{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:32:57Z","timestamp":1784698377375,"version":"3.55.0"},"reference-count":46,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T00:00:00Z","timestamp":1663545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Purpose: this systematic review aimed to assess the effects of dietary liberalization following tetrahydrobiopterin (BH4) treatment on anthropometric measurements, nutritional biomarkers, quality of life, bone density, mental health and psychosocial functioning, and burden of care in PKU patients. Methods: the PubMed, Cochrane, and Embase databases were searched on 7 April 2022. We included studies that reported on the aforementioned domains before and after dietary liberalization as a result of BH4 treatment in PKU patients. Exclusion criteria were: studies written in a language other than English; studies that only included data of a BH4 loading test; insufficient data for the parameters of interest; and wrong publication type. Both within-subject and between-subject analyses were assessed, and meta-analyses were performed if possible. Results: twelve studies containing 14 cohorts and 228 patients were included. Single studies reported few significant differences. Two out of fifteen primary meta-analyses were significant; BMI was higher in BH4-treated patients versus controls (p = 0.02; standardized mean difference (SMD) (95% confidence interval (CI)) = \u22120.37 (\u22120.67, \u22120.06)), and blood cholesterol concentrations increased after starting BH4 treatment (p = 0.01; SMD (CI) = \u22120.70 (\u22121.26, \u22120.15)). Conclusion: there is no clear evidence that dietary liberalization after BH4 treatment has a positive effect on anthropometric measurements, nutritional biomarkers, or quality of life. No studies could be included for bone density, mental health and psychosocial functioning, and burden of care.<\/jats:p>","DOI":"10.3390\/nu14183874","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T04:28:55Z","timestamp":1663648135000},"page":"3874","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Dietary Liberalization in Tetrahydrobiopterin-Treated PKU Patients: Does It Improve Outcomes?"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1697-3571","authenticated-orcid":false,"given":"Roeland A. F.","family":"Evers","sequence":"first","affiliation":[{"name":"Division of Metabolic Diseases, Beatrix Children\u2019s Hospital, University Medical Center Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9402-4833","authenticated-orcid":false,"given":"Annemiek M. J.","family":"van Wegberg","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases, Beatrix Children\u2019s Hospital, University Medical Center Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Dietetic Department, Birmingham Children\u2019s Hospital, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan C. J.","family":"Huijbregts","sequence":"additional","affiliation":[{"name":"Department of Clinical Child and Adolescent Studies-Neurodevelopmental Disorders, Faculty of Social Sciences, Leiden University, 2300 RB Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2314-6139","authenticated-orcid":false,"given":"Vincenzo","family":"Leuzzi","sequence":"additional","affiliation":[{"name":"Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francjan J.","family":"van Spronsen","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases, Beatrix Children\u2019s Hospital, University Medical Center Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41572-021-00267-0","article-title":"Phenylketonuria","volume":"7","author":"Blau","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/jimd.12065","article-title":"The neurological and psychological phenotype of adult patients with early-treated phenylketonuria: A systematic review","volume":"42","author":"Burlina","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s13023-018-0839-x","article-title":"Status of nutrients important in brain function in phenylketonuria: A systematic review and meta-analysis","volume":"13","author":"Singh","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"de Castro, M.J., de Lamas, C., S\u00e1nchez-Pintos, P., Gonz\u00e1lez-Lamu\u00f1o, D., and Couce, M.L. (2020). Bone Status in Patients with Phenylketonuria: A Systematic Review. Nutrients, 12.","DOI":"10.3390\/nu12072154"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rodrigues, C., Pinto, A., Faria, A., Teixeira, D., van Wegberg, A.M.J., Ahring, K., Feillet, F., Calhau, C., MacDonald, A., and Moreira-Ros\u00e1rio, A. (2021). Is the Phenylalanine-Restricted Diet a Risk Factor for Overweight or Obesity in Patients with Phenylketonuria (PKU)? A Systematic Review and Meta-Analysis. Nutrients, 13.","DOI":"10.3390\/nu13103443"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ilgaz, F., Pinto, A., G\u00f6kmen-\u00d6zel, H., Rocha, J.C., Van Dam, E., Ahring, K., B\u00e9langer-Quintana, A., Dokoupil, K., Karabulut, E., and Macdonald, A. (2019). Long-term growth in phenylketonuria: A systematic review and meta-analysis. Nutrients, 11.","DOI":"10.3390\/nu11092070"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/8904_2012_168","article-title":"A systematic review of BH4 (Sapropterin) for the adjuvant treatment of phenylketonuria","volume":"Volume 8","author":"Lindegren","year":"2013","journal-title":"JIMD Reports"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Somaraju, U.R., and Merrin, M. (2015). Sapropterin dihydrochloride for phenylketonuria. Cochrane Database Syst. Rev., 2015.","DOI":"10.1002\/14651858.CD008005.pub4"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1111\/bcp.13886","article-title":"Efficacy and safety of sapropterin dihydrochloride in patients with phenylketonuria: A meta-analysis of randomized controlled trials","volume":"85","author":"Qu","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ymgme.2010.06.015","article-title":"Sapropterin therapy increases stability of blood phenylalanine levels in patients with BH4-responsive phenylketonuria (PKU)","volume":"101","author":"Burton","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_11","first-page":"2196","article-title":"Optical Coherence Tomography to Assess Neurodegeneration in Phenylalanine Hydroxylase Deficiency","volume":"12","author":"Schiergens","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ilgaz, F., Marsaux, C., Pinto, A., Singh, R., Rohde, C., Karabulut, E., G\u00f6kmen-\u00f6zel, H., Kuhn, M., and Macdonald, A. (2021). Protein Substitute Requirements of Patients with Phenylketonuria on BH4 Treatment: A Systematic Review and Meta-Analysis. Nutrients, 13.","DOI":"10.3390\/nu13031040"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/s41436-018-0081-x","article-title":"Allelic phenotype values: A model for genotype-based phenotype prediction in phenylketonuria","volume":"21","author":"Garbade","year":"2018","journal-title":"Genet. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1056\/NEJMoa021654","article-title":"Tetrahydrobiopterin as an Alternative Treatment for Mild Phenylketonuria","volume":"347","author":"Muntau","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/gim.2013.157","article-title":"Phenylalanine hydroxylase deficiency: Diagnosis and management guideline","volume":"16","author":"Vockley","year":"2014","journal-title":"Genet. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.clnu.2011.09.001","article-title":"Optimising growth in phenylketonuria: Current state of the clinical evidence base","volume":"31","author":"Dokoupil","year":"2012","journal-title":"Clin. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ymgme.2016.04.008","article-title":"Updated, web-based nutrition management guideline for PKU: An evidence and consensus based approach","volume":"118","author":"Singh","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1136\/bmj.b2535","article-title":"Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement","volume":"339","author":"Moher","year":"2009","journal-title":"BMJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan-a web and mobile app for systematic reviews","volume":"5","author":"Ouzzani","year":"2016","journal-title":"Syst. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"280","DOI":"10.7326\/0003-4819-158-4-201302190-00009","article-title":"Assessing bias in studies of prognostic factors","volume":"158","author":"Hayden","year":"2013","journal-title":"Ann. Intern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"GRADE: An emerging consensus on rating quality of evidence and strength of recommendations","volume":"336","author":"Guyatt","year":"2008","journal-title":"BMJ"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/gim.2014.109","article-title":"Long-term developmental progression in infants and young children taking sapropterin for phenylketonuria: A two-year analysis of safety and efficacy","volume":"17","author":"Longo","year":"2015","journal-title":"Genet. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ymgme.2015.03.007","article-title":"6R-tetrahydrobiopterin treated PKU patients below 4years of age: Physical outcomes, nutrition and genotype","volume":"115","author":"Bueno","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13023-017-0600-x","article-title":"Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: Results from the SPARK open-label, multicentre, randomized phase IIIb trial","volume":"12","author":"Muntau","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.ymgme.2013.05.017","article-title":"Tetrahydrobiopterin therapy vs phenylalanine-restricted diet: Impact on growth in PKU","volume":"109","author":"Bueno","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1186\/s13023-021-01968-1","article-title":"Long-term efficacy and safety of sapropterin in patients who initiated sapropterin at <4 years of age with phenylketonuria: Results of the 3-year extension of the SPARK open-label, multicentre, randomised phase IIIb trial","volume":"16","author":"Muntau","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ymgme.2005.05.014","article-title":"Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy","volume":"86","author":"Lambruschini","year":"2005","journal-title":"Mol. Genet. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/s10545-010-9224-1","article-title":"BH4 therapy impacts the nutrition status and intake in children with phenylketonuria: 2-Year follow-up","volume":"33","author":"Singh","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1007\/s10545-012-9458-1","article-title":"Tetrahydrobiopterin (BH4) in PKU: Effect on dietary treatment, metabolic control, and quality of life","volume":"35","author":"Ziesch","year":"2012","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"S49","DOI":"10.1016\/j.ymgme.2013.09.015","article-title":"Evaluation of quality of life in PKU before and after introducing tetrahydrobiopterin (BH4); a prospective multi-center cohort study","volume":"110","author":"Demirdas","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/1477-7525-11-218","article-title":"Longitudinal quality of life analysis in a phenylketonuria cohort provided sapropterin dihydrochloride","volume":"11","author":"Douglas","year":"2013","journal-title":"Health Qual. Life Outcomes"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13023-015-0227-8","article-title":"Long-term follow-up of patients with phenylketonuria treated with tetrahydrobiopterin: A seven years experience","volume":"10","author":"Scala","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1515\/jpem-2015-0337","article-title":"Long-term BH4 (sapropterin) treatment of children with hyperphenylalaninemia\u2014Effect on median Phe\/Tyr ratios","volume":"29","author":"Tansek","year":"2016","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1111\/apa.13799","article-title":"Sapropterin treatment does not enhance the health-related quality of life of patients with phenylketonuria and their parents","volume":"106","author":"Feldmann","year":"2017","journal-title":"Acta Paediatr. Int. J. Paediatr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1186\/s13023-018-0923-2","article-title":"One-year follow-up of B vitamin and Iron status in patients with phenylketonuria provided tetrahydrobiopterin (BH4)","volume":"13","author":"Brantley","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.ymgme.2018.06.009","article-title":"Anthropomorphic measurements and nutritional biomarkers after 5 years of BH 4 treatment in phenylketonuria patients","volume":"124","author":"Evers","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"ref_37","unstructured":"(2021, August 11). Drug Approval Package: Kuvan (Sapropterin Dihydrochloride) NDA #022181, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2007\/022181TOC.cfm."},{"key":"ref_38","unstructured":"(2021, August 11). Kuvan|European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/kuvan."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s13023-017-0685-2","article-title":"The complete European guidelines on phenylketonuria: Diagnosis and treatment","volume":"12","author":"MacDonald","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.advms.2019.08.001","article-title":"Overweight in classical phenylketonuria children: A retrospective cohort study","volume":"64","author":"Walkowiak","year":"2019","journal-title":"Adv. Med. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/8904_2012_176","article-title":"Nutritional changes and micronutrient supply in patients with phenylketonuria under therapy with tetrahydrobiopterin (BH4)","volume":"Volume 9","author":"Thiele","year":"2013","journal-title":"JIMD Reports"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ymgmr.2015.07.002","article-title":"The challenge of long-term tetrahydrobiopterin (BH4) therapy in phenylketonuria: Effects on metabolic control, nutritional habits and nutrient supply","volume":"4","author":"Thiele","year":"2015","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1037\/0003-066X.61.4.305","article-title":"Beyond the hedonic treadmill: Revising the adaptation theory of well-being","volume":"61","author":"Diener","year":"2006","journal-title":"Am. Psychol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s13023-015-0294-x","article-title":"Assessment of the impact of phenylketonuria and its treatment on quality of life of patients and parents from seven European countries","volume":"10","author":"Bosch","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.ymgme.2018.07.002","article-title":"The impact of metabolic control and tetrahydrobiopterin treatment on health related quality of life of patients with early-treated phenylketonuria: A PKU-COBESO study","volume":"125","author":"Huijbregts","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s13023-015-0261-6","article-title":"Development and psychometric validation of measures to assess the impact of phenylketonuria and its dietary treatment on patients\u2019 and parents\u2019 quality of life: The phenylketonuria\u2014Quality of life (PKU-QOL) questionnaires","volume":"10","author":"Regnault","year":"2015","journal-title":"Orphanet J. Rare Dis."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/18\/3874\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:34:18Z","timestamp":1760142858000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/18\/3874"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,19]]},"references-count":46,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["nu14183874"],"URL":"https:\/\/doi.org\/10.3390\/nu14183874","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,19]]}}}