Chapter 117

## Abstract

Abstract

1. Three inherited disorders have been described in which chylomicrons accumulate in plasma: familial lipoprotein lipase deficiency (MIM 238600), familial apolipoprotein C-II deficiency (MIM 207750), and familial inhibitor to lipoprotein lipase (MIM 118830). Chylomicronemia can also occur in individuals with common familial forms of hypertriglyceridemia who also have an acquired cause of hypertriglyceridemia such as untreated diabetes mellitus, estrogen or antihypertensive drug therapy, or alcohol use.

2. Familial lipoprotein lipase deficiency is a rare autosomal recessive disorder characterized by absence of LPL activity and a massive accumulation of chylomicrons in plasma and a corresponding increase of plasma triglyceride concentration. The concentration of VLDL may be fairly normal. The disease is usually detected in childhood based on repeated episodes of abdominal pain, recurrent attacks of pancreatitis, eruptive cutaneous xanthomatosis, and hepatosplenomegaly. The severity of symptoms is proportional to the degree of chylomicronemia, which, in turn, is dependent on dietary fat intake. Over 60 structural defects in the lipoprotein lipase gene have been demonstrated to cause deficiency of the activity of lipoprotein lipase. This lipolytic enzyme is present on vascular endothelial cells of extrahepatic tissues and is essential for hydrolysis of chylomicron and VLDL triglycerides to provide free fatty acids to tissues for energy. The enzyme is released into the blood by heparin and can be assayed in postheparin plasma or directly in biopsies of adipose tissue. Diagnosis is based on low or absent enzyme activity in an assay system that excludes other lipolytic enzymes and contains normal plasma or apoprotein C-II, a necessary cofactor of the enzyme; diagnosis is confirmed by demonstration of a defect in the structure of the lipoprotein lipase gene. The disorder is probably not associated with atherosclerotic vascular disease, but recurrent pancreatitis may threaten the patient's life. Restriction of dietary fat to 20 g/day or less is usually sufficient to reduce plasma triglyceride levels and keep the patient free of symptoms. Available lipid-lowering drugs are not effective. Heterozygotes exhibit a 50 percent decrease of lipoprotein lipase in postheparin plasma but have normal or only slightly abnormal plasma lipid levels.

3. Familial apolipoprotein C-II deficiency is a very rare autosomal recessive disorder in which apo C-II is absent, the clearance of chylomicrons from the blood is greatly impaired, and triglycerides accumulate in plasma. VLDL may also be elevated. The disorder is diagnosed in children or adults based on recurrent attacks of pancreatitis or by detection of milky fasting plasma on screening. Over 10 structural defects in the apolipoprotein C-II gene have been associated with absence of or production of defective apolipoprotein C-II, a cofactor for lipoprotein lipase. Absence of this protein creates a functional enzyme deficiency with accumulation of the substrate lipoproteins in the blood. The diagnosis is based on assay of lipoprotein lipase activity in postheparin plasma and on gel electrophoresis of VLDL apolipoproteins. Transfusion of normal plasma into the patient is followed by a dramatic fall in the plasma triglyceride level. Treatment involves use of a moderate fat-restricted diet throughout life. In the case of severe pancreatitis, transfusion of normal plasma may be helpful. Heterozygotes have a 50 percent reduction in apo C-II levels, but normal lipid levels.

4. Familial hepatic lipase deficiency (MIM 151670) is a rare autosomal recessive disorder characterized by moderate hypertriglyceridemia and premature coronary artery disease. Low-density and high-density lipoproteins are very triglyceride-rich with an accumulation of apo B containing lipoproteins that range from small, very low-density lipoproteins to buoyant LDL. These VLDL have β motility on agarose gel. Twelve individuals in six families have been reported with hepatic lipase deficiency; most have onset of clinical atherosclerosis in their forties and fifties. Treatment consists of diet and the use of lipid-lowering drugs. Heterozygotes and individuals with a fairly common promoter variant have reduced hepatic lipase activity. Men have higher hepatic lipase activity than women, particularly centrally obese men. High hepatic lipase activity is associated with accumulation of small dense LDL and decreases in HDL2-C, changes that increase risk for early atherosclerosis.

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