Is the Phenylalanine-Restricted Diet a Risk Factor for Overweight or Obesity in Patients with Phenylketonuria (PKU)? A Systematic Review and Meta-Analysis

Abstract

Although there is a general assumption that a phenylalanine (Phe)-restricted diet promotes overweight in patients with phenylketonuria (PKU), it is unclear if this presumption is supported by scientific evidence. This systematic review aimed to determine if patients with PKU are at a higher risk of overweight compared to healthy individuals. A literature search was carried out on PubMed, Cochrane Library, and Embase databases. Risk of bias of individual studies was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, and the quality of the evidence for each outcome was assessed using the NutriGrade scoring system. From 829 articles identified, 15 were included in the systematic review and 12 in the meta-analysis. Body mass index (BMI) was similar between patients with PKU and healthy controls, providing no evidence to support the idea that a Phe-restricted diet is a risk factor for the development of overweight. However, a subgroup of patients with classical PKU had a significantly higher BMI than healthy controls. Given the increasing prevalence of overweight in the general population, patients with PKU require lifelong follow-up, receiving personalised nutritional counselling, with methodical nutritional status monitoring from a multidisciplinary team in inherited metabolic disorders.

Keywords: body mass index; obesity; overweight; phenylalanine restriction; phenylalanine-restricted diet; phenylketonuria.

Figure 1

PRISMA study flow diagram describing the process of study selection. Abbreviation: PECO: Population, Exposure, Comparator, Outcome.

Figure 2

Risk of bias: judgements about each risk of bias item presented as percentages across all included studies.

Figure 3

Forest plot comparing the BMI between patients with PKU and healthy controls. Abbreviations: BMI: body mass index; CI: confidence interval; df: degrees of freedom; IV: inverse variance; PKU: phenylketonuria; SE: standard error; Std: standardised. Moderate risk of bias: Couce 2018, Evans 2019, Huemer 2007, and Rocha 2012. High risk of bias: Albersen 2010, Azabdaftari 2019, Doulgeraki 2014, Evans 2017, Hermida-Ameijeiras 2017, Mazzola 2016, Sailer 2020, and Schulpis 2000. Time of diagnosis: Couce 2018 included 70 early and 13 late diagnosed patients, Hermida-Ameijeiras 2017 included both early and late diagnosed patients, Mazzola 2016 included 11 early and 16 late diagnosed patients, and Schulpis 2000 did not provide information on the time of diagnosis. Metabolic control: Azabdaftari 2019 included only one patient with good metabolic control (Phe blood levels < 600 $$\mathsf{\mu }$$mol/L). BH4 treatment: Couce 2018 included 10 (12%) patients taking BH4, Evans 2017 included 5 (14%), Hermida-Ameijeiras 2017 included 7 (17%), and Sailer 2020 included 4 (13%).

Figure 4

Forest plot comparing the BMI between patients with classical PKU and healthy controls. Abbreviations: BMI: body mass index; CI: confidence interval; df: degrees of freedom; IV: inverse variance; PKU: phenylketonuria; SE: standard error; Std: standardised. Moderate risk of bias: Couce 2018, Evans 2019, Huemer 2007, and Rocha 2012. High risk of bias: Albersen 2010, Azabdaftari 2019, Doulgeraki 2014, Sailer 2020, and Schulpis 2000. Time of diagnosis: Couce 2018 included 70 early- and 13 late-diagnosed patients, and Schulpis 2000 did not provide information on the time of diagnosis. Metabolic control: Azabdaftari 2019 included only one patient with good metabolic control (Phe blood levels < 600 $$\mathsf{\mu }$$mol/L). BH4 treatment: Couce 2018 included 1 (3%) patient taking BH4, and Sailer 2020 included 4 (13%) patients.