Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Chylomicronaemia—current diagnosis and future therapies

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Triglyceride-rich lipoprotein metabolism.

References

  1. Hegele, R. A. et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2, 655–666 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Fredrickson, D. S. & Lees, R. S. A system for phenotyping hyperlipoproteinemia. Circulation 31, 321–327 (1965).

    Article  CAS  PubMed  Google Scholar 

  3. Chokshi, N., Blumenschein, S. D., Ahmad, Z. & Garg, A. Genotype–phenotype relationships in patients with type I hyperlipoproteinemia. J. Clin. Lipidol. 8, 287–295 (2014).

    Article  PubMed  Google Scholar 

  4. Gotoda, T. et al. Diagnosis and management of type I and type V hyperlipoproteinemia. J. Atheroscler. Thromb. 19, 1–12 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Yuan, G., Al-Shali, K. Z. & Hegele, R. A. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ 176, 1113–1120 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Rahalkar, A. R. & Hegele, R. A. Monogenic pediatric dyslipidemias: classification, genetics and clinical spectrum. Mol. Genet. Metab. 93, 282–294 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Hegele, R. A. & Pollex, R. L. Hypertriglyceridemia: phenomics and genomics. Mol. Cell. Biochem. 326, 35–43 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Hegele, R. A. Plasma lipoproteins: genetic influences and clinical implications. Nat. Rev. Genet. 10, 109–121 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Johansen, C. T., Kathiresan, S. & Hegele, R. A. Genetic determinants of plasma triglycerides. J. Lipid Res. 52, 189–206 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sugandhan, S., Khandpur, S. & Sharma, V. K. Familial chylomicronemia syndrome. Pediatr. Dermatol. 24, 323–325 (2007).

    Article  PubMed  Google Scholar 

  11. Brunzell, J. D. & Bierman, E. L. Chylomicronemia syndrome. Interaction of genetic and acquired hypertriglyceridemia. Med. Clin. North Am. 66, 455–468 (1982).

    Article  CAS  PubMed  Google Scholar 

  12. Leaf, D. A. Chylomicronemia and the chylomicronemia syndrome: a practical approach to management. Am. J. Med. 121, 10–12 (2008).

    Article  PubMed  Google Scholar 

  13. Rouis, M. et al. Therapeutic response to medium-chain triglycerides and ω-3 fatty acids in a patient with the familial chylomicronemia syndrome. Arterioscler. Thromb. Vasc. Biol. 17, 1400–1406 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Whitcomb, D. C. Clinical practice. Acute pancreatitis. N. Engl. J. Med. 354, 2142–2150 (2006).

    Article  PubMed  Google Scholar 

  15. Valdivielso, P., Ramirez-Bueno, A. & Ewald, N. Current knowledge of hypertriglyceridemic pancreatitis. Eur. J. Intern. Med. 25, 689–694 (2014).

    Article  CAS  PubMed  Google Scholar 

  16. Ranson, J. H. Etiological and prognostic factors in human acute pancreatitis: a review. Am. J. Gastroenterol. 77, 633–638 (1982).

    CAS  PubMed  Google Scholar 

  17. Balthazar, E. J., Robinson, D. L., Megibow, A. J. & Ranson, J. H. Acute pancreatitis: value of CT in establishing prognosis. Radiology 174, 331–336 (1990).

    Article  CAS  PubMed  Google Scholar 

  18. Fortson, M. R., Freedman, S. N. & Webster, P. D. 3rd. Clinical assessment of hyperlipidemic pancreatitis. Am. J. Gastroenterol. 90, 2134–2139 (1995).

    CAS  PubMed  Google Scholar 

  19. Sandhu, S., Al-Sarraf, A., Taraboanta, C., Frohlich, J. & Francis, G. A. Incidence of pancreatitis, secondary causes, and treatment of patients referred to a specialty lipid clinic with severe hypertriglyceridemia: a retrospective cohort study. Lipids Health Dis. 10, 157 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Christian, J. B. et al. Clinical and economic benefits observed when follow-up triglyceride levels are less than 500 mg/dL in patients with severe hypertriglyceridemia. J. Clin. Lipidol. 6, 450–461 (2012).

    Article  PubMed  Google Scholar 

  21. Feoli-Fonseca, J. C., Levy, E., Godard, M. & Lambert, M. Familial lipoprotein lipase deficiency in infancy: clinical, biochemical, and molecular study. J. Pediatr. 133, 417–423 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Khokhar, A. S. & Seidner, D. L. The pathophysiology of pancreatitis. Nutr. Clin. Pract. 19, 5–15 (2004).

    Article  PubMed  Google Scholar 

  23. Gaudet, D. et al. Medical resource use and costs associated with chylomicronemia. J. Med. Econ. 16, 657–666 (2013).

    Article  PubMed  Google Scholar 

  24. Benlian, P. et al. Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene. N. Engl. J. Med. 335, 848–854 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Pirillo, A., Norata, G. D. & Catapano, A. L. Postprandial lipemia as a cardiometabolic risk factor. Curr. Med. Res. Opin. 30, 1489–1503 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Mohandas, M. K., Jemila, J., Ajith Krishnan, A. S. & George, T. T. Familial chylomicronemia syndrome. Indian J. Pediatr. 72, 181 (2005).

    CAS  PubMed  Google Scholar 

  27. Cuchel, M. et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection andclinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur. Heart J. 35, 2146–2157 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Martin-Campos, J. M. et al. Molecular analysis of chylomicronemia in a clinical laboratory setting: diagnosis of 13 cases of lipoprotein lipase deficiency. Clin. Chim. Acta 429, 61–68 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Stefanutti, C. et al. A three month-old infant with severe hyperchylomicronemia: molecular diagnosis and extracorporeal treatment. Atheroscler. Suppl. 14, 73–76 (2013).

    Article  PubMed  Google Scholar 

  30. Voss, C. V. et al. Mutations in lipoprotein lipase that block binding to the endothelial cell transporter GPIHBP1. Proc. Natl Acad. Sci. USA 108, 7980–7984 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Pasalic, D. et al. Missense mutation W86R in exon 3 of the lipoprotein lipase gene in a boy with chylomicronemia. Clin. Chim. Acta 343, 179–184 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Jap, T. S., Jenq, S. F., Wu, Y. C., Chiu, C. Y. & Cheng, H. M. Mutations in the lipoprotein lipase gene as a cause of hypertriglyceridemia and pancreatitis in Taiwan. Pancreas 27, 122–126 (2003).

    Article  PubMed  Google Scholar 

  33. Henderson, H. E. et al. Ile225Thr loop mutation in the lipoprotein lipase (LPL) gene is a de novo event. Am. J. Med. Genet. 78, 313–316 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Foubert, L. et al. Compound heterozygosity for frameshift mutations in the gene for lipoprotein lipase in a patient with early-onset chylomicronemia. Hum. Mutat. Suppl. 1, S141–S144 (1998).

    Article  Google Scholar 

  35. Ma, Y. et al. A missense mutation (Asp250Asn) in exon 6 of the human lipoprotein lipase gene causes chylomicronemia in patients of different ancestries. Genomics 13, 649–653 (1992).

    Article  CAS  PubMed  Google Scholar 

  36. Murthy, V., Julien, P. & Gagne, C. Molecular pathobiology of the human lipoprotein lipase gene. Pharmacol. Ther. 70, 101–135 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Okubo, M., Toromanovic, A., Ebara, T. & Murase, T. Apolipoprotein C-II: a novel large deletion in APOC2 caused by AluAlu homologous recombination in an infant with apolipoprotein C-II deficiency. Clin. Chim. Acta 438, 148–153 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Lam, C. W., Yuen, Y. P., Cheng, W. F., Chan, Y. W. & Tong, S. F. Missense mutation Leu72Pro located on the carboxyl terminal amphipathic helix of apolipoprotein C-II causes familial chylomicronemia syndrome. Clin. Chim. Acta 364, 256–259 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Streicher, R. et al. A single nucleotide substitution in the promoter region of the apolipoprotein C-II gene identified in individuals with chylomicronemia. J. Lipid Res. 37, 2599–2607 (1996).

    CAS  PubMed  Google Scholar 

  40. Calandra, S., Priore Oliva, C., Tarugi, P. & Bertolini, S. APOA5 and triglyceride metabolism, lesson from human APOA5 deficiency. Curr. Opin. Lipidol. 17, 122–127 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Nilsson, S. K., Heeren, J., Olivecrona, G. & Merkel, M. Apolipoprotein A-V; a potent triglyceride reducer. Atherosclerosis 219, 15–21 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Brahm, A. & Hegele, R. A. Hypertriglyceridemia. Nutrients 5, 981–1001 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Albers, K. et al. Homozygosity for a partial deletion of apoprotein A-V signal peptide results in intracellular missorting of the protein and chylomicronemia in a breast-fed infant. Atherosclerosis 233, 97–103 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Okubo, M. et al. A novel APOA5 splicing mutation IVS2+1g>a in a Japanese chylomicronemia patient. Atherosclerosis 207, 24–25 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Young, S. G. et al. GPIHBP1, an endothelial cell transporter for lipoprotein lipase. J. Lipid Res. 52, 1869–1884 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Plengpanich, W. et al. Multimerization of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) and familial chylomicronemia from a serine-to-cysteine substitution in GPIHBP1 Ly6 domain. J. Biol. Chem. 289, 19491–19499 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gin, P. et al. Chylomicronemia mutations yield new insights into interactions between lipoprotein lipase and GPIHBP1. Hum. Mol. Genet. 21, 2961–2972 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rios, J. J. et al. Deletion of GPIHBP1 causing severe chylomicronemia. J. Inherit. Metab. Dis. 35, 531–540 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Beigneux, A. P. GPIHBP1 and the processing of triglyceride-rich lipoproteins. Clin. Lipidol. 5, 575–582 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Olivecrona, G. et al. Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia. J. Lipid Res. 51, 1535–1545 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Beigneux, A. P. et al. Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. Arterioscler. Thromb. Vasc. Biol. 29, 956–962 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Beigneux, A. P., Davies, B. S., Bensadoun, A., Fong, L. G. & Young, S. G. GPIHBP1, a GPI-anchored protein required for the lipolytic processing of triglyceride-rich lipoproteins. J. Lipid Res. 50 (Suppl.), S57–S62 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang, J. & Hegele, R. A. Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650). Lipids Health Dis. 6, 23 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Young, S. G. et al. GPIHBP1: an endothelial cell molecule important for the lipolytic processing of chylomicrons. Curr. Opin. Lipidol. 18, 389–396 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Peterfy, M. Lipase maturation factor 1: a lipase chaperone involved in lipid metabolism. Biochim. Biophys. Acta 1821, 790–794 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Johansen, C. T. & Hegele, R. A. Genetic bases of hypertriglyceridemic phenotypes. Curr. Opin. Lipidol. 22, 247–253 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Johansen, C. T. & Hegele, R. A. Allelic and phenotypic spectrum of plasma triglycerides. Biochim. Biophys. Acta 1821, 833–842 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Johansen, C. T. & Hegele, R. A. The complex genetic basis of plasma triglycerides. Curr. Atheroscler. Rep. 14, 227–234 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Johansen, C. T. et al. An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia. Arterioscler. Thromb. Vasc. Biol. 31, 1916–1926 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Johansen, C. T. et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat. Genet. 42, 684–687 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Johansen, C. T. et al. Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia. Circ. Cardiovasc. Genet. 5, 66–72 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Teslovich, T. M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Goldberg, I. J., Eckel, R. H. & McPherson, R. Triglycerides and heart disease: still a hypothesis? Arterioscler. Thromb. Vasc. Biol. 31, 1716–1725 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Beil, U., Grundy, S. M., Crouse, J. R. & Zech, L. Triglyceride and cholesterol metabolism in primary hypertriglyceridemia. Arteriosclerosis 2, 44–57 (1982).

    Article  CAS  PubMed  Google Scholar 

  65. Basel-Vanagaite, L. et al. Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1. Am. J. Hum. Genet. 90, 49–60 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rahalkar, A. R. et al. Novel LPL mutations associated with lipoprotein lipase deficiency: two case reports and a literature review. Can. J. Physiol. Pharmacol. 87, 151–160 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Johansen, C. T. et al. LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias. J. Lipid Res. 55, 765–772 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jialal, I., Amess, W. & Kaur, M. Management of hypertriglyceridemia in the diabetic patient. Curr. Diab. Rep. 10, 316–320 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Leaf, D. A., Connor, W. E., Illingworth, D. R., Bacon, S. P. & Sexton, G. The hypolipidemic effects of gemfibrozil in type V hyperlipidemia. A double-blind, crossover study. JAMA 262, 3154–3160 (1989).

    Article  CAS  PubMed  Google Scholar 

  70. Gotto, A. M. Jr & Moon, J. E. Pharmacotherapies for lipid modification: beyond the statins. Nat. Rev. Cardiol. 10, 560–570 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Staels, B. et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 98, 2088–2093 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Sahebkar, A., Chew, G. T. & Watts, G. F. Recent advances in pharmacotherapy for hypertriglyceridemia. Prog. Lipid Res. 56, 47–66 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Kamanna, V. S. & Kashyap, M. L. Mechanism of action of niacin. Am. J. Cardiol. 101, 20B–26B (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Goldberg, A. et al. Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. Am. J. Cardiol. 85, 1100–1105 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Maki, K. C., Bays, H. E. & Dicklin, M. R. Treatment options for the management of hypertriglyceridemia: strategies based on the best-available evidence. J. Clin. Lipidol. 6, 413–426 (2012).

    Article  PubMed  Google Scholar 

  76. Chan, D. C. et al. Effect of atorvastatin on chylomicron remnant metabolism in visceral obesity: a study employing a new stable isotope breath test. J. Lipid Res. 43, 706–712 (2002).

    CAS  PubMed  Google Scholar 

  77. Tremblay, A. J., Lamarche, B., Hogue, J. C. & Couture, P. Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia. J. Lipid Res. 50, 1463–1471 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Davidson, M. H. Mechanisms for the hypotriglyceridemic effect of marine ω-3 fatty acids. Am. J. Cardiol. 98, 27i–33i (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Skulas-Ray, A. C., West, S. G., Davidson, M. H. & Kris-Etherton, P. M. ω-3 fatty acid concentrates in the treatment of moderate hypertriglyceridemia. Expert Opin. Pharmacother. 9, 1237–1248 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Connor, W. E., DeFrancesco, C. A. & Connor, S. L. N-3 fatty acids from fish oil. Effects on plasma lipoproteins and hypertriglyceridemic patients. Ann. NY Acad. Sci. 683, 16–34 (1993).

    Article  CAS  PubMed  Google Scholar 

  81. Berglund, L., Brunzell, J. D., Goldberg, A. C., Goldberg, I. J. & Stalenhoef, A. Treatment options for hypertriglyceridemia: from risk reduction to pancreatitis. Best Pract. Res. Clin. Endocrinol. Metab. 28, 423–437 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Slivkoff-Clark, K. M., James, A. P. & Mamo, J. C. The chronic effects of fish oil with exercise on postprandial lipaemia and chylomicron homeostasis in insulin resistant viscerally obese men. Nutr. Metab. (Lond.) 9, 9 (2012).

    Article  CAS  Google Scholar 

  83. Park, Y. & Harris, W. S. ω-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. J. Lipid Res. 44, 455–463 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Pschierer, V., Richter, W. O. & Schwandt, P. Primary chylomicronemia in patients with severe familial hypertriglyceridemia responds to long-term treatment with (n-3) fatty acids. J. Nutr. 125, 1490–1494 (1995).

    CAS  PubMed  Google Scholar 

  85. Richter, W. O., Jacob, B. G., Ritter, M. M. & Schwandt, P. Treatment of primary chylomicronemia due to familial hypertriglyceridemia by ω-3 fatty acids. Metabolism 41, 1100–1105 (1992).

    Article  CAS  PubMed  Google Scholar 

  86. Sisman, G. et al. Familial chylomicronemia syndrome related chronic pancreatitis: a single-center study. Hepatobiliary Pancreat. Dis. Int. 13, 209–214 (2014).

    Article  CAS  PubMed  Google Scholar 

  87. Hen, K., Bogdanski, P. & Pupek-Musialik, D. Successful treatment of severe hypertriglyceridemia with plasmapheresis—case report [Polish]. Pol. Merkur Lekarski 26, 62–64 (2009).

    PubMed  Google Scholar 

  88. Basar, R. et al. Therapeutic apheresis for severe hypertriglyceridemia in pregnancy. Arch. Gynecol. Obstet. 287, 839–843 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Lennertz, A., Parhofer, K. G., Samtleben, W. & Bosch, T. Therapeutic plasma exchange in patients with chylomicronemia syndrome complicated by acute pancreatitis. Ther. Apher. 3, 227–233 (1999).

    Article  CAS  PubMed  Google Scholar 

  90. Manzella, D. J., Scalise, D. H. & Melero, M. J. Vacuum sign of cerebrospinal fluid flow [Spanish]. Medicina (B. Aires) 74, 54 (2014).

    Google Scholar 

  91. Seda, G., Meyer, J. M., Amundson, D. E. & Daheshia, M. Plasmapheresis in the management of severe hypertriglyceridemia. Crit. Care Nurse 33, 18–23 (2013).

    Article  PubMed  Google Scholar 

  92. Izquierdo-Ortiz, M. J. & Abaigar-Luquin, P. Severe hypertriglyceridaemia. Treatment with plasmapheresis. Nefrologia 32, 417–418 (2012).

    PubMed  Google Scholar 

  93. Syed, H., Bilusic, M., Rhondla, C. & Tavaria, A. Plasmapheresis in the treatment of hypertriglyceridemia-induced pancreatitis: a community hospital's experience. J. Clin. Apher. 25, 229–234 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Ewald, N. & Kloer, H. U. Severe hypertriglyceridemia: an indication for apheresis? Atheroscler. Suppl. 10, 49–52 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Iskandar, S. B. & Olive, K. E. Plasmapheresis as an adjuvant therapy for hypertriglyceridemia-induced pancreatitis. Am. J. Med. Sci. 328, 290–294 (2004).

    Article  PubMed  Google Scholar 

  96. Dominguez-Munoz, J. E. et al. Hyperlipidemia in acute pancreatitis. Relationship with etiology, onset, and severity of the disease. Int. J. Pancreatol. 10, 261–267 (1991).

    CAS  PubMed  Google Scholar 

  97. Chen, J. H., Yeh, J. H., Lai, H. W. & Liao, C. S. Therapeutic plasma exchange in patients with hyperlipidemic pancreatitis. World J. Gastroenterol. 10, 2272–2274 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Piolot, A., Nadler, F., Cavallero, E., Coquard, J. L. & Jacotot, B. Prevention of recurrent acute pancreatitis in patients with severe hypertriglyceridemia: value of regular plasmapheresis. Pancreas 13, 96–99 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Ewald, N. & Kloer, H. U. Treatment options for severe hypertriglyceridemia (SHTG): the role of apheresis. Clin. Res. Cardiol. Suppl. 7 (Suppl. 1), 31–35 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Thuzar, M., Shenoy, V. V., Malabu, U. H., Schrale, R. & Sangla, K. S. Extreme hypertriglyceridemia managed with insulin. J. Clin. Lipidol. 8, 630–634 (2014).

    Article  PubMed  Google Scholar 

  101. Rader, D. J. & Kastelein, J. J. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation 129, 1022–1032 (2014).

    Article  PubMed  Google Scholar 

  102. Wierzbicki, A. S., Hardman, T. C. & Viljoen, A. New lipid-lowering drugs: an update. Int. J. Clin. Pract. 66, 270–280 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Marbach, J. A., McKeon, J. L., Ross, J. L. & Duffy, D. Novel treatments for familial hypercholesterolemia: pharmacogenetics at work. Pharmacotherapy 34, 961–972 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Sacks, F. M., Stanesa, M. & Hegele, R. A. Severe hypertriglyceridemia with pancreatitis: thirteen years' treatment with lomitapide. JAMA Intern. Med. 174, 443–447 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. Cuchel, M. et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 381, 40–46 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Vuorio, A., Tikkanen, M. J. & Kovanen, P. T. Inhibition of hepatic microsomal triglyceride transfer protein—a novel therapeutic option for treatment of homozygous familial hypercholesterolemia. Vasc. Health Risk Manag. 10, 263–270 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. deGoma, E. M. Lomitapide for the management of homozygous familial hypercholesterolemia. Rev. Cardiovasc. Med. 15, 109–118 (2014).

    Article  PubMed  Google Scholar 

  108. Gaudet, D., Methot, J. & Kastelein, J. Gene therapy for lipoprotein lipase deficiency. Curr. Opin. Lipidol. 23, 310–320 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Carpentier, A. C. et al. Effect of alipogene tiparvovec (AAV1-LPLS447X) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J. Clin. Endocrinol. Metab. 97, 1635–1644 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Gaudet, D. et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther. 20, 361–369 (2013).

    Article  CAS  PubMed  Google Scholar 

  111. Rip, J. et al. AAV1-LPLS447X gene therapy reduces hypertriglyceridemia in apoE2 knock in mice. Biochim. Biophys. Acta 1761, 1163–1168 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Wierzbicki, A. S. & Viljoen, A. Alipogene tiparvovec: gene therapy for lipoprotein lipase deficiency. Expert Opin. Biol. Ther. 13, 7–10 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Schober, G. et al. Diacylglycerol acyltransferase-1 inhibition enhances intestinal fatty acid oxidation and reduces energy intake in rats. J. Lipid Res. 54, 1369–1384 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Naik, R. et al. Therapeutic strategies for metabolic diseases: small-molecule diacylglycerol acyltransferase (DGAT) inhibitors. ChemMedChem 9, 2410–2424 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. DeVita, R. J. & Pinto, S. Current status of the research and development of diacylglycerol O-acyltransferase 1 (DGAT1) inhibitors. J. Med. Chem. 56, 9820–9825 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. Cao, J. et al. Targeting acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases. J. Biol. Chem. 286, 41838–41851 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Denison, H. et al. Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial. Diabetes Obes. Metab. 16, 334–343 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Denison, H. et al. Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single-dose study. Diabetes Obes. Metab. 15, 136–143 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Meyers, C. et al. The DGAT1 inhibitor LCQ908 decreases triglyceride levels in patients with the familial chylomicronemia syndrome. J. Clin. Lipidol. 6, 266–267 (2012).

    Article  Google Scholar 

  120. Prakash, T. P. et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 42, 8796–8807 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Furtado, J. D., Wedel, M. K. & Sacks, F. M. Antisense inhibition of apoB synthesis with mipomersen reduces plasma apoC-III and apoC-III-containing lipoproteins. J. Lipid Res. 53, 784–791 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Huff, M. W. & Hegele, R. A. Apolipoprotein C-III: going back to the future for a lipid drug target. Circ. Res. 112, 1405–1408 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Jorgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G. & Tybjaerg-Hansen, A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371, 32–41 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. Graham, M. J. et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ. Res. 112, 1479–1490 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Gaudet, D. et al. Targeting APOC3 in the familial chylomicronemia syndrome. N. Engl. J. Med. 371, 2200–2206 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Mattijssen, F. & Kersten, S. Regulation of triglyceride metabolism by angiopoietin-like proteins. Biochim. Biophys. Acta 1821, 782–789 (2012).

    Article  CAS  PubMed  Google Scholar 

  127. Sehgal, A., Vaishnaw, A. & Fitzgerald, K. Liver as a target for oligonucleotide therapeutics. J. Hepatol. 59, 1354–1359 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Isis starts phase I trial of ISIS-ANGPTL3Rx to treat hyperlipidemia patients. Drugdevelopment-technology.com [online], (2014).

  129. Zimmer, M. et al. CAT-2003 is a novel small molecule that inhibits proprotein convertase subtilisin/kexin type 9 production and lowers non-high-density lipoprotein cholesterol. Presented at the Arteriosclerosis, Thrombosis and Vascular Biology Scientific Sessions 2014.

  130. US National Library of Medicine. ClinicalTrials.gov [online], (2015).

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Robert A. Hegele.

Ethics declarations

Competing interests

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.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2015.26

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing