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60 Cards in this Set
- Front
- Back
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CL and TG travel in plasma as part of ___
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lipoproteins - water-soluble macromolecules
- 30% free cholesterol (polar, nonesterified form) - 70% cholesterol ester (hydrophobic, bound to fatty acids) Apolipoproteins - the protein part of lipoproteins |
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4 major lipoprotein classes are __
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CM (chylomicrons)
VLDL LDL HDL Minor lipoproteins include lipoprotein(a)(Lp(a)) and intermediate-density lipoprotein (IDL) |
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The various lipoprotein classes contain specific apolipoproteins
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CM: ApoB-48, C, E
VLDL: ApoB-100, C, E LDL: ApoB-100 HDL: ApoA-I, A-II, C |
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Lipoproteins on agarose gel electrophoresis
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CM - stay at origin
HDL - fastest, in alpha(1) region VLDL - pre-beta or alpha(2) region LDL and IDL - beta region |
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Lipoproteins can be categorized into two broad groups based lower-density and higher-density particles
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lower-density apoB-containing particles (CM, VLDL, LDL, IDL)
- distribute CL and TG to tissues higher-density apoA-containing particles (HDL) - made by liver - role in reverse CL transport; excess CL returned from tissues to liver for reuse or excretion in bile |
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LDL receptor
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- binds ApoB-100 and ApoE, but not ApoB-48, found in CM
- found on macrophages, adipoctyes, and hepatocytes |
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CM and VLDL
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CM formed in intestine from dietary fat
VLDL formed in liver - both are TG-rich particles - both are metabolized in the circulation into higher density particles -- metabolized by lipoprotein lipase (LPL), shedding TG and cholesterol esters, leaving behind cholesterol -- results in CM-remnants and LDL-C -- LDL-C is the highest density metabolite -- CM-remnants and LDL-C are both metabolized by hepatocytes, while LDL-C is also metabolizecd by other tissues throughout body |
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Block in progression from CM to CM-remnants leads to ___
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Type 1 or 5 disease
- accumulation of CM - presents with high TG and nml CL |
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Block in progression from VLDL to IDL and LDL leads to __
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Type 4 disease
- accumulation of VLDL - presents with high TG and often high CL too |
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Often the cause of Types 1, 5, and 4 disease is __
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LPL deficiency and inability to break down TG
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Type 2 disease is due to __
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Block in LDL metabolism
- may be hereditary - defect in ApoB that does not bind LDL-R - defective LDL-R that does not bind ApoB |
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CM - large particles made by the intestine, that transport dietary lipids to tissues
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- rich in TG
- poor in free CL and protein Interaction with LPL at luminal surface of capillary endothelial cells results in depletion of TG = CM-remnants CM-remnants removed from circulation by liver |
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CM-remnants are removed from circulation by the __, primarily through interaction with __
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- liver
- apoE |
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milky plasma with creamy layer vs turbid plasma
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milky plasma - high CM
- high in CM (TG) - separates without centrifugation if left undisturbed for several hours turbid plasma - high VLDL - particles are much smaller than CM particles |
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VLDL
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- produced by liver
- supply tissues with endogenous (hepatic) TG and CL - rich in TG, but less than CM - LPL hydrolyzes VLDL into IDL and VLDL-remnants which can be further metabolized to LDL |
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LDL receptor
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- binds ApoB-100 and ApoE, but not ApoB-48, found in CM
- found on macrophages, adipoctyes, and hepatocytes |
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CM and VLDL
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CM formed in intestine from dietary fat
VLDL formed in liver - both are TG-rich particles - both are metabolized in the circulation into higher density particles -- metabolized by lipoprotein lipase (LPL), shedding TG and cholesterol esters, leaving behind cholesterol -- results in CM-remnants and LDL-C -- LDL-C is the highest density metabolite -- CM-remnants and LDL-C are both metabolized by hepatocytes, while LDL-C is also metabolizecd by other tissues through body |
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Block in progression from CM to CM-remnants leads to ___
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Type 1 or 5 disease
- accumulation of CM - presents with high TG and nml CL |
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Block in progression from VLDL to IDL and LDL leads to __
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Type 4 disease
- accumulation of VLDL - presents with high TG and often high CL too |
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Often the cause of Types 1, 5, and 4 disease is __
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LPL deficiency and inability to break down TG
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Type 2 disease is due to __
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Block in LDL metabolism
- may be hereditary - defect in ApoB that does not bind LDL-R - defective LDL-R that does not bind ApoB |
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CM - large particles made by the intestine, that transport dietary lipids to tissues
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- rich in TG
- poor in free CL and protein Interaction with LPL at luminal surface of capillary endothelial cells results in depletion of TG = CM-remnants CM-remnants removed from circulation by liver |
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CM-remnants are removed from circulation by the __, primarily through interaction with __
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- liver
- apoE |
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milky plasma with creamy layer vs turbid plasma
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milky plasma - high CM
- high in CM (TG) - separates without centrifugation if left undisturbed for several hours turbid plasma - high VLDL - particles are much smaller than CM particles |
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VLDL
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- produced by liver
- supply tissues with endogenous (hepatic) TG and CL - rich in TG, but less than CM - LPL hydrolyzes VLDL into IDL and VLDL-remnants which can be further metabolized to LDL |
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LDL is produced from ___, and it comprises __%of the total lipoprotein in plasma
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- metabolism of VLDL in the circulation
- 50% total lipoprotein |
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LDL particles are __ and __ scatter light or alter the clarity of plasma at high levels
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- small
- do NOT |
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LDL contents
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50% CL
25% protein 20% phospholipid only trace TG |
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Most of the circulating LDL is taken up by __
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- the liver (75%) via apoB-100 binding LDL-R
- rest is taken up by other tissues and scavenger cells such as those found in atheromatous plaques |
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HDL is removed from circulation by __
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apoE binding LDL-R on hepatocytes
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Subpopulations of HDL
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HDL2 and HDL3
- HDL2 is more cardioprotective than HDL3 |
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Friedewald equation
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used to calculate LDL
LDL= total CL - HDL - TG/5 - Note: not valid if TG >400, if CM are present (should be fasting!), or in Type 3 disease which has TG-rich B-VLDL (not normal VLDL) Because most of the plasma TG is in VLDL, the VLDL-C is estimated by using the ratio of TG/chol in VLDL (TG/5) |
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Wait at least __weeks and the patient is not ___, before checking cholesterol levels, after change in diet
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2 weeks and not gaining or losing weight
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wait at least __ before checking lipids after trauma, acute infection, or child birth
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8 weeks for trauma, infection
3-4 months after child birth - due to transient deviations in these settings |
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prior to checking lipids, patient should fast at least __ hours
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12 hours
- CM cleared w/in 6-9 hrs - presence of CM afte 12 hrs is ABNormal |
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Fasting has no real affect on total chol?
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true
- could use a nonfasting sample to chect TC and HDL, but not TG or LDL-C |
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Posture affects on lipids
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- 10% decrease can be seen in TC, LDL, HDL after 20 minutes recumbent
- NCEP guideline - pt sitting 5 minutes prior to venipuncture - in recumbent position, tissue fluids return to intravascular space and dilute nonsoluble constiuents |
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Prolonged turniquet (venous occlusion) can lead to ___ cholesterol levels
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increased, due to hemoconcentration (up to 15%)
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Serum or plasma can be used to measure lipids, however ...
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- either is fine if you are going to measure TC, HDL, TG to calculate LDL-C
- plasma is preferred if ultracentrifugation or electrophoresis is going to be used - EDTA is the antiocoagulant of choice -- citrate has osmotic effects that can lead to dilution of values -- heparin can alter electrophoretic mobility |
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Beta-VLDL "floating Beta lipoprotein
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Has the density of VLDL but migrates electrophorectically with LDL
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High cholesterol with high LDL
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All share hyperbetalipoproteinemia (Fredrickson type 2A)
1. Polygenic (Nonfamilial) hypercholesterolemia - 85% of all hypercholesterolemia - must rule out hereditary or other secondary causes 2. Familial hypercholesterolemia - autosomal dom - one of several mutations in LDL-R Heterozygotes: -- untreated LDL >220 -- 1 in 500 -- presents in adulthood (men 40's, women 50's) Homozygotes: -- present in childhood with with LDL>400 mg/dL stigmata: corneal arcus, tendinous xanthoma, xanthelasma (develop in adulthood in heterozygotes and childhood in homozygotes) Statins: work in part by increasing LDL-R, so not all pts will respond, especially homozygotes unless statin + apheresis is used LDL-R gene on chr 19 3. Familial defective ApoB - auto dom - defective apoB gene on chr 2 - interferes with recognition of apoB by the LDL-R - similar clinical findings as familial hypercholesterolemia (FH) - statins are effective therapy |
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High TG with normal cholesterol
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- due to elevated TG-rich particles (VLDL and CM)
- Fredrickson type 1 and 4 1. diabetic dyslipidemia 2. familial hypertriglyceridemia (isolated hyperTG or type 4 hyperlipidemia) - common 1 in 300 - auto dom - presents in adulthood with fasting TG 200-500 - abnormally TG-rich VLDL 3. Lipoprotein lipase deficiency (hyperlipoproteinemi type 1, hyperchylomicronemia) - RARE - auto recessive - presents in childhood with abd pain and pancreatitis - defective or absent LPL leading to inablility to clear CM - fasting TG >100 (>10,000 postprandial!) -DO NOT develop premature CHD!!! - heterozygotes are common 1 in 500 - low fat diet, maybe Rx 4. ApoC-II deficiency - rare, auto reces - apoC-II activates LPL; these patients present as a functional LPL deficiency with similar presentation as LPL deficiency - plasma exch can be useful when severe hyperTG; it provides apoC-II to activate endogenous LPL |
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High cholesterol and high TG
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- elevated LDL and TG (type 2B and 3)
1. Familial combined hyperlipidemia (type 2B) - relatively common 1 in 100 - heterogenous presentations (can have simple hypercholesterolemia, simple hypertriglyceridemia, or mixed defect) - a family MUST have >1 pattern of lipid disorder to meet criteria - unknown genetic basis 2. dysbetalipoproteinemia (type 3) - apoE is present in CM,VLDL,IDL, and CM-remnants - 3 isoforms of apoE: apoE3 is most common (normal); apoE2 and apoE4 are less common - apoE2 has lower affinity for LDL-R leading to less clearance of CM, CM-r,VLD, IDL in homozygotes for apoE2 - leads to broad abn band on electrophoresis due to IDL (abnormally migrating beta lipoprotein or B-VLDL) (pathognomonic) - also get increased TG content in VLDL (VLDL/TG ratio increased) - premature atherosclerotic disease is prevelant 3. hepatic lipase deficiency - rare - mutation in HL gene |
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Isolated low total chol
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- uncommon
- a/w defective apoB synthesis or metabolism 1. Abetalipoproteinemia - rare, auto rec - defect in a hepatic microsomal transport protein required for normal apoB production - present in childhood/early adolescence - fat malabsorbtion - hypolipidemia - retinitis pigmentosa - cerebellar ataxia - acanthocytosis TC <50 fat soluble vit deficiencies (A, E, K), but NOT vit D; because vit D does not require CM for absorption (which is particularly important for Vit E absorption) - need low fat diet with vit supplementation, esp vit E for retinal and neuropathic symptoms 2. Hypobetalipoproteinemia - auto dom - mutation in apoB gene itself 3. chylomicron retention disease - only apoB-48 affected |
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Isolated low HDL
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1. Familial hypoalphalipoproteinemia
- common auto dom - 1 in 400 - men HDL < 30 - women HDL <40 - a/w premature CHD 2. Apo-AI deficiency - rare auto rec - characterized by reduced HDL production - HDL <5 3. Tangier disease - rare auto rec - very low chol (unknown reasons) and high TG - in homozygotes: -- low to absent HDL -- hepatosplenomegaly -- peripheral neuropathy -- orange tonsils -- premature coronary disease - mutations in ABCA1 gene - in absence fo ABCA1 acitivity, chol accumulates in cells - in peripheral tissues, excess cholesterol is exported from cells in part by action of ABCA1 protein - the free cholesterol can then be accumulated by HDL and esterified via LCAT |
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Types 1,5,4
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- all have high TG with normal chol (excpet 4 with low chol)
- type 1,5: CM --- type 1 hereditary while type 5 is acquired - type 4: VLDL - all are low cardiac risk |
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type 3
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Dysbetalipoproteinemia
- increased IDL - high TG and high chol - high cardiac risk - dietary control - presence of B-VLDL - VLDL/plasma TG ratio >0.3 |
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type 2A and 2B
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type 2A
- LDL - low TG and high chol - high cardiac risk type 2B - LDL, VLDL - high TG and high chol - high cardiac risk |
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Most methods used to measure TG rely on hydrolysis of TG and the measurement of __
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- glycerol
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Direct LDL-C measurements are used when____
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- TG are elevated (>400 mg/dL)
- if the TG <400, there is no need to run this assay, the Friedewald calculation is just as good at risk stratifying patients for treatment decisions |
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A standing plasma sample left overnight, refrigerated, that remains turbid
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- high VLDL
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A standing plasma sample left overnight, refrigerated, that develops a floating cream layer
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- high CM
Note: if it is turbid too, then both high VLDL and CM likely present |
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chylomicrons in a fasting plasma sample is __
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abnormal
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Statins
Fibric acid derivatives bile acid resins niacin (nicotinic acid) |
Statins
- lower LDL-C 20-60% - inhibit HMG-CoA reductase - rhabdomyolysis is one side effect Fibric acid derivatives - lower TG 20-50% - mechanism no clear bile acid resins - lowers LDL-C 10-20% - bind bile acids in intestine to increase excretion niacin (nicotinic acid) - lowers TG 20-50% - raises HDL 15-35% |
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Isolated high HDL-C
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CETP defects (cholesteryl ester transferase protein gene defects)
- CETP normally facilitates transfer of cholesteryl esters from HDL to apoB-100-rich proteins (VLDL and LDL) in exchange for TG - rare auto rec - HDL>100 in homo |
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dysbetalipoproteinemia vs. abetalipoproteinemia
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dysbetalipoproteinemia:
- ApoE2 isoform (normal is ApoE3) - type 3 hyperlipidemia - high TG nml Chol - elevated IDL (B-VLDL, with broad beta band) and TG-rich VLDL abetalipoproteinemia - rare auto rec - defect in hepatic microsomal transport protein required for normal apoB production (no apoB-100 or apoB-48 present in plasma!) - LOW chol (TC <50) - present in childhood/adolescence with : -- hypolipidemia -- fat malabsorption (vit defeciiencies - A, E, K) -- retinitis pigmentosa -- neuropathy -- cerebellar ataxia -- acanthocytosis Heterozygotes are otherwise normal |
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high chol(LDL-C)/nml TG
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Type 2A phenotype
(high LDL-C) 1. polygenic (nonfamilial) hypercholesterolemia -- 85% of hypercholesterolemia 2. familial hypercholesterolemia (mutation in LDL-R gene, chr 19) 3. familial defective apoB (mutation in apoB gene, chr 2) |
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nml chol/high TG
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Type 1,5,4 phenotypes
(high CM or VLDL) 1. LPL deficiency (type 1, CM) -- auto rec 2. ApoCII defeciency (results in a functional LPL deficiency) (type 1, CM) -- auto rec 3. familial hypertriglyceridemia (type 4, VLDL) 4. diabetic dyslipidemia (type 5, CM, acquired!!) |
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high chol/high TG
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Type 2B, 3
1. familial combined hyperlipidemia (type 2B, LDL & VLDL) -- unknown genetics 2. dysbetalipoproteinemia (type 3, IDL) -- ApoE2 isoform (homozygous with additional factors such as obesity, diabetes) 3. hepatic lipase deficiency -- rare aut rec -- HL gene mutation |
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hepatic lipase deficiency vs. dysbetalipoproteinemia
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Both have high chol and high TG
dysbetalipoproteinemia -- ApoE2 -- high IDL (B-VLDL) and VLDL/TG ratio increased (>0.3) Hepatic lipase deficiency -- high IDL (B-VLDL)too, BUT, VLDL/TG ratio is NOT increased |
