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Chylomicronaemia—current diagnosis and future therapies

Nature Reviews Endocrinology volume 11, pages 352–362 (2015)Cite this article

Subjects

Key Points

  • Primary chylomicronaemia affects ∼1:600 adult individuals; of these ∼95% are affected by polygenic inherited susceptibility and ∼5% show monogenic autosomal recessive inheritance

  • The 'chylomicronaemia syndrome' refers to the presence of at least one clinical feature accompanying primary chylomicronaemia, such as eruptive xanthomas, lipaemia retinalis, pancreatitis or hepatosplenomegaly

  • >90% of monogenic chylomicronaemia cases are caused by mutations in LPL; however, causative mutations in other genes, such as APOC2, APOA5, LMF1 and GPIHBP1, have been identified

  • Increased understanding of the genetic basis of primary chylomicronaemia might result in a change to the classification of the disease that reflects the underlying molecular cause

  • Traditional management of primary chylomicronaemia has focused on diet, lifestyle and mitigation of secondary risk factors; pharmacologic management with fibrates, niacin, statins and ω-3 fatty acids has achieved variable, but, in general, limited success

  • Targeting the lipolytic pathway by use of gene therapy, inhibitors and antisense oligonucleotides might provide effective treatment options for this disease

Abstract

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.

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Figure 1: Triglyceride-rich lipoprotein metabolism.

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Acknowledgements

R.A.H. is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Martha Blackburn Chair in Cardiovascular Research, and operating grants from the Canadian Institutes for Health Research (MOP-13430 and MOP-79533), the Heart and Stroke Foundation of Ontario (T6066 and 000353) and Genome Canada through Genome Quebec.

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  1. Department of Medicine, Schulich School of Medicine and Dentistry, Western University, 4288A–1151 Richmond Street North, London, N6A 5B7, ON, Canada

    Amanda J. Brahm & Robert A. Hegele

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A.J.B. and R.A.H. researched data for the article, provided substantial contributions to discussions of the content, wrote and reviewed and/or edited the manuscript before submission.

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Correspondence to Robert A. Hegele.

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R.A.H. declares that he is a consultant and speaker's bureau member for Aegerion, Amgen, Eli Lilly, Pfizer, Sanofi and Valeant. A.J.B. declares no competing interests.

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Brahm, A., Hegele, R. Chylomicronaemia—current diagnosis and future therapies. Nat Rev Endocrinol 11, 352–362 (2015). https://doi.org/10.1038/nrendo.2015.26

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