What is hyperlipidemia? |

Causes and Symptoms

Although elevated triglyceride levels have been implicated in clinical ischemic diseases, most investigators believe that cholesterol-rich
lipids are a more significant risk factor. Although measurements of bothcholesterol and triglyceride levels have been used to predict coronary disease, studies suggest that the determination of the alpha-lipoprotein/beta-lipoprotein ratio is a more reliable predictor. Because the alpha-lipoprotein has a higher density than the beta-lipoprotein, they are more often designated as high-density lipoprotein (HDL) and low-density lipoprotein (LDL), respectively. HDL is often referred to as “good cholesterol,” and LDL is referred to as “bad cholesterol.” The latter is implicated in the development of atherosclerosis.

Atherosclerosis is a disease that begins in the innermost lining of the arterial wall. Its lesions occur predominantly at arterial forks and branch openings, but they can also occur at sites where there is injury to the arterial lining. The initial lesion usually appears as fatty streaks or spots, which have been detected even at birth. With passing years, more of these lesions appear, and they may develop into elevated plaques that obstruct the flow of blood in the artery. The lesions are rich in cholesterol derived from beta-lipoproteins in the plasma. In addition to elevated blood lipids, other risk factors associated with atherosclerosis include hypertension, faulty arterial structure, obesity, smoking, and stress.

Treatment and Therapy

The treatment of hyperlipidemia involves both dietary and drug therapies. Although studies in nonhuman primates indicate that the reduction of hyperlipidemia results in decreased morbidity and mortality rates from arterial vascular disease, studies in humans are less conclusive. Initial treatment involves restricting the dietary intake of cholesterol and saturated fat. Drug therapy is instituted when further lowering of the serum
lipids is desired. Among the drugs that have been used as antihyperlipidemic agents are lovastatin and its analogues, clofibrate and its analogues (particularly gemfibrozil), nicotinic acid, D-thyroxine, cholestyramine, probucol, and heparin. A simplified diagram of the endogenous biosynthesis and biotransformation of cholesterol is given below.

acetate → C acetyl SCoA → HMGCoA → MVA → squalene → desmosterol → cholesterol → bile acids

Lovastatin blocks the synthesis of cholesterol by inhibiting the enzyme (HMGCoA reductase) that catalyzes the conversion of beta-hydroxy-beta-methyl glutaryl coenzyme A (HMGCoA) to mevalonic acid (MVA), the regulatory step in the biosynthesis of cholesterol. Both lovastatin and MVA are beta, delta-dihydroxy acids, but lovastatin has a much more lipophilic (fat-soluble) group attached to it. Clofibrate and gemfibrozil block the synthesis of cholesterol prior to the HMGCoA stage. For this reason, they are likely to inhibit triglyceride formation as well. Nicotinic acid inhibits the synthesis of acetyl coenzyme A (acetyl SCoA) and thus would be expected to block the synthesis of both cholesterol and the triglycerides. To be effective in lowering the serum level of lipids, nicotinic acid must be taken in large amounts, which often produces an unpleasant flushing sensation in the patient. A way to inhibit the synthesis of cholesterol at the post-MVA stages has also been sought. Agents such as triparanol, which inhibit biosynthesis near the end of the synthetic sequence, have been developed. Although they are effective in lowering serum cholesterol, they had to be withdrawn from clinical use because of their adverse side effects on the muscles and eyes. Moreover, the penultimate product in the biosynthesis of cholesterol proved to be atherogenic.

D-thyroxine promotes the metabolism of cholesterol in the liver, transforming it into the more hydrophilic (water-soluble) bile acids, thereby facilitating its elimination from the body. An approach to reducing the serum level of cholesterol by a process involving the sequestering of the bile acids utilizes the resin cholestyramine as the sequestrant. The sequestered bile acids cannot be reabsorbed into the enterohepatic system and are eliminated in the feces. Consequently, more cholesterol is oxidized to the bile acids, resulting in the reduction of the serum level of cholesterol. Unfortunately, a large quantity of cholestyramine is required. Sequestration of cholesterol with beta-sitosterol prevents both the absorption of dietary cholesterol and the reabsorption of endogenous cholesterol in the intestines. Here, too, a large quantity of the sequestrant needs to be administered.

Probucol is an antioxidant. Because, structurally, it is a sulfur analogue of a hindered hydroquinone, it acts as a free radical scavenger. Evidence suggests that the antihyperlipidemic effect of probucol is attributable to its ability to inhibit the oxygenation of LDL. The oxygenated LDL is believed to be the atherogenic form of LDL. Heparin promotes the hydrolysis of triglycerides as it activates lipoprotein lipase, thereby reducing lipidemia. Because of its potent anticoagulant properties, however, its use in therapy must be closely monitored. Cholesterol that is present in atherosclerotic plaques is acylated, generally by the more saturated fatty acids. The enzyme catalyzing the acylation process is acyl-CoA cholesterol acyl transferase (ACAT). The development of regulators of ACAT and the desirability of reducing the dietary intake of saturated fatty acids are based on this rationale.

Cholesterol within the cell is able to inhibit further synthesis of cholesterol by a feedback mechanism. Cholesterol that is associated with LDL is transported into the hepatic cell by means of the LDL receptor on the surface of the cell. In individuals who are afflicted with familial hypercholesterolemia, an inherited disorder that causes death at an early age, the gene that is responsible for the production of the LDL receptor is either absent or defective. Studies in gene therapy have shown that transplant of the normal LDL receptor gene to such an individual results in a dramatic decrease in the level of the “bad cholesterol” in the serum. Cholesterol derivatives that are oxygenated at various positions have also been found to regulate the serum level of cholesterol by either inhibiting its synthesis or promoting its catabolism.

Bibliography

Alan, Rick. "Hyperlipidemia." Health Library, September 1, 2011.

Anderson, J. W. “Diet First, Then Medication for Hypercholesterolemia.” Journal of the American Medical Association 290, 4. (July 23, 2003): 531–533.

Ball, Madeleine, and Jim Mann. Lipids and Heart Disease: A Guide for the Primary Care Team. 2d ed. New York: Oxford University Press, 1994.

Farnier, Michel, and Jean Davignon. “Current and Future Treatment of Hyperlipidemia: The Role of Statins.” American Journal of Cardiology 82, 4B. (August 27, 1998): 3J–10J.

Haffner, Steven M. “Diabetes, Hyperlipidemia, and Coronary Artery Disease.” American Journal of Cardiology 83, 9B. (May 13, 1999): 17F–21F.

Hirsch, Anita. Good Cholesterol, Bad Cholesterol: An Indispensable Guide to the Facts About Cholesterol. New York: Avalon, 2002.

McGowan, Mary P., and Jo McGowan Chopra. Fifty Ways to Lower Cholesterol. New York: McGraw-Hill, 2002.

Rifkind, Basil M., ed. Drug Treatment of Hyperlipidemia. New York: Marcel Dekker, 1991.

Safeer, Richard S., and Cynthia L. Lacivita. “Choosing Drug Therapy for Patients with Hyperlipidemia.” American Family Physician 61, 11. (June 1, 2000): 3371–3382.

Sorrentino, Matthew J., ed. Hyperlipidemia in Primary Care: A Practical Guide to Risk Reduction. New York: Springer, 2011.

Sniderman, Allan, and Paul Durrington. Fast Facts: Hyperlipidemia. 5th ed. Oxford: Health Press Limited, 2010.

Witiak, D. T., H. A. I. Newman, and D. R. Feller, eds. Antilipidemic Drugs: Medicinal, Chemical, and Biochemical Aspects. New York: Elsevier, 1991.