Dyslipidemia Flashcards
What are the causes of dyslipidemia?
PRIMARY
- single of multiple gene mutation
- over production or defective clearance of triglycerides & LDL, underproduction or excessive clearance of HDL
SECONDARY
- sedentary life style
- Diet: excessive intake of saturated fat, alcohol consumption
- Drugs: thiazides, retinoids, antiretroviral agents, cyclosporin, tacrolimus, estrogen & progestins, & glucocorticoids
- Disease: diabetes, hypothyroidism, obesity, chronic liver disease, primary biliary cirrhosis, chronic renal failure
Where are triglycerides stored?
in adipocytes & muscle cells
store unused calories
What is the physiology of lipid digestion?
1- dietary triglycerides are digested in the stomach & duodenum by gastric lipase, stomach peristalsis, & pancreatic lipase INTO monoglycerides & FFAs
2- monoglycerides, FFA, & free cholesterol are solubilized in the intestine by bile acid -> absorbed into intestinal villi
3- in enterocytes they are reassembled into TGs & packaged with cholesterol into chylomicrons
4- chylomicrons transport dietary TGs & cholesterol into the circulation
5- Apolipoprotein C-II (apo C-II) on chylomicron activates endothelial lipoprotein lipase (LPL)
6- LPL converts the TGs in chylomicron to fatty acids & glycerol
7- fatty acids & glycerol are taken up by adipocytes & muscle cells for energy use or storage
8- cholesterol rich chylomicron remnants circulate back to the liver to be cleared by apolipoprotein E (apo E)
What is the largest lipoprotein?
Chylomicrons
What leads to elevated plasma cholesterol & TG levels?
stimulation of hepatic lipoprotein synthesis
What is the function of VLDL?
- contains apolipoprotein B-100
- synthesized in the liver & transports TGs & cholesterol to peripheral tissue
- its synthesis increases with increased intrahepatic FFA (to export excess TG out of the liver)
- apoprotein C-II -> activates LPL
What is the function of IDL?
- product of LPL processing of VLDV & chylomicrons
- either cleared by the liver or metabolized by hepatic lipase into LDL (retains apo B)
What is the function of LDL?
- the MOST CHOLESTEROL RICH of all lipoproteins
- product of VLDL & IDL metabolism
- 40 - 60% of all LDL are cleared by the liver by apo B & hepatic LDL receptors
- hepatic LDL receptors are down-regulated by increased dietary saturated fat intake & chylomicrons
- hepatic LDL receptors are up-regulated by decreased dietary fat & cholesterol
What is the function of HDL?
- synthesized in enterocytes & liver
- obtains cholesterol from peripheral tissues & other lipoproteins & transport it to the liver for clearance
- ANTI-ATHEROGENIC EFFECT
What is lipoprotein a?
- an LDL that contains apoprotein a
- inhibits fibrinolysis -> promotes thrombus formation
- directly promotes atherosclerosis
What is the function of PCSK9?
- regulates levels of LDL receptors
- binds to LDL receptors -> stops LDL from being removed from the blood -> increased LDL levels
- gain of function mutations -> reduce LDL receptors in the liver -> high levels of plasma LDL -> increased susceptibility to coronary heart disease
- loss of function mutations -> higher levels of LDL receptors -> lower plasma LDL -> protection from coronary heart disease
What is the genetic classification of dyslipidemias?
TYPE I - chylomicronemia syndrome
- LPL or ApoCII genetic defect
- Triglyceride levels -> 1000 - 10 000
- eruptive xanthomas & pancreatitis
TYPE IIa - increased LDL
- polygenic hypercholesterolemia: LDL-C > 130
- > increased risk of ASCVD
- heterogenous familial hypercholesterolemia: LDL-C > 190
- homogenous familial hypercholesterolemia: LDL-C > 350
- > increased risk of premature ASCVD
- > tendon xanthoma
TYPE IV - increased triglycerides & VLDL
- familial hypertriglyceridemia
- TG > 150
What levels of triglyceride could lead to acute pancreatitis?
> 500mg/dL (>5.65 mmol/L)
What are the signs & symptoms of high LDL levels?
- corneal arcus
- xanthelasma
- tendon xanthomas -> at achilles, elbow, knee tendons, & over metacarpophalageal joints
- tuberous xanthomas -> painless, firm nodules located over extensor surfaces of joints
- eruptive xanthomas -> over the trunk, back, elbows, buttocks, knees, hands, & feet
- severe elevations of TGs can give a lactescent (milky) appearance to blood plasma
What should be done to diagnose dyslipidemia?
- serum lipid profile (total cholesterol, TG, HDL & calculated LDL) -> measured while fasting for 12 hours for maximum accuracy
- non-HDL cholesterol (TC - HDL cholesterol) can be measured without fasting -> predictive of CAD risk (N < 130)
- TC/HDL ratio -> predicts risk of ischemic heart disease (N < 5)
- Lp(a) is checked in patients with premature atherosclerotic cardiovascular disease but normal or near normal lipid levels
primary lipid disorders should be suspected in which patients?
- physical signs of dyslipidemia
- premature atherosclerotic disease (< 60 years)
- family history of atherosclerotic disease
- serum cholesterol > 240 mg/dL
When should screening for dyslipidemia begin?
at 20 years & every 5 years after
What is the goal of treatment?
Primary prevention of ASCVD
Secondary prevention for all patient with ASCVD
What is used for treatment go high levels of LDL?
- Diet:
- Exercise
- STATINS (treatment of choice)
- Cholesterol absorption inhibitors -> EZETIMIBE
- PCSK9 monoclonal antibodies
Statins are indicated in which patients?
- history of ASCVD
- adult with LDL > 190mg
- age 40 - 75 & LDL is 70 - 189 with diabetes
- age 40 - 75 & LDL is 70 - 189 with estimated 10-year risk of ASCVD >7.5%
What is the function of Statins?
- inhibits hydroxymethylglutaryl CoA reductase -> up regulation of LDL hepatic receptors
- reduces LDL levels by 60%
- produces small increases in HDL & decreases in TGs
goals
- lower LDL > 50%
- keep LDL < 100 in low risk patients (ASCVD risk < 20%)
- keep LDL < 70 in high risk patients (ASCVD risk >20%)
- additional therapy if goals are not reached
What are the side effects & contraindications for statins?
- liver enzyme elevations
- myositis
- rhabdomyolysis
contraindicated in pregnancy
What is the function of Ezetimibe?
inhibits intestinal absorption of cholesterol
- lowers LDL by 15 - 20%
- could be used as mono-therapy in patients intolerant to statins
What is the function of PCSK9 monoclonal antibodies?
- prevents PCSK9 from attaching to LDL receptors
- subcutaneous injections once or twice per month
- LDL cholesterol lowered by 40 - 70%
How are elevated level of triglycerides treated?
- diet & exercise
FIBRATES (of choice)
- reduce TGs by 50%
- stimulate LPL -> increased fatty acid oxidation in the liver & muscle, decreased hepatic VLDL synthesis
- increases HDL by 20%
- CAUSES MUSCLE TOXICITY with statins
OMEGA 3 FATTY ACIDS (of choice)
indicated for
- triglyceride levels > 150 in diabetic patients
- > 500 in non diabetic patients
STATINS
- high TGs < 500 IF LDL cholesterol elevations are also present
