Polygenic Hypercholesterolemia

http://emedicine.medscape.com/article/121424-overview

Polygenic Hypercholesterolemia
Author: Elena Citkowitz, MD, PhD, FACP; Chief Editor: George T Griffing, MD more... Updated: Jun 9, 2011

Background
Polygenic hypercholesterolemia is the most common cause of elevated serum cholesterol concentrations. Low-density lipoprotein cholesterol (LDL-C) elevations are moderate (140-300 mg/dL) with serum triglyceride concentrations within the reference range. However, practically speaking, the material in this article is also relevant to patients with mixed dyslipidemias with triglyceride levels of less than 350 mg/dL. This condition is caused by a susceptible genotype aggravated by 1 or more factors, including atherogenic diet (excessive intake of saturated fat, trans fat, and, to a lesser extent, cholesterol), obesity, and sedentary lifestyle. The involved genes have yet to be discovered. Polygenic hypercholesterolemia is associated with an increased risk for coronary heart disease (CHD), as displayed in the image below.

Relative risk of coronary heart disease (CHD) mortality versus baseline serum cholesterol over time in 3 large cohorts of young men. CHA is Chicago Heart Association Detection Project in Industry, PG is Chicago Peoples Gas Company, and MRFIT is Multiple Risk Factor Intervention Trial. Adapted from Stamler, 2000.

In the United States, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) guidelines are the most commonly used reference for determining therapeutic target LDL-C levels. The guidelines were first published in 1988 (ATP I),[1] were revised in 1993 (ATP II)[2] and 2001 (ATP III),[3] with an update published in 2004.[4] The revisions and update have reflected the results of randomized placebo controlled clinical trials that have demonstrated reduced morbidity and mortality in subjects with moderate hypercholesterolemia treated with cholesterol-lowering agents, particularly (though not exclusively) statins.[5]

Pathophysiology
Low-density lipoprotein (LDL) particles are the major plasma carriers of cholesterol. Therefore, in patients with normal or minimally elevated triglyceride levels and average high-density cholesterol levels (HDL-C), the total serum cholesterol measurement can be used as a surrogate for the LDL-C level. Hypertriglyceridemia is caused by excessive numbers of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and/or chylomicron particles; and in this situation the total cholesterol level is not a reflection of the LDL-C level. For a simplified diagram of cholesterol metabolism, see the image below. Elevated LDL-C concentrations may be the consequence of elevated LDL production or decreased LDL hepatic uptake. Diets high in saturated fat, trans fat, and cholesterol cause a reduction in LDL receptors in the liver, thus retarding LDL catabolism.[6, 7]

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Polygenic Hypercholesterolemia

http://emedicine.medscape.com/article/121424-overview

Simplified diagram of cholesterol metabolism. LDL is low-density lipoprotein, VLDL is very low-density lipoprotein, IDL is intermediatedensity lipoprotein, HDL is high-density lipoprotein, and LPL is lipoprotein lipase.

The liver is responsible for high LDL-C levels: 1. overproduction of VLDL particles, which are converted to VLDL remnants or IDL particles by lipoprotein lipase and then to LDL particles by hepatic lipase; or 2. inefficient uptake by the LDL receptors. Some patients with mixed dyslipidemias (elevations of both LDL-C and triglycerides) may have polygenic hypercholesterolemia along with some other condition such as insulin resistance or obesity that causes high triglyceride values.

Epidemiology
Frequency
United States The guidelines of the American Heart Association and the NCEP Adult Treatment Panel III (ATP III) define hypercholesterolemia as a blood cholesterol concentration of greater than or equal to 240 mg/dL. Desirable cholesterol concentrations are less than 200 mg/dL. The National Health and Nutrition Examination Survey III, performed from 1988-1991, found that 26% of American adults had high blood cholesterol concentrations and 49% had desirable values. According to the NCEP ATP III guidelines, all adults aged 20 years or older should have a fasting lipid profile determined at least every 5 years to assess CHD risk. Sixty-five million American adults qualify for therapeutic lifestyle changes, while 36 million US adults need pharmacologic therapy to reach NCEP ATP III goals. International Serum cholesterol concentrations vary widely throughout the world. Generally, countries associated with low serum cholesterol concentrations (eg, Japan) have lower CHD event rates, while countries associated with very high serum cholesterol concentrations (eg, Finland) have very high CHD event rates. However, some populations with similar total cholesterol levels have very different CHD event rates, as would be expected given that other risk factors (e.g. prevalence of smoking or diabetes mellitus) also influence CHD risk. The cholesterol levels in developing countries tend to increase as western dietary habits (the MacDonald's syndrome) replace traditional diets.

Mortality/Morbidity
The primary manifestation of hypercholesterolemia is increased CHD risk.[8] Data from epidemiological studies (eg, the Multiple Risk Factor Intervention Trial and the Framingham Heart Study) show a relationship between elevated LDL-C concentrations and CHD events and CHD mortality rates. In the prestatin era, randomized clinical trials showed a clear correlation between CHD morbidity and mortality but not total mortality. The advent of the statins, medications that are more easily tolerated and substantially more powerful than older cholesterol-lowering medications, increased the likelihood of substantial LDL-C lowering (increased power). Thus, the statins showed benefits that drugs used in previous studies had not. Placebo-controlled statin trials have demonstrated not only reduced coronary morbidity and mortality in primary and secondary prevention populations, but also decreased total mortality. The causative relationship between LDL-C levels and ischemic stroke and transient ischemic attack (TIA) was suggested by decreased cerebrovascular events in several major statin trials in which stroke was a secondary endpoint. The SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study definitively showed that in patients who had suffered a recent stroke or TIA but who had no CHD, high-dose statin reduced the overall incidence of stroke and cardiovascular events despite a small, but statistically significant, increase in the incidence of hemorrhagic stroke.[9]

Race
Among adults, National Health and Nutrition Examination Survey III data (1988-1992) show more frank hypercholesterolemia among non-Hispanic white persons (19%) than Mexican Americans (15%) or non-Hispanic black persons (16%).

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Polygenic Hypercholesterolemia

http://emedicine.medscape.com/article/121424-overview

Sex
Hypercholesterolemia is more common in men younger than 55 years and in women older than 55 years.

Age
In adults, hypercholesterolemia increases with advancing age, as shown in the image below.

National Health and Nutrition Examination Survey data for hypercholesterolemia among American adults.

Contributor Information and Disclosures

Author Elena Citkowitz, MD, PhD, FACP Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael Elena Citkowitz, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Heart Association, National Lipid Association, and Sigma Xi Disclosure: Nothing to disclose. Coauthor(s) William L Isley, MD Senior Associate Consultant, Associate Professor of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic of Rochester William L Isley, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, and Phi Beta Kappa Disclosure: Nothing to disclose. Specialty Editor Board Steven R Gambert, MD, MACP Chairman, Department of Medicine, Physician-in-Chief, Sinai Hospital of Baltimore; Professor of Medicine, Program Director, Internal Medicine Program, Johns Hopkins University School of Medicine Steven R Gambert, MD, MACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American Geriatrics Society, Association of Professors of Medicine, Endocrine Society, and Gerontological Society of America Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment Yoram Shenker, MD Chief of Endocrinology Section, Veterans Affairs Medical Center of Madison; Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical Research, and Endocrine Society Disclosure: Nothing to disclose.

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Polygenic Hypercholesterolemia

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Mark Cooper, MBBS, PhD, FRACP Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University Disclosure: Nothing to disclose. Chief Editor George T Griffing, MD Professor of Medicine, St Louis University School of Medicine George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation Disclosure: Nothing to disclose.

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