Hostname: page-component-8448b6f56d-xtgtn Total loading time: 0 Render date: 2024-04-19T12:41:19.765Z Has data issue: false hasContentIssue false
  • English
  • Français

Comparison of atherogenic risk factors among poorly controlled and well-controlled adolescent phenylketonuria patients

Published online by Cambridge University Press:  17 August 2015

Mehmet Gündüz ,
Sevim Çakar ,
Pınar Kuyum ,
Balahan Makay  and
Nur Arslan
Mehmet Gündüz
Affiliation:
Division of Metabolism, Ankara Children Education and Research Hospital, Ankara, Turkey
Sevim Çakar
Affiliation:
Department of Pediatrics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
Pınar Kuyum
Affiliation:
Department of Pediatrics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
Balahan Makay
Affiliation:
Department of Pediatrics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
Nur Arslan*
Affiliation:
Department of Pediatrics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey Department of Molecular Medicine, Izmir, Turkey
*
Correspondence to: Dr N. Arslan, MD, PhD, Department of Pediatrics, Division of Pediatric Gastroenterology, Nutrition and Metabolism, Faculty of Medicine, Department of Molecular Medicine, Dokuz Eylul University, Izmir, Turkey. Tel: +0090 2324126107; Fax: +0090 2324126005; E- mail: nur.arslan@deu.edu.tr
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Previous studies investigating the known risk factors of atherosclerosis in phenylketonuria patients have shown conflicting results. The primary aim of our study was to investigate the serum atherogenic markers in adolescent classical phenylketonuria patients and compare these parameters with healthy peers. The secondary aim was to compare these atherogenic markers in well-controlled and poorly controlled patients.

Methods

A total of 59 patients (median age: 12.6 years, range: 11–17 years) and 44 healthy controls (median age: 12.0 years, range: 11–15 years) were enrolled in our study. Phenylketonuria patients were divided into two groups: well-controlled (serum phenylalanine levels below 360 µmol/L; 24 patients) and poorly controlled patients (serum phenylalanine levels higher than 360 µmol/L).

Results

The mean high-density lipoprotein cholesterol levels of well-controlled patients (1.0±0.2 mmol/L) were significantly lower compared with poorly controlled patients and controls (1.1±0.2 mmol/L, p=0.011 and 1.4±0.2 mmol/L, p<0.001, respectively). Poorly controlled patients had lower high-density lipoprotein cholesterol levels than healthy controls (p=0.003). Homocysteine levels of both well-controlled (9.8±6.4 µmol/L) and poorly controlled (9.2±5.6 µmol/L) patients were higher compared with controls (5.8±1.8 µmol/L, p<0.01). The mean platelet volume of well-controlled patients (9.5±1.1 fL) was higher than that of poorly controlled patients and controls (8.9±0.8 fL, p=0.024 and 7.7±0.6 fL, p<0.001, respectively).

Conclusion

Lower high-density lipoprotein cholesterol and higher homocysteine and mean platelet volume levels were detected in phenylketonuria patients. In particular, these changes were more prominent in well-controlled patients. We conclude that phenylketonuria patients might be at risk for atherosclerosis, and therefore screening for atherosclerotic risk factors should be included in the phenylketonuria therapy and follow-up in addition to other parameters.

Keywords

Phenylketonurialow-density lipoprotein cholesterolhigh-density lipoprotein cholesterolmean platelet volumehomocysteine
Type
Original Articles
Information
Cardiology in the Young , Volume 26 , Issue 5 , June 2016 , pp. 901 - 908
Check for updates
Copyright
© Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Jahja, R, Huijbregts, SC, de Sonneville, LM, van der Meere, JJ, van Spronsen, FJ. Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria. J Pediatr 2014; 164: 895–899.Google Scholar
2. Rocha, JC, Martins, MJ. Oxidative stress in phenylketonuria: future directions. J Inherit Metab Dis 2012; 35: 381–398.Google Scholar
3. Schulpis, KH, Papassotiriou, I, Tsakiris, S, Vounatsou, M, Chrousos, GP. Increased plasma adiponectin concentrations in poorly controlled patients with phenylketonuria normalize with a strict diet: evidence for catecholamine-mediated adiponectin regulation and a complex effect of phenylketonuria diet on atherogenesis risk factors. Metabolism 2005; 54: 1350–1355.Google Scholar
4. Okano, Y, Nagasaka, H. Optimal serum phenylalanine for adult patients with phenylketonuria. Mol Genet Metab 2013; 110: 424–430.Google Scholar
5. Sanayama, Y, Nagasaka, H, Takayanagi, M, et al. Experimental evidence that phenylalanine is strongly associated to oxidative stress in adolescents and adults with phenylketonuria. Mol Genet Metab 2011; 103: 220–225.Google Scholar
6. Nagasaka, H, Tsukahara, H, Okano, Y, et al. Changes of lipoproteins in phenylalanine hydroxylase-deficient children during the first year of life. Clin Chim Acta 2014; 433C: 1–4.Google Scholar
7. Rocha, JC, van Spronsen, FJ, Almeida, MF, et al. Dietary treatment in phenylketonuria does not lead to increased risk of obesity or metabolic syndrome. Mol Genet Metab 2012; 107: 659–663.Google Scholar
8. Colomé, C, Artuch, R, Lambruschini, N, Cambra, FJ, Campistol, J, Vilaseca, M. Is there a relationship between plasma phenylalanine and cholesterol in phenylketonuric patients under dietary treatment? Clin Biochem 2001; 34: 373–376.Google Scholar
9. Schulpis, KH, Karikas, GA, Papakonstantinou, E. Homocysteine and other vascular risk factors in patients with phenylketonuria on a diet. Acta Paediatr 2002; 91: 905–909.Google Scholar
10. Ait-Oufella, H, Sage, AP, Mallat, Z, Tedgui, A. Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis. Circ Res 2014; 114: 1640–1660.Google Scholar
11. Perk, J, De Backer, G, Gohlke, H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012): the fifth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Int J Behav Med 2012; 19: 403–488.Google Scholar
12. Li, S, Chen, W, Srinivasan, SR, et al. Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. JAMA 2003; 290: 2271–2276.CrossRefGoogle ScholarPubMed
13. Raitakari, OT, Juonala, M, Kähönen, M, et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the cardiovascular risk in young finns study. JAMA 2003; 290: 2277–2283.CrossRefGoogle ScholarPubMed
14. Agostoni, C, Scaglioni, S, Bonvissuto, M, Bruzzese, MG, Giovannini, M, Riva, E. Biochemical effects of supplemented long-chain polyunsaturated fatty acids in hyperphenylalaninemia. Prostaglandins Leukot Essent Fatty Acids 2001; 64: 111–115.Google Scholar
15. Nagasaka, H, Okano, Y, Kimura, A, et al. Oxysterol changes along with cholesterol and vitamin D changes in adult phenylketonuric patients diagnosed by newborn mass-screening. Clin Chim Acta 2013; 416: 54–59.Google Scholar
16. Schulpis, KH, Karakonstantakis, T, Bartzeliotou, A, Karikas, GA, Papassotiriou, I. The association of serum lipids, lipoproteins and apolipoproteins with selected trace elements and minerals in phenylketonuric patients on diet. Clin Nutr 2004; 23: 401–407.CrossRefGoogle ScholarPubMed
17. Schulpis, KH, Bartzeliotou, A, Tsakiris, S, Gounaris, A, Papassotiriou, I. Serum paraoxonase/arylesterase activities in phenylketonuric patients on diet. Eur J Clin Nutr 2007; 61: 803–808.Google Scholar
18. Lucock, M, Yates, Z, Hall, K, et al. The impact of phenylketonuria on folate metabolism. Mol Genet Metab 2002; 76: 305–312.Google Scholar
19. Huemer, M, Födinger, M, Bodamer, OA, et al. Total homocysteine, B-vitamins and genetic polymorphisms in patients with classical phenylketonuria. Mol Genet Metab 2008; 94: 46–51.Google Scholar
20. Huemer, M, Simma, B, Mayr, D, et al. Free asymmetric dimethylarginine (ADMA) is low in children and adolescents with classical phenylketonuria (PKU). J Inherit Metab Dis 2012; 35: 817–821.CrossRefGoogle ScholarPubMed
21. Colomé, C, Artuch, R, Sierra, C, et al. Plasma thiols and their determinants in phenylketonuria. Eur J Clin Nutr 2003; 57: 964–968.Google Scholar
22. Mütze, U, Beblo, S, Kortz, L, et al. Metabolomics of dietary fatty acid restriction in patients with phenylketonuria. PLoS One 2012; 7: e43021.Google Scholar
23. Walter, JH, Lachmann, RH, Burgard, P. Hyperphenylalaninemia. In: Saudubray JM, van den Berge G, Walter JH (eds). Inborn Metabolic Diseases: Diagnosis and Treatment, 5th edn. Springer-Verlag, Berlin Heidelberg, 2012: 253–264.Google Scholar
24. Cole, TJ, Lobstein, T. Extended international (IOTF) body mass index cut-offs for thinness, overweight and obesity. Pediatr Obes 2012; 7: 284–294.Google Scholar
25. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: a working group report from the National High Blood Pressure Education Program. Pediatrics 1996; 98: 649–658.Google Scholar
26. Blau, N, van Spronsen, FJ, Levy, HL. Phenylketonuria. Lancet 2010; 376: 1417–1427.CrossRefGoogle ScholarPubMed
27. Das, AM, Goedecke, K, Meyer, U, et al. Dietary habits and metabolic control in adolescents and young adults with phenylketonuria: self-imposed protein restriction may be harmful. JIMD Rep 2014; 13: 149–158.CrossRefGoogle Scholar
28. Friedewald, WT, Levy, RI, Fredrickson, DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499–502.Google Scholar
29. Jian, ZH, Chiang, YC, Lung, CC, et al. Vegetarian diet and cholesterol and TAG levels by gender. Public Health Nutr 2015; 18: 721–726.Google Scholar
30. Huang, YW, Jian, ZH, Chang, HC, et al. Vegan diet and blood lipid profiles: a cross-sectional study of pre and postmenopausal women. BMC Womens Health 2014; 14: 55.Google Scholar
31. Chiang, JK, Lin, YL, Chen, CL, et al. Reduced risk for metabolic syndrome and insulin resistance associated with ovo-lacto-vegetarian behavior in female Buddhists: a case-control study. PLoS One 2013; 8: e71799.Google Scholar
32. Bradbury, KE, Crowe, FL, Appleby, PN, Schmidt, JA, Travis, RC, Key, TJ. Serum concentrations of cholesterol, apolipoprotein A-I and apolipoprotein B in a total of 1694 meat-eaters, fish-eaters, vegetarians and vegans. Eur J Clin Nutr 2014; 68: 178–183.Google Scholar
33. Holven, KB, Aukrust, P, Retterstøl, K, et al. The antiatherogenic function of HDL is impaired in hyperhomocysteinemic subjects. J Nutr 2008; 138: 2070–2075.Google Scholar
34. Castillo, M, Zafra, MF, Garcı´a-Peregrin, E. Inhibition of brain and liver 3-hydroxy-3-methylglutaryl-CoA reductase and mevalonate-5-pyrophosphate decarboxylase in experimental hyperphenylalaninemia. Neurochem Res 1988; 13: 551–555.Google Scholar
35. Yu, S, Yarnell, JW, Sweetnam, P, Bolton, CH. High density lipoprotein subfractions and the risk of coronary heart disease: 9-years follow-up in the Caerphilly Study. Atherosclerosis 2003; 166: 331–338.Google Scholar
36. Jacobs, DR, Mebane, IL, Bangdiwala, SI, Criqui, MH, Tyroler, HA. High density cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the lipid research clinics prevalence. Am J Epidemiol 1990; 131: 32–47.Google Scholar
37. Ware, J, Corken, A, Khetpal, R. Platelet function beyond hemostasis and thrombosis. Curr Opin Hematol 2013; 20: 451–456.Google Scholar
38. Rondina, MT, Weyrich, AS, Zimmerman, GA. Platelets as cellular effectors of inflammation in vascular diseases. Circ Res 2013; 112: 1506–1519.Google Scholar
39. Chesnutt, JK, Han, HC. Platelet size and density affect shear-induced thrombus formation in tortuous arterioles. Phys Biol 2013; 10: 056003.Google Scholar
40. Martin, JF, Trowbridge, EA, Salmon, G, Plumb, J. The biological significance of platelet volume: Its relationship to bleeding time, thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb Res 1983; 32: 443–460.Google Scholar
41. Berger, JS, Eraso, LH, Xie, D, Sha, D, Mohler, ER. Mean platelet volume and prevalence of peripheral artery disease, the National Health and Nutrition Examination Survey, 1999-2004. Atherosclerosis 2010; 213: 586–591.CrossRefGoogle ScholarPubMed
42. Chu, SG, Becker, RC, Berger, PB, et al. Mean platelet volume as a predictor of cardiovascular risk: a systematic review and meta-analysis. J Thromb Haemost 2009; 8: 148–155.Google Scholar
43. Makay, B, Turkyilmaz, Z, Unsal, E. Mean platelet volume in children with familial Mediterranean fever. Clin Rheumatol 2009; 28: 975–978.Google Scholar
44. Arslan, N, Makay, B. Mean platelet volume in obese adolescents with nonalcoholic fatty liver disease. J Pediatr Endocrinol Metab 2010; 23: 807–813.Google Scholar
45. Arslan, N, Makay, B, Hızlı, S, et al. Assesment of atherosclerosis in obese adolescents: positive corelation of mean platelet volume and carotid intima media thickness. J Paediatr Child Health 2013; 49: 963–968.Google Scholar
46. Dolasık, I, Sener, SY, Celebi, K, Aydın, ZM, Korkmaz, U, Canturk, Z. The effect of metformin on mean platelet volume in diabetic patients. Platelets 2013; 24: 118–121.Google Scholar
47. Khode, V, Sindhur, J, Kanbur, D, Ruikar, K, Nallulwar, S. Mean platelet volume and other platelet volume indices in patients with stable coronary artery disease and acute myocardial infarction: a case control study. J Cardiovasc Dis Res 2012; 3: 272–275.Google Scholar
48. Verdoia, M, Camaro, C, Barbieri, L, et al. Mean platelet volume and the risk of periprocedural myocardial infarction in patients undergoing coronary angioplasty. Atherosclerosis 2013; 228: 136–141.Google Scholar
49. Ahluwalia, N, Blacher, J, Szabo de Edelenyi, F, et al. Prognostic value of multiple emerging biomarkers in cardiovascular risk prediction in patients with stable cardiovascular disease. Atherosclerosis 2013; 228: 478–484.CrossRefGoogle ScholarPubMed
50. Steed, MM, Tyagi, SC. Mechanisms of cardiovascular remodeling in hyperhomocysteinemia. Antioxid Redox Signal 2011; 15: 1927–1943.Google Scholar
51. Signorello, MG, Pascale, R, Leoncini, G. Reactive oxygen species accumulation induced by homocysteine in human platelets. Ann N Y Acad Sci 2002; 973: 546–549.Google Scholar
52. Holven, KB, Aukrust, P, Pedersen, TM, Ose, L, Nenseter, MS. Enhanced platelet activation in hyperhomocysteinemic individuals. J Thromb Haemost 2007; 5: 193–195.Google Scholar
53. Becker, JS, Adler, A, Schneeberger, A, et al. Hyperhomocysteinemia, a cardiac metabolic disease: role of nitric oxide and the p22phox subunit of NADPH oxidase. Circulation 2005; 111: 2112–2118.Google Scholar
54. Vugteveen, I, Hoeksma, M, Monsen, AL, et al. Serum vitamin B12 concentrations within reference values do not exclude functional vitamin B12 deficiency in PKU patients of various ages. Mol Genet Metab 2011; 102: 13–17.Google Scholar
55. Thiele, AG, Weigel, JF, Ziesch, B, et al. Nutritional changes and micronutrient supply in patients with phenylketonuria under therapy with tetrahydrobiopterin (BH(4)). JIMD Rep 2013; 9: 31–40.Google Scholar
56. Rohde, C, von Teeffelen-Heithoff, A, Thiele, AG, et al. PKU patients on a relaxed diet may be at risk for micronutrient deficiencies. Eur J Clin Nutr 2014; 68: 119–124.Google Scholar