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SD2 > Lipoprotein and Lipid Disorders > Flashcards

Lipoprotein and Lipid Disorders Flashcards

1
Q

Abbreviations:

  1. ASCVD:
  2. CAD:
A
  1. ASCVD: Atherosclerotic cardiovascular disease
    • Heart attacks + strokes + peripheral arterial disease
  2. CAD: Coronary atherosclerotic disease
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2
Q

Atherosclerosis Timeline:

  • Growth mainly by lipid accumulation
    • From 1st decade:
    • From 3rd decade:
  • Smooth muscle and collagen:
    • From 4th decade:
  • Thrombosis and hematoma:
    • From 4th decade:
A

Increasing endothelial dysfunction

  • Growth mainly by lipid accumulation:
    • From 1st decade:
      1. foam cells
      2. fatty streak
    • From 3rd decade:
      1. intermediate lesion
      2. atheroma
  • Smooth muscle and collagen:
    • From 4th decade:
      1. fibrous plaque
  • Thrombosis and hematoma:
    • From 4th decade:
      1. complicated lesion/rupture
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3
Q

Cardiovascular disease death rates have declined but CVD is still the leading cause of what?

A

Cardiovascular disease remains the leading cause of premature morbidity and mortality

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4
Q

What is the leading risk factor of MI?

A

LDL:HDL (Q5 to Q 1)

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5
Q

How can an unhealthy lifestyle promote or unmask the genetic tendency to lipid disorder?

A
  • To increase LDL:
    • High-trans- and saturated fat, high-cholesterol diets
  • To increase trigs or cause insulin resistance and dyslipidemia, which increases risk of ASCVD:
    • Eat SAD
    • High sugar (soda) refined carb diets
    • Sedentary lifestyle
    • Smoke
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6
Q

Why do we measure and treat lipids when it’s the lipoproteins that actually cross the endothelium?

A
  • Huge epidemiological data and pathology show that cholesterol is causally linked to atherosclerosis
  • Numerous outcome studies showing the benefit of cholesterol treatment have been based on lipid values
    • No outcome studies on lipoproteins
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7
Q

What is on a classic lipid profile?

What else can you measure?

A
  • Classic lipid profile:
    1. Total cholesterol
    2. Triglycerides
    3. HDL
    4. LDL (calculated)
    5. Non-HDL (calculated)
  • Other measures:
    • apoB
    • LDL-P (the LD-Particles, which in some conditions diverge from LDL-C)
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8
Q

What do you use the Friedwald equation for?

How do you calculate non-HDL?

A

Friedewald equation

  • LDL-C = TC – (HDL-C + VLDL-C)
  • LDL-C = TC – (HDL-C + TG/5)

non-HDL

  • Non-HDL = TC – HDL
    • = sum of all potentially atherogenic cholesterol
    • = cholesterol in all VLDL + VLDL remnants + LDL particles
  • goal is < LDL goal + 30
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9
Q

Values that increase risk of ASCVD or CVD:

  • LDL
  • HDL
  • TG
A
  • LDL-C > 100 ⇒ risk for ASCVD
  • HDL < 40 ⇒ risk for ASCVD
  • Trigs 200 - 499 ⇒ risk for CAD
    • Trigs > 1000 ⇒ risk for pancreatitis
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10
Q

Lipid disorders can be…

A
  1. Genetic
    • Dominant
    • Recessive
  2. Genetic disorder that is unmasked or promoted by lifestyle or environment
  3. Environmental
    • Western diet and sedentary lifestyle
    • Other medications or diseases
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11
Q
  1. Which genetic lipid disorders can be made better or worse with lifestyle?
  2. Which genetic lipid disorders are predominately genetic?
  3. Which genetic lipid disorders are unmasked later in life due to lifestyle?
A
  1. All genetic disorders can be made worse by a poor lifestyle or environment and better by a good lifestyle
  2. Types I and IIA are predominantly genetic with minimal lifestyle influence
  3. Types IIB, III, IV, and V are usually dormant until lifestyle (diabesity) or other diseases (diabetes) unmask or promote them
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12
Q

Fredrickson Genetic Hyperlipidemia Classification:

  • Type I
  • Type IIa
  • Type IIb
  • Type III
  • Type IV
  • Type V
A
  • Type I:
    • Severe hypertriglyceridemia
  • Type IIa:
    • Familial Hypercholesterolemia
  • Type IIb:
    • Familial Combined Hyperlipidemia or with Metabolic Syndrome
  • Type III:
    • Dysbetalipoproteinemia
  • Type IV:
    • Hypertriglyceridemia
  • Type V:
    • Hypertriglyceridemia
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13
Q

Type I: Severe hypertriglyceridemia

  • Common presentation:
  • Lipoprotein in excess:
  • Primary defect:
  • Frequency:
  • Main abnormal lipid:
A
  • Common presentation:
    • Childhood with trigs > 2000
  • Lipoprotein in excess:
    • Chylomicron
  • Primary defect:
    • LPL or apo C2 or C3
  • Frequency:
    • Very rare
  • Main abnormal lipid:
    • TG > 2000
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14
Q

Type IIa: Familial Hypercholesterolemia

  • Common presentation:
  • Lipoprotein in excess:
  • Primary defect:
  • Frequency:
  • Main abnormal lipid:
A
  • Common presentation:
    • CAD < age 60
  • Lipoprotein in excess:
    • LDL
  • Primary defect:
    • LDL-R
  • Frequency:
    • Common
  • Main abnormal lipid:
    • ​TC > 275, LDL-C > 190
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15
Q

Type IIb: Familial Combined Hyperlipidemia or with Metabolic Syndrome

  • Common presentation:
  • Lipoprotein in excess:
  • Primary defect:
  • Frequency:
  • Main abnormal lipid:
A
  • Common presentation:
    • ​CAD risk 2X normal despite borderline lipid numbers
  • Lipoprotein in excess:
    • LDL, VLDL
  • Primary defect:
    • Overproduction of apoB100
  • Frequency:
    • Common
  • Main abnormal lipid:
    • LDL 100, trigs 200 – 500, HDL < 40
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16
Q

Type III: Dysbetalipoproteinemia

  • Common presentation:
  • Lipoprotein in excess:
  • Primary defect:
  • Frequency:
  • Main abnormal lipid:
A
  • Common presentation:
    • Premature CAD
  • Lipoprotein in excess:
    • VLDL, IDL
  • Primary defect:
    • Apo E2 + overproduction
  • Frequency:
    • Rare
  • Main abnormal lipid:
    • TC and trigs both 200 to 500
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17
Q

Type IV: Hypertriglyceridemia

  • Common presentation:
  • Lipoprotein in excess:
  • Primary defect:
  • Frequency:
  • Main abnormal lipid:
A
  • Common presentation:
    • Pancreatitis
  • Lipoprotein in excess:
    • VLDL
  • Primary defect:
    • LPL or apoC3
  • Frequency:
    • Common
  • Main abnormal lipid:
    • Trigs 500 - 1000
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18
Q

Type V: Hypertriglyceridemia

  • Common presentation:
  • Lipoprotein in excess:
  • Primary defect:
  • Frequency:
  • Main abnormal lipid:
A
  • Common presentation:
    • Pancreatitis, usually diabetic
  • Lipoprotein in excess:
    • VLDL, chylo
  • Primary defect:
    • LPL or apoC3
  • Frequency:
    • Uncommon
  • Main abnormal lipid:
    • Trigs > 1000
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19
Q

What is the primary defect of Type I Chylomicronemia?

What is the consequence of this defect?

A
  • Primary defect:
    • LPL or apo C2 or C3
  • Consequence:
    • trigs not removed from chylomicron
20
Q

What is the primary defect in Type IIA Familial Hypercholesterolemia?

What is the consequence of this defect?

A
  • Primary defect:
    • LDL-R is defective
  • Consequence:
    • LDL accumulates
21
Q

Describe the role of visceral adiposity and insulin resistance in lipoprotein changes:

What is the defect for Type II Familial Combined Hyperlipidemia?

What is the consequence of this defect?

A
  • ↑Central Adiposity ⇔ Insulin Resistance:
    • ↑VLDL ⇒ LDL and HDL via CETP
  • Primary Defect:
    • Overproduction of apoB100
  • Consequence:
    • ​high trigs, low HDL, increased LDL-P
    • high trigs drive CETP ⇒ moves trigs to LDL and HDL prompting further LPL/HL activity
    • Apo-A1 is rapidly degraded and HDL is subsequently excreted via the kidneys
22
Q

What is the primary defect in Type III Dysbetalipoproteinemia?

What is the reason of this defect?

A
  • Primary defect:
    • Apo E2 + overproduction
  • Reason:
    • Because apoE2/E2 on IDL is poorly recognized by LDL-R
23
Q

What is the primary defect in Type IV Hypertriglyceridemia?

What is the consequence of this defect?

A
  • Primary defect:
    • ​LPL or apoC3
  • Consequence:
    • ApoC2 or apoC3 on VLDL not work ⇒ VLDL accumulates
24
Q

What is the primary defect in Type V Hypertriglyceridemia?

A
  • Primary defect
    • LPL or apoC3
  • Consequence
    • ApoC2 or apoC3 on both VLDL & Chylomicrons defective ⇒ accumulation of VLDL & Chylomicrons
25
Q

What can TGs > 1000 potentially cause?

A

pancreatitis

26
Q

What are medical conditions that can increase TGs?

A
  1. Metabolic syndrome, insulin resistance
  2. Diabetes
  3. Hypothyroidism
  4. Anorexia
  5. HIV
  6. Pregnancy
  7. Alcohol
  8. Fructose > 50 grams/d
27
Q

What are medications that can increase TGs?

A
  1. Estrogens
  2. Birth control
  3. Beta blockers
  4. Thiazide diuretics
  5. Cyclosporine
  6. Retinoids
  7. Steroids
  8. Protease inhibitors
  9. Bile acid sequestrants
28
Q

What are the atherosclerogenic lipoproteins?

A
  • 90% of circulating cholesterol is in LDL
  • IDL (aka VLDL remnants) + LDL cause atherosclerosis
  • IDL or VLDL remnants are also atherogenic
29
Q

Characteristics of lipid disorders that cause ASCVD:

A
  1. Elevated total cholesterol or LDL levels
  2. Excess numbers of apoB lipoproteins
  3. Often seen in patients with metabolic syndrome or Familial Hypercholesterolemia
  4. Depressed HDL levels
  5. Elevated Lp(a)
  • But most ASCVD happens in people with “normal” cholesterol
30
Q

Lipid disorders that increase risk of ASCVD:

A
  1. Type IIA Familial Hypercholesterolemia
  2. Type IIB
    • If inherited:
      • Familial combined hyperlipidemia
    • If environmental:
      • Insulin resistance (metabolic syndrome or excess VLDL remnants and increased LDL-P, which are atherogenic)
  3. Type III
    • Excess of both VLDL and LDL due to apoE2/2
31
Q

What can raise HDL?

A
  • Aerobic exercise
  • Alcohol
  • Estrogens
32
Q

What can lower HDL?

A
  • Insulin resistance and metabolic syndrome
  • Anabolic steroids
  • Progestins
  • Trans-fats
  • Smoking
33
Q

Lp(a) is homologous between ___ and ___________, and can increase the risk of ASCVD

A

Lp(a) is homologous between LDL and plasminogen, and can increase the risk of ASCVD.

34
Q

What is the basis of treating lipid disorders that cause ASCVD?

A
  • Lowering LDL with statins lowers risk
  • Base treatment on risk
  • Secondary prevention (already has ASCVD event) is treated aggressively with high intensity statin
  • Primary prevention (no clinical disease) is assessed
35
Q

What is the most common potentially lethal inherited disease in the world?

A

Familial hypercholesterolemia

  • Heterozygote 1 in 500
  • Homozygote 1 in 1,000,000
  • Autosomal dominant
36
Q

What is the prognosis of Familial Hypercholesterolemia?

How is it treated?

A
  • 50% of males have MI or die from MI by age 55 and 50% of females by age 65
    • LDL 2 X to 5 X normal since birth
  • ​Treatment with statin to lower LDL by > 50% starts as soon as diagnosis made if > age 12
37
Q

What are the different mutations for familial hypercholesterolemia?

A
  1. LDL-R mutation (decreased number or function)
    • 90% of FH
    • 1600 known mutations
  2. apoB mutation
    • can’t bind to LDL-R
  3. PCSK9
    • gain of function mutation
38
Q

What is the function of PCSK9?

A

PCSK9 catabolizes LDL-Receptor

39
Q

What happens if PCSK9 is mutated?

A
  1. PCSK9 gain of function mutation
    • One cause of FH
    • better catabolism so fewer LDL-R ⇒ LDL accumulates in circulation
  2. PCSK 9 loss of function mutation
    • Loss of function means less catabolism ⇒ increases the number of LDL-lowering LDL-R
    • Next major lipid-lowering drug class with approval expected fall 2015
40
Q

Therapeutic goals for FH:

A
  • Make diagnosis as young as possible
  • Treat with statins by age 12 or 18 for sure
  • Once make diagnosis, need to test all first-degree family members
  • Treatment with statins is lifetime (except when pregnant)
    • And soon PCSK9 inhibitors
  • If treatment started when young, ASCVD risk approaches that of normal population
41
Q

What can cause Type IIb dyslipidemia?

A
  • Metabolic syndrome
  • Insulin resistance
    • Environmental
    • Genetic tendency in South Asians
  • Visceral adiposity
  • Western lifestyle
  • Diabesity
42
Q

How does metabolic syndrome doubles the risk of CAD even in absence of diabetes?

A

Metabolic syndrome causes an atherogenic dyslipidemia

  • Increased numbers of LDL-P
  • Increased VLDL remnants
    • Which are very atherogenic
43
Q

Visceral adiposity and insulin resistance drive ___ to liver where trig-rich ____ are pushed into circulation where ____ tries to balance ratio of ____ to ___ in lipoproteins

A

Visceral adiposity and insulin resistance drive FFA to liver where trig-rich VLDL are pushed into circulation where CETP tries to balance ratio of trigs to CEs in lipoproteins

44
Q

What do excess trigs promote and what is the result?

What is the mechanism relevant to?

A
  • excess trigs promote ongoing LPL activity that reduces size of HDL and LDL-P
  • small LDL-P do not fit well into LDL-R ⇒ stay in circulation longer
    • HDL is excreted via kidneys (due to rapid breakdown of apo A-1)
  • Mechanism for Type IIb Familial Combined Hyperlipidemia
45
Q

Why is metabolic syndrome rapidly becoming the leading cause of premature CAD?

A

It’s the cumulative effect of a sedentary and a Western diet

  • Atherogenic dyslipidemia (TG : HDL > 4)
  • Increased inflammatory cytokines
  • Insulin resistance
  • Hypertension
  • Increased thrombosis

SD2 (12 decks)

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