178 DISORDERS OF LIPID METABOLISM
Harrison’s Manual of Medicine
DISORDERS OF LIPID METABOLISM
Hypercholesterolemia and Hypertriglyceridemia
Prevention of the Complications of Atherosclerosis
More than half of the coronary artery disease (CAD) in the U.S. is attributable to abnormalities in the levels and metabolism of plasma lipids and lipoproteins. Hyperlipoproteinemia may be characterized by hypercholesterolemia, isolated hypertriglyceridemia, or both (Table 178-1). Diabetes mellitus, ethanol consumption, oral contraceptives, renal disease, hepatic disease, and hypothyroidism can cause secondary hyperlipoproteinemias or worsen underlying hyperlipoproteinemic states.
Table 178-1 Characteristics of Common Hyperlipidemias
Standard lipoprotein analysis assesses total cholesterol, HDL, and triglycerides with a calculation of LDL levels using the equation: LDL = total cholesterol – HDL – triglycerides/5. The LDL cholesterol concentration can be estimated using this method only if triglycerides are <4.5 mmol/L (< 400 mg/ dL). Both LDL and HDL cholesterol levels are temporarily decreased for several weeks after myocardial infarction or acute inflammatory states but can be accurately measured if blood is obtained within 8 h of the event.
Elevated levels of fasting plasma total cholesterol [>5.2 mmol/L (>200 mg/ dL)] in the presence of normal levels of triglycerides are almost always associated with increased concentrations of plasma LDL cholesterol. A rare individual with markedly elevated HDL cholesterol may also have increased plasma total cholesterol levels. Elevations of LDL cholesterol can result from single- gene defects, polygenic disorders, or from the secondary effects of other disease states.
FAMILIAL HYPERCHOLESTEROLEMIA (FH) FH is a codominant genetic disorder that is due to mutations in the gene for the LDL receptor. Plasma LDL levels are elevated at birth and remain so throughout life. In untreated heterozygous adults, total cholesterol levels range from 7.1–12.9 mmol/ L (275–500 mg/dL). Plasma triglyceride levels are typically normal, and HDL cholesterol levels are normal or reduced. Heterozygotes, especially men, are prone to accelerated atherosclerosis and premature CAD. Tendon xanthomas (most commonly of the Achilles tendons and the extensor tendons of the knuckles), tuberous xanthomas (softer, painless nodules on the ankles and buttocks), and xanthelasmas (deposits on the eyelids) are common.
FAMILIAL DEFECTIVE APO B This autosomal dominant disorder impairs the synthesis and/or function of apo B100, thereby reducing the affinity for the LDL receptor, slowing LDL catabolism, and causing a phenocopy of FH.
POLYGENIC HYPERCHOLESTEROLEMIA Most moderate hypercholesterolemia [<9.1 mmol/L (<350 mg/dL)] arises from an interaction of multiple genetic defects and environmental factors such as diet, age, and exercise. Plasma HDL and triglyceride levels are normal, and xanthomas are not present.
An algorithm for the evaluation and treatment of hypercholesterolemia is displayed in Fig. 178-1. Therapy for all of these disorders includes restriction of dietary cholesterol, HMG-CoA reductase inhibitors, and bile acid–binding resins (Table 178-2).
FIGURE 178-1. Algorithms for the evaluation and treatment of hypercholesterolemia (A) and hypertriglyceridemia (B). Statin, HMG-CoA reductase inhibitor; Chol, cholesterol; HDL, high- density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride; TSH, thyroid-stimulating hormone; CHD, coronary heart disease.
Table 178-2 Hypolipidemic Drugs
The diagnosis of hypertriglyceridemia is made by measuring plasma lipid levels after an overnight fast. Hypertriglyceridemia in adults is defined as a triglyceride level >2.3 mmol/L (>200 mg/dL). An isolated increase in plasma triglycerides indicates that chylomicrons and/or very low density lipoprotein (VLDL) are increased. Plasma is usually clear when triglyceride levels are <4.5 mmol/L (<400 mg/dL) and cloudy when levels are higher due to VLDL (and/or chylomicron) particles becoming large enough to scatter light. When chylomicrons are present, a creamy layer floats to the top of plasma after refrigeration for several hours. Tendon xanthomas and xanthelasmas do not occur with isolated hypertriglyceridemia, but eruptive xanthomas (small orange-red papules) can appear on the trunk and extremities and lipemia retinalis (orange-yellow retinal vessels) may be seen when the triglyceride levels are >11.3 mmol/L (>1000 mg/dL). Pancreatitis is associated with these high concentrations.
FAMILIAL HYPERTRIGLYCERIDEMIA In this autosomal dominant disorder, increased plasma VLDL causes plasma triglyceride concentrations to range from 2.3–5.6 mmol/L (200–500 mg/dL). Obesity, hyperglycemia, and hyperinsulinemia are characteristic, and diabetes mellitus, ethanol consumption, oral contraceptives, and hypothyroidism may exacerbate the condition. Because atherosclerosis is accelerated, vigorous attempts should be made to control all exacerbating factors, and intake of saturated fat should be severely restricted.
FAMILIAL LIPOPROTEIN LIPASE DEFICIENCY This rare autosomal recessive disorder results from the absence or deficiency of lipoprotein lipase, which in turn retards the metabolism of chylomicrons. Accumulation of chylomicrons in plasma causes recurrent bouts of pancreatitis, usually beginning in childhood. Eruptive xanthomas occur on buttocks, trunk, and extremities. The plasma is milky or creamy (lipemic). Accelerated atherosclerosis is not a feature.
FAMILIAL APO CII DEFICIENCY This rare autosomal recessive disorder is due to the absence of apo CII, an essential cofactor for lipoprotein lipase. As a result, chylomicrons and triglycerides accumulate and cause manifestations similar to those in lipoprotein lipase deficiency. Diagnosis is made by protein electrophoresis, which reveals the absence of apo CII.
An algorithm for the evaluation and treatment of hypertriglyceridemia is displayed in Fig. 178-1. All pts with hypertriglyceridemia should be placed on a fat-free diet. In those with familial hypertriglyceridemia, fibric acid derivatives should be administered if dietary measures fail.
HYPERCHOLESTEROLEMIA AND HYPERTRIGLYCERIDEMIA
Elevations of both triglycerides and cholesterol are caused by elevations in both VLDL and LDL or in VLDL remnant particles.
FAMILIAL COMBINED HYPERLIPIDEMIA (FCHL) This inherited disorder can cause different lipoprotein abnormalities in affected individuals, including hypercholesterolemia, hypertriglyceridemia, or both. Atherosclerosis is accelerated. All pts should restrict dietary cholesterol and fat and avoid alcohol and oral contraceptives. Elevated triglycerides may respond to fibric acid derivatives. An HMG-CoA reductase inhibitor plus a bile acid–binding resin may be used when cholesterol is elevated. Combinations of reductase inhibitors and niacin or fibric acid derivatives is associated with a 2–3% risk of myositis.
DYSBETALIPOPROTEINEMIA This rare disorder is associated with homozygosity for apo E2, but the development of disease requires additional environmental and/or genetic factors. Plasma cholesterol and triglycerides are increased due to accumulation of VLDL and chylomicron remnant particles. Severe atherosclerosis involves the coronary arteries, internal carotids, and the abdominal aorta and causes premature MI, intermittant claudication, and gangrene. Cutaneous xanthomas are distinctive, in the form of xanthoma striata palmaris and tuberous or tuberoeruptive xanthomas. Triglycerides and cholesterol are both elevated. Diagnosis is established by finding a broad beta band on lipoprotein electrophoresis. If present, hypothyroidism and diabetes mellitus should be treated, and fibric acid derivatives may be necessary.
PREVENTION OF THE COMPLICATIONS OF ATHEROSCLEROSIS
The National Cholesterol Education Program guidelines (Fig. 178-1) are based on plasma LDL levels and estimations of other risk factors. The goal in pts with the highest risk (secondary prevention after MI, primary treatment of known atherosclerotic heart disease, and diabetes mellitus) is to lower LDL cholesterol to <2.6 mmol/L (<100 mg/dL). The goal is an LDL cholesterol <3.4 mmol/ L (<130 mg/dL) in pts with two or more risk factors for atherosclerotic heart disease. Risk factors include (1) men >age 45, women > age 55 or after menopause; (2) family history of early CAD (< 55 years in a male parent or sibling and <65 years in a female parent or sibling); (3) hypertension (even if it is controlled with medications); (4) cigarette smoking (>10 cigarettes/day); (5) diabetes mellitus; or (6) HDL cholesterol <0.9 mmol/L (<35 mg/dL). Note that one risk factor may be subtracted if HDL cholesterol >1.6 mmol/L (>60 mg/ dL). Therapy begins with a low-fat diet, but pharmacologic intervention is often required (Table 178-2).
For a more detailed discussion, see Ginsberg HN, Goldberg IJ: Disorders of Lipoprotein Metabolism, Chap. 344, p. 2245, in HPIM-15.