Carbohydrate status in patients with phenylketonuria

doi:10.1186/s13023-018-0847-x

. 2018 Jun 27;13(1):103.

doi: 10.1186/s13023-018-0847-x.

Carbohydrate status in patients with phenylketonuria

Affiliations

¹ Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, S. Neonatology, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), A Choupana, s/n, 15706 Santiago de Compostela, A Coruña, Spain. maria.luz.couce.pico@sergas.es.
² Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, S. Neonatology, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), A Choupana, s/n, 15706 Santiago de Compostela, A Coruña, Spain.
³ Unit of Metabolopathies, Hospital Universitario la Fe, Bulevar sur s/n, 46021, Valencia, Spain.
⁴ Unit of Metabolism, Department of Pediatrics, Hospital de Cruces. Group of Metabolism, Biocruces Health Research Institute, CIBERER, Plaza de Cruces s/n, 48903, Barakaldo, Vizcaya, Spain.
⁵ Unit of Gastroenterology and Nutrition, Department of Pediatrics, Hospital Clinico Universitario de Santiago, IDIS, Travesía da Choupana s/n,15706 Santiago de Compostela, A Coruña, Spain.

PMID: 29945661
PMCID: PMC6020344
DOI: 10.1186/s13023-018-0847-x

Carbohydrate status in patients with phenylketonuria

María L Couce et al. Orphanet J Rare Dis. 2018.

. 2018 Jun 27;13(1):103.

doi: 10.1186/s13023-018-0847-x.

Affiliations

¹ Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, S. Neonatology, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), A Choupana, s/n, 15706 Santiago de Compostela, A Coruña, Spain. maria.luz.couce.pico@sergas.es.
² Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, S. Neonatology, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), A Choupana, s/n, 15706 Santiago de Compostela, A Coruña, Spain.
³ Unit of Metabolopathies, Hospital Universitario la Fe, Bulevar sur s/n, 46021, Valencia, Spain.
⁴ Unit of Metabolism, Department of Pediatrics, Hospital de Cruces. Group of Metabolism, Biocruces Health Research Institute, CIBERER, Plaza de Cruces s/n, 48903, Barakaldo, Vizcaya, Spain.
⁵ Unit of Gastroenterology and Nutrition, Department of Pediatrics, Hospital Clinico Universitario de Santiago, IDIS, Travesía da Choupana s/n,15706 Santiago de Compostela, A Coruña, Spain.

PMID: 29945661
PMCID: PMC6020344
DOI: 10.1186/s13023-018-0847-x

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: HOMA index; Insulin; Nutrition; Phenylalanine; Tetrahydrobiopterin.

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Conflict of interest statement

Ethics approval and consent to participate

The study protocol was approved by the Research Ethics Committee of Santiago-Lugo (2016/470).

Consent for publication

Consent to publish was obtained from the people and / or relatives who participated in the study.

Competing interests

The authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
Differences in basal insulin levels (mIU/L) according to a type of diagnosis (PKU vs MHPA); b Phe tolerance (high or free vs low); c age (under 18 years vs over 18 years); d BMI (normal and underweight vs overweight and obesity); and e WC (normal and underweight vs overweight and obesity). PKU: phenylketonuria; MHPA: mild hyperphenylalaninemia; Phe: phenylalanine; BMI: body mass index; WC: waist circumference; n: sample size; p: p-value

**Fig. 2**
Differences in HOMA-IR scores according to a type of diagnosis (PKU vs MHPA); b Phe tolerance (high and free vs low); c age (under 18 years vs over 18 years); d BMI (normal and underweight vs overweight and obesity); and e WC (normal and underweight vs overweight and obesity). HOMA-IR: homeostasis model assessment insulin resistance; PKU: phenylketonuria, MHPA: mild hyperphenylalaninemia; Phe: phenylalanine; BMI: body mass index; WC: waist circumference; n: sample size; p: p-value

**Fig. 3**
Differences between basal and postpandrial levels in: a insulin (mIU/L); b HOMA-IR; c ghrelin (pg/mL); d fructosamine (μmol/L); and e IGF1 (mg/mL). HOMA-IR: homeostasis model assessment insulin resistance; IGF1: insulin-like growth factor 1; n: sample size; p: p-value

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References

1. Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376:1417–1427. doi: 10.1016/S0140-6736(10)60961-0. - DOI - PubMed
1. 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. doi: 10.1007/s10545-007-0567-1. - DOI - PubMed
1. Burlina A, Blau N. Effect of BH(4) supplementation on phenylalanine tolerance. J Inherit Metab Dis. 2009;32:40–45. doi: 10.1007/s10545-008-0947-1. - DOI - PubMed
1. 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;154:700–707. doi: 10.1016/j.jpeds.2008.11.040. - DOI - PubMed
1. Giovannini M, Verduci E, Salvatici E, Paci S, Riva E. Phenylketonuria: nutritional advances and challenges. Nutr Metab. 2012;9(1):7. doi: 10.1186/1743-7075-9-7. - DOI - PMC - PubMed

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[1] Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376:1417–1427. doi: 10.1016/S0140-6736(10)60961-0. - DOI - PubMed

[2] Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376:1417–1427. doi: 10.1016/S0140-6736(10)60961-0. - DOI - PubMed

[3] 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. doi: 10.1007/s10545-007-0567-1. - DOI - PubMed

[4] 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. doi: 10.1007/s10545-007-0567-1. - DOI - PubMed

[5] Burlina A, Blau N. Effect of BH(4) supplementation on phenylalanine tolerance. J Inherit Metab Dis. 2009;32:40–45. doi: 10.1007/s10545-008-0947-1. - DOI - PubMed

[6] Burlina A, Blau N. Effect of BH(4) supplementation on phenylalanine tolerance. J Inherit Metab Dis. 2009;32:40–45. doi: 10.1007/s10545-008-0947-1. - DOI - PubMed

[7] 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;154:700–707. doi: 10.1016/j.jpeds.2008.11.040. - DOI - PubMed

[8] 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;154:700–707. doi: 10.1016/j.jpeds.2008.11.040. - DOI - PubMed

[9] Giovannini M, Verduci E, Salvatici E, Paci S, Riva E. Phenylketonuria: nutritional advances and challenges. Nutr Metab. 2012;9(1):7. doi: 10.1186/1743-7075-9-7. - DOI - PMC - PubMed

[10] Giovannini M, Verduci E, Salvatici E, Paci S, Riva E. Phenylketonuria: nutritional advances and challenges. Nutr Metab. 2012;9(1):7. doi: 10.1186/1743-7075-9-7. - DOI - PMC - PubMed

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