Hyperlipidemia Flashcards
Where is cholesterol metabolized?
In the liver.
Outline the process of lipid metabolism from the liver to the rest of the body
What happens if we can’t metabolize lipid remnants properly?
**see below** (alert: the slide is a doozy, will take a few mins)
**
CMR: chylomicrons – little fat packages that form after you eat a fatty meal; if those and LDL aren’t metabolized properly, they can be taken up through other means e.g. in macrophages that line our blood vessels
Protective mechanism to remove excess cholesterol involves HDL: HDL can pick up extra cholesterol and deposit it in the gonads, or it can bind to receptors in the skin and be added to the cholesterol pool in the liver
What are the diseases of lipid metabolism? (4)
High LDLs
High remnants
Low HDLs
High triglycerides
High levels of LDL an accumulate when LDL cannot ___
High levels of LDL can accumulate when LDL cannot bind to its receptor (so it can’t be added to the cholesterol pool)
High levels of LDL can manifest as ___ (genetic condition)
High levels of LDL can manifest as familial hypercholesterolemia
What are the clinical manifestations of familial hypercholesterolemia? (4)
Premature vascular disease
Corneal arcus
Xanthelasma
Tendon and Cutaneous xanthomas
What are the conditions below?
Signs of familial hypercholesterolemia
**see below**
What is 2ndary hypercholesterolemia and what are conditions ass’d with it?(5)
Secondary hypercholesterolemia occurs 2ndary to some pre-existing condition
Conditions preceding 2ndary hypercholesterolemia: hypothyroidism
nephrotic syndrome
obstructive liver disease
diabetes mellitus
drugs (e.g. steroids)
What class of drugs is the first line of treatment for familial hypercholesterolemia?
Statins
What is the MOA of statins?
Statins inhibit HMG CoA-reductase >> cholesterol reduction (block further progression of cholesterol synthesis pathway)
**statins also reduce the production of inflammatory byproducts of cholesterol synthesis thus statins also have anti-inflammatory effects
What is the effect of using a statin or bile acid resin in the cholesterol synthesis pathway?
Statins block HMG-CoA, hereby reducing intracellular cholesterol synthesis. Less cholesterol synthesis = upregulation of LDL receptors for more LDL uptake
Can also use a bile acid resin which reduces reabsorption of bile acids >> block bile acid recycling
What are cholesterol reduction guidelines if a pt has high cholesterol and pre-existing disease?
What are the guidelines if a pt does not have pre-existing disease but is at high risk?
If pre-existing disease: get LDL down by 50%, then down to 70%
If no pre-existing disease but high risk, need to reduce LDL down below 100
__ is a cholesterol absorption inhibitor that can be added to statins if pts can’t tolerate statins or are on low dose statins
Ezetimibe is a cholesterol absorption inhibitor that can be added to statins if pts can’t tolerate statins or are on low dose statins
Describe how ezetimibe blocks cholesterol absorption in the gut
Ezetimibe works by inhibiting cholesterol absorption in the gut thru the Niemann Pick-like receptor (NPCL1)
Allows more cholesterol to be excreted through fecal sterols
How do PCSK9 proteins cause increased plasma cholesterol levels/how do they work?
PCSK9 proteins bind to the LDL receptor and make it non-functional >> receptor is degraded by lysosomes and doesn’t recycle back to the surface
Pts with ___ mutations in PCSK9 have high LDL levels
Pts with ___mutations in PCSK9 have low LDL levels (higher LDL receptor levels >> higher LDL clearance)
Pts with gain of function mutations in PCSK9 have high LDL levels
Pts with loss of function mutations in PCSK9 have low LDL levels (higher LDL receptor levels >> higher LDL clearance)
Describe the mechanism of action of PCSK9 inhibitors
Inhibiting PCSK9 = increasing number of LDL receptors available >> reduced plasma LDL levels
T/F: Remnant particles are less cholesterol enriched because they’re still attached to triglycerides
What are the effects of a defect in the ability to breakdown remnant particles?
Falsehood. Remnant particles are more cholesterol enriched because they’ve shed of the triglycerides)
If there is a defect in ability to catabolize these remnants then there’s buildup of lipids (IDL) (issues with ApoE
Describe the function of the ApoE-E3 chylomicron receptor and contrast that with the ApoE-E2 receptor
Having which isoform contributes to increased cholesterol levels?
ApoE-E3 – normal isoform that allows for chylomicron clearance
ApoE-E2 – abnormal isoform where you can’t clear chylomicron remnants
Can’t clear remnants = too many remnants in the circulation >> taken up by macrophages >> artherosclerosis
What is the condition below?
Palmar creases - Familial dysbetalipoproteinemia
(creases are yellow-ish orange instead of being clear)
**but I’m black light skinned and my creases are yellowish :/ **
What is the impact of low levels of HDL cholesterol on coronary heart disease?
Greater likelihood of coronary disease with lower levels of HDL cholesterol
Name the factors associated with lower HDL-cholesterol levels (6)
Sedentary behavior - think of how the blacks exercise not
Obesity
Cigarrete smoking
B-blockers
Anabolic steroids
Progestins
What is the function of the ABCA1 or ABCG1 transporter in cholesterol clearence?
ABCA1 or ABCG1 proteins carry HDL with its cofactor ApoA-I >> esterified to free cholesterols via LCAT >> HDL cholesterol delivered to steroidal tissues that can clear excess cholesterol
A patient presents with enlarged tonsils with a yellow-orange discoloration. Pt also has hepatosplenomegaly and needs a biopsy. Biopsy shows yellow-orange discoloration of liver and spleen tissue. What condition are you thinking of?
What is the cause of this condition?
Tangier disease
Tangier disease arises from a mutation in the ABCA1 gene leading to build up of lipids in macrophages >> yellow-orange discoloration of lipid build up in RES organs (liver, spleen etc)
**defects in APO-A-I can also cause similar problems**
What is the condition below?
Tangier disease (lipid buildup in RES system due to mutations in ABCA1 or ApoA1)
Describe the role of the LCAT enzyme in cholesterol transport from macrophages to the liver
What are the effects of an LCAT deficiency/defect?
LCAT is the enzyme that esterifies free cholesterol
LCAT defect/deficiency = lipid build up (free cholesterol) and build up of circulating phosphatidylcholine
