George Lyman Duff Memorial Lecture. Multifactorial etiology of hypercholesterolemia. Implications for prevention of coronary heart disease.

This review underlines the concept that multiple factors are responsible for hypercholesterolemia in the American public. Dietary factors (cholesterol, saturated fatty acids, and obesity) clearly raise the cholesterol level, and they are important causes of borderline-high cholesterol. Still, the unexplained decline of LDL receptor activity with aging contributes importantly to borderline-high levels and cannot be ignored. The loss of estrogen-stimulated LDL receptor synthesis after menopause is an important contributor to elevated cholesterol in postmenopausal women. In addition, several genetic defects inherited singly appear to be responsible for moderate hypercholesterolemia. Some of these defects may represent genetic hypersensitivity to diet, and dietary therapy alone may provide adequate cholesterol lowering. Other defects impart resistance to dietary control, and use of a single cholesterol-lowering drug may be required. With the exception of heterozygous FH, most cases of severe hypercholesterolemia appear to be the result of the coexistence of at least two defects in LDL metabolism, and as a rule, they can be treated successfully only by using cholesterol-lowering drugs in combination.