Disorders of Lipid Metabolism

  • Rushika Conroy
  • Stewart A. Mackie
  • Charlotte M. Boney
Chapter

Abstract

Lipid physiology is a complex process involving lipid production and metabolism through exogenous, endogenous, and reverse cholesterol transport pathways. Malfunctions in these processes can result in lipid abnormalities that lead to early cardiovascular disease, premature cardiovascular death, and pancreatitis. The causes of these lipid abnormalities can be acquired, most commonly due to obesity, or genetic, as is the case in familial hypercholesterolemia. This chapter discusses normal lipid physiology, general screening guidelines, as well as the diagnosis, presentation, and management of disorders of HDL, LDL, and triglyceride metabolism.

Keywords

Familial hypercholesterolemia Hyperlipidemia Hypertriglyceridemia Statin Omega-3 fatty acid Niacin Fibrate CHILD diet Lipoprotein lipase Tangier disease Hypolipoproteinemia HMG-CoA reductase inhibitor Cholesterol ester transfer protein HDL Cholesterol screening guidelines 

References

  1. 1.
    Nguyen D, Kit B, and Carroll, M. Abnormal cholesterol among children and adolescents in the United States, 2011–2014; 2015. NCHS Data Brief, 228.Google Scholar
  2. 2.
    Mahley RW, Weisgraber KH, Berson TP. Disorders of lipid metabolism. In: Williams textbook of endocrinology. 11th ed: Saunders Elsevier; 2008.Google Scholar
  3. 3.
    Chait A, Subramanian S, Brunzell JD. Genetic disorders of triglyceride metabolism. Endotext [internet]. South Dartmouth: MDText.com, Inc; 2000.Google Scholar
  4. 4.
    Bamba V. Update on screening, etiology and treatment of dyslipidemia in children. J Clin Endocrinol Metab. 2014;99(9):3093–102.CrossRefGoogle Scholar
  5. 5.
    Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176(8):1113–20.CrossRefGoogle Scholar
  6. 6.
    National Heart Lung Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2014;128(6):s213–56.Google Scholar
  7. 7.
    Brinton EA. Management of Hypertriglyceridemia for prevention of atherosclerotic cardiovascular disease. Cardiol Clin. 2015;33:309–23.CrossRefGoogle Scholar
  8. 8.
    Watts GF, Ooi EMM, Chan DC. Demystifying the management of hypertriglyceridemia. Nat Rev Cardiol. 2013;10:648–61.CrossRefGoogle Scholar
  9. 9.
    Gotoda T, Shirai K, Ohta T, Kobayashi J, Yokoyama S, Oikawa S, et al. Diagnosis and management of Type I and Type V hyperlipoproteinemia. J Atheroscler Thromb. 2012;19:1–12.CrossRefGoogle Scholar
  10. 10.
    Brown WV, Goldberg IJ, Young SG. JCL roundtable: hypertriglyceridemia due to defects in lipoprotein lipase function. J Clin Lipidol. 2015;9(3):274–80.CrossRefGoogle Scholar
  11. 11.
    Kei AA, Filippatos TD, Tsimihodimos V, Elisaf MS. A review of the role of apolipoprotein C-II in lipoprotein metabolism and cardiovascular disease. Metabolism. 2012;61:906–21.CrossRefGoogle Scholar
  12. 12.
    Forte TM, Ryan RO. Apolipoprotein A5: extracellular and intracellular roles in triglyceride metabolism. Curr Drug Targets. 2015;16:1274–80.CrossRefGoogle Scholar
  13. 13.
    Fried SK, Rao SP. Sugars, hypertriglyceridemia and cardiovascular disease. Am J Clin Nutr. 2003;78(suppl):873S–80S.CrossRefGoogle Scholar
  14. 14.
    Rizos CV, Elisaf MS, Liberopoulos EN. Effects of thyroid dysfunction on lipid profile. Open Cardiovasc Med J. 2011;5:76–84.CrossRefGoogle Scholar
  15. 15.
    Kawano Y, Cohen DE. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol. 2013;48:434–41.CrossRefGoogle Scholar
  16. 16.
    Van De Wiel A. The effect of alcohol on postprandial and fasting triglycerides. Int J Vasc Med. 2012;2012(2012):862504.  https://doi.org/10.1155/2012/862504. 4 pages.CrossRefPubMedGoogle Scholar
  17. 17.
    Brunzell JD. Familial Lipoprotein Lipase Deficiency. Gene Reviews [Internet], NCBI Bookshelf, 1993–2016.Google Scholar
  18. 18.
    Chahal N, Manlhiot C, Wong H, McCrindle BW. Effectiveness of omega-3 polysaturated fatty acids (fish oil) supplementation for treating hypertriglyceridemia in children and adolescents. Clin Pediatr. 2014;53(7):645–51.CrossRefGoogle Scholar
  19. 19.
    Zhao A, Lam S. Omega-3-carboxylic acid (Epanova) for hypertriglyceridemia. Cardiol Rev. 2015;23(3):148–52.PubMedGoogle Scholar
  20. 20.
    Soto GA, McIntyre A, Agrawal S, Bialo S, Hegele RA, et al. Severe hypertriglyceridemia due to a novel p.Q240H mutation in the lipoprotein lipase gene. Lipids Health Dis. 2015;14:102.CrossRefGoogle Scholar
  21. 21.
    Ahmad Z, Wilson DP. Familial Chylomicronemia syndrome and response to medium-chain triglyceride therapy in an infant with novel mutations in GPIHBP1. J Clin Lipidol. 2014;8:635–9.CrossRefGoogle Scholar
  22. 22.
    Manlhiot C, Larrsson P, Gurofsky RC, Smith RW, Fillingham C, et al. Spectrum and management of hypertriglyceridemia among children in clinical practice. Pediatrics. 2009;123:458–65.CrossRefGoogle Scholar
  23. 23.
    Karlson BW, Palmer MK, Nicholls SJ, Lundman P, Barter PJ. A VOYAGER meta-analysis of the impact of statin therapy on low-density lipoprotein cholesterol and triglyceride levels in patients with hypertriglyceridemia. Am J Cardiol. 2016. In press.Google Scholar
  24. 24.
    Blackett P, Tryggestad J, Krishnan S, Li S, Xu W, Alaupovic P, et al. Lipoprotein abnormalities in compound heterozygous lipoprotein lipase deficiency after treatment with a low-fat diet and orlistat. J Clin Lipidol. 2013;7(2):132–9.CrossRefGoogle Scholar
  25. 25.
    Gidding SS, Prospero C, Hossain J, Zappalla F, Balagopal P, Falkner B, et al. A double-blind randomized trial of fish oil to lower triglycerides and improve cardiometabolic risk in adolescents. J Pediatr. 2014;165:497–503.CrossRefGoogle Scholar
  26. 26.
    Harris WS, Bulchandani D. Why do omega-3 fatty acids lower serum triglycerides? Curr Opin Lipidol. 2006;17:387–93.CrossRefGoogle Scholar
  27. 27.
    Rouis M, Dugi KA, Previato L, Patterson AP, Brunzell JD, Brewer HB, et al. Therapeutic response to medium-chain triglycerides and omega-3 fatty acids in a patient with the familial chylomicronemia syndrome. Arterioscler Thromb Vasc Biol. 1997;17:1400–6.CrossRefGoogle Scholar
  28. 28.
    Haddley K. Alipogene tiparvovec for the treatment of lipoprotein lipase deficiency. Drugs Today. 2013;49(3):161–70.PubMedGoogle Scholar
  29. 29.
    Stefanutti C, Julius U. Treatment of primary hypertriglyceridemia states- general approach and the role of extracorporeal methods. Atheroscler Suppl. 2015;18:85–94.CrossRefGoogle Scholar
  30. 30.
    Gaudet D, Alexander VJ, Baker BF, Brisson D, Tremblay K, Singleton W, et al. Antisense inhibition of Apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015;373(5):438–47.CrossRefGoogle Scholar
  31. 31.
    Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill Medical Publishing Division; 2000. p. 2863–913.Google Scholar
  32. 32.
    Soufi M, Kurt B, Schweer H, Sattler AM, Klaus G, et al. Genetics and kinetics of familial hypercholesterolemia, with the special focus on FH-(Marburg) P.W566R. Atheroscler Suppl. 2009;10:5–11.CrossRefGoogle Scholar
  33. 33.
    Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;11:1795–803.CrossRefGoogle Scholar
  34. 34.
    Naukkarinen J, Ehnholm C, Peltonen L. Genetics of familial combined hyperlipidemia. Curr Opin Lipidol. 2006;17:285–90.CrossRefGoogle Scholar
  35. 35.
    Innerarity T, Mahley R, Weisgraber K, Bersot T, Krauss R, Vega G, Grundy S, Friedl W, Davignon J, McCarthy B. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res. 1990;31:1337–49.PubMedGoogle Scholar
  36. 36.
    Miller M, Zhan M. Genetic determinants of low high-density lipoprotein cholesterol. Curr Opin Cardiol. 2004;19:380–4.CrossRefGoogle Scholar
  37. 37.
    Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCKS9, low LDL and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.CrossRefGoogle Scholar
  38. 38.
    Talmud P, Shah S, Whittall R, Futema M, Howard P, Cooper J, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolemia: a case-control study. Lancet. 2013;381(9874):1293–301.CrossRefGoogle Scholar
  39. 39.
    McNeal C. Lipoprotein (a):its relevance to the pediatric population. J Clin Lipidol. 2015;9:S57–66.CrossRefGoogle Scholar
  40. 40.
    Srinivasan SR, Dahlen GH, Jarpa RA, Webber LS, Berenson GS. Racial (black-white) differences in serum lipoprotein (a) distribution and its relation to parental myocardial infarction in children. Bogalusa heart study. Circulation. 1991;84:160–7.CrossRefGoogle Scholar
  41. 41.
    Yamauchi A, Fukuhara Y, Yamamoto S, Yano F, Takenaka M, Imai E, et al. Oncotic pressure regulates gene transcriptions of albumin and apolipoprotein B in cultured rat hepatoma cells. Am J Phys. 1992;263:c397.CrossRefGoogle Scholar
  42. 42.
    Kwiterovich PO Jr, Frederickson DS, Levy RI. Familial hypercholesterolemia (one form of familial type II hyperlipoproteinemia); a study of its biochemical, genetic and clinical presentation in childhood. J Clin Invest. 1974;53:1237–49.CrossRefGoogle Scholar
  43. 43.
    Goldber A, Hopkins P, Toth P, Ballantyne C, Rader D, Robinson J, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients. Clinical Guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S1–8.CrossRefGoogle Scholar
  44. 44.
    Sorensen KE, Celermajer DS, Georgakopoulos D, et al. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(s) level. J Clin Invest. 1994;93:50–5.CrossRefGoogle Scholar
  45. 45.
    Godenber NA, Bernard TJ, Hillhouse J, et al. Elevated lipoprotein(a), small apolipoprotein (a), and the risk of arterial ischemic stroke in North American children. Haematologica. 2013;98:802–7.CrossRefGoogle Scholar
  46. 46.
    Smolders B, Lemmens R, Thijs V. Lipoprotein (a) and stroke: a meta-analysis of observational studies. Stroke. 2007;38:1959–66.CrossRefGoogle Scholar
  47. 47.
    Brouwers M, de Graaf J, van Greevenbroek M, Schaper N, Stehouwer CD, Stalenhoef AF. Novel drugs in familial combined hyperlipidemia: lessons from type 2 diabetes mellitus. Curr Opin Lipidol. 2010;21:530–8.CrossRefGoogle Scholar
  48. 48.
    Gaddi A, Cicero A, Odoo FO, Poli A, Paoletti R. On behalf of the atherosclerosis and metabolic diseases study group. Practical guidelines for familial combined hyperlipidemia diagnosis: an up-date. Vasc Health Risk Manag. 2007;3(6):877–86.PubMedPubMedCentralGoogle Scholar
  49. 49.
    De Bruin TWA, Castro-Cabezas M, Dallinga-Thie G and Erkelens DW. Familial combined hyperlipidemia-do we understand the pathophysiology and genetics? Lipids: Current Perspectives. London; 1996. p. 101–9.Google Scholar
  50. 50.
    Tammi A, Ronnemaa T, Gylling H, Rask-Nissila L, Vilkari J, Tuomimen J, et al. Plant stanol ester margarine lowers serum total and low density lipoprotein cholesterol concentrations of health children: the STRIP project. Special Turku Coronary Risk Factors Intervention Project. J Pediatr. 2000;136(4):503–10.CrossRefGoogle Scholar
  51. 51.
    Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011;128S5:S213–56.Google Scholar
  52. 52.
    Lamber M, Lupien PJ, Gagne C, Levy E, Blaichman S, Langlois S, et al. Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Pediatrics. 1996;97:619–28.Google Scholar
  53. 53.
    Knipscheer HC, Boelen CC, Kastelstein JJ, van Diermen DE, Groenemeiger BE, van den Ende A, et al. Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia in children. Pediatr Res. 1993;92:78–82.Google Scholar
  54. 54.
    de Jongh S, Ose L, Szamosi T, Gagne C, Lambert M, Scott R, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blinded, placebo-controlled trial with simvastatin. Circulation. 2002;106:2231–7.CrossRefGoogle Scholar
  55. 55.
    Avis HJ, Vissers MN, Stein EA, Wijburg FA, Trip MD, Kastelein JJP, et al. A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2007;27:1803–10.CrossRefGoogle Scholar
  56. 56.
    van der Graaf A, Nierman MC, Firth JC, Womarens KH, Marais AD, de Groot E. Efficacy and safety of fluvastatin in children and adolescents with heterozygous familial hypercholesterolemia. Acta Paediatr. 2006;95:1461–6.CrossRefGoogle Scholar
  57. 57.
    Braamskamp MJ, Langslet G, McCrindle BW, Cassiman D, Francis GA, et al. Efficacy and safety of rosuvastatin therapy in children and adolescents with familial hypercholesterolemia: results from the CHARON study. J Clin Lipidol. 2015;9(6):741–50.CrossRefGoogle Scholar
  58. 58.
    McCrindle B, Ose L, Marais D. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial. J Pediatr. 2003;142:74–80.CrossRefGoogle Scholar
  59. 59.
    Tonstad S, Knudtzon J, Siversten M, Refsum H, Ose L. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia. J Pediatr. 1996;129(1):42–9.CrossRefGoogle Scholar
  60. 60.
    Stein EA, Marais AD, Szamosi T, Raal FH, Schurr D, et al. Colesevelam hydrochloride: efficacy and safety in pediatric subjects with heterozygous familial hypercholesterolemia. J Pediatr. 2010;156(2):231–6.CrossRefGoogle Scholar
  61. 61.
    Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. New Engl J Med. 2008;358:1431–43.CrossRefGoogle Scholar
  62. 62.
    Yeste D, Chacon P, Clemente M, Albisu MA, Gussingye M, Carrascosa A. Ezetimbe as monotherapy in the treatment of hypercholesterolemia in children and adolescents. J Pediatr Endocrinol Metab. 2009;22(6):487–92.CrossRefGoogle Scholar
  63. 63.
    Clauss S, Wai KM, Kavey REW, Kuehl K. Ezetimibe treatment of pediatric patients with hypercholesterolemia. J Pediatr. 2009;154(6):869–72.CrossRefGoogle Scholar
  64. 64.
    Hamilton-Craig I, Kostner K, Colquhoun D, Woodhouse S. Combination therapy of statin and ezetimibe for the treatment of familial hypercholesterolemia. Vasc Health Risk Manag. 2010;6:1023–37.  https://doi.org/10.2147/VHRM.S13496.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Joshi PH, Krivitsky E, Qian Z, Vazquez G, Voros S, Miller J. Do we know when and how to lower lipoprotein(a)? Curr Treat Options Cardiovasc Med. 2010;12:396–407.CrossRefGoogle Scholar
  66. 66.
    Hooper AJ, Burnett JR. Update on primary Hypobetalipoproteinemia. Curr Atheroscler Rep. 2014;16:423.CrossRefGoogle Scholar
  67. 67.
    Welty FK. Hypobetalipoproteinemia and Abetalipoproteinemia. Curr Opin Lipidol. 2014;25(3):161–8.CrossRefGoogle Scholar
  68. 68.
    Miniocci I, Santini S, Cantisani V, Stitziel N, Kathiresan S, Arroyo JA, et al. Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis. J Lipid Res. 2013;54(12):3481–90.CrossRefGoogle Scholar
  69. 69.
    Schaefer EJ, Santos RD, Asztalos BF, Marked HDL. Deficiency and premature coronary heart disease. Curr Opin Lipidol. 2010;21:289–97.CrossRefGoogle Scholar
  70. 70.
    Puntoni M, Sbrana F, Bigazzi F, Sampietro T. Tangier disease: epidemiology, pathophysiology and management. Am J Cardiovasc Drugs. 2012;12(5):303–11.CrossRefGoogle Scholar
  71. 71.
    Forey BA, Fry JS, Lee PN, Thornton AJ, Coombs KJ. The effect of quitting smoking on HDL-cholesterol – a review based on within-subject changes. Biomark Res. 2013;1(26):1–12.Google Scholar
  72. 72.
    Rashid S, Watanabe T, Sakaue T, Lewis GF. Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: the combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity. Clin Biochem. 2003;36:421–9.CrossRefGoogle Scholar
  73. 73.
    Kwiterovich PO Jr. The metabolic pathways of high-density lipoprotein, low-density lipoprotein, and triglycerides: a current review. Am J Cardiol. 2000;86(suppl):5L–10L.CrossRefGoogle Scholar
  74. 74.
    Hirashio S, Ueno T, Naito T, Masaki T. Characteristic kidney pathology, gene abnormality and treatments in LCAT deficiency. Clin Exp Nephrol. 2014;18:189–93.CrossRefGoogle Scholar
  75. 75.
    Rader DJ, deGoma EM. Approach to the patient with extremely low HDL-cholesterol. J Clin Endocrinol Metab. 2012;97(10):3399–407.CrossRefGoogle Scholar
  76. 76.
    Clark RW. Raising high-density lipoprotein with cholesteryl ester transfer protein inhibitors. Curr Opin Pharmacol. 2006;6:162–8.CrossRefGoogle Scholar
  77. 77.
    Barter PJ, Nicholls SJ, Kastelein JJP, Rye KA. Is cholesteryl ester transfer protein inhibition an effective strategy to reduce cardiovascular risk? Circulation. 2013;132:423–32.CrossRefGoogle Scholar
  78. 78.
    Kees Hovingh G, Ray KK, Boekholdt SM. Is cholesteryl ester transfer protein inhibition an effective strategy to reduce cardiovascular risk? Circulation. 2013;132:433–40.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Rushika Conroy
    • 1
  • Stewart A. Mackie
    • 2
  • Charlotte M. Boney
    • 1
  1. 1.Pediatrics, Division of EndocrinologyBaystate Children’s Hospital/UMass Medical Center-BaystateSpringfieldUSA
  2. 2.Pediatrics, Division of CardiologyBaystate Children’s Hospital/UMass Medical Center-BaystateSpringfieldUSA

Personalised recommendations