Hyperlipidemia genetic disorders

Hyperlipidemia is a major cause of atherosclerosis and atherosclerosis-associated conditions, such as coronary heart disease (CHD), ischemic cerebrovascular disease, and peripheral vascular disease. These conditions account for most morbidity and mortality among middle-aged and older adults. DysUpidemias, including hyperhpidemia (hypercholesterolemia) and low levels of high-density-hpoprotein cholesterol (HDL-C), are major causes of increased atherogenesis both genetic disorders and lifestyle (sedentary behavior and diets high in calories, saturated fat, and cholesterol) contribute to the dysUpidemias seen in developed countries. 

The vascular defense mechanisms associated with most genetic disorders are nonspecific. These mechanisms can aggravate the development of atherosclerotic plaques at predisposition sites. Other nonspecific mechanisms lead to peripheral forms of atherosclerosis by causing a thickening of the vascular wall throughout the arterial system. This peripheral form of vascular disease is characteristic for angiopathies associated with Type 111 hyperlipidemia, diabetes, and many other inherited metabolic diseases. 

Primary or genetic lipoprotein disorders are classified into six categories for the phenotypic description of dyslipidemia. The types and corresponding lipoprotein elevations include the following I (chylomicrons), Ha (LDL), lib (LDL + very low density lipoprotein, or VLDL), III (intermediate-density lipoprotein), IV (VLDL), and V (VLDL + chylomicrons). Secondary forms of hyperlipidemia also exist, and several drug classes may elevate lipid levels... 

Many patients treated for primary hyperlipidemia have no symptoms or clinical manifestations of a genetic lipid disorder (e.g., xanthomas), so monitoring is solely laboratory based. 

Lipoprotein disorders are detected by measuring lipids in serum after a 10-hour fast. Risk of heart disease increases with concentrations of the atherogenic lipoproteins, is inversely related to levels of HDL, and is modified by other risk factors (Table 35-1). Evidence from clinical trials suggests that LDL cholesterol levels of 60 mg/dL may be optimal for patients with coronary disease. Ideally, triglycerides should be below 120 mg/dL. Differentiation of the disorders requires identification of the lipoproteins involved (Table 35-2). Diagnosis of a primary disorder usually requires further clinical and genetic data as well as ruling out secondary hyperlipidemias (Table 35-3). 

Goldstein L, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. II, Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperhpidemia. J Clm Invest 1973 52 1544-68. 

Accumulating evidence for important functions of enzymes involved in lipid synthesis and its control has been obtained through targeted disruption in rodent models of the corresponding genes (Fig. 11.2). However, direct links between abnormal expression or genetic variants and human disorders, such as obesity, hyperlipidemia, insulin resistance, and NIDDM await further clarification. Glycerol-... 

In addition to diabetes mellitus, Mr. Applebod has a hyperlipidemia (high blood lipid level—elevated cholesterol and triacylglycerols), another risk factor for cardiovascular disease. A genetic basis for Mr. Applebod s disorder is inferred from a positive family history of hypercholesterolemia and premature coronary artery disease in a brother. 

In a large population study Goldstein et al. discussed three frequent lipid disorders, familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyperlipidemia. Ascorbate deficiency unmasks these underlying genetic defects and leads to an increased plasma concentration of lipids (e.g. cholesterol, triglycerides) and Hpoproteins (e.g. LDL, VLDL) as well as to their deposition in the impaired vascular wall. As with Lp(a), this deposition is a defense measure counteracting the increased permeability. It should, however, be noted that the deposition of lipoproteins other than Lp(a) is a less S[>ecific defense mechanism and fre-... 

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