Gestational hypercholesterolemia helps detect familial hypercholesterolemia and prevent late pregnancy complications
Article Sidebar
Main Article Content
Abstract
Introduction: In this retrospective study, we comment on the cause and diagnostic potential of the elevated serum total cholesterol and some non-cholesterol sterols in a population of healthy pregnant women from Prague, Czech Republic.
Methods: Based on a total of 21,000 clinical biochemistry tests of healthy pregnant women with hypercholesterolemia observed during pregnancy, a testing group of 84 women with a total cholesterol (TC) above 7.0 mmol/l was established to analyze their non-cholesterol sterols (NCS) by Gas Chromatography–Mass Spectrometry. Lathosterol (Lat) and desmosterol (Des) were evaluated as markers of endogenous cholesterol synthesis, whereas campesterol (Cam) and sitosterol (Sit) were analysed as markers of intestinal absorption.
Results: In the basic population, the frequency of gestational hypercholesterolemia with the serum TC levels > 7.0mmol/l was 1 to 136.The mean values were: TC 6.8 mmol/l, LDL-C 4.6 mmol/l, and HDL-C 2.2 mmol/l. In the selected testing group of 84, the mean values were: Lat 7.8+/-1.7 μmol/l, Des 4.7+/-0.9 μmol/l, Cam 9.8+/-2.6 μmol/l, and Sit 9.6+/-3.8 μmol/l. Lat correlated with TC (r = 0.53), LDL-C (r = 0.36), and non-HDL-C (r = 0.35). No such correlations were observed for Cam or Sit.
Conclusion: Our findings prove that gestational hypercholesterolemia is caused by increased endogenous cholesterol synthesis via lathosterol. Subsequently, we demonstrate how a single cholesterol test taken in the fifth to sixth month gestation can efficiently help detect familial hypercholesterolemia, and prevent related late pregnancy circulatory complications.
Article Details
Copyright (c) 2019 Hyánek J, et al.
This work is licensed under a Creative Commons Attribution 4.0 International License.
Feingold KR, Wiley T, Moser AH, Lear SR, Wiley MH.De novo cholesterogenesis in pregnancy. J Lab Clin Med. 1983; 101: 256-263. Ref.: http://bit.ly/2KRPVVI
Hyánek J. Hypercholesterolemia in pregnancy – pathobiochemical and pathophysiological implication for atherosclerosis and evaluation in metabolic surgery [in Czech with English summary]. Klinická Biochemie a Metabolismus. 2013; 21: 208-214. Ref.: http://bit.ly/2XCE6c4
Desoye G, Schweditsch MO, Pfeiffer KP, Zechner R, Kostner GM. Correlation of hormones with lipid and lipoprotein levels during normal pregnancy and postpartum. J Clin Endocrinol Metab. 1987; 64: 704-712. Ref.: http://bit.ly/2KW6BLQ
Amundsen AL, Khoury J, Iversen PO, Bergei C, Ose L, et al. Marked changes in plasma lipids and lipoproteins during pregnancy in women with familial hypercholesterolemia. Atherosclerosis. 2016; 189: 451‑457. Ref.: http://bit.ly/2YrwSVx
Herrera E, Amusquivar E, López-Soldado I, Ortega H. Maternal lipid metabolism and placental lipid transfer. Horm Res. 2006; 65(supp 3): 59-64. Ref.: http://bit.ly/2xrmAbT
Woollett LA. Maternal cholesterol in fetal development: transport of cholesterol from the maternal to the fetal circulation 1-5. The Am J Clin Nutr. 2006; 82: 1155-1161. Ref.: http://bit.ly/2FMioIt
Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature. 1996; 383: 407-413. Ref.: http://bit.ly/2NsMsiH
Bertrand N, Dahmane N. Sonic hedgehog signalizing in forebrain development and its interactions with pathways that modify its effects. Trends Cell Biol. 2006; 16: 597-605. Ref.: http://bit.ly/31Xi1Ei
Herman GE. Disorders of cholesterol biosynthesis: prototypic metabolic malformations syndromes. Hum Mol Genet. 2003; 12(sup 1, 2): R75-R88. Ref.: http://bit.ly/2XHK8bg
Hoffmann GF, Nyhan WL, Zschocke J, Kahler SG, Mayatepek E. Inherited metabolic diseases. Philadelphia: Lippincott Williams & Wilkins. 2002. Ref.: http://bit.ly/3240gDt
Porter FD, Herman GE. Malformation syndromes caused by disorders of cholesterol synthesis. J Lipid Res. 2010; 52: 6-34. Ref.: http://bit.ly/321OSrC
Palinski W. Maternal-fetal cholesterol transport in the placenta: Good, bad, and target for modulation. Circ Res. 2009; 104: 569-571. Ref.: http://bit.ly/2KScvxp
Napoli C, Glass CK, Witztum JL, Deutsch R, D'Armiento FP, et al. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet. 1999; 354: 1234-41. Ref.: http://bit.ly/2xrJtw1
Bartels Ä, O’Donoghue K. Cholesterol in pregnancy: A Review of knowns and unknowns. Obstet Med. 2011; 4: 147–151. Ref.: http://bit.ly/323sL45
Martin U, Davies C, Hayavi S, Hartland A, Dunne F. Is normal pregnancy atherogenic? Clin Sci (Lond). 1999; 96: 421-425. Ref.: http://bit.ly/2KSiYbA
Vogt A. The genetics of familial hypercholesterolemia and emerging therapies. Appl Clin Genet. 2015; 8: 27-36. Ref.: http://bit.ly/2RM6qn1
Wiegman A, Gidding SS2, Watts GF3, Chapman MJ4, Ginsberg HN, et al. Familial hypercholesterolaemia in children and adolescents: Gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015; 36: 2425-2437. Ref.: http://bit.ly/32131VX
Nordestgaard BG1, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013; 34: 3478-3490. Ref.: http://bit.ly/2Nqvlhm
Glueck CJ, Christopher C, Tsang RC, Mellies MJ. Cholesterol-free diet and the physiologic hyperlipidemia of pregnancy in familial hypercholesterolemia. Metabolism. 1980; 29: 949-955. Ref.: http://bit.ly/2KVwTxB
Salameh WA1, Mastrogiannis DS. Maternal hyperlipidemia in pregnancy. Clinical obstetrics and gynecology. 1994; 37: 66-77. Ref.: http://bit.ly/2XqUxsQ
Toleikyte I, Retterstøl K, Leren TP, Iversen PO. Pregnancy outcomes in familial hypercholesterolemia: A register-based study. Circulation. 2011; 124: 1606-1614. Ref.: http://bit.ly/2ZYIK1A
Spracklen CN, Smith CJ, Saftlas AF, Robinson JG, Ryckman KK. Maternal hyperlipidemia and the risk of preeclampsia: A Meta-analysis. Am J Epidemiol. 2014; 180: 346-358. Ref.: http://bit.ly/2KS7tkF
Hyánek J, Pehal F, Dubská L, Míková B, Gombíková L, et al. Hypercholesterolemia during pregnancy is caused by increased endogenous cholesterol synthesis. Let’s use it for screening of familial hypercholesteroemias too! Journal of Nutritional Therapeutics. 2018; 6: 79-83. Ref.: http://bit.ly/2LD1JKW
Wadsack C, Hammer A, Levak-Frank S, Desoye G, Kozarsky KF, et al. Selection cholesterol ester uptake from high density lipoprotein by human first trimester and villous trophoblast cells. Placenta. 2003; 24: 131-143. Ref.: http://bit.ly/305EOvS
Bhattacharjee J1, Ietta F, Giacomello E, Bechi N, Romagnoli R, et al. Expression and localisation of ATP binding cassette transport A1 (ABCAl) in the first trimester and term human placenta. Placenta. 2010; 31: 423-430. Ref.: http://bit.ly/2XjLBFy
Stefulj J, Panzenboeck U, Becker T, Hirschmugl B, Schweinzer C, et al. Human endothelial cells of the placental barrier efficiently deliver cholesterol to the foetal circulation via ABCA1 a ABCG-1. Circ Res. 2009 104: 600-608. Ref.: http://bit.ly/2NrMqYo
Beigel Y, Bar J, Cohen M, Hod M. Pregnancy outcome in familial homozygous hypercholesterolemic females treated with long-term plasma exchange. Acta obstetricia et gynecologica scandinavica. 1998; 77: 603-608. Ref.: http://bit.ly/2J3R4Hw ss
Anedda S, Mura S, Marcello C, Pintus P. HELP LDL-apheresis in two cases of familial hypercholesterolemic pregnant women. Transfus Apher Sci. 2011; 44: 21-24. Ref.: https://tinyurl.com/y43adqp8
Bláha M, Lánská M, Bláha V, Boudyš L, Žák, P. Pregnancy in homozygous familial hypercholesterolemia: Importance of LDL-apheresis. Atheroscler Suppl. 2015; 18: 134-139. Ref.: https://tinyurl.com/yysgfv5p
Eapen DJ, Valiani K, Reddy S, Sperling L. Management of familial hypercholesterolemia during pregnancy: case series and discussion. J Clin Lipidol. 2012; 6: 88-91. Ref.: https://tinyurl.com/y6z9srmb
Kusters DM, Homsma SJM, Hutten BA, Twickler M, Avis HJ, et al. Dilemmas in treatment of women with familial hypercholesterolaemia during pregnancy. Neth J Med. 2010; 68: 299-303. Ref.: https://tinyurl.com/yykheef8
Kempten HJM, Glatz JFC, Gevers Leuven JA, van der Voort HA, Katan MB. Serum lathosterol concentration is an indicator for whole-body cholesterol synthesis in humans. J Lipid Res. 1988; 29: 1149-1155. Ref.: https://tinyurl.com/y4r8egpr
Teunissen CE, de Vente J, von Bergman K, Bosma H, van Boxtel MPJ, et al. Serum cholesterol precursors and metabolites and cognitive performance in an aging population. Neurobiol Aging. 2003; 24: 147-155. Ref.: https://tinyurl.com/y5kbqh55
Miettinen TA, Gylling H. Effect of statins on noncholesterol levels: Implication for use of plant stanols and sterols. Am J Cardiol. 2005; 96: 40D-46D. Ref.: https://tinyurl.com/y435nqfd
Hyánek J, Pehal F, Dubská L, Dvořáková J, Maťoška V, et al. Noncholesterol sterols in healthy children and during the dietary treatment of hypercholesterolemias. [in Czech with English summary]. Česko-slovenská pediatrie. 2006; 61: 493-501.
Lupatelli G, Pirro M, Siepi D, Mannarino MR, Roscini AR, et al. Non-cholesterol sterols in different forms of primary hyperlipidemias. Nutr Metab Cardiovasc Dis. 2012; 22: 231-236. Ref.: https://tinyurl.com/y2nhgpt9
Vrablík M, Vaclová M, Tichý L, Soska V, Bláha V, et al. Familial hypercholesterolemia in the Czech Republic: More than 17 years of systematic screening within the MedPed Project. Physiol Res. 2017; 66: S1-S9. Ref.: https://tinyurl.com/yxrvlbal
Hyánek J, Pehal F, Dubská L, Martiníková V, Privarová J, et al. Lathosterol and noncholesterol sterols in routine use for the differentiation and monitoring of dietary and drug induced treatment of hypercholesterolemias in children and adolescents. Journal of nutritional therapeutics. 2014; 3: 1-12.
Mudd LM, Holzman CB, Catov JM, Senagore P, Evans R. Maternal lipids at mid-pregnancy and the risk of preterm delivery. Acta Obstet Gynecol Scand. 2012; 91: 726-735. Ref.: https://tinyurl.com/y2st443j
Catov JM, Bodnar LM, Kevin E. Early pregnancy lipid concentrations and spontaneous preterm birth. Am J Obstet Gynecol. 2007; 197: 610-617. Ref.: https://tinyurl.com/y4n92nvt
Edison RJ, Berg K, Remaley A, Kelley RI, Rotimi C. Adverse birth outcome among mothers with low serum cholesterol. Pediatrics. 2007; 120: 723-733. Ref.: https://tinyurl.com/y2t69m7e
Smith CJ, Baer RJ, Oltman SP, Breheny PJ, Bao W, et al. Maternal dyslipidemia and risk for preterm birth. PLOS One. 2018; 13: e0209579. Ref.: https://tinyurl.com/yykvhfbq
Khoury J, Amundsen AL, Tonstad S, Henriksen T, Ose L. Evidence for impaired physiological decrease in the uteroplacental vascular resistance in pregnant women with familial hypercholesterolemia. Acta Obstet Gynecol Scand. 2009; 88: 222-226. Ref.: https://tinyurl.com/yxfszygb
Fuenzalida B, Sobrevia B, Cantin C, Carvajal LP, Salsoso R, et al. Maternal supraphysiological hypercholesterolemia associates with endothelial dysfunction of the placental microvasculature. Sci Rep. 2018; 8: 7690. Ref.: https://tinyurl.com/yxewc5fb
Palinski W, Napoli C. Pathophysiolocial events during pregnancy influence development of atherosclerosis in humans. Trends Cardiovasc Med. 1999; 9: 205-214. Ref.: https://tinyurl.com/yyfhjhjy
Palinski W, Dármiento FP, Vitzum JL, de Nigris FM, Casanada F, et al. Maternal hypercholesterolemia and treatment during pregnancy influence the long-term progression of atherosclerosis in offspring of rabbits. Circ Res. 2001; 89: 991-996. Ref.: https://tinyurl.com/yxdeonjs
Palinski W, Napoli C. The fetal origins of atherosclerosis: maternal hypercholesterolemia, and cholesterol-lowering or antioxidant treatment during pregnancy influence in utero programming and postnatal susceptibility to atherogenesis. FASEB J. 2002; 16: 1348-1360. Ref.: https://tinyurl.com/yxqbv966
deAssis SM, Seguro AC, Helou CMB. Effects of maternal hypercholesterolemia on pregnancy and development of offsprings. Pediatric Nephrology. 2003; 18: 328-334.
Goharkhay N, Tamayo E, Yin H, Hankins GD, Saade GR, et al. Maternal hypercholesterolemia leads to activation of endogenous cholesterol synthesis in the offspring. Am J Obstet Gynecol. 199: 273.e1-273.e6. Ref.: https://tinyurl.com/y6eu3a4m
van den Graaf A, Vissers MN, Gaudet D, Brisson D, Sivapalaratnam S. Dyslipidemia of mothers with familial hypercholesterolemia deteriorates lipids in adult offspring. Arterioscler Thromb Vasc Biol. 2010; 30: 2673-2677. Ref.: https://tinyurl.com/y2nuf6zr
Dumolt JH, Radhakrishnan SK<, Moghadasian MH, Le K, Patel MS, et al. Maternal hypercholesterolemia enhances oxysterol concentration in mothers and newly weaned offspring but is attenuated by maternal phytosterol supplementation. J Nutr Biochem. 2018; 52: 10-17. Ref.: https://tinyurl.com/y6eaztyb
Narverud I, van Lennep JR, Christensen JJ, Versmissen J, Gran JM, et al. Maternal inheritance does not predict cholesterol levels in children with familial hypercholesterolemia. Atherosclerosis. 2015; 243: 155-160. Ref.: https://tinyurl.com/y3gd84dw
Kenis I, Tartakover-Matalon S, Cherepnin N, Drucker L, Fishman A, et al. Simvastatin has deleterious effects on human first trimester placental explants. Hum Reprod. 2005; 20: 2866-2872. Ref.: https://tinyurl.com/y4sxdq4e
Forbes K, Shah VK, Siddals K, Gibson M, Aplin JD, et al. Statins inhibit insulin-like growth factor action in first trimester placenta by altering insulin-like growth factor 1 receptor glycosylation. Mol Hum Reprod. 2015; 21: 105–114. Ref.: https://tinyurl.com/y4x9rkef
Khoury J, Henriksen T, Christophersen B, Tonstad, S. Effect of a cholesterol-lowering diet on maternal cord, and neonatal lipids, and pregnancy outcome: A randomized clinical trial. Am J Obstet Gynecol. 2005; 193: 1292-1301. Ref.: https://tinyurl.com/y4tc5uub
Karalis DG, Hill AN, Clifton S, Wild RA. The risks of statin use in pregnancy: A systematic review. J Clin Lipidol. 2016; 10: 1081-1090. Ref.: https://tinyurl.com/yybgbol5
Botha TC, Pilcher GJ, Wolmarans K, Blom DJ, Raal b FJ. Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: A retrospective review of 39 pregnancies. Atherosclerosis. 2018; 277: 502-507. Ref.: https://tinyurl.com/y6htv3zh
Ofori B, Rey E, Bérard S. Risk of congenital anomalies in pregnant users of NSAIDs. British journal of clinical pharmacology. 2007; 64: 496-509.
Avis HJ, Hutten BA, Twickler MT, Kastelein JJP, van der Post J, et al. Pregnancy in women suffering from familial hypercholesterolemia: A harmful period for both mother and newborn? Curr Opin Lipidol. 2009; 20: 484-490. Ref.: https://tinyurl.com/y6rcv5w8
Godfrey LM, Erramouspe J, Cleveland K. Teratogenic risk of statins in pregnancy. Ann Pharmacother. 2012; 46: 1419-1424. Ref.: https://tinyurl.com/y38az8rf
Bateman BT, Hernandez-Diaz S, Fischer MA, Seely EW, Ecker JL, et al. Statins and congenital malformations: Cohort study. BMJ. 2015; 350: h1035. Ref.: https://tinyurl.com/y4dumxg4
Nasioudis D, Doulaveris G, Kanninen TT. Dyslipidemia in pregnancy and maternal-fetal outcome. Minerva Ginecol. 2019; 71: 155-162. Ref.: https://tinyurl.com/y6zf9zad
Brizzi P. Tonolo G, Esposito F, Puddu L, Dessole S, et al. Lipoprotein metabolism during normal pregnancy. American journal of obstetrics and gynecology. 1999; 181: 430-434.