Lipoprotein physiology Flashcards

Question

The "classic" risk factors are the only ones that go into the online risk estimator. But, technically, what are other risk factors for CVD?

Answer 1

There are other known but less established risk factors for CVD: * life-habit risk factors * obesity, insulin resistance, sedentary lifestyle, atherogenic diet, and psychosocial factors. * emerging risk factors: * apo B, LDL particle number, lipoprotein (a), high sensitivity C - reactive protein (hsCRP), pro-thrombotic factors, and evidence of ‘subclinical’ atherosclerosis

Answer 2

Secondary causes of increased LDL-C: *diets high in saturated and trans fat, hypothyroidism, nephrotic syndrome, obstructive liver disease and cyclosporine. *screening = HandP and send the following lab tests: serum TSH, a urine dipstick for protein and liver function tests

Answer 3

too much production, or not enough catabolism

Answer 4

a. Increased LDL-C Production: * When increases in VLDL particle number ± the triglyceride content of VLDL ensue, increases in plasma apo B are typically present. * In this setting (high VLDL and high apoB) increases in LDL-C relate to the conversion of the increased number of VLDL particles to LDL by the lipoprotein lipase reaction in tissues.

Answer 5

Familial Hypercholesterolemia (FH). * FH is an autosomal dominant disorder that is a partial (heterozygote) or complete (homozygote) absence/defectiveness of the LDL receptor. * Approximately 50% of these patients are LDL receptor-negative; the other 50% are LDL receptor-defective (defects in receptor function). * LDL-C levels are 2-3 times normal (200-300 mg/dl) in heterozygotes and 5-8 fold elevated (500-800 mg/dl) in homozygotes. * Premature death from atherosclerosis is common in both forms, occurring often before age 20 in homozygotes. *Other causes include mutations in the genes for apolipoprotein B, PCSK9 and G5G8 that mediates plant sterol absorption in the intestine.

Answer 6

Familial Hypercholesterolemia (FH). * FH is an autosomal dominant disorder that is a partial (heterozygote) or complete (homozygote) absence/defectiveness of the LDL receptor. * Approximately 50% of these patients are LDL receptor-negative; the other 50% are LDL receptor-defective (defects in receptor function). * LDL-C levels are 2-3 times normal (200-300 mg/dl) in heterozygotes and 5-8 fold elevated (500-800 mg/dl) in homozygotes. * Premature death from atherosclerosis is common in both forms, occurring often before age 20 in homozygotes.

Answer 7

•PCSK9 is an important regulator of LDL receptor degradation, because binding of PCSK9 to the LDL receptor results in degradation of the receptor, thereby preventing LDL receptor recycling. * Loss of function mutations of PCSK9 are associated with increased LDL receptor function, low LDL-C, and reduced ASCVD, * however, gain of function mutations of PCSK9 may lead to clinical FH, because PCSK9 reduces hepatic LDL receptor activity, the site of over 70% of LDL clearance.

Answer 8

• In genetic forms of LDL-C, arcus cornealis, xanthelasma and/or tendinous xanthomata can be seen on physical exam.

Answer 9

Normal fasting triglyceride levels are crudely defined as <150 mg/dl.

Answer 10

When triglyceride concentrations are >500-1000 mg/dl, the clearance of chylomicrons approaches saturation kinetics *>1000 mg/dl means a predictable pathophysiology * Consequently, the serum becomes lipemic (looks like milk), and other manifestations including pancreatitis can occur.

Answer 11

Physical manifestations of severe hypertriglyceridemia, most typically seen with more severe chylomicronemia, include * lipemia retinalis (fatty serum in the small vessels of the retina), * eruptive xanthomas (small yellowish papules on the extensor surfaces of the arms and also on the abdomen and back), and * hepatosplenomegaly (from triglyceride infiltration).

Answer 12

including thiazides, beta-blockers, glucocorticoids, protease inhibitors, oral estrogens and retinoids).

Answer 13

* poorly controlled DM * central obesity * alcohol use, * nephrotic syndrome, * renal failure, * hepatitis

Answer 14

a. Increased VLDL Production: • Increases in VLDL production are most commonly a result of insulin resistance. insulin has a profound anti-lipolysis effect, so in states of insulin resistance there is increased free FA floating back to the liver • Drugs, e.g. protease inhibitors (used to treat HIV infection), oral estrogens, nephrotic syndrome and chronic renal failure may also contribute to this pathophysiology. • Alcohol partially inhibits VLDL secretion (which can result in fatty liver), but also enhances fatty acid production from the ethanol derived carbons; in many people hypertriglyceridemia can result.

Answer 15

Decreased triglyceride is a problem with lipoprotein lipase (LPL) or its activity. • Primary defects can be a result of LPL deficiency, deficiency of apo C2 (the specific apoprotein activator of LPL), *can also be a problem with the GPI-anchoring of LPL to the endothelium • Familial Dysbetalipoproteinemia (described below) • Secondary disorders such as diabetes, alcohol and chronic renal failure can also reduce triglyceride-rich lipoprotein catabolism by decreasing LPL.

Answer 16

*essentially several hits from several angles to the pathway of LDL metabolism (Severe Hypertriglyceridemia): *Since LPL-mediated triglyceride removal is a saturable enzyme system and both chylomicrons and VLDL compete for LPL, severe hypertriglyceridemia is possible when several disorders of lipoprotein triglyceride synthesis and/or catabolism are simultaneously present and fat remains in the diet. *Patients with absolute LPL deficiency or two or more disorders of triglyceride metabolism (e.g. genetic disorder of overproduction of VLDL + an acquired disorder), may have fasting triglyceride levels that exceed 1000 mg/dl and sometimes reach levels of 30,000 mg/dl.

Answer 17

Non-HDL-C levels (total cholesterol - HDL) correlate closely with obesity, especially central or visceral obesity and are a strong predictor of ASCVD events and death. * Some studies have found this parameter to be a better predictor of mortality than LDL-C. * Elevated non-HDL-cholesterol can be associated with high levels of LDL and/or VLDL and is also commonly associated with the “metabolic dyslipidemia” seen in insulin resistant states and the metabolic syndrome. * The metabolic dyslipidemia is manifest by increased triglycerides, low HDL-C, and small dense LDL. Small dense LDL is more likely to be oxidized which may relate to atherosclerosis development.

Answer 18

• Familial Dysbetalipoproteinemia (FD or broad beta disease) * is due to disturbances in IDL and remnant catabolism. * FD is manifest by an approximately equivalent increase in both total cholesterol and triglycerides. (remnants contain a relative balance between Tg and cholesterol) * FD most often occurs due to genetic variation in Apo E, with the ApoE2 isoform conferring increased risk of abnormal triglyceride-rich lipoprotein metabolism. * This is a consequence of defective binding of apo E2 to hepatic receptors that recognize VLDL and chylomicron remnants. * Planar xanthomata, usually on the palms or soles, are characteristic of this condition. * Premature atherosclerosis is common.

Answer 19

Indications for Statin Therapy * Secondary prevention - clinical ASCVD * LDL–C >190 mg/dL, Age >21 years * Primary prevention – Diabetes: Age 40-75 years, LDL–C 70-189 mg/dL * Primary prevention - No Diabetes: ≥7.5% 10-year ASCVD risk (online calculator that plugs in the major risk factors), Age 40-75 years, LDL–C 70-189 mg/dL‡

Answer 20

*Think high intensity when you see this (50% reduction) Atorvastatin Rosuvastatin *think moderate intensity when you see this (30-50% reduction) simvistatin *think low intensity when you see these (less than 30% reduction) pravistatin lovastatan

Answer 21

``` Not recommended to use low intensity use high intensity: * ANY secondary prevention *and in primary prevention when LDL-C >190 mg/dL *when diabetes is present (period) ``` Use moderate-intensity statin: *when the 10-year ASCVD risk is ≥7.5%.

Answer 22

Although the primary mechanism of action for the statins is to inhibit the enzyme HMG CoA reductase, the primary means by which they lower LDL-C is by increasing the number of intra-hepatic LDL receptors and increasing the subsequent uptake and catabolism of circulating LDL.

Answer 23

Overall statins are very well tolerated. *The major serious adverse effects are rare and include hepatic transaminase elevation >3x normal in <0.3% and rhabdomyolysis in 0.01% of patients. *In primary care settings myopathy defined as myalgias and/or elevations in CPK occurs in ~10-20% of statin-treated patients. * There is a higher risk of these complications when a statin is combined with other lipid lowering medications such as fibrates or niacin. * Additionally, combining a statin with drugs that inhibit their metabolism, e.g. CYP3A4 inhibitors such as ketoconazole, protease inhibitors, or large consumptions of grapefruit juice can increase the risk of adverse events including myopathy. * Other conditions including chronic renal insufficiency or hypothyroidism increase the risk of myopathy with statins. *Finally, statins are also associated with a ~10% risk of new-onset type 2 diabetes. Preexisting glucose intolerance or a positive family history of diabetes predispose to this outcome. Despite new-onset diabetes, these patients also benefit from statin therapy and CVD risk reduction, and therefore if indicated a statin should still be prescribed.

Answer 24

Hardly ever, except for specific special circumstances. they just don't work as well * Thus, presently bile acid sequestrants are an add-on therapy and only appropriate to consider as monotherapy if statins are not tolerated, or during pregnancy.

Answer 25

MOA= reduce the enterohepatic circulation of bile acids. *Because bile acids are synthesized in the liver from cholesterol, bile acid sequestrants produce a reduction in the intra-hepatic pool size of cholesterol and reduce circulating LDL-C by increasing intra-hepatic LDL receptors. *Sequestrants reduce LDL-C by 10-30%. The side effects are primarily GI and include nausea, bloating and constipation.

Answer 26

(cholesterol drug) Ezetimibe lowers cholesterol by selectively inhibiting cholesterol absorption. * Because less cholesterol reaches the liver, the LDL-C lowering effect is via increases in the LDL receptor. *Like the bile acid sequestrants, ezetimibe should not be used as monotherapy in the prevention or treatment of ASCVD but the drug may be beneficial in combination with statins to further reduce CVD risk in high risk patients with inadequate lowering of LDL-C with statins. *The IMPROVE-IT Trial whereas in ezetimibe vs. placebo lowered LDL-C by ~20% in addition to simvastatin reduced major CVD events. *Ezetimibe has no side effects.

Answer 27

Although all 3 classes of cholesterol-lowering drugs work through the intra-hepatic LDL receptor, their effects are additive.

Answer 28

PCSK9 Inhibitors: lowers LDL-C by up to 60% *alirocumab and evolocumab have been approved as adjuncts to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C.

Answer 29

These are fibrates * use in secondary prevention of events when added to a statin in patients with diabetes or with existing ASCVD who are hypertriglyceridemic and have lower levels of HDL-C. * they work by Fibrates lower TG by 20-40%, and also raise HDL-C by 5-15%.

Answer 30

Fibrates lower TG by 20-40%, and also raise HDL-C by 5-15%.

Answer 31

Niacin or nicotinic acid lowers LDL-C and TG, and raises HDL-C. * evidence is shaky on the benefit though * Moreover, niacin is associated with many side effects including flushing, rash, GI distress, hepatotoxicity, myopathy, glucose intolerance, hyperuricemia and gout. . * Niacin decreases synthesis of VLDL and secondarily LDL and also increases HDL by decreasing the catabolism of apo AI. * Niacin lowers LDL-C by 5-25%, decreases TG by 15-35%, and raises HDL-C by10-30%.