Lipoprotein lipase deficiency

Familial lipoprotein lipase deficiency is characterized by a massive accumulation of chylomicrons and a corresponding increase in plasma triglycerides or a type I lipoprotein pattern. Presenting manifestations include repeated attacks of pancreatitis and abdominal pain, eruptive cutaneous xanthomatosis, and hepatosplenomegaly beginning in childhood. Symptom severity is proportional to dietary fat intake, and consequently to the elevation of chylomicrons. Accelerated atherosclerosis is not associated with this disease. 

Diagnosis of lipoprotein lipase deficiency is based on low or absent enzyme activity with normal human plasma or apolipoprotein C-II, a cofactor of the enzyme. 

Sandholzer, C., Feussner, G., Brunzell, J., and Utermann, G., Distribution of apolipopro-tein(a) in the plasma from patients with lipoprotein lipase deficiency and with type III hyperlipoproteinemia. J. Clin. Invest. 90, 1958-1965 (1992). 

Type I Lipoprotein lipase deficiency (triglycerides) Type lla LDL (BlOO) receptor deficiency (cholesterol)... 

Answer A. These are the clinical features of lipoprotein lipase deficiency (Type I lipopro-teinemia). LDL receptor defects would result in elevated LDLs. HMG-CoA reductase and ApoB-100 have no direct relationship to chylomicrons. ApoB-48 deficiency would result in decreased production of chylomicrons. 

Severe plasma turbidity due to hyperlipidaemia, as found in lipoprotein lipase deficiency, was shown to result in false-positive newborn screening results when dried blood spots on filter paper are used, but does not usually affect the quantitative colorimetric assay employing plasma samples (reference [21] and our own unpublished experience). 

Santer R, Gokcay G, Demirkol M, Gal A, Lukacs Z (2005) Hyperchylomicronaemia due to lipoprotein lipase deficiency as a cause of false-positive newborn screening for biotinidase deficiency. J Inherit Metab Dis 28 137-140... 

Apo C-ll activates lipoprotein lipase, which degrades the chylomicron s triacylglycerol to fatty acids and glycerol. The fatty acids that are released are stored (in the adipose) or used for energy (by the muscle). The glycerol is metabolized by the liver. Patients with a deficiency of lipoprotein lipase or apo C-ll show a dramatic accumulation of chylomicrons in the plasma (type 1 hyperlipoproteinemia, familial lipoprotein lipase deficiency, or hypertriacylglycerolemia)... 

As the lipoproteins are depleted of triacylglycerol, the particles become smaller. Some of the surface molecules (apoproteins, phospholipids) are transferred to HDL. In the rat, remnants that result from chylomicron catabolism are removed by the liver. The uptake of remnant VLDL also occurs, but much of the triacylglycerol is further degraded by lipoprotein lipase to give the intermediate-density lipoprotein (IDL). This particle is converted into LDL via the action of lipoprotein lipase and enriched in cholesteryl ester via transfer from HDL by the cholesteryl ester transfer protein. The half-life for clearance of chylomicrons from plasma of humans is 4-5 min. Patients with the inherited disease, lipoprotein lipase deficiency, clear chylomicrons from the plasma very slowly. When on a normal diet, the blood from these patients looks like tomato soup. A very-low-fat diet greatly relieves this problem. 

Watts GF, Cameron J, Henderson A, Richmond W. Lipoprotein lipase deficiency due to long-term heparinization presenting as severe hypertriglyceridaemia in pregnancy. Postgrad Med J 1991 67(794) 1062-4. 

A disorder of lipid metabolism, in which absence of lipoprotein lipase activity due to an absolute apoC-II deficiency results in marked hypertriglyceridemia (Type I phenotype), has been reviewed elsewhere (N8). There are some unexplained differences in the clinical picture and plasma lipoprotein pattern between apoC-II deficiency and primary lipoprotein lipase deficiency. In apoC-II deficiency, symptoms appear to be milder (but recurrent abdominal pain, caused apparently by acute pancreatitis, is a frequently reported symptom). Patients do not show xanthomas or hepatomegaly, and few have splenomegaly (all features of lipoprotein lipase deficiency). Diagnosis is by electrophoresis of the C apolipoproteins, and a plasma triglyceride concentration usually 1000-3000 mg/dl (N8). There may be an increase in plasma VLDL concentration, whereas in classical lipoprotein lipase deficiency plasma VLDL concentration is nearly normal (N8). 

In functional lipoprotein lipase deficiency there appears to be a normal removal rate for VLDL from the plasma (B31, F19, N7), and an unimpaired rate for the conversion of VLDL apoB to LDL apoB (N7). It may be that VLDL is hydrolyzed by hepatic triglyceride lipase (unaffected in lipoprotein lipase deficiency) (N7). Hepatic triglyceride lipase does not require apoC-II as a cofactor (E2). 

Lipoprotein lipase (EC 3.1.1.34) is an enzyme or group of enzymes which catalyze the hydrolysis of the 1(3) ester bond(s) of triacylglycerols and the 1 ester bond of phospholipids. The enzyme plays a central role in lipoprotein metabolism, being responsible in particular for the hydrolysis of chylomicron and VLDL triglycerides and the formation of remnant particles from these lipoproteins. There have been reviews of this enzyme [e.g., (N9, Ql)] and lipoprotein lipase will not be discussed in detail in this review. Familial lipoprotein lipase deficiency and related disorders of chylomicron metabolism have also been reviewed (B58, N8) and will not be discussed in detail. 

N8. Nikkila, E. A., Familial lipoprotein lipase deficiency and related disorders of chylomicron metabolism. In The Metabolic Basis of Inherited Disease 0. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, J. L. Goldstein, and M. S. Brown, eds.), 5th Ed., pp. 622-642. McGraw-Hill, New York, 1983. 

A. Familial lipoprotein lipase deficiency (Type I lipoprotein pattern on electrophoresis). Serum triglycerides become elevated with particular elevation of chylomicrons. Tliere are xanthomas, rather than atherosclerosis. Pancreatitis may result from the action of pancreatic lipase on these elevated chylomicrons, with resultant excess triglyceride breakdown in the pancreas, pancreatic injury, and release of more pancreatic lipase. (Note that the body contains different kinds of lipases. There is a pancreatic lipase, which is a digestive enzyme a lipoprotein lipase, which is an extracellular enzyme that breaks down plasma triglycerides, thereby enabling fatty acids to enter cells and an intracellular lipase that breaks down stored triglycerides). 

K. A. Siblings with hepatosplenomegaly and lipoprotein lipase deficiency. Lancet 2002 360 1150. 

Brunzell JD, Deeb SS. FamiHal Lipoprotein Lipase Deficiency, Apo C-II Deficiency, And Hepatic Lipase Deficiency. In Scriver CR, Beaudet AL, Sly WS, Valle... 

Fatty acid synthase deficiency Tay-Sachs disease Carnitine deficiency Biotin deficiency Lipoprotein lipase deficiency... 

A control and two patients with hyperlipidemia are studied after an overnight fast. Their plasma lipoprotein electrophoresis patterns are shown below, the control being in the middle lane. One of the patients has a pattern typical of type I lipoprotein lipase deficiency, and the other of type Ila familial hypercholesterolemia. Which of the bands observed in the electrophoretic gel patterns represents a lipoprotein fraction that is abnormally abundant after fasting and that is most enriched in triacylglycerides ... 

The answer is a. (Murray, pp 258-297. Scriver, pp 2705-2716. Sack, pp 121-138. Wilson, pp 362-367.) Patients with type 1 lipoprotein lipase deficiency are not able to rapidly delipidate chylomicrons, which carry dietary triacylglycerides, or VLDLs, which carry lipids packaged by the liver. The electrophoretic pattern (left lane in the figure) after fasting is thus similar to that of a normal patient after a meal—the chylomicrons (band A), LDLs with P-lipoproteins (band B), VLDLs with pre-p-lipoproteins (band C), and HDLs with a-lipoproteins (band D) are all present because chylomicrons and VLDLs are not degraded normally. Hepatic lipase, ordinarily released by the liver to deal with chylomicron... 

ANSWERS TO CASE 35 HYPERTRIGLYCERIDEMIA (LIPOPROTEIN LIPASE DEFICIENCY)... 

I Familial lipoprotein lipase deficiency Increased chylomicrons decreased HDL levels Absence of certain apoproteins... 

Lipoprotein lipase deficiency Reduced levels of functional LPL 1 Pancreatitis... 

Type I hyperlipoproteinaemia, known also as familial exogenous hyperlipaemia and familial hyperchylomicronaemia, is a rare recessive condition characterized by lipoprotein lipase deficiency with consequentially elevated plasma triacylglycerol concentrations. Pancreatitis rather than accelerated atherosclerosis is usually the immediate cause of death in these patients. 

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