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At a glance

An inborn error of metabolism characterized by increased plasma levels of triglycerides and chylomicrons. Diabetes mellitus, recurrent acute pancreatitis, and epigastric pain are often associated.

Synonyms for LPL-Deficiency

Monogenic Chylomicronemia; Familial Chylomicronemia Syndrome; Lipoprotein Lipase Deficiency; Lipase-D Deficiency; Hyperlipoproteinemia, Type IA; Familial Hyperchylomicronemia; Idiopathic Hyperlipemia Burger-Grutz Type; Essential Familial Hyperlipemia.

Synonyms for APOC2-Deficiency

Monogenic Chylomicronemia; Hyperlipoproteinemia Type IB; C-II Anapolipoproteinemia.

Incidence

LPL-Deficiency affects approximately 1:1,000,000 and APOC2-Deficiency is significantly less frequent (around 10 families have been reported). Both genders are equally affected.

Genetic inheritance

Autosomal recessive for both, LPL- and APOC2-Deficiency. For the former, the genetic defect has been mapped to the LPL-gene on chromosome 8p21.3, while for the latter it has been mapped to the APOC2-gene on chromosome 19q13.32. To date, more than 114 mutations have been detected for the LPL-gene and 24 for the APOC2-gene. Less frequently, other genes (eg, APOA5, GPI-HBP1) have been implicated in the pathogenesis of Familial Chylomicronemia Syndrome.

Pathophysiology

In the plasma, triglycerides (TG) are transported as TG-rich lipoproteins, which either originate from the intestine (chylomicrons) or the liver (very low density lipoproteins; VLDL). Apolipoprotein C-II is a cofactor required in the activation of lipoprotein lipase (LPL; triacylglycerol acylhydrolase), the primary catabolic enzyme located on endothelial cells and responsible for triglyceride hydrolysis in triglyceride-rich lipoproteins in the plasma. The resulting lipoprotein remnants are subsequently taken up by the liver and the free fatty acids by peripheral tissues. Deficiency of APOC2 or LPL leads to marked elevation of plasma triglycerides and chylomicrons. Clinically, LPL- and APOC2-deficiency are indistinguishable, but functional or molecular (gene sequencing) studies allow to differentiate them. Severe cases of pancreatitis in APOC2-deficiency can be treated with fresh frozen plasma since it contains APOC2. In contrast, LPL-deficiency has been treated (where approved) with the gene therapy alipogene tiparvovec, but it takes approximately 3 months to become clinically effective. These different treatment paths explain why molecular and/or functional diagnostic studies are important.

Diagnosis

Based on the presence of plasma chylomicrons following a fasting period of 12 to 14 hours (chylomicrons are normally cleared from plasma within 3-4 hour of eating). The presence of fasting chylomicrons is associated with fasting triglyceride levels higher than 10 mmol/L or 900 mg/dL (normal 1.7 mmol/L or 150 mg/dL). (More common causes for hyperchylomicronemia, such as uncontrolled diabetes mellitus Type I or II, hypothyroidism, poor diet, alcohol abuse, nephrotic syndrome or use of medications that can potentially worsen hypertriglyceridemia [eg, beta-blockers, estrogens, corticosteroids, retinoids, thiazide diuretics] should be excluded first.)

Clinical aspects

Despite hypertriglyceridemia, these patients often do not seem to be at significantly increased risk of premature atherosclerosis, although it has been reported occasionally. Recurrent bouts of pancreatitis are ...

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