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CMDT 2013

Lipid Disorders Robert B. Baron, MD, MS

For patients with known cardiovascular disease (secondary prevention), cholesterol lowering leads to a consistent reduction in total mortality and recurrent cardiovascular events in men and women and in middle-aged and older patients. Among patients without cardiovascular disease (primary prevention), the data are less conclusive, with rates of cardiovascular events, heart disease mortality, and all-cause mortality differing among studies. Nonetheless, treatment algorithms have been designed to assist clinicians in selecting patients for cholesterol-lowering therapy based on their lipid levels and their overall risk of developing cardiovascular disease.

Lipoproteins & Atherogenesis The plaques in the arterial walls of patients with atherosclerosis contain large amounts of cholesterol. The higher the level of low-density lipoproteins (LDL) cholesterol, the greater the risk of atherosclerotic heart disease; conversely, the higher the high-density lipoproteins (HDL) cholesterol, the lower the risk of coronary heart disease (CHD). This is true in men and women, in different racial and ethnic groups, and at all ages up to age 75 years. Because most cholesterol in serum is LDL, high total cholesterol levels are also associated with an increased risk of CHD. Middle-aged men whose serum cholesterol levels are in the highest quintile for age (above about 230 mg/dL or 5.95 mmol/L) have a risk of coronary death before age 65 years of about 10%; men in the lowest quintile (below about 170 mg/dL or 4.40 mmol/L) have a 3% risk. Death from CHD before age 65 years is less common in women, with equivalent risks one-third those of men. In men, each 10-mg/dL or 0.26-mmol/L increase in cholesterol (or LDL cholesterol) increases the risk of CHD by about 10%; each 5-mg/dL or 0.13-mmol/L increase in HDL reduces the risk by about 10%. The effect of HDL cholesterol is greater in women, whereas the effects of total and LDL cholesterol are smaller. There are several genetic disorders that provide insight into the pathogenesis of lipid-related diseases. Familial hypercholesterolemia, rare in the homozygous state (about one per million) is a condition in which the cell-surface receptors for the LDL molecule are absent or defective,

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resulting in unregulated synthesis of LDL. Patients with two abnormal genes (homozygotes) have extremely high ­levels—up to eight times normal—and present with atherosclerotic disease in childhood. Homozygotes may require liver transplantation to correct their severe lipid abnormalities. Those with one defective gene (heterozygotes) have LDL concentrations twice normal; persons with this condition may develop CHD in their 30s or 40s. Another rare condition is caused by an abnormality of lipoprotein lipase, the enzyme that enables peripheral tissues to take up triglyceride from chylomicrons and verylow-density lipoproteins (VLDL) particles. Patients with this condition, one cause of familial hyperchylomicronemia, have marked hypertriglyceridemia with recurrent pancreatitis and hepatosplenomegaly in childhood. Numerous other genetic abnormalities of lipid metabolism are named for the abnormality noted when serum is electrophoresed (eg, dysbetalipoproteinemia) or from combinations of lipid abnormalities in families (eg, familial combined hyperlipidemia). Thus, family members of patients with severe lipid disorders are appropriately studied. Other patients have abnormalities in the production of apoproteins, such as increased apoprotein B and its affiliated lipoproteins, LDL and VLDL; reduced apoprotein AII and its affiliated particle; or excess lipoprotein(a). Other mutations occur in lipoprotein lipase and in the gene encoding for cholesterol efflux regulatory protein. Genome-wide association studies have identified additional genetic variants responsible for differences in serum lipids.

``When to Refer • Known genetic lipid disorders. • Striking family history of hyperlipidemia or premature atherosclerosis. • Extremely high serum LDL cholesterol or triglyceride, or extremely low serum HDL cholesterol. Alwaili K et al. High-density lipoproteins and cardiovascular disease: 2010 update. Expert Rev Cardiovasc Ther. 2010 Mar;8(3):413–23. [PMID: 20222819]


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