Olive Oil: Chemical composition and health benefits
Abstract
Adherence to a Mediterranean diet, of which olive oil is the main fat source, is associated with a lower risk of cardiovascular and neurodegenerative diseases, diabetes, and cancer. Olive oil contains several bioactive constituents, including phenolic compounds, tocopherols, and fatty acids, that possess various bioactivities such as anti-inflammatory, antimicrobial, antioxidant, anticancer, neuroprotective, and thus it benefits human health through multiple ways as it can prevent the development of various diseases and improve the general clinical picture of patients. Oleic acids and phenolic compounds have been found to reduce low-density lipoproteins (LDL) and triglyceride concentrations while they are increasing high-density lipoprotein (HDL) concentrations, showing thus a cardioprotective effect that prevents the development of atherosclerosis and cardiovascular diseases. Phenolic compounds and tocopherols, acting as free radical scavengers, prevent the development of several types of cancer, diabetes mellitus, Parkinson’s disease (PD) and Alzheimer’s disease (AD). Due to their antimicrobial, and anti-inflammatory properties, the phenolic compounds of olive oil exhibit potent microbiostatic/microbicidal activities while also reducing infections caused by microbes. Safety tests that have been carried out showed that daily olive oil consumption, while caloric intake factor is taken into account, is safe, indicating that olive oil can be used in order to prevent various diseases development and improve general health and clinical picture of patients.
References
of Environmental Science and Biotechnology, Vol. 7, No. 1, 2008, pp. 1-26. doi:10.1007/s11157-007-9120-9
2. Tamasi G, Bonechi C, Belyakova A, et all. The Olive Tree, A Source Of Antioxidant Compounds. Journal of the
Siena Academy of Sciences, 2017; 8(1):. doi:10.4081/ jsas.2016.6952
3. Rodrigues N, Casal S, Pinho T, et al. Ancient olive trees as a source of olive oils rich in phenolic compounds.
Food Chem. 2019;276:231-239. doi:10.1016/j.foodchem. 2018.09.106
4. Massaro M, Scoditti E, Carluccio MA, et al. Effects of Olive Oil on Blood Pressure: Epidemiological, Clinical, and Mechanistic Evidence. Nutrients. 2020;12(6):1548. Published 2020 May 26. doi:10.3390/nu12061548
5. Ilak Peršurić AS, Težak Damijanić A. Connections between Healthy Behaviour, Perception of Olive Oil Health
Benefits, and Olive Oil Consumption Motives. Sustainability. 2021; 13(14):7630. doi:10.3390/su13147630
6. Campestre C, Angelini G, Gasbarri C, et al. The Compounds Responsible for the Sensory Profile in Monovarietal
Virgin Olive Oils. Molecules. 2017;22(11):1833. Published 2017 Oct 27.doi:10.3390/molecules22111833
7. Moudache M, Colon M, Nerín C, Zaidi F. Phenolic content and antioxidant activity of olive by-products
and antioxidant film containing olive leaf extract. Food Chem. 2016;212:521-527. doi:10.1016/j.foodchem.
2016.06.001
8. Ahmed M, Okasha M. Olive Oil: Quality Indices. LAP LambertAcademic Publishing Kalogeropoulos N, Tsimidou
MZ. Antioxidants in Greek Virgin Olive Oils. Antioxidants (Basel). 2014;3 2016;(2):387-413. Published 2014 May 13. doi:10.3390/antiox3020387
9. Delgado AM, Issaoui M, Chammem N. Analysis of Main and Healthy Phenolic Compounds in Foods. J AOAC Int.
2019;102(5):1356-1364. doi:10.5740/jaoacint.19-0128
10. Choe E. Min DB. Mechanisms and Factors for Edible Oil Oxidation. Comprehensive Reviews in Food Science
and Food Safety, 2006; 5, 169-186. doi:10.1111/j.1541- 4337.2006.00009.x
11. Trapani G, Vagliano L, Giribaldi M, Cavallarin L, Coscia A. Olive oil: maternal and pediatric health. J Pediatr Neonat Individual Med. 2017;6(1):e060133. doi:10.7363/060133.
12. Cicerale S, Conlan XA, Sinclair AJ, Keast RS. Chemistry and health of olive oil phenolics. Crit Rev Food Sci Nutr.
2009;49(3):218-236. doi:10.1080/10408390701856223
13. Guclu G, Kelebek H, Selli S, Antioxidant activity in olive oils. In Olives and Olive Oil in Health and Disease Prevention; Academic Press: Amsterdam, Netherlands, 2021; pp. 313–325. doi:10.1016/B978-0-12-819528-
4.00031-6
14. Papanikolaou C, Melliou E, Magiatis P. Olive Oil Phenols [Internet]. Functional Foods. Intech Open; 2019. doi:
10.5772/intechopen.81394
15. Starec M, Calabretti A, Berti F, Forzato C. Oleocanthal Quantification Using 1H NMR Spectroscopy and Polyphenols HPLC Analysis of Olive Oil from the Bianchera/ Belica Cultivar. Molecules. 2021;26(1):242. Published
2021 Jan 5. doi:10.3390/molecules26010242
16. Medina E, Romero C, Brenes M. et all. Antimicrobial Activity of Olive Oil, Vinegar an Various Beverages against Foodborne Pathogens. Journal of Food Protection, 2007; 70, 1194-1199. doi:10.4315/0362-028X-70.5.1194
17. Romero C, Medina E, Vargas J, et all. In vitro activity of olive oil polyphenols against Helicobacter pylori. J
Agric Food Chem. 2007;55(3):680-686. doi:10.1021/ jf0630217
18. Sameh B K, Dorsaf M, Masarra M, Effects of Minor Components of Olive Oil on Health. J Complement Med Alt Healthcare. 2018; 5(2): 555658. doi:10.19080/ Jcmah.2018.05.555658.
19. Blekas G, Tsimidou M, Boskou, D.Olive Oil Composition. In Olive Oil; AOCS Publishing: 2006. doi: 10.1201/
9781439832028.pt2.
20. Giuliani A, Cerretani L, Cichelli A. Chlorophylls in olive and in olive oil: Chemistry and occurrences. Critical Reviews in Food Science and Nutrition. 51: 678–690 (2011). doi:10.1080/10408391003768199
21. Abenavoli L, Milanović M, Milić N, et all. Olive oil antioxidants and non-alcoholic fatty liver disease. Expert
Rev Gastroenterol Hepatol. 2019;13(8):739-749. doi: 10.1080/17474124.2019.1634544
22. Yubero-Serrano EM, Lopez-Moreno J, Gomez-Delgado et all. Extra virgin olive oil: More than a healthy fat.
Eur J Clin Nutr. 2019;72(Suppl 1):8-17. doi:10.1038/ s41430-018-0304-x
23. Babu S, Jayaraman S. An update on β-sitosterol: A potential herbal nutraceutical for diabetic management.
Biomed Pharmacother. 2020;131:110702. doi:10.1016/j.biopha.2020.110702
24. Vurmaz A, Ertekin A, Sabaner MC,et all. Effects of vitamin E in a glucocorticoid induced cataract model in
chicken embryos. Biotech Histochem. 2021;96(6):431- 438. doi:10.1080/10520295.2020.1818284
25. Bermúdez B, Pacheco YM, López S, et all. Digestion and absorption of olive oil. Grasas y Aceites. 55, 1 (Mar.
2004), 1–10. doi:10.3989/gya.2004.v55.i1.141
26. Beauchamp GK, Keast RS, Morel D, et al. Phytochemistry: ibuprofen-like activity in extra-virgin olive oil.
Nature. 2005;437(7055):45-46. doi:10.1038/437045a
27. Agrawal K, Melliou E, Li X, et al. Oleocanthal-rich extra virgin olive oil demonstrates acute anti-platelet effects in healthy men in a randomized trial. J Funct Foods. 2017;36:84-93. doi:10.1016/j.jff.2017.06.046
28. Kiritsakis, AK. Flavor components of olive oil—A review. J Amer Oil Chem Soc 75, 673–681 (1998). doi:10.1007/
s11746-998-0205-6
29. Visioli F, Bogani P, Galli C. Healthful Properties of Olive Oil Minor Components. Olive Oil (Second Edition) Chemistry and Technology, Editor(s): Dimitrios Boskou, AOCS Press, 2006; 173–190. doi:10.1201/9781439832028.
ch8.
30. Rus A, Molina F, Martínez-Ramírez MJ, et all. , Del Moral ML. Effects of Olive Oil Consumption on Cardiovascular Risk Factors in Patients with Fibromyalgia. Nutrients. 2020;12(4):918. Published 2020 Mar 27. doi:10.3390/ nu12040918
31. Medina E, de Castro A, Romero C, et all. Comparison of the concentrations of phenolic compounds in olive oils and other plant oils: correlation with antimicrobial activity. J Agric Food Chem. 2006;54(14):4954-4961. doi:10.1021/jf0602267
32. Difonzo G, Squeo G, Calasso M. et al. Olive leaf extract as natural preservative. Ital. J. Food Sci. 31, 187–191.
Available online at: 2019; https://itjfs.com/index.php/ ijfs/issue/view/36
33. Medina E, Romero C, Brenes M, De Castro A. Antimicrobial activity of olive oil, vinegar, and various beverages against foodborne pathogens. J Food Prot. 2007;70(5):1194-1199. doi:10.4315/0362- 028x-70.5.1194
34. Guo L, Sun Q, Gong S, et al. Antimicrobial Activity and Action Approach of the Olive Oil Polyphenol Extract Against Listeria monocytogenes. Front Microbiol. 2019;10:1586. Published 2019 Jul 23. doi:10.3389/fmicb.2019.01586
35. Visioli F, Caruso D, Grande S, et al. Virgin Olive Oil Study (VOLOS): vasoprotective potential of extra virgin olive oil in mildly dyslipidemic patients. Eur J Nutr. 2005;44(2):121-127. doi:10.1007/s00394-004-0504-0
36. Mehmood A, Usman M, Patil P, Zhao L, Wang C. A review on management of cardiovascular diseases by olive polyphenols. Food Sci Nutr. 2020;8(9):4639-4655. Published 2020 Aug 13. doi:10.1002/fsn3.1668
37. Stevens Y, Winkens B, Jonkers D, Masclee A. The effect of olive leaf extract on cardiovascular health markers:
a randomized placebo-controlled clinical trial. Eur J Nutr. 2021;60(4):2111-2120. doi:10.1007/s00394- 020-02397-9
38. Marcelino G, Hiane PA, Freitas KC, et al. Effects of Olive Oil and Its Minor Components on Cardiovascular Diseases, Inflammation, and Gut Microbiota. Nutrients. 2019;11(8):1826. Published 2019 Aug 7. doi:10.3390/
nu11081826
39. Violi F, Pastori D, Pignatelli P, Carnevale R. Nutrition, Thrombosis, and Cardiovascular Disease. Circ Res.
2020;126(10):1415-1442. doi:10.1161/CIRCRESAHA. 120.315892
40. Covas MI, Konstantinidou V, Fitó M. Olive oil and cardiovascular health. J Cardiovasc Pharmacol. 2009;54(6):477- 482. doi:10.1097/FJC.0b013e3181c5e7fd
41. Covas MI, Nyyssönen K, Poulsen HE, et al. The effect of polyphenols in olive oil on heart disease risk factors:
a randomized trial. Ann Intern Med. 2006;145(5):333- 341. doi:10.7326/0003-4819-145-5-200609050-00006
42. Machowetz A, Poulsen HE, Gruendel S, et al. Effect of olive oils on biomarkers of oxidative DNA stress in Northern and Southern Europeans. FASEB J. 2007;21(1):45- 52. doi:10.1096/fj.06-6328com
43. Turner R, Etienne N, Alonso MG, et al. Antioxidant and anti-atherogenic activities of olive oil phenolics. Int J
Vitam Nutr Res. 2005;75(1):61-70. doi:10.1024/0300- 9831.75.1.61
44. Mazzocchi A, Leone L, Agostoni C, Pali-Schöll I. The Secrets of the Mediterranean Diet. Does [Only] Olive Oil Matter?. Nutrients. 2019;11(12):2941. Published 2019 Dec 3. doi:10.3390/nu11122941
45. Lopez-Miranda J, Delgado-Lista J, Perez-Martinez P, et al. Olive oil and the haemostatic system. Mol Nutr Food Res. 2007;51(10):1249-1259. doi:10.1002/ mnfr.200600307
46. Cariello M, Contursi A, Gadaleta RM, et al. Extra-Virgin Olive Oil from Apulian Cultivars and Intestinal Inflammation. Nutrients. 2020;12(4):1084. Published 2020 Apr 14. doi:10.3390/nu12041084
47. Pérez-Jiménez F, Lista JD, Pérez-Martínez P, et al. Olive oil and haemostasis: a review on its healthy effects. Public Health Nutr. 2006;9(8A):1083-1088. doi:10.1017/ S1368980007668566
48. Devaraj S, Li D, Jialal I. The effects of alpha tocopherol supplementation on monocyte function. Decreased lipid oxidation, interleukin 1 beta secretion, and monocyte adhesion to endothelium. J Clin Invest. 1996;98(3):756-
763. doi:10.1172/JCI118848
49. Gorzynik-Debicka M, Przychodzen P, Cappello F, et al. Potential Health Benefits of Olive Oil and Plant Polyphenols. Int J Mol Sci. 2018;19(3):686. Published 2018 Feb 28. doi:10.3390/ijms19030686
50. Zamora-Zamora F, Martínez-Galiano J M, Gaforio J J, et al. Effects of olive oil on blood pressure: A systematic
review and meta-analysis.Grasas Y Aceites, 2018; 69(4):, e272. doi:10.3989/gya.0105181
51. Martín-Peláez S, Castañer O, Konstantinidou V, et al. Effect of olive oil phenolic compounds on the expression
of blood pressure-related genes in healthy individuals. Eur J Nutr. 2017;56(2):663-670. doi:10.1007/s00394-
015-1110-z
52. Moreno-Luna R, Muñoz-Hernandez R, Miranda ML, et al. Olive oil polyphenols decrease blood pressure and
improve endothelial function in young women with mild hypertension. Am J Hypertens. 2012;25(12):1299- 1304. doi:10.1038/ajh.2012.128
53. Bondia-Pons I, Schröder H, Covas MI, et al. Moderate consumption of olive oil by healthy European men
reduces systolic blood pressure in non-Mediterranean participants. J Nutr. 2007;137(1):84-87. doi:10.1093/
jn/137.1.84
54. Muzammil S, Kanwal H, Shahzad T, et al. Chapter 2 - Olive oil,Green Sustainable Process for Chemical and Environmental Engineering and Science.Elsevier.2021,Pages 17-29. doi:10.1016/B978-0-12-821886-0.00009-9
55. Khalatbary AR. Olive oil phenols and neuroprotection. Nutr Neurosci. 2013;16(6):243-249. doi:10.1179/147
6830513Y.0000000052
56. Martínez-Huélamo M, Rodríguez-Morató J, Boronat A, de la Torre R. Modulation of Nrf2 by Olive Oil and Wine
Polyphenols and Neuroprotection. Antioxidants (Basel). 2017;6(4):73. Published 2017 Sep 26. doi:10.3390/
antiox6040073
57. Visioli F, Franco M, Toledo E, et al. Olive oil and prevention of chronic diseases: Summary of an International
conference. Nutr Metab Cardiovasc Dis. 2018;28(7):649- 656. doi:10.1016/j.numecd.2018.04.004
58. Salvini S, Sera F, Caruso D, et al. Daily consumption of a high-phenol extra-virgin olive oil reduces oxidative
DNA damage in postmenopausal women. Br J Nutr. 2006;95(4):742-751. doi:10.1079/bjn20051674
59. Bu Y, Rho S, Kim J, et al. Neuroprotective effect of tyrosol on transient focal cerebral ischemia in rats. Neurosci Lett. 2007;414(3):218-221. doi:10.1016/j. neulet.2006.08.094
60. Angeloni C, Malaguti M, Barbalace MC, Hrelia S. Bioactivity of Olive Oil Phenols in Neuroprotection. Int J Mol Sci. 2017;18(11):2230. Published 2017 Oct 25. doi:10.3390/ijms18112230
61. Omar SH. Cardioprotective and neuroprotective roles of oleuropein in olive. Saudi Pharm J. 2010;18(3):111-
121. doi:10.1016/j.jsps.2010.05.005
62. Pérez AG, León L, Pascual M, de la Rosa R, Belaj A, Sanz C. Analysis of Olive (Olea Europaea L.) Genetic Resources in Relation to the Content of Vitamin E in Virgin Olive Oil. Antioxidants (Basel). 2019;8(8):242. Published 2019 Jul 25. doi:10.3390/antiox8080242
63. Bazoti FN, Bergquist J, Markides KE, Tsarbopoulos A. Noncovalent interaction between amyloid-beta-peptide
(1-40) and oleuropein studied by electrospray ionization mass spectrometry. J Am Soc Mass Spectrom. 2006;17(4):568-575. doi:10.1016/j.jasms.2005.11.016
64. Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. Oxidative stress and the amyloid
beta peptide in Alzheimer’s disease. Redox Biol. 2018;14:450-464. doi:10.1016/j.redox.2017.10.014
65. Butterfield DA, Lauderback CM. Lipid peroxidation and protein oxidation in Alzheimer’s disease brain:
potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative
stress. Free Radic Biol Med. 2002;32(11):1050-1060. doi:10.1016/s0891-5849(02)00794-3
66. Querfurth HW, LaFerla FM. Alzheimer’s disease [published correction appears in N Engl J Med. 2011 Feb 10;364(6):588]. N Engl J Med. 2010;362(4):329-344. doi:10.1056/NEJMra0909142
67. Visioli F, Galli C, Plasmati E, et al. Olive phenol hydroxytyrosol prevents passive smoking-induced oxidative
stress. Circulation. 2000;102(18):2169-2171. doi:10.1161/01.cir.102.18.2169
68. Villareal MO, Sasaki K, Margout D, et al. Neuroprotective effect of Picholine virgin olive oil and its hydroxycinnamic acids component against β-amyloid-induced toxicity in SH-SY5Y neurotypic cells. Cytotechnology. 2016;68(6):2567-2578. doi:10.1007/s10616-016-9980-3
69. Gonzalo-Gobernado R, Ayuso MI, Sansone L, et al. Neuroprotective Effects of Diets Containing Olive Oil and DHA/EPA in a Mouse Model of Cerebral Ischemia. Nutrients. 2019;11(5):1109. Published 2019 May 18. doi:10.3390/nu11051109
70. Crespo MC, Tomé-Carneiro J, Dávalos A, Visioli F. Pharma-Nutritional Properties of Olive Oil Phenols. Transfer of New Findings to Human Nutrition. Foods. 2018;7(6):90. Published 2018 Jun 11. doi:10.3390/ foods7060090
71. Visioli F, Davalos A, López de Las Hazas MC, et all. An overview of the pharmacology of olive oil and its active
ingredients. Br J Pharmacol. 2020;177(6):1316-1330. doi:10.1111/bph.14782
72. Bulotta S, Celano M, Lepore SM, et al. Beneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: focus on protection against cardiovascular and metabolic diseases. J Transl Med. 2014;12:219. Published 2014 Aug 3. doi:10.1186/s12967-014-0219-9
73. Fernández del Río L, Gutiérrez-Casado E, Varela-López A, Villalba JM. Olive Oil and the Hallmarks of Aging.
Molecules. 2016;21(2):163. Published 2016 Jan 29. doi:10.3390/molecules21020163
74. Xin Y, Li XY, Sun SR, et all. Vegetable Oil Intake and Breast Cancer Risk: a Meta-analysis. Asian Pac J Cancer
Prev. 2015;16(12):5125-5135. doi:10.7314/apjcp. 2015.16.12.5125
75. Hatimy A, El Kadmiri N. 2021 “Benefits of Phenolic Compounds Isolated from Olive Oil on Prevention of Cancer ”,Health Sciences, 2020. doi:10.15342/hs.2020.288.
76. Baumann L, Weisberg E Chapter 122—olive oil in botanical cosmeceuticals. In: Preedy VR, Watson RR (eds)
Olives and olive oil in health and disease prevention. Academic Press, San Diego, 2010; pp 1117–1124. doi:10.1016/B978- 0-12-374420-3.00122-4
77. Baci D, Gallazzi M, Cascini C, et al. Downregulation of Pro-Inflammatory and Pro-Angiogenic Pathways in Prostate Cancer Cells by a Polyphenol-Rich Extract from Olive Mill Wastewater. Int J Mol Sci.2019;20(2):307. Published 2019 Jan 14. doi:10.3390/ijms20020307
78. Farràs M, Almanza-Aguilera E, Hernáez Á, et al. Beneficial effects of olive oil and Mediterranean diet on
cancer physio-pathology and incidence. Semin Cancer Biol. 2021;73:178-195. doi:10.1016/j.semcancer. 2020.11.011
79. Azzeh FS, Alshammari EM, Alazzeh AY, et al. Healthy dietary patterns decrease the risk of colorectal cancer
in the Mecca Region, Saudi Arabia: a case-control study. BMC Public Health. 2017;17(1):607. Published 2017
Jun 29. doi:10.1186/s12889-017-4520-4
80. Juan ME, Planas JM. Cancer chemopreventive activity of maslinic acid, a pentacyclic triterpene from olives
and olive oil. Olives and Olive Oil in Health and Disease Prevention.2021;525–35. doi:10.1016/B978-0- 12-819528-4.00026-2
81. Yumi ZHY Hashim, M Eng, Chris IR Gill, et all. Components of Olive Oil and Chemoprevention of Colorectal Cancer, Nutrition Reviews, Volume 63, Issue 11, November 2005, Pages 374–386. doi:10.1111/j.1753-4887.2005.
tb00374.x
82. Stoneham M, Goldacre M, Seagroatt V, et all. diet and colorectal cancer: an ecological study and a hypothesis.
J Epidemiol Community Health. 2000;54(10):756-760. doi:10.1136/jech.54.10.756
83. López S, Pacheco YM, Bermúdez B, et all. Olive oil and cancer. Grasasaceites . 2004 Mar.30 [cited 2023Apr.30];55(1):33-41. doi:10.3989/gya.2004.v55. i1.145
84. Borzì AM, Biondi A, Basile F, et all. M. Olive Oil Effects on Colorectal Cancer. Nutrients. 2018;11(1):32. Published 2018 Dec 23. doi:10.3390/nu11010032
85. Yousefi Z, Rezaeigolestani M, Hashemi M. Biological Properties of Olive Oil. J Hum Environ Health Promot.
2018; 4(2): 50-4. doi: 10.29252/jhehp.4.2.2
86. Xiao J. Natural polyphenols and diabetes: understanding their mechanism of action. Curr Med Chem.
2015;22(1):2-3. doi:10.2174/092986732166614101 2173816
87. Ray NB, Hilsabeck KD, Karagiannis TC, McCord DE. Bioactive Olive Oil Polyphenols in the Promotion of Health.
In: Singh RB, Watson RR, Takahashi T, eds. The Role of Functional Food Security in Global Health. Oxford: Elsevier Inc.; 2019: 623–637. doi:10.1016/B978-0-12- 813148-0.00036-0
88. Wu L, Velander P, Liu D, et all. Olive Component Oleuropein Promotes β-Cell Insulin Secretion and Protects β Cells from Amylin Amyloid-Induced Cytotoxicity. Biochemistry. 2017;56(38):5035-5039. doi:10.1021/ acs.biochem.7b00199
89. Taqui B, Asadi F, Capobianco E, et all. Addition of olive oil to diet of rats with mild pre-gestational diabetes
impacts offspring β-cell development. J Endocrinol. 2020;246(2):175-187. doi:10.1530/JOE-20-0047
90. Rajput T, Yousaf M, Naveed A, et all. Hypolipidemic Effect of Extra Virgin Olive Oil in Diabetic Rats. J. Rawalpindi Med. Coll. 2012, 16, 70–72.
91. Keceli TM, Kamiloglu S, Capanoglu E. Phenolic Compounds of Olives and Olive Oil and their Bioavailability.
In Olives and Olive Oil as Functional Foods 2017; (eds F. Shahidi and A. Kiritsakis). doi:10.1002/9781119135340.
ch24
92. Franconi F, Campesi I, Romani A. Is Extra Virgin Olive Oil an Ally for Women’s and Men’s Cardiovascular Health?. Cardiovasc Ther. 2020;2020:6719301. Published 2020 Apr 24. doi:10.1155/2020/6719301
93. Quintero-Flórez A, Pereira-Caro G, Sánchez-Quezada C, et al. Effect of olive cultivar on bioaccessibility and
antioxidant activity of phenolic fraction of virgin olive oil. Eur J Nutr. 2018;57(5):1925-1946. doi:10.1007/
s00394- 017-1475-2