This Review discusses new developments in understanding the basis of chylomicronaemia--a challenging metabolic disorder for which there is an unmet clinical need. Chylomicronaemia presents in two distinct primary forms. The first form is very rare monogenic early-onset chylomicronaemia, which presents in childhood or adolescence and is often caused by homozygous mutations in the gene encoding lipoprotein lipase (LPL), its cofactors apolipoprotein C-II or apolipoprotein A-V, the LPL chaperone lipase maturation factor 1 or glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1. The second form, polygenic late-onset chylomicronaemia, which is caused by an accumulation of several genetic variants, can be exacerbated by secondary factors, such as poor diet, obesity, alcohol intake and uncontrolled type 1 or type 2 diabetes mellitus, and is more common than early-onset chylomicronaemia. Both forms of chylomicronaemia are associated with an increased risk of life-threatening pancreatitis; the polygenic form might also be associated with an increased risk of cardiovascular disease. Treatment of chylomicronaemia focuses on restriction of dietary fat and control of secondary factors, as available pharmacological therapies are only minimally effective. Emerging therapies that might prove more effective than existing agents include LPL gene therapy, inhibition of microsomal triglyceride transfer protein and diacylglycerol O-acyltransferase 1, and interference with the production and secretion of apoC-III and angiopoietin-like protein 3.
Hypertriglyceridemia (HTG) is commonly encountered in lipid and cardiology clinics. Severe HTG warrants treatment because of the associated increased risk of acute pancreatitis. However, the need to treat, and the correct treatment approach for patients with mild to moderate HTG are issues for ongoing evaluation. In the past, it was felt that triglyceride does not directly contribute to development of atherosclerotic plaques. However, this view is evolving, especially for triglyceride-related fractions and variables measured in the non-fasting state. Our understanding of the etiology, genetics and classification of HTG states is also evolving. Previously, HTG was considered to be a dominant disorder associated with variation within a single gene. The old nomenclature includes the term “familial” in the names of several hyperlipoproteinemia (HLP) phenotypes that included HTG as part of their profile, including combined hyperlipidemia (HLP type 2B), dysbetalipoproteinemia (HLP type 3), simple HTG (HLP type 4) and mixed hyperlipidemia (HLP type 5). This old thinking has given way to the idea that genetic susceptibility to HTG results from cumulative effects of multiple genetic variants acting in concert. HTG most is often a “polygenic” or “multigenic” trait. However, a few rare autosomal recessive forms of severe HTG have been defined. Treatment depends on the overall clinical context, including severity of HTG, concomitant presence of other lipid disturbances, and the patient's global risk of cardiovascular disease. Therapeutic strategies include dietary counselling, lifestyle management, control of secondary factors, use of omega-3 preparations and selective use of pharmaceutical agents.
Given the current state of genetic understanding, CHL may be best conceptualized as a syndrome with common clinical presentation but multigenic causes, similar to other common conditions such as type 2 diabetes.
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