Lipoprotein Physiology II: Genetic Lipid Disorders

Question 1

Measurement equation for LDL

Answer 1

LDLc= TC- (HDL+TG/2.2)

Friedewald Equation

Question 2

fasting OR non-fasting lipid panels are generally acceptable for most people, but a ___

is still needed if there is a suspected or known TG disorder

Answer 2

but a fasting lipid panel is still needed if there is a suspected or known TG disorder

Question 3

• if high ­ TG, even with fasting, (& unable to calculate LDL-C), you have 2 choices as to why things are elevated. Why?what is their relationship?

Answer 3

1. non-HDL cholesterol is high
2. apoB level is low

the relationship between LDL,nonHDL Cholesterol, and apoB is that LDL is a form of nonHDL cholesterol. ApoB is what allows LDL to be taken up by cells. if there is no APoB, LDL stays in the blood.

Question 4

what is LP(A)? What is it linked to?

Answer 4

• very bad LDL particle with apoB100 protein linked to apo(A)
• sharply increases the risk of MI and stroke

Question 5

Question 6

lipid disorders can be classified as primary or seconday and can co-exist together. The lipid disorder can be characterized as primary if:

Answer 6

1. premature coronary disease or stroke
2. compatible family history
3. severe elevation of lipids: TC>6.5-7, or TG>4-5mmol/L

Question 7

what levels are to be considered as “severely elevated” in terms of lipids?

Answer 7

: TC>6.5-7, or TG>4-5mmol/L. if there is this severe of elevation, consider primary lipid disorders.

Question 8

hypertriglyceridemia is characterized by triglyceride excess. what 3 causes causes TG excess?

Answer 8

1. excess CM (contains triglycerides)
2. excess VLDL
3. both

note: both CM and VLDL contain cholesterol,
∴ TC levels may also be modestly increased—but
always to a much smaller extent compared to TG

Question 9

assess

Answer 9

there is high cholesterol, but TG is way higher

Question 10

clinical manifestations of hypertriglyceridemia (dermataological features, plasma color)

Answer 10

1. lipemia retinalis (white case on venous bed)
2. eruptive xanthomas (yellow eruption 2-5 mm in diameters, on extensor surfaces and buttocks, hepatosplenomegaly
3. milky plasma

Question 11

when someone presents with “lipemic specimens”, elevated triglycerides, and eruptive xanthomas, you think they have hypertriglyceridemia. what are primary and secondary cuases of this?

Answer 11

1. primary; LPL deficiency. ApoCII deficinecy (recall that apoCII is needed for chylomicrons to enter the lymph system via LPL. if they cannot, CM stays in circulation, causing elevated levels on lab). or familial hypertriglyceridemia.
2. secondary; fatty diet, alcohol, uncontrolled diabetes mellitus,
   obesity, hypothyroidism, chronic kidney disease,
   drugs (glucocorticoids, estrogens, thiazides,
   protease inhibitors, beta-blockers, retinoids
   [Accutane]), Cushing’s syndrome

Question 12

LPL deficiency & ___ deficiency are rare autosomal recessive disorders (both ~1/million) that result in ELEVATED ­­­ TGs

Answer 12

LPL deficiency & apoCII deficiency are rare autosomal recessive disorders (both ~1/million) that result in ELEVATED­­­ TGs

LPL is the enzyme that hydrolyzes TGs found
in CMs & VLDL; apoCII is an obligatecofactor;
when absent CMs and VLDL accumulate

Question 13

LPL DEFICIENCY can cause hypertriglyceridemia, and accounts for 50% of primary cases. What population is most affected by it?

Answer 13

French Canadians (founder effect)

Question 14

ApoCII deficiency can cause hypertriglyceridemia and is most common in ___ families.

Answer 14

greek amilies.

Question 15

note; LPL deficiencies can cause hypertriglyceridemias, but acquired deficiencies in LPL activity
are much more common than primary
(genetic) disorders—and can occur
from uncontrolled __, __,
and __ disease (“uremia”)

Answer 15

acquired deficiencies in LPL activity
are much more common than primary
(genetic) disorders—and can occur
from uncontrolled diabetes, obesity,
and kidney disease (“uremia”)

Question 16

genetic inheritance of familial hypertriglyceridemia, and moa

Answer 16

• autosomal dominant
• overproduction of TGs in the liver, leading to the secretion highly TG-enriched VLDL particles

Question 17

how do secondary causes (ex/ fatty diet) cause hypertriglyceridemia?

Answer 17

increased estrogen, fatty food, alcoholism, hypercortisolism, uncontrolled diabetes and alcoholism can cause the liver to incease it’s VLDL production because there is an inherent increase in FFAs in the blood.

Question 18

hypercholesterolemia is characterized by cholesterol excess due to which causes?

Answer 18

1. due to increase LDL (apoB)
2. due to increase in HDL

recall that these “DL” products contain cholesterol, and some TGs

Question 19

hypertriglyceridemia or hypercholesterolemia/

Answer 19

triglycerides are normal, but the cholesterol is high. this is hyperchoelsterolemia

Question 20

physical exam findings of hyeprcholesterolemia

Answer 20

gall stones, XANTHELASMAS (xanthomas on the eyelid), TUBEROUS XANTHOMAS ((shiny red/orrange noduels), CORNEAL ARCUS (if hypercholesterolemia is premature), might also see TENDON XANTHOMAS with familial hypercholesterolemia

-sequelae also includes atherosclerosis, aortic sclerosis.

Question 21

specific dermatological finding in ppeople with familial hyperchoelsterolemia

Answer 21

tendon xanthomas (esp. Achilles tendon &
knuckles) with familial hypercholesterolemia

Question 22

primary causes and secondary causes of hypercholesterolemia

Answer 22

most common primary cause; familial hypercholesterolemia,

secondary causes; diet, hypothyroidism, nephrotic syndrome, cholestatic liver disease, thiazides

Question 23

what is the MOA of familial hyperchoelsterolemia? what population is most affected? what is the inheritance patterns?

Answer 23

MOA: LDL receptor gene mutation. recall that LDL is used to transport LDL into the cells with the help of ApoB100. if there is dysfunction, LDL cholesterol stays in circulation once it was released from the liver.

• LDL receptor mutation is autosomal dominant.
• heterozygous is common– seen in FRENCH CANADIANS. At times there can be homozygeous cases.

Question 24

how is polygenic hyperchoelsterolemia diagnosed?

Answer 24

it’s a diagnosis of exclusion

Question 25

interpret

Answer 25

combined hyperlipidemia

Question 26

exm findings of combined hyperlipidemia

Answer 26

look for stigmata of hypertriglyceridemia and hypercholesterolemia.

• can lead to atherosclerosis and pancreatitis

- palma xanthomas common, esepcially if the combined hyperlipidemia is due to familial dysbetalipoproteinemia.

Question 27

primary causes of combined hyperlipidemia

Answer 27

1. familial combined hyperlipidemia
2. familial dysbeetalipoproteinemia (would see palmar xanthomas)
3. hepatic lipase deficiency (recall that hepatic lipase creates LDL from IDL. You woyld have an accumulation of IDL in your body

Question 28

secondary causes of combined hyperlipidemia

Answer 28

diet, hypothyroidism, nephrotic syndrome, uncontrolled diabetes mellitus, acromegaly.

Question 29

outline the MOA and inhertiance pattern of combined familial hyperlipidemia

Answer 29

• multiple genes with overlapping features with metabolic syndrome. AUTOSOMAL DOMINANT. most common formof hyperlipidemia
• MOA: overproduction of ApoB (increase in VLDL, LDL, or both). recall that ApoB is used to shuttle LDL from blood into cells. If ApoB is absent/nonfucntional, LDL and cholsterol products will accumualte

Question 30

MOA of familial dysbetalipoproteinemia

Answer 30

• remnant removal disease – due to mutation in apoE gene, accumualtion of remnant particals (therefore, CM remnants and IDl will stay outside of the cells, CM remnant will not be able to get transfered to the liver)
• clnical manifestation of disease usually requires a 2ndary exacerbating factor that causes VLDL overproduction (ex/ alcohol, uncontrollled diabetes, etc)
• palma xanthomas are frequently seen in familial dysbetalipoproteinemia

Question 31

how do secondary causes (ex/ obesity, fatty diet) cause combined hyperlipidemia?

Answer 31

Question 32

hypolipidemia is the reduction of lipids in the blood/lipid deficiency. main causes?

Answer 32

1. reduction of HDL particles- cells aren’t secreting enough HDL (without HDL, you cannot shuttle cholesterol around) and choelsterol. HDL IS A GOOD THING
2. due to reduction of apoB-containing particles. recall that apoB shuttles cholsterol into cells.

Question 33

secondary causes of decreased HDL (a cause of hypolipidemia)

Answer 33

Question 34

causes of decreased LDL/apoB (cause of hypolipidemia)

Answer 34