Carbohydrate status in patients with phenylketonuria
Tóm tắt
In patients with phenylketonuria (PKU), a low-phenylalanine (Phe) diet supplemented with low-protein foods and a Phe-free amino acid mixture favors a dietary intake rich in carbohydrates, but little is known about how these molecules are metabolized in this setting. The objective of the present study was to analyze carbohydrate metabolism in patients with hyperphenylalaninemia. We conducted a multicenter cross-sectional study to investigate biochemical markers of basal and postprandial carbohydrate metabolism in PKU patients according to age, Phe tolerance, waist circumference and body mass index (BMI), diet, tetrahydrobiopterin (BH4) supplementation, and adherence to treatment. Basal biomarkers and anthropometric parameters were also evaluated in patients with mild hyperphenylalaninemia (MHPA) and in healthy controls. A total of 83 patients aged 4–52 years were studied; 68.7% had PKU and 31.3% had MHPA. 68 healthy controls of similar sex and age were also evaluated Metabolic control was adequate in 71.9% of PKU patients. Fasting glucose levels (mean 80.77 ± 8.06 mg/dL) were high in just one patient, but fasting insulin levels, with a mean of 12.74 ± 8.4 mIU/L, were altered in 15 PKU patients (26.3%) and markedly higher than in patients with MPHA (p = 0.035). Fasting insulin levels and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) were significantly higher than in healthy controls and correlated with body mass index, waist circumference, age, and also showed statistically significant differences according to diagnosis and Phe tolerance (p < 0.05). Patients under BH4 therapy had lower insulin levels and HOMA-IR. A higher mean carbohydrate intake from AA mixtures was observed in classic PKU patients. The caloric intake in the form of carbohydrates was also higher in PKU than MHPA patients (p = 0.038) and it was correlated with basal insulin (rho = 0.468, p = 0.006), HOMA-IR (rho = 0.423, p = 0.02), BMI (rho 0.533, p = 0.002), and waist circumference (rho 0.584, p = 0.0007). This study shows that PKU patients are at risk of carbohydrate intolerance and insulin resistance, more evident in adults and overweight patients, probably related to their higher caloric intake in form carbohydrate content. A higher dependency of AA mixtures was demonstrated in PKU patients.
Tài liệu tham khảo
Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376:1417–27.
Bóveda MD, Couce ML, Castiñeiras DE, Cocho JA, Pérez B, Ugarte M, Fraga JM. The tetrahydrobiopterin loading test in 36 patients with hyperphenylalaninaemia: evaluation of response and subsequent treatment. J Inherit Metab Dis. 2007;30:8–12.
Burlina A, Blau N. Effect of BH(4) supplementation on phenylalanine tolerance. J Inherit Metab Dis. 2009;32:40–5.
Trefz FK, Burton BK, Longo N, Casanova MM, Gruskin DJ, Dorenbaum A, Kakkis ED, Crombez EA, Grange DK, Harmatz P, Lipson MH, Milanowski A, Randolph LM, Vockley J, Whitley CB, Wolff JA, Bebchuk J, Christ-Schmidt H, Hennermann JB. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr. 2009;154:700–7.
Giovannini M, Verduci E, Salvatici E, Paci S, Riva E. Phenylketonuria: nutritional advances and challenges. Nutr Metab. 2012;9(1):7.
Yi S, Singh RH. Protein substitute for children and adults with phenylketonuria. Cochrane Database Syst Rev. 2008;4:CD004731.
Mirás A, Bóveda MD, Leis MR, A. Mera A, Aldámiz-Echevarría, L, Fernández-Lorenzo JR, Fraga JM, Couce ML. Risk factors for developing mineral bone disease in phenylketonuric patients. Mol Genet Metab 2013; 108:149–154.
Crujeiras V, Aldámiz-Echevarría L, Dalmau J, Vitoria I, Andrade F, Roca I, Leis R, Fernandez-Marmiesse A, Couce ML. Vitamin and mineral status in patients with hyperphenylalaninemia. Mol Genet Metab. 2015;115:145–50.
Evans S, Daly A, MacDonald J, Preece MA, Santra S, Vijay S, Chakrapani A, MacDonald A. The micronutrient status of patients with phenylketonuria on dietary treatment: an ongoing challenge. Ann Nutr Metab. 2014;65:42–8.
Rocha JC, van Rijn M, van Dam E, Ahring K, Bélanger-Quintana A, Dokoupil K, Gokmen Ozel H, Lammardo AM, Robert M, Heidenborg C, MacDonald A. Weight management in phenylketonuria: what should be monitored. Ann Nutr Metab 2016. 68:60–5.
Pena MJ, de Almeida MF, van Dam E, Ahring K, Bélanger-Quintana DK, Gokmen-Ozel H, Lammardo AM, MacDonald A, Robert M, Rocha JC. Protein substitutes for phenylketonuria in Europe: access and nutritional composition. Eur J Clin Nutr. 2016;70:785–9.
Acosta PB, Yannicelli S, Singh RH, Elsas LJ, Mofidi S, Steiner RD. Iron status of children with phenylketonuria undergoing nutrition therapy assessed by transferring receptors. Genet Med. 2004;6:96–101.
Couce ML, Vitoria I, Aldámiz-Echevarría L, Fernández-Marmiesse A, Roca I, Llarena M, Sánchez-Pintos P, Leis R, Hermida A. Lipid profile status and other related factors in patients with Hyperphenylalaninaemia. Orphanet J Rare Dis. 2016;11:123.
Moretti F, Pellegrini N, Salvatici E, Rovelli V, Banderali G, Radaelli G, Scazzina F, Giovannini M, Verduci E. Dietary glycemic index, glycemic load and metabolic profile in children with phenylketonuria. Nutr Metab Cardiovasc Dis. 2017;27:176–82.
Kanufre VC, Soares RD, Alves MR, Aguiar MJ, Starling AL, Norton RC. Metabolic syndrome in children and adolescents with phenylketonuria. J Pediatr. 2015;91:98–103.
Verduci E, Banderali G, Moretti F, Lassandro C, Cefalo G, Radaelli G, Salvatici E, Giovannini M. Diet in children with phenylketonuria and risk of cardiovascular disease: a narrative overview. Nutr Metab Cardiovasc Dis. 2016;26:171–7.
Stewart RM, Hemli S, Kolodny EH, Miller AL, Pallotta JA. Carbohydrate metabolism in phenylketonuria. Pediatr Res. 1980;14:849–53.
Güttler F, Kühl C, Pedersen L, Påby P. Effects of oral phenylalanine load on plasma glucagon, insulin, amino acid and glucose concentrations in man. Scand J Clin Lab Invest. 1978;38:255–60.
Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA. American College of Medical Genetics and Genomics. Therapeutics committee, phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16:188–200.
Campistol J, Lambruschini N, Castejón E, Gutierrez A, Fusté E, Gassió R, Vilaseca MA. Hiperfenilalaninemia. In: sanjurjo P, Baldellou A, editors. Diagnóstico y Tratamiento de las Enfermedades Metabólicas Hereditarias. 4ªed ed. Madrid: Ergón; 2014. p. 455–77.
van Spronsen FJ, van Wegberg AM, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, Trefz FK, van Rijn M, Walter JH, MacDonald A. Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol. 2017;5:743–56.
Martínez-Pardo M, Marchante C, Dalmau J, Pérez M, Bellón C. Protocolo de diagnóstico, tratamiento y seguimiento de las hiperfenilalaninemias. An Esp Pediatr. 1998;114:3–18.
Acosta PB, Yannicelli S, Singh R, Mofidi S, Steiner R, De Vincentis E, Jurecki E, Bernstein L, Gleason S, Chetty M, Rouse B. Nutrient intakes and physical growth of children with phenylketonuria undergoing nutrition therapy. J Am Diet Assoc. 2003;103:1167–73.
WHO. Physical status: the use and interpretation of anthropometry. Report of a WHO expert committee. World Health Organ Tech Rep Ser. 1995;854:1–452.
WHO Multicentre Growth Reference Study Group. WHO child growth standards based on length/height, weight and age. Acta Paediatr. 2006;450:S76–85.
Tojo Sierra R, Leis Trabazo R. Estudio Galinut. In: Valores Estandar de Galicia. Santiago de Compostela: Universidad de Santiago de Compostela; 1999.
Zimmet P, Alberti G, Shaw J. Nueva definición mundial de la IDF del Síndrome metabólico. Diabetes Voice. 2005;50:31–3.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner C. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.
Mojiminiyi OA, Abdella NA. Effect of homeostasis model assessment computational method on the definition and associations of insulin resistance. Clin Chem Lab Med. 2010;48:1629–34.
Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85:2402–10.
R Core Team. R: a language and environment for statistical computing. In: R Foundation for Statistical Computing. Vienna, Austria; 2017. URL https://www.R-project.org/.
Haffner SM, Miettinen H, Stern MP. The homeostasis model in the San Antonio heart study. Diabetes Care. 1997;20:1087–92.
Matsumoto K, Miyake S, Yano M, Ueki Y, Yamaguchi Y, Akazawa S, Tominaga Y. Glucose tolerance, insulin secretion, and insulin sensitivity in nonobese and obese Japanese subjects. Diabetes Care. 1997;20:1562–8.
Dubinina IA, Chistiakov DA, Eremina IA, Brovkin AN, Zilberman LI, Nikitin AG, Kuraeva TL, Nosikov VV, Peterkova VA, Dedov II. Studying progression from glucose intolerance to type 2 diabetes in obese children. Diabetes Metab Syndr. 2014;8:133–7.
Pratyush DD, Tiwari S, Singh S, Singh SK. Risk factors of diabetes in north Indians with metabolic Sndrome. Diabetes Metab Syndr. 2016;10:S68–71.
Levy-Marchal C, Arslanian S, Cutfield W, Sinaiko A, Druet C, Loredana M, Chiarelli F, On behalf of ESPE-LWPES-ISPAD-APPES-APEG-SLEP-JSPE, and the insulin resistance in children consensus conference group. Insulin resistance in children: consensus, perspective. J Clin Endocrinol Metab. 2010;95:5189–98.
Ballerini MG, Bergadá I, Rodríguez ME, Kaselman A, Bengolea VS, Pipman V, Domené HM, Jasper HG, Ropelato MG. Insulin level and insulin sensitivity índices among healthy children and adolescents. Arch Argent Pediatr. 2016;114:329–36.
Rojo-Martínez G, Esteva I, de Adana SR, Catalá M, Merelo MJ, Tinahones F, Gómez-Zumaquero JM, Cuesta AL, Cardona F, Soriguer F. Patterns of insulin resistance in the general population of Southeast Spain. Diabetes Res Clin Pract. 2004;65:247–56.
Tomé M, Botana M, Cadarso-Suárez C, Rego-Iraeta A, Fernández-Mariño A, Mato JA, Solache I, Perez-Fernandez R. Prevalence of metabolic syndrome in Galicia (NW Spain) on four alternative definitions and association with insulin resistance. J Endocrinol Investig. 2009;32:505–11.
Wang F, Han L, Hu D. Fasting insulin, insulin resistance and risk of hypertension in the general population: a meta-analysis. Clin Chim Acta. 2017;464:57–63.
Gast KB, Tjeerdema N, Stijnen T, Smit JW, Dekkers OM. Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PLoS One. 2012;7:e52036.
Macdonald IA. A review of recent evidence relating to sugars, insulin resistance and diabetes. Eur J Nutr. 2016;55:S17–23.
SACN. Carbohydrates and Health. Published for Public Health England under licence from the controller of her majesty’s stationery Office 2015. ISBN: 978 0 11 708284 7.
Balkau B, Charles MA. Comment of the provisional report from WHO consultation. European Group for de study of insulin resistance (EGIR) Diabet Med. 1999;16:442–3.
World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation. In: Geneve: WHO; 1999.
American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care. 2017;40:S11–24.
Rocha JC, van Spronsen FJ, Almeida MF, Soares G, Quelhas D, Ramos E, Guimarães JT, Borges N. Dietary treatment in phenylketonuria does not lead to increased risk of obesity or metabolic syndrome. Mol Genet Metab. 2012;107:659–63.
Aldámiz-Echevarría L, Bueno MA, Couce ML, Lage S, Dalmau J, Vitoria I, Andrade F, Blasco J, Alcalde C, Gil D, García MC, González-Lamuño D, Ruiz M, Peña-Quintana L, Ruiz MA, González D, Sánchez-Valverde F. Anthropometric characteristics and nutrition in a cohort of PAH-deficient patients. Clin Nutr. 2014;33:702–17.
Dokoupil K, Gokmen-Ozel H, Lammardo AM, Motzfeldt K, Robert M, Rocha JC, van Rijn M, Ahring K, Bélanger-Quintana A, MacDonald A. Optimising growth in phenylketonuria: current state of the clinical evidence base. Clin Nutr. 2012;31:16–21.
Giovannini M, Verduci E, Salvatici E, Fiori L, Riva E. Phenylketonuria: dietary and therapeutic challenges. J Inherit Metab Dis. 2006;30:145–52.
Scaglioni S, Verduci E, Fiori L, Lammardo AM, Si R, Radaelli G, Riva E, Giovannini M. Body mass index rebound and overweight at 8 years of age in hyperphenylalaninaemic children. Acta Paediatr. 2004;93:1596–600.
Overweight and obesity and their impact on health. Global Status Report on noncommunicable diseases 2014. World Health Organization (WHO).
Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86:5992.
Weigel C, Rauh M, Kiener C, Eascher W, Kner I. Effects of various dietary amino acid preparations for phenylketonuric patients on the metabolic profiles along with postprandial insulin an ghrelin responses. Ann Nutr Metab. 2007;51:352–8.