Lecture 22: Lipid Disorders Flashcards
What is the primary reason US adults do not care that much about treating their cholesterol?
They are asymptomatic for a long time.
What are lipids?
Molecules composed of both fats and fatty acids.
* Cholesterol: backbone of steroids and bile acid synthesis.
* Triglycerides: Assist of transfer of energy into cell.
also in cell membranes
What are apolipoproteins? Function?
Protein required for assembly, structure, function, and metabolism of lipoproteins.
Function: Activate enzymes for lipoprotein metabolism and acts as a ligand for cell surface receptors.
Where are apolipoproteins synthesized?
Liver and SI
What are lipoproteins?
Complex molecules made of lipids and apolipoproteins.
What do lipoproteins do?
Transport cholesterol, TGs, and fat-soluble vitamins between tissues.
What are the 5 types of lipoproteins?
- Chylomicrons
- VLDL
- IDL
- LDL
- HDL
What is denser in a lipoprotein?
Apolipoproteins are MORE dense.
TGs are less dense.
Describe the composition of a lipoprotein.
- Core: hydrophobic lipids with TGs and cholesterol esters.
- Shell: Hydrophilic lipids with phospholipids, unesterified cholesterol, and apolipoproteins.
What are the two lipid pathways?
- Exogenous: absorption of dietary lipids and formation of chylomicrons.
- Endogenous: secretion of VLDL by liver, transitioning to IDL and then LDL.
Exogenous Pathway Step 1
Where is a chylomicron formed and what is it composed of?
SI absorbs dietary TGs, cholesterol, fatty acids, and retinol (Vit A).
All of these combine with apoC, apoE, and apoB-48
Exogenous Pathway Step 2
Where are chylomicrons first absorbed into? What allows them to then enter peripheral tissue?
Into the capillaries.
To enter peripheral tissue, they use apoC.
Exogenous Pathway Step 2
What breaks down TGs? Why?
TGs are broken down by lipoprotein lipase (LPL) for release of energy to muscles and adipose tissue.
Exogenous Pathway Step 3
What happens to the chylomicron remnant?
Goes to the liver to be uptaked by LDL receptors using apoE.
Endogenous Pathway Step 1
How is VLDL derived in the liver?
Substituting the apoB-48 group on the chylomicron remnant with an apoB-100.
Endogenous Pathway Step 2
Before the VLDL leaves the liver, what is added to it and from what?
- ApoE
- ApoC
- All from HDL molecules.
Endogenous Pathway Step 3
What happens to VLDL in the peripheral tissues?
TGs broken down by LPL again.
VLDL is now IDL.
Getting denser and dense as TGs get broken down.
Endogenous Pathway Step 4
What happens to IDL once it is formed?
- 40-60% are reuptaked by the liver using apoE and LDLR.
- Remaining is broken down further by hepatic lipase to form LDL.
Endgenous Pathway Step 5
How is LDL removed from circulation?
- 70% removed via liver (ApoB & LDLR)
- 30% (lipolysis in peripheral tissues)
Endgenous Pathway Step 6
What happens to the LDL in the liver?
Broken down.
The cholesterol components are excreted into bile.
Where is HDL formed?
Immature HDL is formed in the liver and intestines.
What is the function of HDL?
Collecting all cholesterol and VLDL/chylomicrons, cleaning up the arteries.
What Apo does HDL use?
ApoA
What happens to all the cholesterol collected by the immature HDL?
Lecithin-cholesterol acetyltransferase (LCAT) converts it to cholesterol esters so it can go through the bloodstream more easily.
This is when the mature HDL is formed.
How does HDL transport cholesterol to the liver?
- Direct uptake by hepatocytes
- Transfer of cholesterol for TGs with LDL & chylomicrons
What happens to HDL once it enters the liver?
Broken down into smaller HDL molecules so it is easy to excrete.
What is bad cholesterol? Good?
- Bad: LDL, which deposits cholesterol onto the vascular wall and impedes blood flow.
- Good: HDL, which sweeps cholesterol off the vascular wall to clean it up.
What is dyslipidemia?
Increase in plasma cholesterol, TGs, or BOTH.
Often accompanied by low HDL.
What are the main etiologic factors that contribute to dyslipidemia?
- Genetic predisposition
- Environmental factors
What are the 4 main pathways that lead to dyslipidemia?
- Excessive hepatic secretion of VLDL.
- Impaired lipolysis of TG-rich lipoproteins
- Impaired hepatic uptake of ApoB containing lipoproteins (except HDL)
- Inherited low levels of HDL
How does excessive hepatic secretion of VLDL typically present lab-wise?
- Elevated fasting TGs
- Low HDL-C levels
What factors tend to increase VLDL secretion?
- Obesity
- Insulin Resistance
- High-carb diet
- Nephrotic syndrome
- ETOH use
- Cushing’s
- Exogenous estrogens
- Familial combined hyperlipidemia
- Lipodystrophy
What is the pathophysiology behind impaired lipolysis of TG-rich lipoproteins?
Lipoprotein lipase dysfunction.
Caused either by genetics or insulin resistance.
What is the pathophysiology behind impaired hepatic uptake of apoB-containing lipoproteins?
Down regulation of LDLRs in the liver lead to elevated LDL.
What are the etiologies of impaired hepatic uptake of apoB-containing lipoproteins?
- Saturated fat intake reduces LDL activity
- Hypothyroidism
- Estrogen deficiency
- CKD or liver disease
- Drugs (thiazides, cyclosporine, carbamazepine)
- Genetic disorders
What is the pathophysiology behind low HDL?
Accelerated HDL catabolism and apoA.
What are the etiologies that contribute to low HDL levels?
- Obesity
- Insulin resistance
- Genetic disorders
How is dyslipidemia typically diagnosed?
Routine lab screenings showing elevated TGs and LDL with low HDL.
What PE findings can be seen with really bad dyslipidemia?
- Eruptive xanthomas (high TGs or VLDL)
- Tendinous xanthomas (high LDL)
- Lipemia retinalis (high TGs)
- Milky serum (high TGs)
What are eruptive xanthomas? MC location?
Patches on skin, often pruiritic or painful.
MC found on the buttocks.
What are tendinous xanthomas? MC location?
Lipid deposits MC found in the tendons of the hands, feet, and heel.
How does lipemia retinalis present?
Milky arteries and veins in the retina.
What is the ACC/AHA recommendation for dyslipidemia screening?
- Screen all adults starting at age 20.
- Screen children by age 2 if FMHx of EARLY CV disease or significant primary hypercholesterolemia.
What are the ASCVD risk factors?
- Tobacco use
- DM
- HTN
- Obesity
- FMHx of premature heart disease (55m, 65f)
- Personal Hx of CAD or non-coronary atherosclerosis.
What falls under non-coronary atherosclerosis?
- AAA
- PAD
- Carotid artery stenosis
How do we screen for dyslipidemia?
Fasting total cholesterol (TC) and HDL (preferred initial and preferred fasting)
Full fasting lipids if TC > 250 or HDL < 40.
If non-fasting TC is elevated, what is the next step?
Repeat with fasting.
In a lipid panel, what values do we want lower? Higher?
- TC < 200
- LDL < 100
- HDL > 40 (ideally 60 for cardioprotective)
- TGs < 150
How often do we screen for dyslipidemia?
- 5 years for average adult.
- 3 years for lipids close to therapeutic levels.
If a patient presents with elevated fasting lipids, what is the next step?
Rule out secondary causes.
* Hyperglycemia (BG)
* Nephrotic syndrome/chronic renal insufficiency (urine protein and serum creatinine)
* Hepatitis/cholestasis (LFTs)
* Hypothyroidism (TSH)
When were statins first FDA approved?
1987, with lovastatin being the first.
What are the 4 indications to begin statin therapy according to the 2018 AHA/ACC guidelines?
- Clinical ASCVD
- LDL >= 190
- DM
- Primary prevention with ASCVD >= 7.5%
What qualifies as ASCVD?
- ACS
- Coronary or arterial stenting
- Ischemic CVA or TIA
- PAD due to atherosclerosis
What qualifies as high-risk ASCVD?
2 major ASCVD events OR
1 major ASCVD event + 2 high-risk conditions.
What are the 4 major ASCVD events?
- ACS in past 12 months
- History of MI
- History of ischemic stroke
- Symptomatic PAD
When do we use high-intensity statins for ASCVD?
Very high risk ASCVD OR <= 75y.
When do we use moderate statins for ASCVD?
Not very high risk and older than 75y.
Titrate to high intensity if possible.
What are the high-intensity statins?
- Atorvastatin/lipitor 40mg/80mg
- Rosuvastatin/Crestor 20mg/40mg
If someone is high risk ASCVD, what is the LDL-C reduction goal?
50%, so we choose high intensity and reassess every 4-12 weeks until stable, then 3-12 months.
When would we want someone with ASCVD to have a LDL < 55? < 70?
- < 55 is for high-risk ASCVD or baseline LDL > 190 with FH.
- < 70 is for normal ASCVD or baseline LDL > 190 without FH.
If a patient presents with a baseline LDL-C of >= 190, what is the management?
High intensity statin for 50% reduction and then a secondary goal of < 100.
If a patient presents with DM and is between the ages of 40-75 with an LDL between 70-190, what is the first step in management? Second?
- Calculate 10-year ASCVD risk.
- Review DM-specific high risk features.
What are the DM-specific high-risk features?
- Having DM2 more than 10 years or DM1 more than 20 years.
- Albuminuria >= 30mcg
- eGFR < 60
- Retinopathy
- Neuropathy
- Ankle-brachial index < 0.9 (indicates PAD)
What kind of information do we need for an ASCVD risk estimation?
- Age, Sex, Race
- TC/HDL
- SBP
- Tx for HTN/DM
- Smoking status
Only ages 20-79 qualify.
If a patient with DM is positive for 10 year risk >= 7.5% or a high-risk DM feature, what is the treatment?
- High intensity statin for 50% reduction
- LDL < 70
If a patient with DM lacks any high-risk factors or DM-specific high risk features and has a LDL between 70-190, what is the treatment?
- Moderate intensity statin for 30-49% reduction.
- LDL < 100
For a patient with NO clinical ASCVD or DM that presents with a LDL between 70-189, what is the first step in management?
Calculate an estimated 10-year ASCVD risk.
For a patient with a 10-year risk of ASCVD between 7.5-19.9% and no ASCVD or DM and we are unsure if they want statins, what is the next step?
Coronary calcium score (CCS)
What CCS indicates statin therapy?
- > 100 is consider adding statin
- 1-99 is considering adding statin if age >= 55
- 0 is lifestyle modifications
If we decide on no statin therapy and CCS is 0 for a patient with no other risk factors other than elevated LDL, what is the next step in management?
No therapy, recalculate risk again in 5 years.
Primary prevention of ASCVD 2018 AHA/ACC Guidelines (Image)
What is the goal for daily cholesterol intake for those undergoing lifestyle modification for HLD? What are the primary macronutrients to avoid?
< 200mg daily, which is one egg yolk.
Avoid carbs, trans fats, sat fats, and cholesterol.
How do statins work?
- Inhibition of HMG-CoA, which is an enzyme needed for cholesterol synthesis in the liver.
- Increasing LDLRs present on hepatocyte membranes
- Stimulating LDL catabolism
What are the 5 main statins/HMG CoA reductase inhibitors?
- Rosuvastatin
- Atorvastatin
- Simvastatin
- Lovastatin
- Pravastatin
What do statins reduce?
LDL and TG levels, dose-dependent.
How are statins metabolized/excreted?
Liver metabolism with bile excretion.
What are the main SE of statins?
- Myalgias (with normal CK)
- Myopathy/Rhabdo (elevated CK)
- Hyperglycemia (new onset DM)
- Hepatotoxicity/liver failure
When are statins CI due to liver toxicity?
LFTs > 3x ULN or symptomatic.
What are the CIs to statins?
- Active liver disease
- Pregnancy/nursing/becoming pregnant
What should we always check for prior to starting a statin?
- LFTs
- Drug interactions (CYP450)
What is the approximate dosing ratio of atorvastatin to rosuvastatin?
4:1.
40mg of atorvastatin is 10mg of rosuvastatin.
Rosuvastatin 40mg is the highest dose statin possible.
Atorvastatin maxes out at 80mg.
Why are statins first-line?
Only drug class that demonstrates clear improvements in overall mortality for both primary and secondary prevention.
What if a patient can’t tolerate a high-intensity statin?
Try lower-intensity statins
What are the second-line therapies for HLD management?
- Ezetimibe/Zetia (most cost-efficient)
- Alicuromab/Praluent or evolocumab/Repatha
- Bempedoic acid (Nexletol)
- Inclisiran (Leqvio)
What is ezetimibe? Why do we use it and how?
Adjunctive therapy to statins, decreasing absorption of dietary cholesterol synergistically with statins.
No effect on HDL or TGs.
What should we monitor when adding ezetimibe?
LFTs, metabolism by SI and liver.
Fecal excretion.
OK in pregnancy, but must weight benefit/risk.
What is a PCSK9 inhibitor? How do they work?
Proprotein convertase subtilisin kexin type 9
MOA: MABs inhibit PCSK9 from binding to LDLRs, decreasing the degradation of LDLRs and increase LDL clearance
Given SC q2 weeks, (repatha can be given qmo)
What are the primary SEs of PCSK9 inhibitors?
- Injection site reactions
- URI symptoms
- Gastroenteritis
- Dizziness
- Mylagias
What is bempedoic acid? What is it used for?
HLD agent/adenosine triphosphate-citrate lyase (ACL) inhibitor.
Used for additional LDL reduction if statin is maxed out.
Often combined with ezetimibe into Nexlizet.
What are the 3 MOAs of Nexlizet?
- Inhibition of ACL, which inhibits cholesterol synthesis in the liver.
- Increases LDLRs on hepatocyte membranes
- Stimulates LDL catabolism
Works about 2 steps prior to where statins work.
What is the main SE of nexletol?
Gout/hyperuricemia
When is inclisiran indicated?
PCSK9 small interfering RNA agent.
Indicated for failure to tolerate max-intensity statin and PCSK9 inhibitor.
How is inclisiran dosed?
In clinic injections.
Day 1, 3 months, then q6mo.
What is the MOA of inclisiran?
- Blocks the physiologic production of mRNA for PCSK9.
- Less PCSK9 leads to less breakdown for LDLRs, so higher reuptake of LDL from circulation.
What is the third-line therapy for HLD?
Bile acid sequestrants.
What are the bile acid sequestrants?
- Cholestyramine
- Colestipol
- Colesevelam (welchol)
How do bile acid sequestrants work?
Binds bile acids in the intestines, requiring the liver to secrete even more bile. Bile is made from hepatic cholesterol, which means increased clearance of LDL.
What should we counsel patients on that are taking bile acid sequestrants?
Take it 1 hour before any other medication or 4 hours after any other medication.
Safe in pregnancy and lactation.
It can bind and impair the absorption of drugs.
What qualifies as hypertriglyceridemia?
Serum level > 150mg
What is the main concern with hypertriglyceridemia?
Pancreatitis in severe cases.
For a patient >= 20y and moderate hypertriglyceridemia, what is the management?
- Treat underlying causes.
- Avoid meds that worsen lipid levels
- Low fat diet
- Avoid alcohol, refined carbs, sat/trans fats.
What would prompt us to treat hypertriglyceridemia with statins?
40-75 y/o with TGs > 500 and ASCVD risk >= 7.5%
OR
TGs > 1000
What is the other drug we can treat hypertriglyceridemia with besides statins?
Fibrates, such as gemfibrozil or fenofibrate.
How do fibrates work?
- Stimulate LPL activity (clearing TGs from blood)
- Reduce apoC-3 synthesis (enhancing lipoprotein remnant clearance)
- Promote breakdown of fatty acids
- Can reduce VLDL-TG production
What are the primary SEs of fibrates?
- Dyspepsia
- Increased gallstone risk
- Myopathy (usually if combined with statin)
- Hepatotoxicity
What drug does a fibrate interact with?
Warfarin
How are fibrates excreted?
Kidneys. Caution in CKD.
What OTCs might we recommend for hypertriglyceridemia?
- Omega-3 Fatty Acids (4g/day needed)
- Nicotonic acid/B3/Niacin (increased LPL activity and reduced ApoA-1 clearance)
What are the primary concerns with taking niacin supplements?
- Flushing. Recommend taking baby ASA 30 mins prior.
- Avoid if Hx of gout
