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INTRODUCTION

Disorders of lipid and lipoprotein metabolism are characterized by dyslipidemia, which is defined as either elevated or low levels of 1 or more of the major lipoprotein classes: chylomicrons, very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). Dyslipidemia can result from a mutation in a single gene that plays an important role in lipoprotein metabolism. However, more commonly, dyslipidemia reflects the influence of multiple genes. Environmental influences such as excessive dietary intake of fat and calories and limited physical activity, particularly when associated with obesity, can also contribute significantly to dyslipidemia. Much of what has been learned about dyslipidemia derives from studies of rare single-gene disorders. This chapter presents a theoretical and practical approach to the diagnosis and treatment of dyslipidemia in infants, children, and adolescents. The major clinical complication of dyslipidemia is a predilection to atherosclerosis starting early in life and leading to cardiovascular disease (CVD) in adulthood. At the extremes of dyslipidemia, where inherited disorders of lipid and lipoprotein metabolism are more likely to occur, premature CVD is more frequent and can be accompanied by deposition of lipid in various tissues. Conversely, certain single-gene loss-of-function mutations may also protect the individual from CVD, providing insights into novel therapies. Children with profound hypertriglyceridemia are at high risk of pancreatitis.

BACKGROUND

A number of clinical, epidemiologic, metabolic, genetic, and randomized clinical trials strongly support the tenet that the origins of atherosclerosis and CVD risk factors begin in childhood and adolescence and that treatment should begin early in life. Several longitudinal pathologic studies from the general population have found that early atherosclerotic lesions of fatty streaks and fibrous plaques in children, adolescents, and young adults who died from accidental causes are significantly related to higher antecedent levels of total cholesterol (TC) and LDL cholesterol (LDL-C); to lower levels of HDL cholesterol (HDL-C); and to other CVD risk factors such as obesity, higher blood pressure, and cigarette smoking. The effect of these risk factors on coronary lesion severity is multiplicative rather than additive.

Four major prospective population studies from the Coronary Artery Risk Development in Young Adults (CARDIA) and the Special Turku Coronary Risk Factor Intervention Project (STRIP) trials showed that CVD risk factors in children and adolescents, particularly LDL-C and obesity, predicted clinical manifestations of atherosclerosis in young adults, as judged by coronary artery calcium, carotid intima-medial thickness (IMT), or brachial flow-mediated dilatation.

Hyperlipidemias have historically been classified by the type of lipoprotein particle that is elevated or reduced in those thought to have primary dyslipidemia, also known as the Fredrickson classification. Studies have also been performed in high-risk youth who were selected because 1 parent had CVD or because they have inherited a known metabolic disorder of lipoprotein metabolism that produces premature CVD. Half of the children of men who had CVD before age 50 had 1 of 7 dyslipidemic profiles: elevated LDL-C alone (type IIa) or ...

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