Porth's Essentials of Pathophysiology, 4e

407

Disorders of Blood Flow and Blood Pressure

C h a p t e r 1 8

A

B

FIGURE 18-5. Xanthomas in the skin and tendons (A, C, D) . Arcus lipoides represents the deposition of lipids in the peripheral cornea (B). (From Gotlieb AI, Lui A. Blood vessels. In: Rubin R, Strayer DS, eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams &Wilkins; 2012:459.)

C

D

Several factors, including nutrition, genetics, comor- bid conditions, medications, and metabolic diseases, can raise blood lipid levels. Most cases of elevated levels of cholesterol are probably multifactorial. Hypercholesterolemia can be divided into two types: primary or secondary. In primary hypercholesteremia elevated cholesterol levels develop independent of other causes. Secondary hypercholesterolemia is associated with other health problems and behaviors. Many types of primary hypercholesterolemia have a genetic basis. There may be a defective synthesis of the apolipoproteins, a lack of lipoprotein receptors, defective receptors, or defects in the handling of cho- lesterol in the cell that are genetically determined. 1,2,9 For example, the LDL receptor is deficient or defec- tive in the genetic disorder known as familial hyper- cholesterolemia (type 2A). This autosomal dominant type of hyperlipidemia results from a mutation in the gene specifying the receptor for LDL. It is one of the most common of all Mendelian disorders, with hetero- zygotes having one defective gene representing about 1 in 500 persons in the general population. 1,2,9 Because most of the circulating cholesterol is removed by recep- tor-dependent mechanisms, blood cholesterol levels are markedly elevated in persons with this disorder. Plasma LDL levels in heterozygotes range between 250 and 500 mg/dL, whereas in homozygotes LDL cholesterol levels may rise to 1000 mg/dL. Although heterozygotes commonly have an elevated cholesterol level from birth, the disorder does not typically manifest until adult life, when xanthomas (i.e., cholesterol deposits) develop along the tendons, and atherosclerosis appears (Fig. 18-5). Myocardial infarction before 40 years of age is common. Homozygotes are much more severely affected; they have cutaneous xanthomas in childhood and may experience myocardial infarction by as early as 1 to 2 years of age. Secondary causes of hypercholesterolemia include obesity with high-calorie intake, sedentary lifestyle, and

diabetes mellitus. 9,11 High-calorie diets increase the pro- duction of VLDL, with triglyceride elevation and high conversion of VLDL to LDL. Excess ingestion of cho- lesterol may reduce the formation of LDL receptors and thereby decrease LDL removal from the blood. Diets that are high in saturated fats increase cholesterol syn- thesis and suppress LDL receptor activity. A sedentary lifestyle influences interactions among lipids and lipo- proteins. Diabetes mellitus and the metabolic syndrome are associated with elevated triglycerides, low HDL, and minimal or modest elevation of LDL. Other systemic disorders that can elevate lipids include hypothyroidism, the nephrotic syndrome, and obstructive liver disease. Medications such as beta-blockers, estrogens, and prote- ase inhibitors (used in the treatment of human immuno- deficiency virus [HIV] infection) can also increase lipid levels. Diagnosis of Hyperlipidemia. Diagnosis of hyperlip- idemia depends on a person’s complete lipid profile (total cholesterol, LDL, HDL, and triglyceride levels) after an overnight fast. 9,11 Most clinical laboratories measure the total serum cholesterol, total triglycerides, and the amount of cholesterol carried in the HDL fraction. The LDL is then estimated by subtracting the HDL from the total serum cholesterol and the triglycerides divided by5 * (i.e.,LDL[mg/dL]=totalcholesterol[mg/dL]−HDL [mg/dL] − triglycerides [mg/dL]/5). The relationship between the different lipid fractions can then be used as a means for determining an individual’s risk for developing coronary heart disease and other athero- sclerosis-related diseases. Cholesterol is carried in the blood as VLDL, LDL, and HDL, with the total serum cholesterol being equal to the sum of these three com- ponents. 11,12 Thus, total serum cholesterol levels may

*When using SI units (expressed in mmol/L), the triglycerides are divided by 2.2.