ester] & some surface
Proteins and Enzymes
->
-
-
->
-
- > LPL - Lipoprotein Lipase ** most important one
- removes TG from lipoproteins
- found on the surface of cells that line the capillaries within muscles & adipose tissue
- > LCAT - Lecithin: cholesterol acyltransferase * found in lipoprotein
- Enzyme bound to HDLs + LDLs in the blood plasma that esterifies [moves from surface -> core of lipoprotein — ensures cholesterol doesn’t become free cholesterol + makes it to the liver] cholesterol taken up by the lipoprotein (particularly HDL)
- > ACAT - Acyl cholesterol acyltransferase * found in cells
- Intracellular protein located in the endoplasmic reticulum of many cells that esterifies free cholesterol to cholesterol esters
-> CETP - Cholesterol ester transfer protein
- Plasma protein that facilitates the transport of cholesterol esters & triglycerides btw the lipoproteins — exchanges btw HDL/ LDL etc
HDL wants all lipoprotein to transport cholesterol esters
Apoproteins (apolipoproteins) - - Functions: - - - -
- Protein component of lipoprotein - on surface - classifies lipoprotein
- Apo - B, E, AI-IV, CI-III (Apo-B48 = common on chylomicrons)
Functions: - Structural components of the lipoproteins
- confers specificity to the lipoproteins
- Solubilize lipids in the bloodstream
- Stimulate enzymatic rxns
- Act as ligands for the cell-surface receptors — binding to certain tissues etc
Lipoproteins Types
5 classes of lipoproteins classified by ____ + _____
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From Chylomicrons TO HDL
:
* chart SLIDE 9** look at for comparison of chylo, VLDL, LDL, HDL
by size + density
- were 1st characterized by layers during ultra-centrifugation of blood
- Lipid: cholesterol: protein varies
- More lipid - rise to top
- More protein increase density
: increased density, decreased size, decreased TG, increased cholesterol (except for HDL), increased phospholipid / increased protein
- Chylo = largest
VLDL =
LDL = most cholesterol
HDL = decreased TG, increased protein, increased density, smallest
***SLIDE 11-13 show visuals to the following information*** Lipoprotein Metabolism 1 2 3 4 \_\_\_\_\_ -> \_\_\_\_\_ [lipids from the liver to peripheral tissues] 1 2 3 4 5
[reverse cholesterol transport]
6
1 chylo are formed in the intestinal enterocytes (intestinal cells) from dietary lipids (re-esterified to TGs) — Apo B-48 aids in formation
2 chylo enters the bloodstream & undergo lipolysis by lipoprotein lipase (LPL)
[LPL helps tissues breakdown TGs & take into tissues]
3 Chylo then lose their TGs at the capillary surface of tissues
4 Chylo remnants (what is remaining after TGs lost) are taken up by the liver VIA Apo-E receptors (or LPL receptors)
CHYLO –> VLDL
1 Assembly of VLDL, mostly in liver
2 secretion of VLDL into circulation - Apo- B100 + Apo-E involved
3 Hydrolysis of VLDL by LPL & TG entry into cells
4 VLDL remnants = richer in cholesterol, less TG + take multiple routes
a) converted to IDL (intermediate density lipoproteins) + take up by liver
b) converted to LDL (doesn’t come from liver - converted in blood)
5 LDL is the major cholesterol- carrying lipoprotein
a) catabolized in the liver VIA LDL receptors
b) modified or oxidized & taken up VIA receptors in various tissues
6 HDL are synthesized in liver & return lipids from the peripheral tissues to the liver - Apo-A1 is the main protein [Apo-A2 as well]
a) Lecithin: cholesterol acyl transferase (LCAT) esterifies cholesterol in HDLs (+ other lipoprotein); more free cholesterol can be accepted from tissues
b) cholesterol enter transfer protein (CETP) moves cholesterol esters from HDL to chylo & VLDL - CETP is also involved in the exchange of neutral lipid core constituents (CE + TG) btw other lipoproteins
* YOUTUBE LINK http://www.youtube.com/watch?v=97uiV4RiSAY
What is Dyslipidemia = Related to: - - - - -
- 5 main patterns:
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-
Familial hypercholesterolemia [Type 2a] - - - -
= Abnormality in circulatory lipid metabolism that increase risk of CVD
Related to:
- lipoproteins levels in blood are too high or low
- apoproteins defective
- receptors defective
- no symptoms usually
- peak prevalence of abnormality in middle age
- see patterns or 'profiles' 1 very high LDL - isolated 2 High LDL & High TG 3 High LDL & low HDL 4 High TG - isolated 5 Low HDL - isolated
- Genetic play a large role - polygenic, specific genetic defects -> similar alterations in blood levels
- 5 main familial phenotypes
- ~15% of those with dyslipidemia
- very high risk of CVD
- LDL receptors are absent/don’t function
- cholesterol deposits appear
- called xanthomas
- can appear in different parts of body
- corneal arcusis another sign oh hypercholesterolemia
- fat accumulates under skin / around eye/on face
- LDL accumulation in blood
Harmonized definition Met S - changes overtime
Other common defects combined hyperlipidemia [Type 2b] - - - - hypertriglyceridemia [Type 4] - - -
other factors:
ETIOLOGY - other 85% -> - - -> - -> - -> - ->
*** look at SLIDE 20 for specifics
- very high LDL or TG levels
- > 90th percentile
- often co morbid with DM & HT
- 2+ members of family
- Very high TG > 90th percentile
- very low HDL <10th percentile
- 2+ members of family
: lifestyle, diet, met S, obesity, PA decreased, age
- > Metabolic Syndrome (Met S)
- decreased HDL-C & increased TG markers for syndrome
- tend to have modest elevation of LDL-C
- > Obesity in absence of Met S
- may have different profiles
- > PA
- decreased TG, increased HDL-C with activity
- > Diet
- High SFA diets lead to increase VLDL & LDL & suppression of LDL receptors
- > Risk factors are often correlated
= have to have 3 risk factors to have classified metabolic syndrome
[BG, BP, TG, HDL-C, WC]
Medical Management - controversy - - Current Guidelines: **** there is an article you should probably read
Lab Testing
3 commonly measured =
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LDL as the target:
* LDL alone may not be risk factor
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-
- must be treated long term to achieve benefits
- treatment has been controversial for many years — USA much more aggressive with drugs than other countries
: CAN cardiovascular society = lifestyle (1st) then drugs - HDL, LDL, TG
- need complete lipid profile from fasting blood sample
- in past, LDL was derived from measurement of other lipids
LDL -C = TC - [HDL-C + 0.37 (TG)] - LDL-C can also be directly measured - cumbersome & expensive process called ultra-centrifugation
- Hallmark particle causing damage
- confers high risk for CVD
- ** Small dense LDL: greater atherogenic potential than other LDL sub-fractions
- better predictor of CVD than total LDL cholesterol levels
Diagnostic & treatment process STEP 1: *** review slides 25 - 29 *** STEP 2: STEP 3:
: assess CVD risk
- complete 3 lipid profiles
- day to day variability
- use Framingham Risk Score to assess risk
: Health behaviour options
- > PA most days/wk (30-60 min MVPA)
- > stop smoking
- > stress management
- > moderate alcohol
- > eat a ‘healthy diet’
- decreased S FA & trans fat
- avoid refined CHO
- decrease salt
- increase fruit & veg
- > Weight Reduction
: Consider drug therapy drug classes
[Statins]
- inhibits cholesterol synthesis
- HMG CoA reductase inhibitor } Mevalonate pathway *** slide 32
[Resins] “Bile acid sequestrates”
- Bind bile acids [essential for the emulsification of lipids] -> excrete - this makes the body make more & more bile acids using the bodys’ cholesterol
- divert cholesterol to liver to make bile acids
- up regulate liver receptors of LDL -> decrease LDL levels in blood — catabolized
[Nicotinic Acid] (Niacin)
- Inhibits adipose lipolysis, decreased VLDL synthesis (in liver)
[Fibrates]
- increase Hepatic FA uptake & conversion to acyl- CoA (used for energy)
- decreased hepatic TG production
- increased hydrolysis of VLDL
70% of body cholesterol is produced in LIVER; key step inhibited with ______
Recommendations for treatment LDL-C -> -> HDL-C -> ->
STATINS, they inhibit HMG-CoA reductase
LDL-C
- > Most patients will achieve target LDL-C levels on STATIN monotherapy
- > Ezetimibe, cholestyramine, colestipol (inhibit cholesterol/bile acid reabsorption) or nicacin may be required in a minority of cases
HDL-C
- > Meds may not increase HDL-C to a clinically significant extent (some studies on niacin)
- > PA, stop smoking & mod alcohol interventions increase HDL-C
Recommendations for treatment CON'D Triglycerides -> - - - Combo Therapy - - -
STEP 4: - - - - - -
Triglycerides
- > No specific target level for high risk
- lower TG levels associated with decreased CVD risk
- *** Health beh interventions are 1st line
- Fibrates may prevent pancreatitis in patients with extreme hypertriglyceridemia (>10mmol/L)
Combo Therapy
- Statin with Niacin: for combined dyslipidemia & low HDL-C
- Statin with a fibrate *** Rhabdomyloysis = breakdown/damage in skeletal muscles
- close patient follow-up required
- Statin with omega-3 FA
- may lower TG & help achieve TC/HDL-C ratio target in patients with mod hypertriglyceridemia
: Follow-up
- In metabolic studies, effects seen in 2-3weeks
- in community, effects seen in 6 wks
- initial follow-up @ 3 months
- Long term follow up @ 6-12months
- more frequent follow up for those on combo therapy & max dose
- increase long term compliance with meds & lifestyle is the major goal
