High-density lipoprotein

Jake P, a 29-year-old construction worker, makes an appointment to see Dr. Cush. Jake complains of hard, elevated swellings around his Achilles tendon that seem to rub constantly against his construction boots. Jake had been hesitant to see the doctor (his last appointment was 10 years ago), but he remembers that his dad, who died at age 42 of a heart attack, had similar swellings. On examination, Dr. Cush recognizes the Achilles swellings as xanthomas (lipid deposits); the physical exam is otherwise within normal limits. Jake comments that his diet is quite “fatty,” including three to four donuts each day and frequent hamburgers. Dr. Cush explains that the xanthomas on Jake’s feet are the result of cholesteryl ester deposition, probably from high cholesterol levels in his blood. Dr. Cush orders a fasting plasma cholesterol level and recommends that Jake reduce his intake of foods high in saturated fat and cholesterol and increase his intake of poultry, fish, whole cereal grains, fruits, and vegetables. Jake has gained about 15 pounds since he was 19 and has a small paunch. Dr. Cush recommends regular exercise and weight loss. Results of the blood test reveal a total plasma cholesterol concentration of$$315\mathrm{mg}/\mathrm{dL}$$(normal, <200), with elevated low-density lipoprotein cholesterol of$$250\mathrm{mg}/\mathrm{dL}$$(desirable,$$<100$$), low HDL of$$35\mathrm{mg}/\mathrm{dL}$$(normal, 35 to 100 ), and normal concentrations of triglycerides and very-low-density lipoprotein . Based on these test results, his age, the Achilles heel xanthomas, and a positive family history for an early myocardial infarction, Dr. Cush tells Jake that he likely has an inherited disorder of cholesterol metabolism known as heterozygous familial hypercholesterolemia. This disease puts Jake at very high risk for early atherosclerosis and myocardial infarction. The low high-density lipoprotein cholesterol level also contributes to his increased risk of cardiovascular disease. Dr. Cush tells Jake that aggressive lowering of cholesterol levels can ameliorate many of the disease sequelae. In addition to the dietary changes, Dr. Cush prescribes a statin to help reduce Jake’s cholesterol. A starting dose of a statin reduces his low-density lipoprotein by$$45\%$$to$$138\mathrm{mg}/\mathrm{dL}$$, while his high-density lipoprotein increases slightly. Dr. Cush then increases the statin dose, and this produces an additional$$12\%$$reduction in low-density lipoprotein. Because low-density lipoprotein has still not reached$$<100\mathrm{mg}/\mathrm{dL}$$, and$$\mathrm{HDL}$$remains low, Dr. Cush adds the cholesterol absorption inhibitor ezetimibe as well as extended-release niacin. After these modifications, Jake’s low-density lipoprotein drops below 100 , and his HDL increases to$$45\mathrm{mg}/\mathrm{dL}$$. Jake experiences cutaneous lushing during the first few months of niacin treatment, ut after that period, he has only occasional flushing bisodes.

1. How do high cholesterol levels predispose to cardiovascular disease?

2. What is the etiology of familial hypercholesterolemia?

3. How do statins, ezetimibe, niacin, lomitapide, mipomersen, and Proprotein convertase subtilisin/kexin type 9(PCSK 9) inhibitors act pharmacologically?

4. What are the major adverse effects of concomitant statin and niacin therapy about which Jake should be aware?