2Select pharmacologically compatible reductase inhibitor (see text).
genetic data as well as ruling out secondary hyperlipidemias (Table 35–2).
Phenotypes of abnormal lipoprotein distribution are described in this section. Drugs mentioned for use in these conditions are described in the following section on basic and clinical pharmacology.
TABLE 35–2 Secondary causes of hyperlipoproteinemia.
Hypertriglyceridemia is associated with increased risk of coronary disease. Chylomicrons, VLDL, and IDL are found in atherosclerotic plaques. These patients tend to have cholesterol-rich VLDL of small particle diameter and small, dense LDL. Hypertriglyceridemic patients with coronary disease or risk equivalents should be treated aggressively. Patients with triglycerides above 700 mg/dL should be treated to prevent acute pancreatitis because the LPL clearance mechanism is saturated at about this level.
Hypertriglyceridemia is an important component of the metabolic syndrome, which also includes insulin resistance, hypertension, and abdominal obesity. Reduced levels of HDL-C are usually observed due to transfer of cholesteryl esters to the triglyceride-rich lipoprotein particles. Hyperuricemia is frequently present. Insulin resistance appears to be central to this disorder. Management of these patients frequently requires, in addition to a fibrate, the use of metformin, another antidiabetic agent, or both (see Chapter 41). The severity of hypertriglyceridemia of any cause is increased in the presence of the metabolic syndrome or type 2 diabetes.
Chylomicrons are not present in the serum of normal individuals who have fasted 10 hours. The recessive traits of deficiency of LPL, its cofactor apo C-II, the LMF1 or GPIHBP1 proteins, or ANGPTL4 and Apo A-V, are usually associated with severe lipemia (2000 mg/dL of triglycerides or higher when the patient is consuming a typical American diet). These disorders might not be diagnosed until an attack of acute pancreatitis occurs. Patients may have eruptive xanthomas, hepatosplenomegaly, hypersplenism, and lipid-laden foam cells in bone marrow, liver, and spleen. The lipemia is aggravated by estrogens because they stimulate VLDL production, and pregnancy may cause marked increases in triglycerides despite strict dietary control. Although these patients have a predominant chylomicronemia, they may also have moderately elevated VLDL, presenting with a pattern called mixed lipemia (fasting chylomicronemia and elevated VLDL). Deficiency of lipolytic activity can be diagnosed after intravenous injection of heparin. A presumptive diagnosis is made by demonstrating a pronounced decrease in triglycerides 72 hours after elimination of daily dietary fat. Marked restriction of total dietary fat and abstention from alcohol are the basis of effective long-term treatment. Niacin, a fibrate, or marine omega-3 fatty acids may be of some benefit if VLDL levels are increased. Apo C-III antisense is a potential adjunct to therapy.
The primary hypertriglyceridemias probably reflect a variety of genetic determinants. Many patients have centripetal obesity with insulin resistance. Other factors, including alcohol and estrogens, that increase secretion of VLDL aggravate the lipemia. Impaired removal of triglyceride-rich lipoproteins with overproduction of VLDL can result in mixed lipemia. Eruptive xanthomas, lipemia retinalis, epigastric pain, and pancreatitis are variably present depending on the severity of the lipemia. Treatment is primarily dietary, with restriction of total fat, avoidance of alcohol and exogenous estrogens, weight reduction, exercise, and supplementation with marine omega-3 fatty acids. Most patients also require treatment with a fibrate. If insulin resistance is not present, niacin may be useful.