{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:00:37Z","timestamp":1787029237012,"version":"build-2736575974"},"reference-count":31,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["The study was funded within an EU grant awarded to Norsa Pharma."],"award-info":[{"award-number":["The study was funded within an EU grant awarded to Norsa Pharma."]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Fat-soluble vitamin deficiency remains a challenge in cystic fibrosis (CF), chronic pancreatitis, and biliary atresia. Liposomes and cyclodextrins can enhance their bioavailability, thus this multi-center randomized placebo-controlled trial compared three-month supplementation of fat-soluble vitamins in the form of liposomes or cyclodextrins to medium-chain triglycerides (MCT) in pancreatic-insufficient CF patients. The daily doses were as follows: 2000 IU of retinyl palmitate, 4000 IU of vitamin D3, 200 IU of RRR-\u03b1-tocopherol, and 200 \u00b5g of vitamin K2 as menaquinone-7, with vitamin E given in soybean oil instead of liposomes. All participants received 4 mg of \u03b2-carotene and 1.07 mg of vitamin K1 to ensure compliance with the guidelines. The primary outcome was the change from the baseline of all-trans-retinol and 25-hydroxyvitamin D3 concentrations and the percentage of undercarboxylated osteocalcin. Out of 75 randomized patients (n = 28 liposomes, n = 22 cyclodextrins, and n = 25 MCT), 67 completed the trial (89%; n = 26 liposomes, n = 18 cyclodextrins, and n = 23 MCT) and had a median age of 22 years (IQR 19\u201328), body mass index of 20.6 kg\/m2 [18.4\u201322.0], and forced expiratory volume in 1 s of 65% (44\u201384%). The liposomal formulation of vitamin A was associated with the improved evolution of serum all-trans-retinol compared to the control (median +1.7 ng\/mL (IQR \u221244.3\u201386.1) vs. \u221238.8 ng\/mL (\u221271.2\u20136.8), p = 0.028). Cyclodextrins enhanced the bioavailability of vitamin D3 (+9.0 ng\/mL (1.0\u201317.0) vs. +3.0 ng\/mL (\u22124.0\u20137.0), p = 0.012) and vitamin E (+4.34 \u00b5g\/mL (0.33\u20136.52) vs. \u22120.34 \u00b5g\/mL (\u22121.71\u20132.15), p = 0.010). Liposomes may augment the bioavailability of vitamin A and cyclodextrins may strengthen the supplementation of vitamins D3 and E relative to MCT in pancreatic-insufficient CF but further studies are required to assess liposomal vitamin E (German Clinical Trial Register number DRKS00014295, funded from EU and Norsa Pharma).<\/jats:p>","DOI":"10.3390\/nu13124554","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T02:50:18Z","timestamp":1639968618000},"page":"4554","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Fat-Soluble Vitamin Supplementation Using Liposomes, Cyclodextrins, or Medium-Chain Triglycerides in Cystic Fibrosis: A Randomized Controlled Trial"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0953-2188","authenticated-orcid":false,"given":"Jan K.","family":"Nowak","sequence":"first","affiliation":[{"name":"Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2737-8946","authenticated-orcid":false,"given":"Paulina","family":"Sobkowiak","sequence":"additional","affiliation":[{"name":"Department of Pneumonology, Allergology and Clinical Immunology, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u0142awomira","family":"Drzyma\u0142a-Czy\u017c","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"},{"name":"Department of Bromatology, Poznan University of Medical Sciences, Marcelinska 42, 60-354 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8676-9803","authenticated-orcid":false,"given":"Patrycja","family":"Krzy\u017canowska-Jankowska","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Sapiejka","sequence":"additional","affiliation":[{"name":"The Specialist Centre for Medical Care of Mother and Child, Polanki 119, 80-308 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Skorupa","sequence":"additional","affiliation":[{"name":"Department of Lung Diseases, Institute for Tuberculosis and Lung Diseases, Plocka 26, 01-138 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej","family":"Pogorzelski","sequence":"additional","affiliation":[{"name":"Department of Pneumology and Cystic Fibrosis, Institute of Tuberculosis and Lung Diseases, Rudnika 3, 34-700 Rabka-Zdroj, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Nowicka","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Allergology and Respiratory Oncology, Poznan University of Medical Sciences, Szamarzewskiego 84, 60-569 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6724-1499","authenticated-orcid":false,"given":"Irena","family":"Wojsyk-Banaszak","sequence":"additional","affiliation":[{"name":"Department of Pneumonology, Allergology and Clinical Immunology, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szymon","family":"Kurek","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Zieli\u0144ska-Psuja","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Poznan University of Medical Sciences, Dojazd 30, 60-631 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Lisowska","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5813-5707","authenticated-orcid":false,"given":"Jaros\u0142aw","family":"Walkowiak","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.clnu.2016.03.004","article-title":"ESPEN-ESPGHAN-ECFS Guidelines on Nutrition Care for Infants, Children, and Adults with Cystic Fibrosis","volume":"35","author":"Turck","year":"2016","journal-title":"Clin. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.jconrel.2012.03.020","article-title":"(Chezy) Doxil\u00ae\u2014The First FDA-Approved Nano-Drug: Lessons Learned","volume":"160","author":"Barenholz","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_3","unstructured":"(2012). Commission Implementing Regulation (EU) No 468\/2012 of 1 June 2012 Amending Regulation (EU) No 28\/2012 Laying Down Requirements for the Certification for Imports into and Transit through the Union of Certain Composite Products, Official Journal of the European Union."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"84","DOI":"10.3945\/ajcn.115.109496","article-title":"Fecal Menaquinone Profiles of Overweight Adults Are Associated with Gut Microbiota Composition during a Gut Microbiota-Targeted Dietary Intervention","volume":"102","author":"Karl","year":"2015","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_5","first-page":"298","article-title":"Determination of Phylloquinone and Menaquinones in Food. Effect of Food Matrix on Circulating Vitamin K Concentrations","volume":"30","author":"Schurgers","year":"2000","journal-title":"Haemostasis"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1007\/s00198-013-2325-6","article-title":"Three-Year Low-Dose Menaquinone-7 Supplementation Helps Decrease Bone Loss in Healthy Postmenopausal Women","volume":"24","author":"Knapen","year":"2013","journal-title":"Osteoporos. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1530\/EJE-16-0498","article-title":"Vitamin K2 (Menaquinone-7) Prevents Age-Related Deterioration of Trabecular Bone Microarchitecture at the Tibia in Postmenopausal Women","volume":"175","author":"Pedersen","year":"2016","journal-title":"Eur. J. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.jpeds.2004.06.033","article-title":"Assessment of Maldigestion in Cystic Fibrosis","volume":"145","author":"Walkowiak","year":"2004","journal-title":"J. Pediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/S1569-1993(02)00096-6","article-title":"Fecal Elastase-1 Cut-off Levels in the Assessment of Exocrine Pancreatic Function in Cystic Fibrosis","volume":"1","author":"Walkowiak","year":"2002","journal-title":"J. Cyst. Fibros."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S29","DOI":"10.1016\/S1569-1993(11)60006-4","article-title":"Best Practice Guidance for the Diagnosis and Management of Cystic Fibrosis-Associated Liver Disease","volume":"10","author":"Debray","year":"2011","journal-title":"J. Cyst. Fibros."},{"key":"ref_11","first-page":"345","article-title":"Vitamin A Status and Its Determinants in Patients with Cystic Fibrosis","volume":"16","author":"Sapiejka","year":"2017","journal-title":"Acta Sci. Pol. Technol. Aliment."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S66","DOI":"10.1016\/j.jcf.2019.08.022","article-title":"Vitamin D Deficiency and Its Treatment in Cystic Fibrosis","volume":"18","author":"Daley","year":"2019","journal-title":"J. Cyst. Fibros."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.advms.2018.04.001","article-title":"Vitamin E Status and Its Determinants in Patients with Cystic Fibrosis","volume":"63","author":"Sapiejka","year":"2018","journal-title":"Adv. Med. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12000","DOI":"10.1038\/srep12000","article-title":"Exogenous and Endogenous Determinants of Vitamin K Status in Cystic Fibrosis","volume":"5","author":"Pogorzelski","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1365-2710.1993.tb00563.x","article-title":"Vitamin Therapy in Cystic Fibrosis--a Review and Rationale","volume":"18","author":"Peters","year":"1993","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s10620-006-9489-2","article-title":"Bioavailability of a Novel, Water-Soluble Vitamin E Formulation in Malabsorbing Patients","volume":"52","author":"Papas","year":"2007","journal-title":"Dig. Dis. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.dld.2017.01.155","article-title":"Vitamin K Status in Cystic Fibrosis Patients with Liver Cirrhosis","volume":"49","author":"Pogorzelski","year":"2017","journal-title":"Dig. Liver Dis."},{"key":"ref_18","first-page":"e19","article-title":"Prevalence of Vitamin K Deficiency and Associated Factors in Non-Supplemented Cystic Fibrosis Patients","volume":"116","author":"Rohovyk","year":"2018","journal-title":"Arch. Argent. Pediatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e39","DOI":"10.1016\/j.jcf.2018.04.007","article-title":"Apolipoprotein E Polymorphism Determines Vitamin K Supplementation Effectiveness in Cystic Fibrosis Patients","volume":"17","author":"Sobkowiak","year":"2018","journal-title":"J. Cyst. Fibros."},{"key":"ref_20","first-page":"7077","article-title":"Apolipoprotein E Polymorphism and Vitamin K Status in Cystic Fibrosis Patients Not Supplemented with Vitamin K","volume":"24","author":"Walkowiak","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10938","DOI":"10.1021\/acs.chemrev.5b00046","article-title":"New Developments in Liposomal Drug Delivery","volume":"115","author":"Pattni","year":"2015","journal-title":"Chem. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.tifs.2020.08.009","article-title":"Applications of Cyclodextrins in Food Science. A Review","volume":"104","author":"Matencio","year":"2020","journal-title":"Trends Food Sci. Technol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.1021\/acs.jafc.5b00103","article-title":"Controlled Release of Retinyl Acetate from \u03b2-Cyclodextrin Functionalized Poly(Vinyl Alcohol) Electrospun Nanofibers","volume":"63","author":"Lemma","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_24","first-page":"358","article-title":"Stabilization of Retinol through Incorporation into Liposomes","volume":"35","author":"Lee","year":"2002","journal-title":"J. Biochem. Mol. Biol."},{"key":"ref_25","first-page":"189","article-title":"Preparation, Properties and Biological Activity of Beta-Cyclodextrin Inclusion Complex of Menadione","volume":"38","author":"Szejtli","year":"1983","journal-title":"Pharmazie"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1248\/yakushi1947.108.11_1093","article-title":"Improvement of bioavailability of menaquinone-4 by dimethyl-beta-cyclodextrin complexation following oral administration]","volume":"108","author":"Horiuchi","year":"1988","journal-title":"Yakugaku Zasshi"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1080\/08982104.2018.1502314","article-title":"In Vitro and in Vivo Assessment of Vitamin A Encapsulation in a Liposome-Protein Delivery System","volume":"29","author":"Rovoli","year":"2019","journal-title":"J. Liposome Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.jconrel.2015.04.003","article-title":"Liposomal Delivery Systems for Anti-Cancer Analogues of Vitamin E","volume":"207","author":"Koudelka","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.rmed.2019.07.005","article-title":"Vitamin K and Cystic Fibrosis: A Gordian Knot That Deserves Our Attention","volume":"155","author":"Hatziparasides","year":"2019","journal-title":"Respir. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.clnesp.2017.12.001","article-title":"Effect of High Dose Vitamin D3 Therapy on Serum Vitamin D3 Levels in Vitamin D Insufficient Adults with Cystic Fibrosis","volume":"23","author":"Porhownik","year":"2018","journal-title":"Clin. Nutr. ESPEN"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"106112","DOI":"10.1016\/j.intimp.2019.106112","article-title":"Vitamin D and microbiota: Two sides of the same coin in the immunomodulatory aspects","volume":"79","author":"Malaguarnera","year":"2020","journal-title":"Int. Immunopharmacol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/12\/4554\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:52:16Z","timestamp":1760169136000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/12\/4554"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,20]]},"references-count":31,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["nu13124554"],"URL":"https:\/\/doi.org\/10.3390\/nu13124554","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,20]]}}}