Lipoprotein Physiology II: Genetic Lipid Disorders Flashcards
Measurement equation for LDL
LDLc= TC- (HDL+TG/2.2)
Friedewald Equation
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
but a fasting lipid panel is still needed if there is a suspected or known TG disorder
• 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?
- non-HDL cholesterol is high
- 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.
what is LP(A)? What is it linked to?
- very bad LDL particle with apoB100 protein linked to apo(A)
- sharply increases the risk of MI and stroke
lipid disorders can be classified as primary or seconday and can co-exist together. The lipid disorder can be characterized as primary if:
- premature coronary disease or stroke
- compatible family history
- severe elevation of lipids: TC>6.5-7, or TG>4-5mmol/L
what levels are to be considered as “severely elevated” in terms of lipids?
: TC>6.5-7, or TG>4-5mmol/L. if there is this severe of elevation, consider primary lipid disorders.
hypertriglyceridemia is characterized by triglyceride excess. what 3 causes causes TG excess?
- excess CM (contains triglycerides)
- excess VLDL
- 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
assess
there is high cholesterol, but TG is way higher
clinical manifestations of hypertriglyceridemia (dermataological features, plasma color)
- lipemia retinalis (white case on venous bed)
- eruptive xanthomas (yellow eruption 2-5 mm in diameters, on extensor surfaces and buttocks, hepatosplenomegaly
- milky plasma
when someone presents with “lipemic specimens”, elevated triglycerides, and eruptive xanthomas, you think they have hypertriglyceridemia. what are primary and secondary cuases of this?
- 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.
- 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
LPL deficiency & ___ deficiency are rare autosomal recessive disorders (both ~1/million) that result in ELEVATED TGs
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
LPL DEFICIENCY can cause hypertriglyceridemia, and accounts for 50% of primary cases. What population is most affected by it?
French Canadians (founder effect)
ApoCII deficiency can cause hypertriglyceridemia and is most common in ___ families.
greek amilies.
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”)
acquired deficiencies in LPL activity
are much more common than primary
(genetic) disorders—and can occur
from uncontrolled diabetes, obesity,
and kidney disease (“uremia”)
genetic inheritance of familial hypertriglyceridemia, and moa
- autosomal dominant
- overproduction of TGs in the liver, leading to the secretion highly TG-enriched VLDL particles
how do secondary causes (ex/ fatty diet) cause hypertriglyceridemia?
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.
hypercholesterolemia is characterized by cholesterol excess due to which causes?
- due to increase LDL (apoB)
- due to increase in HDL
recall that these “DL” products contain cholesterol, and some TGs
hypertriglyceridemia or hypercholesterolemia/
triglycerides are normal, but the cholesterol is high. this is hyperchoelsterolemia
physical exam findings of hyeprcholesterolemia
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.
specific dermatological finding in ppeople with familial hyperchoelsterolemia
tendon xanthomas (esp. Achilles tendon & knuckles) with familial hypercholesterolemia
primary causes and secondary causes of hypercholesterolemia
most common primary cause; familial hypercholesterolemia,
secondary causes; diet, hypothyroidism, nephrotic syndrome, cholestatic liver disease, thiazides
what is the MOA of familial hyperchoelsterolemia? what population is most affected? what is the inheritance patterns?
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.
how is polygenic hyperchoelsterolemia diagnosed?
it’s a diagnosis of exclusion
