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(C) CM 1A: Heme/Onc/Endo > Lecture 22: Lipid Disorders > Flashcards

Lecture 22: Lipid Disorders Flashcards

1
Q

What is the primary reason US adults do not care that much about treating their cholesterol?

A

They are asymptomatic for a long time.

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2
Q

What are lipids?

A

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

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3
Q

What are apolipoproteins? Function?

A

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.

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4
Q

Where are apolipoproteins synthesized?

A

Liver and SI

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5
Q

What are lipoproteins?

A

Complex molecules made of lipids and apolipoproteins.

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6
Q

What do lipoproteins do?

A

Transport cholesterol, TGs, and fat-soluble vitamins between tissues.

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7
Q

What are the 5 types of lipoproteins?

A
  • Chylomicrons
  • VLDL
  • IDL
  • LDL
  • HDL
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8
Q

What is denser in a lipoprotein?

A

Apolipoproteins are MORE dense.
TGs are less dense.

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9
Q

Describe the composition of a lipoprotein.

A
  • Core: hydrophobic lipids with TGs and cholesterol esters.
  • Shell: Hydrophilic lipids with phospholipids, unesterified cholesterol, and apolipoproteins.
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10
Q

What are the two lipid pathways?

A
  • Exogenous: absorption of dietary lipids and formation of chylomicrons.
  • Endogenous: secretion of VLDL by liver, transitioning to IDL and then LDL.
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11
Q

Exogenous Pathway Step 1

Where is a chylomicron formed and what is it composed of?

A

SI absorbs dietary TGs, cholesterol, fatty acids, and retinol (Vit A).
All of these combine with apoC, apoE, and apoB-48

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12
Q

Exogenous Pathway Step 2

Where are chylomicrons first absorbed into? What allows them to then enter peripheral tissue?

A

Into the capillaries.
To enter peripheral tissue, they use apoC.

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13
Q

Exogenous Pathway Step 2

What breaks down TGs? Why?

A

TGs are broken down by lipoprotein lipase (LPL) for release of energy to muscles and adipose tissue.

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14
Q

Exogenous Pathway Step 3

What happens to the chylomicron remnant?

A

Goes to the liver to be uptaked by LDL receptors using apoE.

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15
Q

Endogenous Pathway Step 1

How is VLDL derived in the liver?

A

Substituting the apoB-48 group on the chylomicron remnant with an apoB-100.

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16
Q

Endogenous Pathway Step 2

Before the VLDL leaves the liver, what is added to it and from what?

A
  • ApoE
  • ApoC
  • All from HDL molecules.
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17
Q

Endogenous Pathway Step 3

What happens to VLDL in the peripheral tissues?

A

TGs broken down by LPL again.

VLDL is now IDL.

Getting denser and dense as TGs get broken down.

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18
Q

Endogenous Pathway Step 4

What happens to IDL once it is formed?

A
  • 40-60% are reuptaked by the liver using apoE and LDLR.
  • Remaining is broken down further by hepatic lipase to form LDL.
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19
Q

Endgenous Pathway Step 5

How is LDL removed from circulation?

A
  • 70% removed via liver (ApoB & LDLR)
  • 30% (lipolysis in peripheral tissues)
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20
Q

Endgenous Pathway Step 6

What happens to the LDL in the liver?

A

Broken down.
The cholesterol components are excreted into bile.

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21
Q

Where is HDL formed?

A

Immature HDL is formed in the liver and intestines.

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22
Q

What is the function of HDL?

A

Collecting all cholesterol and VLDL/chylomicrons, cleaning up the arteries.

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23
Q

What Apo does HDL use?

A

ApoA

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24
Q

What happens to all the cholesterol collected by the immature HDL?

A

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.

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25
Q

How does HDL transport cholesterol to the liver?

A
  • Direct uptake by hepatocytes
  • Transfer of cholesterol for TGs with LDL & chylomicrons
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26
Q

What happens to HDL once it enters the liver?

A

Broken down into smaller HDL molecules so it is easy to excrete.

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27
Q

What is bad cholesterol? Good?

A
  • 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.
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28
Q

What is dyslipidemia?

A

Increase in plasma cholesterol, TGs, or BOTH.
Often accompanied by low HDL.

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29
Q

What are the main etiologic factors that contribute to dyslipidemia?

A
  • Genetic predisposition
  • Environmental factors
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30
Q

What are the 4 main pathways that lead to dyslipidemia?

A
  • 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
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31
Q

How does excessive hepatic secretion of VLDL typically present lab-wise?

A
  • Elevated fasting TGs
  • Low HDL-C levels
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32
Q

What factors tend to increase VLDL secretion?

A
  • Obesity
  • Insulin Resistance
  • High-carb diet
  • Nephrotic syndrome
  • ETOH use
  • Cushing’s
  • Exogenous estrogens
  • Familial combined hyperlipidemia
  • Lipodystrophy
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33
Q

What is the pathophysiology behind impaired lipolysis of TG-rich lipoproteins?

A

Lipoprotein lipase dysfunction.
Caused either by genetics or insulin resistance.

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34
Q

What is the pathophysiology behind impaired hepatic uptake of apoB-containing lipoproteins?

A

Down regulation of LDLRs in the liver lead to elevated LDL.

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35
Q

What are the etiologies of impaired hepatic uptake of apoB-containing lipoproteins?

A
  • Saturated fat intake reduces LDL activity
  • Hypothyroidism
  • Estrogen deficiency
  • CKD or liver disease
  • Drugs (thiazides, cyclosporine, carbamazepine)
  • Genetic disorders
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36
Q

What is the pathophysiology behind low HDL?

A

Accelerated HDL catabolism and apoA.

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37
Q

What are the etiologies that contribute to low HDL levels?

A
  • Obesity
  • Insulin resistance
  • Genetic disorders
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38
Q

How is dyslipidemia typically diagnosed?

A

Routine lab screenings showing elevated TGs and LDL with low HDL.

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39
Q

What PE findings can be seen with really bad dyslipidemia?

A
  • Eruptive xanthomas (high TGs or VLDL)
  • Tendinous xanthomas (high LDL)
  • Lipemia retinalis (high TGs)
  • Milky serum (high TGs)
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40
Q

What are eruptive xanthomas? MC location?

A

Patches on skin, often pruiritic or painful.
MC found on the buttocks.

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41
Q

What are tendinous xanthomas? MC location?

A

Lipid deposits MC found in the tendons of the hands, feet, and heel.

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42
Q

How does lipemia retinalis present?

A

Milky arteries and veins in the retina.

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43
Q

What is the ACC/AHA recommendation for dyslipidemia screening?

A
  • Screen all adults starting at age 20.
  • Screen children by age 2 if FMHx of EARLY CV disease or significant primary hypercholesterolemia.
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44
Q

What are the ASCVD risk factors?

A
  • Tobacco use
  • DM
  • HTN
  • Obesity
  • FMHx of premature heart disease (55m, 65f)
  • Personal Hx of CAD or non-coronary atherosclerosis.
45
Q

What falls under non-coronary atherosclerosis?

A
  • AAA
  • PAD
  • Carotid artery stenosis
46
Q

How do we screen for dyslipidemia?

A

Fasting total cholesterol (TC) and HDL (preferred initial and preferred fasting)

Full fasting lipids if TC > 250 or HDL < 40.

47
Q

If non-fasting TC is elevated, what is the next step?

A

Repeat with fasting.

48
Q

In a lipid panel, what values do we want lower? Higher?

A
  • TC < 200
  • LDL < 100
  • HDL > 40 (ideally 60 for cardioprotective)
  • TGs < 150
49
Q

How often do we screen for dyslipidemia?

A
  • 5 years for average adult.
  • 3 years for lipids close to therapeutic levels.
50
Q

If a patient presents with elevated fasting lipids, what is the next step?

A

Rule out secondary causes.
* Hyperglycemia (BG)
* Nephrotic syndrome/chronic renal insufficiency (urine protein and serum creatinine)
* Hepatitis/cholestasis (LFTs)
* Hypothyroidism (TSH)

51
Q

When were statins first FDA approved?

A

1987, with lovastatin being the first.

52
Q

What are the 4 indications to begin statin therapy according to the 2018 AHA/ACC guidelines?

A
  • Clinical ASCVD
  • LDL >= 190
  • DM
  • Primary prevention with ASCVD >= 7.5%
53
Q

What qualifies as ASCVD?

A
  • ACS
  • Coronary or arterial stenting
  • Ischemic CVA or TIA
  • PAD due to atherosclerosis
54
Q

What qualifies as high-risk ASCVD?

A

2 major ASCVD events OR
1 major ASCVD event + 2 high-risk conditions.

55
Q

What are the 4 major ASCVD events?

A
  • ACS in past 12 months
  • History of MI
  • History of ischemic stroke
  • Symptomatic PAD
56
Q

When do we use high-intensity statins for ASCVD?

A

Very high risk ASCVD OR <= 75y.

57
Q

When do we use moderate statins for ASCVD?

A

Not very high risk and older than 75y.

Titrate to high intensity if possible.

58
Q

What are the high-intensity statins?

A
  • Atorvastatin/lipitor 40mg/80mg
  • Rosuvastatin/Crestor 20mg/40mg
59
Q

If someone is high risk ASCVD, what is the LDL-C reduction goal?

A

50%, so we choose high intensity and reassess every 4-12 weeks until stable, then 3-12 months.

60
Q

When would we want someone with ASCVD to have a LDL < 55? < 70?

A
  • < 55 is for high-risk ASCVD or baseline LDL > 190 with FH.
  • < 70 is for normal ASCVD or baseline LDL > 190 without FH.
61
Q

If a patient presents with a baseline LDL-C of >= 190, what is the management?

A

High intensity statin for 50% reduction and then a secondary goal of < 100.

62
Q

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?

A
  1. Calculate 10-year ASCVD risk.
  2. Review DM-specific high risk features.
63
Q

What are the DM-specific high-risk features?

A
  • 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)
64
Q

What kind of information do we need for an ASCVD risk estimation?

A
  • Age, Sex, Race
  • TC/HDL
  • SBP
  • Tx for HTN/DM
  • Smoking status

Only ages 20-79 qualify.

65
Q

If a patient with DM is positive for 10 year risk >= 7.5% or a high-risk DM feature, what is the treatment?

A
  1. High intensity statin for 50% reduction
  2. LDL < 70
66
Q

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?

A
  1. Moderate intensity statin for 30-49% reduction.
  2. LDL < 100
67
Q

For a patient with NO clinical ASCVD or DM that presents with a LDL between 70-189, what is the first step in management?

A

Calculate an estimated 10-year ASCVD risk.

68
Q

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?

A

Coronary calcium score (CCS)

69
Q

What CCS indicates statin therapy?

A
  • > 100 is consider adding statin
  • 1-99 is considering adding statin if age >= 55
  • 0 is lifestyle modifications
70
Q

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?

A

No therapy, recalculate risk again in 5 years.

71
Q

Primary prevention of ASCVD 2018 AHA/ACC Guidelines (Image)

72
Q

What is the goal for daily cholesterol intake for those undergoing lifestyle modification for HLD? What are the primary macronutrients to avoid?

A

< 200mg daily, which is one egg yolk.

Avoid carbs, trans fats, sat fats, and cholesterol.

73
Q

How do statins work?

A
  • Inhibition of HMG-CoA, which is an enzyme needed for cholesterol synthesis in the liver.
  • Increasing LDLRs present on hepatocyte membranes
  • Stimulating LDL catabolism
74
Q

What are the 5 main statins/HMG CoA reductase inhibitors?

A
  • Rosuvastatin
  • Atorvastatin
  • Simvastatin
  • Lovastatin
  • Pravastatin
75
Q

What do statins reduce?

A

LDL and TG levels, dose-dependent.

76
Q

How are statins metabolized/excreted?

A

Liver metabolism with bile excretion.

77
Q

What are the main SE of statins?

A
  • Myalgias (with normal CK)
  • Myopathy/Rhabdo (elevated CK)
  • Hyperglycemia (new onset DM)
  • Hepatotoxicity/liver failure
78
Q

When are statins CI due to liver toxicity?

A

LFTs > 3x ULN or symptomatic.

79
Q

What are the CIs to statins?

A
  • Active liver disease
  • Pregnancy/nursing/becoming pregnant
80
Q

What should we always check for prior to starting a statin?

A
  • LFTs
  • Drug interactions (CYP450)
81
Q

What is the approximate dosing ratio of atorvastatin to rosuvastatin?

A

4:1.

40mg of atorvastatin is 10mg of rosuvastatin.

Rosuvastatin 40mg is the highest dose statin possible.

Atorvastatin maxes out at 80mg.

82
Q

Why are statins first-line?

A

Only drug class that demonstrates clear improvements in overall mortality for both primary and secondary prevention.

83
Q

What if a patient can’t tolerate a high-intensity statin?

A

Try lower-intensity statins

84
Q

What are the second-line therapies for HLD management?

A
  • Ezetimibe/Zetia (most cost-efficient)
  • Alicuromab/Praluent or evolocumab/Repatha
  • Bempedoic acid (Nexletol)
  • Inclisiran (Leqvio)
85
Q

What is ezetimibe? Why do we use it and how?

A

Adjunctive therapy to statins, decreasing absorption of dietary cholesterol synergistically with statins.

No effect on HDL or TGs.

86
Q

What should we monitor when adding ezetimibe?

A

LFTs, metabolism by SI and liver.
Fecal excretion.
OK in pregnancy, but must weight benefit/risk.

87
Q

What is a PCSK9 inhibitor? How do they work?

A

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)

88
Q

What are the primary SEs of PCSK9 inhibitors?

A
  • Injection site reactions
  • URI symptoms
  • Gastroenteritis
  • Dizziness
  • Mylagias
89
Q

What is bempedoic acid? What is it used for?

A

HLD agent/adenosine triphosphate-citrate lyase (ACL) inhibitor.

Used for additional LDL reduction if statin is maxed out.

Often combined with ezetimibe into Nexlizet.

90
Q

What are the 3 MOAs of Nexlizet?

A
  • 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.

91
Q

What is the main SE of nexletol?

A

Gout/hyperuricemia

92
Q

When is inclisiran indicated?

A

PCSK9 small interfering RNA agent.

Indicated for failure to tolerate max-intensity statin and PCSK9 inhibitor.

93
Q

How is inclisiran dosed?

A

In clinic injections.
Day 1, 3 months, then q6mo.

94
Q

What is the MOA of inclisiran?

A
  • Blocks the physiologic production of mRNA for PCSK9.
  • Less PCSK9 leads to less breakdown for LDLRs, so higher reuptake of LDL from circulation.
95
Q

What is the third-line therapy for HLD?

A

Bile acid sequestrants.

96
Q

What are the bile acid sequestrants?

A
  • Cholestyramine
  • Colestipol
  • Colesevelam (welchol)
97
Q

How do bile acid sequestrants work?

A

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.

98
Q

What should we counsel patients on that are taking bile acid sequestrants?

A

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.

99
Q

What qualifies as hypertriglyceridemia?

A

Serum level > 150mg

100
Q

What is the main concern with hypertriglyceridemia?

A

Pancreatitis in severe cases.

101
Q

For a patient >= 20y and moderate hypertriglyceridemia, what is the management?

A
  • Treat underlying causes.
  • Avoid meds that worsen lipid levels
  • Low fat diet
  • Avoid alcohol, refined carbs, sat/trans fats.
102
Q

What would prompt us to treat hypertriglyceridemia with statins?

A

40-75 y/o with TGs > 500 and ASCVD risk >= 7.5%
OR
TGs > 1000

103
Q

What is the other drug we can treat hypertriglyceridemia with besides statins?

A

Fibrates, such as gemfibrozil or fenofibrate.

104
Q

How do fibrates work?

A
  • 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
105
Q

What are the primary SEs of fibrates?

A
  • Dyspepsia
  • Increased gallstone risk
  • Myopathy (usually if combined with statin)
  • Hepatotoxicity
106
Q

What drug does a fibrate interact with?

107
Q

How are fibrates excreted?

A

Kidneys. Caution in CKD.

108
Q

What OTCs might we recommend for hypertriglyceridemia?

A
  • Omega-3 Fatty Acids (4g/day needed)
  • Nicotonic acid/B3/Niacin (increased LPL activity and reduced ApoA-1 clearance)
109
Q

What are the primary concerns with taking niacin supplements?

A
  • Flushing. Recommend taking baby ASA 30 mins prior.
  • Avoid if Hx of gout

(C) CM 1A: Heme/Onc/Endo (28 decks)

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