Lipid Disorders - Exam 4 Flashcards
What are lipids composed of? What are the two main lipids?
glycerol and fatty acids
main lipids: cholesterol and triglycerides
What is the role of cholesterol? Triglycerides?
essential element of all animal cell membranes and forms the backbone of steroid hormones and bile acids synthesis
assist in the transfer of energy into cells
What is the function of apolipoproteins? Where are they found? Where are they synthesized?
activate enzymes for lipoprotein metabolism and act as ligands for cell surface receptors
proteins found on the surface of lipids that
synthesized: liver and small intestine
Where is the primary source, lipoprotein association and function of the following: ApoB-48, ApoB-100, ApoC-I, ApoC-II, ApoC-III, ApoE
What are lipoproteins composed of? What is their role?
are complex molecules made up of lipids and apolipoproteins.
transporting cholesterol, triglycerides and fat-soluble vitamins to and from tissues
What is the core of a lipoprotein made out of?
What is the shell composed of?
core: hydrophobic liquid
triglyceride (aka triglycerols)
Free cholesterol
cholesterol esters (bound to free fatty acids)
shell: hydrophilic lipids
phospholipids
apolipoproteins (apo)
How are lipoproteins classified? How is that determined?
based on density
Density is determined by the presence of triglycerides and apolipoproteins
Which is more dense, triglycerides or apolipoproteins? What are the 5 types?
triglycerides are less dense; apolipoproteins are more dense
chylomicrons
VLDL - Very-low-density
IDL - Intermediate-density
LDL - Low-density
HDL - High-density
What are the 2 lipoprotein metabolic pathways? Give a short summary of each
Exogenous lipid pathway: absorption of dietary lipids and formation of chylomicrons
Endogenous lipid pathway: secretion of VLDL by the liver, transition to IDL and LDL
Exogenous pathways Step 1:
Dietary TG’s, cholesterol, fatty acids and retinol (vit. A) are absorbed in small intestine combined with _____ to form _____. They then pick up ____ and ____ from HDL and travel to the capillaries.
apolipoprotein (apoB-48)
chylomicrons
apoC
apoE
Exogenous pathways Step 2: These _____ are absorbed into capillaries where they are utilized in the _____ via ____. TG’s are broken down by ______ into FFA which can be converted to energy for use/storage in muscle and adipose tissue
chylomicrons
peripheral tissue
apoC
lipoprotein lipase (LPL)
Exogenous pathways Step 3: The ____ remnant then travels to the ____ where it is taken up via _____ with the help of ____. _____ is also lost in this process to another receptor
chylomicron
liver
LDL receptors (LDLR)
apoE
ApoB48
Endogenous Pathway Step 1: ____ and _____ are combined in the liver along with ____ to create VLDL
Step 2: ____ acquires apoE and ____ via transfer from ____molecules when leaving the ___
Cholesterol
triglycerides
apoB-100
VLDL
apoC
HDL
liver
Endogenous pathway Step 3: VLDL is utilized in the _____ as TG’s are broken down by ____ for energy (lipolysis) and now are referred to as _____
Step 4: 40-60% of ___ is taken up by the liver (via _____, the remaining IDL is further broken down by ____ during systemic circulation to form ____
peripheral tissues (apoC)
LPL
IDL
IDL
apoE and the LDLR
hepatic lipase (HL)
LDL
Endogenous pathway Step 5: 70% of the ____is removed from circulation by the liver _____ , the remaining 30% is used up by the ______.
Step 6: ____ removed from circulation by the ____ is broken down and the _____ is excreted in the bile
LDL
(via apoB & LDLR)
peripheral tissues (lipolysis)
LDL
liver
cholesterol
HDL: Immature HDL with ____ sees the macrophages full of ____ and “sweeps” up the ____ → HDL matures
ApoA1
LDL
excess LDL
Mature ____ can drop off ____ into peripheral tissues to create more ____ as well as take ____ from lower density lipoproteins
HDL
cholesterol
hormones
triglycerides
Finally, HDL can deposit _____ cholesterol in the ____ for breakdown/excretion and process starts over. What is an additional function of HDL?
“sweeped up”
liver
other functions of HDL include “donating”
apoproteins for lipid metabolism
What are some key differences between LDL and HDL?
LDL: bad
-deposits cholesterol in the blood vessel wall which build up can impede blood flow
-High level of cholesterol esters
HDl: good
-can “sweep” cholesterol out of the blood vessel keeping them clear of build-up
-Picks up cholesterol from peripheries to deposit into the liver
-High protein levels
Watch ninja nerd video included in the lecture about lipoprotein metabolism
DO IT!!
What are 4 pathways that lead to dyslipidemia
- Excessive hepatic secretion of VLDL
- Impaired lipolysis of triglyceride-rich lipoproteins
chylomicrons and VLDL - Impaired hepatic uptake of ApoB containing lipoproteins
all lipoproteins except HDL - Inherited low levels of HDL-C
**______ is one of the MC cause for dyslipidemia. Will fasting TG and HDL be high or low? What are some factors that increase VLDL secretion? **What is the major one?
Excessive Hepatic Secretion of VLDL
elevated fasting TGs
low HDL-C levels
factors:
Obesity
Insulin resistance
High-carb diet
**Nephrotic syndrome
ETOH use
Cushing’s Syndrome
_____ results from a dysfunction in lipoprotein lipase (LPL). What does TGs and HDL look like? What are 2 causes?
Impaired Lipolysis of Triglyceride Rich Lipoproteins aka impaired breakdown
elevated TGs
low HDL-C
**genetic disorder
insulin resistance
______ a down regulation of the LDL receptor (LDLR) in the liver leads to elevated serum LDL-C. What are some common causes?
Impaired Hepatic Uptake of ApoB Containing Lipoproteins
saturated fat intake reduces LDL activity
hypothyroidism
estrogen deficiency
chronic kidney and liver disease
**multiple drugs
thiazides, cyclosporin, carbamazepine
genetic disorders
_____ accelerated catabolism of HDL and its apoA. What are 3 causes?
Disorders of low HDL cholesterol
causes:
obesity
insulin resistance
genetic disorders
**How is dsylipidemia defined? What are 2 contributing factors? Increases risk for ______.
as elevated levels of LDL-C and triglycerides as well as low HDL aka due to increased LDL, more foam cells = increased risk of heart attack
genetics and environmental factors
increases risk for atherosclrotic cardiovascular disease (ASCVD)
patches on skin (MC -buttock) due to lipid deposition
yellow, pink, brown, or skin-colored
can be pruritic or painful
What am I?
What values are normally high?
Eruptive Xanthomas
extremely high chylomicrons (TG’s) or VLDL
_____ are lipid deposit nodules in the tendons of the hands, feet, and heel. What value is high?
tendinous xanthomas
seen with high LDL
_____ milky appearance of the veins and arteries of the retina. What value is high?
lipemia retinalis
extremely high triglycerides
Serum changes in the blood after it is drawn are due to high _____. Describe it
triglycerides
often look opalescent or milky serum
When do you start screening for ASCVD? What test do you order?
adults starting at age 20
or kids beginning at age 2 if family hx of early CVD or significant primary hypercholesterolemia
textbook answer: Total cholesterol (TC) and HDL (fasting sample is preferred but non-fasting is acceptable)
What are the indications if a full lipid panel should be ordered?
Total Cholesterol > 250
HDL-C is < 40
non-fasting may result in higher TG’s leading falsely elevated results
**What are the normal ranges for : TC, LDL, HDL, TG. How long do they need to fast?
TC < 200 mg/dL
LDL < 100 mg/dL - UNLESS THEY HAVE EXISTING ASCVD!
HDL 40-59 mg/dL (> 60 mg/dL is cardioprotective)
TG’s < 150 mg/dL
9-12 hours prior to collection
How often should you screen for hyperlipidemia?
~5 years for the average adult
3 years for lipid levels close to those warranting therapy - if they’re borderline
Annually for those on treatment
not a definitive answer! guideline only
What are some secondary causes of hyperlipidemia?
hyperglycemia
nephrotic syndrome/chronic renal insufficiency
hepatitis/cholestasis
hypothyroidism
What effect does oral contraceptives have on lipids? alcohol use?
increase triglycerides and total cholesterol
increased triglycerides and HDL due to carbs and sugar, liver dysfunction
What are the 4 guidelines we need to consider about statin therapy?
clinical ASCVD
DM
LDL > or equal to 190mg
primary prevention with ASCVD risk of over 7.5%
** What are the 6 risk factors for ASCVD?
- Tobacco use
- DM
- HTN
- Obesity (BMI ≥ 30)
- Family hx of premature heart disease
55 y/o in males
65 y/o in females - Personal hx of CAD or non-coronary atherosclerosis: abdominal aortic aneurysm, peripheral artery disease, carotid artery stenosis
**What are the 4 major ASCVD events that put you in the VERY high risk category? How many of the MAJOR event do you need to be considered VERY high risk?
ACS within past 12 months
History of MI (other than ACS above)
History of ischemic stroke
Symptomatic PAD
2+
**What are the high risk conditions? What is the second way to be considered VERY high risk?
Age ≥ 65 years
CKD (GFR 15-59 mL/min)
Coronary bypass or percutaneous intervention
Current smoker
Diabetes
Hereditary Familial Hyperlipidemia
History of heart failure
Hypertension
LDL-C ≥ 100 mg/dL despite max tolerated statin + ezetimibe
1 of the major and 2+ of the high risk conditions to be very high risk
When should you start high intensity versus moderate intensity statin therapy?
High intensity statin - Very high risk ASCVD or ≤ 75 years of age
Moderate intensity statin - Not “Very High Risk” and older than 75
**What drugs (with dosages) are considered high-intensity statins? What percent do they lowered LDL? Which one has mild evidence to decrease existing plaque?
Rosuvastatin 20mg 40mg
Atorvastatin 40mg 80mg
greater than 50%
Rosuvastatin
How much does moderate statin therapy decrease LDL? Low intensity? What are the low intensity statins with dosages?
Moderate: 30-49%
Low: 30%
Simvastatin 10mg
Pravastatin 10mg 20mg
Lovastatin 20mg
Fluvastatin 20-40mg
What are the 2 goals of lipid management? How often should you monitor?
Reassess lipid panel after 4-12 weeks then every 3-12 months
For a person WITHOUT ASCVD and LDL at or above 190? What is the tx? monitoring? goals?
tx: high intensity statin
Rosuvastatin 20mg 40mg
Atorvastatin 40mg 80mg
monitor: Reassess lipid panel after 4-12 weeks then every 3-12 months
goals:
Goal #1 - 50% reduction in LDL-C
Goal #2 - LDL-C of <100 mg/dL
For a pt age 40-75 with DM and LDL 70-190, what is the protocol?
Step 1: Calculate an estimated 10-year ASCVD risk
Step 2: Review diabetes-specific high-risk features
What is the ASCVD risk estimator calculator tool? What are the criteria?
Predicts 10-year risk for first ASCVD event among patients who are between 20 and 79 years of age
Sex, Age, Race
TC/HDL
SBP
Tx for HTN/DM
Smoking status
Picking statin therapy for pts 40-75 with DM and LDL between 70-190 depends on what two factors? Do they have to have both or one?
ONE FACTOR
**10 year risk ≥ 7.5% or (+) Diabetes specific risk enhancers
know greater than or equal to 7.5% risk
**Picking statin therapy for pts 40-75 with DM and LDL between 70-190 and the answer is YES! What is the tx? What are the 2 goals?
**Picking statin therapy for pts 40-75 with DM and LDL between 70-190 and the answer is no. What is the tx? What are the 2 goals?
For borderline pts between 40-75 without ASCVD or DM and LDL is between 70-189. What are the next steps?
- calculate ASCVD risk
tx depends on risk %
**Aged 40–75 without clinical ASCVD or DM and whose LDL-C is between 70–189 mg/dL and ASCVD risk is between 7.5 and 19.9 need to consider _____. What is it? What do the results indicate?
measuring coronary artery calcium (CAC)
CAC - utilizes a low dose CT scan of the heart, assessing the amount of calcium plaque build up on the vascular walls. Score ranges from 0-400.
CAC ≥100 - consider adding statin
CAC 1-99 - consider adding statin if age ≥ 55 years
CAC score of zero - focus on lifestyle modifications
reassess in 5-10 years, indicates low 10-15 year risk
What are the 3 lifestyle modifications? How long does it take to see an effect?
aerobic exercise
weight loss
diet changes
3-6 months
**______ inhibit HMG-CoA, a key enzyme in cholesterol synthesis in the liver
increases the number of LDL receptors on the hepatocyte cell membrane. Where are they metabolized? What do you need to order before starting?
statins
in the liver
need to order baseline LFTs, 2-3 months after starting/changing dose and annually
What is the MC SE of statins? What drugs have LESS likelyhood of SE?
Myalgias- normal CK
Myopathy/Rhabdomyolysis- with elevated CK
pravastatin and fluvastatin
_____ occurs in those predisposed to DM and use of high intensity statin
hyperglycemia
What are the CI to statin therapy?
active liver dz
preg and nursing mothers
What is the effect of taking statin and CYP450 meds together?
worsening the SE of statins
What if a pt cannot tolerate a statin or its not doing its job, then what?
try a different statin, fluvastatin, pravastatin - most likely to be tolerated but not as effective
2nd line: ezetimibe, PCSK9 inhibitors, bempedoic acid, inclisiran
3rd: -bile acid sequestrants, fenofibrate, niacin (kinda)
______ : blocks appx 60% of dietary cholesterol absorption. Works best when ?? What does it NOT have an effect on?
Ezetimibe (Zetia)
works best in combo with statin
no effect on HDL or TG but statins do
_____ monoclonal antibodies inhibit PCSK9 from binding to LDL receptors decreasing LDL receptor degradation and increasing LDL clearance. What is the route? Any CI?
PCSK9 Inhibitors
alirocumab (Praluent), evolocumab (Repatha)
injection q 2 weeks
no limitation in renal or liver impairment
______ inhibits adenosine triphosphate-citrate lyase (ACL) inhibiting cholesterol synthesis in the liver.
increases the number of LDL receptors on the hepatocyte cell membrane
stimulates LDL catabolism. When it is commonly used?
Bempoic Acid (Nexletol)
Used as adjunct therapy when we need additional LDL reduction after maximally tolerated statin therapy
bempoic acid/ezetimibe = ____. What is the effect? What are the SE? (includes just normal bempoic acid)
Nexlizet
synergistic effect with statins
gout/hyperuricemia, cold/flu s/s, tendon rupture, muscle spasms, abdominal pain
_____ Blocks the production of mRNA needed for PCSK9 production resulting in less LDL. What is the route?
Inclisiran (Leqvio)
Injection day 1, then at 3 months, then q6m thereafter (must be in a clinical setting)
_____ Binds bile acids in the intestines requiring the liver to excrete more bile. The liver uses hepatic cholesterol to make bile which results in the liver taking up more LDL-C from the systemic circulation. What % reduction in LDL? What is the pt education?
Bile Acid Sequestrants
cholestyramine, colestipol and colesevelam (Welchol)
10-24%
take it by itself NOT with other drug. take other drugs 1 hour before or 4 hours after bile acid sequestrants
What is the preferred lowing lipid med for preg pts?
Bile Acid Sequestrants:
cholestyramine, colestipol and colesevelam (Welchol)
**How do you define hypertriglyceridemia? **What is a complication?
Defined by a plasma/serum level >150 mg/dL
pancreatitits: triglycerides over 400
what is the tx for pts older than 20 with triglycerides between 175-499?
treat underlying conditions
Avoid medications that worsen lipid levels
**Avoid refined carbohydrates, saturated and trans fatty acids
**Watch your “white” foods!
Avoid alcohol
**When is statin therapy indicated for hypertriglycerdimia?
40-75 y/o with severe hypertriglyceridemia ≥ 500 mg/dL with an ASCVD risk of ≥ 7.5%
Severe hypertriglyceridemia >1000 mg/dL alone
_____ stimulate LPL activity (enhances TG clearance from blood)
reduce apoC-III synthesis (enhances lipoprotein remnant clearance)
promote breakdown of fatty acids
may reduce VLDL-TG production
How much do they reduce TGs?
Fibrates: gemfibrozil (Lopid), fenofibrate (Trilipix, Tricor)
by 50% or more
dyspepsia, increase risk of gallstones, myopathy, hepatotoxicity are all SE of _____
fibrates: gemfibrozil (Lopid), fenofibrate (Trilipix, Tricor)
**What is a drug interaction of gemfibrozil (Lopid), fenofibrate (Trilipix, Tricor)? When do you need to be cautious?
Drug interaction: increases warfarin
caution in CKD pts: excreted by the kidneys - dose reduction required
______ inhibit the release of TG’s from the liver (reducing VLDL). Stimulates LPL (increases clearance of TG’s from the plasma).
Omega 3 Fatty Acids
Where are Omega 3 Fatty Acids naturally found? What dose is beneficial?
Naturally found in fish and flaxseed, OTC supplement
can reduce TG’s by 50% or more - requires up to 4 grams a day to be beneficial
_____ stronger version of omega 3 fatty acid - contains >95% omega 3 fatty acids in comparison to 30-50% in OTC combinations
Vascepa (Icosapent ethyl)
expensive
What is considered severe for a fasting triglyceride level?
TG greater than or equal to 500
elevated VLDL and chylomicrons
______ inhibits breakdown of TG in adipose tissue. Increases LPL activity (increases clearance of TG’s). Inhibits synthesis of TG in liver (reduces VLDL secretion and subsequently LDL levels). Reduces clearance of apoA-I. What are the SE? What is a way to combat it?
Niacin
SE: niacin flush-> give ASA 81mg 30min prior to reduce flush
also raises uric acid levels- avoid with hx of gout
_____ is approved for use in Europe for patients with genetically confirmed monogenic chylomicronemia but is not approved for clinical use in the United States.
APO C3 Inhibitor
