Abstract
Background:
Cystic fibrosis (CF) stands as the most common chronic multisystem and fatal inherited disease.Objectives:
The present study aimed to assess the clinical presentation and laboratory findings in children with CF.Methods:
This retrospective cross-sectional study reviewed the records of CF patients over a 2-year period beginning in 2018. The diagnosis of CF was confirmed based on clinical manifestations, sweat chloride tests, or genetic studies. Children aged ≥ 2 years were included; nevertheless, patients without sweat chloride tests or genetic studies were excluded. This study recorded demographic features, gastrointestinal manifestations, vitamin D levels, and the number of hospital admissions. A pediatric gastroenterologist conducted fecal elastase and stool fat analyses to evaluate pancreatic insufficiency. Vitamin D levels < 30 ng/mL were considered vitamin D insufficiency; however, levels < 20 ng/mL indicated a vitamin D deficiency. A P-value < 0.05 was considered statistically significant.Results:
This study included 59 children (37 male and 22 female) in the study. Low weight, height, and body mass index (BMI) percentiles (< 5) were most frequently observed. Approximately 86.4% of the patients had consanguineous parents, and 40.7% had affected siblings. Failure to thrive (FTT) (49.2%) and recurrent respiratory infections (45.8%) were the most common clinical presentations. A majority (57.7%) of the patients were diagnosed before the age of 1 year. The mean number of admissions in the past 2 years was 3, and 58% of the cases reported gastrointestinal symptoms. A significant correlation was observed between vitamin D levels and the number of hospital admissions (Pearson coefficient = 0.298, P = 0.042).Conclusions:
In this study, there was a high prevalence of vitamin D insufficiency and FTT in children with CF. Additionally, there was a significant correlation between vitamin D levels and the number of hospital admissions over a 2-year period.Keywords
Cystic Fibrosis Vitamin D Ileus Inflammatory Markers Pancreas
1. Background
Cystic fibrosis (CF) stands as the most common fatal autosomal recessive disorder (1). Cystic fibrosis is the result of a mutation in the CF transmembrane conductance regulator (CFTR) gene located on chromosome 7 (2). In the digestive system, CF often leads to exocrine pancreatic insufficiency and changes in intestinal motility (3, 4). These effects on intestinal motility might manifest as meconium ileus, distal intestinal obstruction, or chronic constipation (5). The incidence of CF varies according to ethnic origin, ranging from 1 in 2 000 to 1 in 3 500 newborns in different countries (6). Respiratory problems are the leading cause of mortality and morbidity among CF patients (7, 8). Children with pancreatic insufficiency (PI) typically require fat-soluble vitamins, including A, D, E, and K.
2. Objectives
This study aimed to evaluate the clinical presentation and laboratory findings in children with CF.
3. Methods
This retrospective cross-sectional study was conducted on children diagnosed with CF over a 2-year period starting in 2018. The medical records of CF patients were reviewed. The diagnosis of CF was confirmed through clinical manifestations, sweat chloride tests, or genetic studies. Children aged ≥ 2 years were included; however, those lacking sweat chloride tests or genetic studies were excluded. This study recorded demographic features, gastrointestinal manifestations, vitamin D levels, and the number of hospital admissions. A pediatric gastroenterologist conducted fecal elastase and stool fat analyses to evaluate PI. Vitamin D levels < 30 ng/mL were considered vitamin D insufficiency, and levels < 20 ng/mL indicated vitamin D deficiency. A P-value < 0.05 was considered statistically significant. Data analysis was performed using SPSS software (version 25.0).
4. Results
The study included 59 children, 37 (62.71%) and 22 (37.28%) of whom were male and female, respectively. The mean age was 7.1 ± 4.6 years, ranging from 2 to 18 years (median: 6 years). Table 1 shows weight percentiles, with 67.8% of children having a weight percentile below 5. Table 1 also displays height percentiles, where 50.8% of children had a height below the 5th percentile. Body mass index (BMI) data are presented in Table 1, and no children were observed with a BMI ≥ 95 kg/m2. Among the 59 children, 51 subjects (86.4%) had parents who were relatives, and 24 cases (40.7%) had a sibling with CF. In one case, a genetic study alone was used for diagnosis; however, 53 children were diagnosed solely through sweat tests. Five children underwent both a sweat chloride test and a genetic study for diagnosis. Age at diagnosis was < 6, 6 - 12, and > 12 months for 27 (45.8%), 7 (11.9%), and 25 (42.3%) of the cases, respectively.
Among all patients, 45.8% were diagnosed within the first 6 months of life. The most common initial clinical presentations were failure to thrive (FTT), observed in 29 (49%) cases, and recurrent upper respiratory tract infections, noticed in 27 (45%) cases (Table 2).
Frequency of Weight, Height, and Body Mass Index Percentiles Among Participants
| Frequency (%) | |
|---|---|
| Weight percentile | |
| Valid | |
| < 5 | 40 (67.8) |
| 5 - 10 | 6 (10.2) |
| 10 - 25 | 6 (10.2) |
| 25 - 50 | 5 (8.5) |
| 50 - 75 | 2 (3.3) |
| Total | 59 (100) |
| Height percentile | |
| Valid | |
| < 5 | 30 (50.8) |
| 5 - 10 | 8 (13.6) |
| 10 - 25 | 5 (8.5) |
| 25 - 50 | 3 (5.1) |
| 50 - 75 | 7 (11.9) |
| 75 - 90 | 6 (10.1) |
| Total | 59 (100) |
| BMI percentile | |
| Valid | |
| < 5 | 34 (57.6) |
| 5 - 10 | 5 (8.5) |
| 10 - 25 | 6 (10.1) |
| 25 - 50 | 5 (8.5) |
| 50 - 75 | 5 (8.5) |
| 75 - 90 | 2 (3.4) |
| 90 - 95 | 2 (3.4) |
| Total | 59 (100) |
First Presentation at Diagnosis
| First Presentation at Diagnosis | No (%) |
|---|---|
| FTT | 29 (49.2) |
| Recurrent RTI | 27 (45.8) |
| Steatorrhea | 11 (18.6) |
| GIO | 5 (8.5) |
| Anemia | 1 (1.7) |
| Chronic cough | 6 (10.2) |
| Salty skin | 6 (10.2) |
| Diarrhea | 2 (3.4) |
| Genetic history | 2 (3.45) |
The number of hospital admissions in the 2 years prior to the study ranged from 1 to 20, with a median of 3 during that period. Out of the 59 cases, 44 subjects (74.6%) received a recommendation for pancreatic enzyme replacement therapy (PERT) from a physician. Thirty-two (54%) of the cases adhered to vitamin D supplementation as prescribed; nevertheless, 27 cases (45%) either did not use it or discontinued it. Among the patients, 34 subjects (58%) reported gastrointestinal complaints, with 19 cases (32%) experiencing abdominal pain, 13 cases (22%) having a loss of appetite, and facing defecation problems, such as constipation or diarrhea was seen in 22% of the patients.
Vitamin D consumption ranged from 0 to 100 000 units per month, with a mean of 100 542 ± 155 691 units among patients. There was no significant correlation between the number of hospital admissions and monthly vitamin D consumption (Pearson coefficient = 0.155, P = 0.240) (Table 3). Among the 47 patients with available vitamin D assessment results, the mean ± standard error (SE) was 26.93 ± 17.02, ranging from 3 to 67 ng/mL. In this group, 60% of children had insufficient vitamin D levels (25-OHD < 30 ng/mL). A significant correlation was observed between the level of vitamin D and the number of hospital admissions (Pearson coefficient = 0.298, P = 0.042).
Correlation Between Level of Vitamin D and Gastrointestinal Complications
| Vitamin D Level (Mean ± SE) | P-Value | |
|---|---|---|
| Abdominal pain | ||
| Yes (n = 16) | 30.519 ± 4.76 | 0.33 |
| No (n = 31) | 25.087 ± 2.85 | |
| Defecation changes | ||
| Yes (n = 12) | 27.975 ± 4.24 | 0.79 |
| No (n = 35) | 26.58 ± 3.03 | |
| Lack of appetite | ||
| Yes | 31.307 ± 4.6 | 0.25 |
| No | 24.888 ± 2.92 |
The mean white blood cell count (WBC) was 13 332.24 ± 6 340.849 /mL, ranging from 5 200 to 46 000. Qualitative C-reactive protein (CRP) results were available for 42 cases, with 25 cases (47.2%) showing negative results, 10 cases (16.9%) displaying a +1 CRP, and 14 cases (23.7%) having 2+ CRP; nevertheless, 4 cases (6.8%) had 3+ CRP.
Children receiving PERT had a mean of 3.59 ± 0.429 hospital admissions; nonetheless, children without PERT had 4.20 ± 1.284 hospital admissions. There was no correlation between PERT and the number of hospital admissions (P = 0.65). Table 3 shows that there was no correlation between the level of vitamin D and abdominal pain, defecation changes, or loss of appetite.
The mean BMI among children receiving PERT was 14.04 ± 1.98 kg/m2; nevertheless, for those without PERT, it was 14.57 ± 3.09 kg/m2. No significant difference was observed in this regard (P = 0.9). The mean height among children receiving PERT was 1.10 ± 0.22 m; however, those without PERT had a mean height of 1.10 ± 0.27 m (P > 0.05).
5. Discussion
In this study, 62% of the cases were male, which is consistent with the findings of Aziz et al. (9), where 58.13% of CF children were male, similar to the current study. In the current study, 40.7% of patients had a sibling with CF; however, in Ziyaee et al.’s study, only 13.3% of CF patients had a sibling with CF (10).
Among all patients, 67% had a weight percentile < 5, according to Centers for Disease Control and Prevention (CDC) standards. However, the prevalence of malnutrition decreased, according to the report of the Cystic Fibrosis Foundation. Among the children, 50.8% had a height percentile below 5, according to the CDC height curve. Increasing caloric intake can lead to higher weight-for-age in children with CF (11). Nutritional management should be initiated as early as possible after diagnosis (12). Weight and height measurements should be performed at each patient visit (13). Growth failure in children with CF might be due to factors such as airway inflammation, chronic inflammation, undernutrition, or malnutrition (14).
In this study, 57% of children were diagnosed before the age of 1 year. According to a report from the Cystic Fibrosis Foundation, the median age of diagnosis was 3 months. In another study, 64% of patients were diagnosed before the age of 3 years (15). In a study from Egypt, the average age at diagnosis was 3.9 years (16). It seems that the diagnosis of CF in the present study was made earlier than in other studies, possibly due to more experience in the investigated center.
In the present study, FTT was the most common clinical presentation at the time of diagnosis, observed in 49.2% of the cases. Farahmand et al. also observed FTT to be the most common clinical presentation in their study (17). Routine screening of newborns for CF in resource-rich communities has decreased the symptomatic presentation of CF (18).
In Aziz et al.’s study, chronic cough was the most common initial symptom of CF (9). Cough was also observed in 77% of Bahreini children in Isa et al.’s study (15). Gastrointestinal obstruction (GIO) was observed in 8.5% of the cases. Intestinal obstruction among CF patients might be due to distal intestinal obstruction syndrome (DIOS) or meconium ileus obstruction (19).
Among the studied cases, 22% had a loss of appetite. Papantoni et al. observed that children with feeding aids, such as gastric tubes or appetite stimulation medications, demonstrated greater food avoidance (20). Tabori et al. reported a lack of appetite in 130 out of 131 children with CF, which is significantly higher than in the present study (21).
Pancreatic insufficiency was present in 74.6% of the current study’s cases. Pancreatic insufficiency can be treated with enzyme replacement therapy (22). In Calvo-Lerma et al.’s study that included 6 European CF centers, PI was reported in 80 - 100% of the children (23). The rate of PI in the current study was slightly lower than in the study by Calvo-Lerma et al. (23). However, the sample size and duration of the study might affect the frequency of PI.
Among the current study’s patients, 54% reported using vitamin D. Additionally, 60% had 25OH-D levels < 30 ng/mL. Vitamin D insufficiency is common in CF patients (24). Lai et al. reported vitamin D insufficiency in 22% of children with CF (25). Children with CF have significantly lower serum levels of 25OH-D than non-CF individuals (26). In another study, 89% of children had 25OH-D levels lower than 30 ng/mL (27). In a study from the USA, 7% of children had vitamin D deficiency, and 36% had insufficiency (28). The rate of vitamin D insufficiency in Iran was higher than in the USA. In Rovner et al.’s study, vitamin D levels remained low despite routine oral supplementation of vitamin D among children and adolescents with CF (29). In another study from Brazil, 64.6% of the children showed vitamin D insufficiency/deficiency (30).
The current CF guidelines recommend ≥ 800 IU/day of vitamin D supplementation for children aged > 1 year (31). Despite the Cystic Fibrosis Foundation’s recommendation, deficiency in vitamin D remains common in children with CF (32). Norton et al. observed vitamin D deficiency in 23 - 26% of children with CF within 2 years of the study (33). Genetic factors might play a role in variable responses to vitamin D supplements in CF (34).
There is a significant correlation between vitamin D levels and the number of hospital admissions in the present study. Another study showed that higher vitamin D levels among children and adolescents with CF were associated with a lower rate of pulmonary exacerbations (35). Queiroz et al. observed an association between vitamin D hypovitaminosis and inflammatory markers in their study (30). In a recent systematic review by Iniesta et al., 25-OHD concentration was positively associated with lung function in children and young adults with CF (36). Dediu et al. observed that vitamin D deficiency was associated with cystic fibrosis-related diabetes (CFRD), cystic fibrosis liver disease (CFLD), and prolonged lung clearance index in their study (37).
The rate of hospital admission among children with CF depends on several factors. In the present study setting, some patients had a lower economic status, which limited their access to certain drugs. For example, Creon was sometimes unavailable for children.
As mentioned earlier, despite early diagnosis and management, the rate of poor weight gain and short stature in the current study was high. This finding might be attributed to the high frequency of malnutrition reported in previous studies unrelated to CF (38).
5.1. Limitations
This study has several limitations, including its single-center design and financial constraints. Due to financial limitations, it was impossible to assess other fat-soluble vitamins and conduct pulmonary function tests. Additionally, the retrospective nature of the study might introduce potential biases. Laboratory examinations were performed in referral laboratories for children with CF, and demographic variables, such as ethnicity, were not reliable and, therefore, were not included in the analysis.
5.2. Conclusions
The present study highlights the common occurrence of vitamin D insufficiency and FTT among children with CF. There was a significant correlation between vitamin D levels and the number of hospital admissions over a 2-year period. To gain a more comprehensive understanding of nutritional status and vitamin D levels in children with CF, it is recommended that a multicenter prospective study be conducted.
References
-
1.
Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361(9358):681-9. [PubMed ID: 12606185]. https://doi.org/10.1016/S0140-6736(03)12567-6.
-
2.
Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066-73. [PubMed ID: 2475911]. https://doi.org/10.1126/science.2475911.
-
3.
Infante Pina D, Redecillas Ferreiro S, Torrent Vernetta A, Segarra Canton O, Maldonado Smith M, Gartner Tizziano L, et al. [Improvement of intestinal function in cystic fibrosis patients using probiotics]. An Pediatr (Barc). 2008;69(6):501-5. Spanish. [PubMed ID: 19128761]. https://doi.org/10.1016/s1695-4033(08)75231-7.
-
4.
Scheers I, Berardis S. Congenital etiologies of exocrine pancreatic insufficiency. Front Pediatr. 2022;10:909925. [PubMed ID: 35935370]. [PubMed Central ID: PMC9354839]. https://doi.org/10.3389/fped.2022.909925.
-
5.
Henen S, Denton C, Teckman J, Borowitz D, Patel D. Review of Gastrointestinal Motility in Cystic Fibrosis. J Cyst Fibros. 2021;20(4):578-85. [PubMed ID: 34147362]. https://doi.org/10.1016/j.jcf.2021.05.016.
-
6.
Rodrigues R, Magalhaes PK, Fernandes MI, Gabetta CS, Ribeiro AF, Pedro KP, et al. Neonatal screening for cystic fibrosis in Sao Paulo State, Brazil: a pilot study. Braz J Med Biol Res. 2009;42(10):973-8. [PubMed ID: 19787152]. https://doi.org/10.1590/s0100-879x2009005000017.
-
7.
Ratjen F, Doring G, Nikolaizik WH. Effect of inhaled tobramycin on early Pseudomonas aeruginosa colonisation in patients with cystic fibrosis. Lancet. 2001;358(9286):983-4. [PubMed ID: 11583754]. https://doi.org/10.1016/S0140-6736(01)06124-4.
-
8.
Pitts J, Flack J, Goodfellow J. Improving nutrition in the cystic fibrosis patient. J Pediatr Health Care. 2008;22(2):137-40. [PubMed ID: 18294585]. https://doi.org/10.1016/j.pedhc.2007.12.011.
-
9.
Aziz DA, Billoo AG, Qureshi A, Khalid M, Kirmani S. Clinical and laboratory profile of children with Cystic Fibrosis: Experience of a tertiary care center in Pakistan. Pak J Med Sci. 2017;33(3):554-9. [PubMed ID: 28811770]. [PubMed Central ID: PMC5510102]. https://doi.org/10.12669/pjms.333.12188.
-
10.
Ziyaee F, Dehghani SM, Hosseini S, Zohalinezhad ME, Aleyasin S, Javaherizadeh H. Clinical manifestation, laboratory findings, and outcome of children with cystic fibrosis over a 10-year period in South Iran. Gaz Egypt Paediatr Assoc. 2020;68(1):33. https://doi.org/10.1186/s43054-020-00045-9.
-
11.
Woestenenk JW, Dalmeijer GW, van der Ent CK, Houwen RH. The relationship between energy intake and body-growth in children with cystic fibrosis. Clin Nutr. 2019;38(2):920-5. [PubMed ID: 29472121]. https://doi.org/10.1016/j.clnu.2018.02.005.
-
12.
Turck D, Braegger CP, Colombo C, Declercq D, Morton A, Pancheva R, et al. ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis. Clin Nutr. 2016;35(3):557-77. [PubMed ID: 27068495]. https://doi.org/10.1016/j.clnu.2016.03.004.
-
13.
Sullivan JS, Mascarenhas MR. Nutrition: Prevention and management of nutritional failure in Cystic Fibrosis. J Cyst Fibros. 2017;16 Suppl 2:S87-93. [PubMed ID: 28986026]. https://doi.org/10.1016/j.jcf.2017.07.010.
-
14.
Scaparrotta A, Di Pillo S, Attanasi M, Consilvio NP, Cingolani A, Rapino D, et al. Growth failure in children with cystic fibrosis. J Pediatr Endocrinol Metab. 2012;25(5-6):393-405. [PubMed ID: 22876530]. https://doi.org/10.1515/jpem-2012-0012.
-
15.
Isa HM, Al-Ali LF, Mohamed AM. Growth assessment and risk factors of malnutrition in children with cystic fibrosis. Saudi Med J. 2016;37(3):293-8. [PubMed ID: 26905352]. [PubMed Central ID: PMC4800894]. https://doi.org/10.15537/smj.2016.3.13476.
-
16.
El-Falaki MM, Shahin WA, El-Basha NR, Ali AA, Mehaney DA, El-Attar MM. Profile of cystic fibrosis in a single referral center in Egypt. J Adv Res. 2014;5(5):563-8. [PubMed ID: 25685524]. [PubMed Central ID: PMC4294314]. https://doi.org/10.1016/j.jare.2013.07.005.
-
17.
Farahmand F, Khalili M, Shahbaznejad L, Hirbod-Mobarakeh A, Najafi Sani M, Khodadad A, et al. Clinical presentation of cystic fibrosis at the time of diagnosis: a multicenter study in a region without newborn screening. Turk J Gastroenterol. 2013;24(6):541-5. [PubMed ID: 24623294]. https://doi.org/10.4318/tjg.2013.0653.
-
18.
Wolfe AG, Gilley SP, Waldrop SW, Olson C, Harding E, Widmer K, et al. Case report: Cystic fibrosis with kwashiorkor: A rare presentation in the era of universal newborn screening. Front Pediatr. 2022;10:1083155. [PubMed ID: 36683818]. [PubMed Central ID: PMC9853421]. https://doi.org/10.3389/fped.2022.1083155.
-
19.
Mayer Lacrosniere S, Gerardin M, Clainche-Viala LL, Houdouin V. Phenotypic Presentations of Cystic Fibrosis in Children of African Descent. Genes (Basel). 2021;12(3):458. [PubMed ID: 33807078]. [PubMed Central ID: PMC8004676]. https://doi.org/10.3390/genes12030458.
-
20.
Papantoni A, Reinblatt SP, Findling RL, Moran TH, Mogayzel PJ, Carnell S. Appetitive characteristics in children with cystic fibrosis: Questionnaire validation and associations with nutritional status. Appetite. 2019;139:90-4. [PubMed ID: 30946864]. https://doi.org/10.1016/j.appet.2019.03.034.
-
21.
Tabori H, Arnold C, Jaudszus A, Mentzel HJ, Renz DM, Reinsch S, et al. Abdominal symptoms in cystic fibrosis and their relation to genotype, history, clinical and laboratory findings. PLoS One. 2017;12(5):e0174463. [PubMed ID: 28472055]. [PubMed Central ID: PMC5417419]. https://doi.org/10.1371/journal.pone.0174463.
-
22.
Olivier AK, Gibson-Corley KN, Meyerholz DK. Animal models of gastrointestinal and liver diseases. Animal models of cystic fibrosis: gastrointestinal, pancreatic, and hepatobiliary disease and pathophysiology. Am J Physiol Gastrointest Liver Physiol. 2015;308(6):G459-71. [PubMed ID: 25591863]. [PubMed Central ID: PMC4360044]. https://doi.org/10.1152/ajpgi.00146.2014.
-
23.
Calvo-Lerma J, Hulst JM, Asseiceira I, Claes I, Garriga M, Colombo C, et al. Nutritional status, nutrient intake and use of enzyme supplements in paediatric patients with Cystic Fibrosis; a European multicentre study with reference to current guidelines. J Cyst Fibros. 2017;16(4):510-8. [PubMed ID: 28320633]. https://doi.org/10.1016/j.jcf.2017.03.005.
-
24.
Pincikova T, Nilsson K, Moen IE, Karpati F, Fluge G, Hollsing A, et al. Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study. Eur J Clin Nutr. 2011;65(1):102-9. [PubMed ID: 20859300]. https://doi.org/10.1038/ejcn.2010.194.
-
25.
Lai HJ, Chin LH, Murali S, Bach T, Sander D, Farrell PM, et al. Vitamins A, D, E status as related to supplementation and lung disease markers in young children with cystic fibrosis. Pediatr Pulmonol. 2022;57(4):935-44. [PubMed ID: 35018747]. [PubMed Central ID: PMC8930603]. https://doi.org/10.1002/ppul.25825.
-
26.
Albedewi H, Bindayel I, Albarrag A, Banjar H. Correlation of Gut Microbiota, Vitamin D Status, and Pulmonary Function Tests in Children With Cystic Fibrosis. Front Nutr. 2022;9:884104. [PubMed ID: 35757256]. [PubMed Central ID: PMC9218790]. https://doi.org/10.3389/fnut.2022.884104.
-
27.
Bravo MP, Balboa P, Torrejon C, Bozzo R, Boza ML, Contreras I, et al. Bone mineral density, lung function, vitamin D and body composition in children and adolescents with cystic fibrosis: a multicenter study. Nutr Hosp. 2018;35(4):789-95. [PubMed ID: 30070865]. https://doi.org/10.20960/nh.1609.
-
28.
Simoneau T, Bazzaz O, Sawicki GS, Gordon C. Vitamin D status in children with cystic fibrosis. Associations with inflammation and bacterial colonization. Ann Am Thorac Soc. 2014;11(2):205-10. [PubMed ID: 24423241]. https://doi.org/10.1513/AnnalsATS.201306-171BC.
-
29.
Rovner AJ, Stallings VA, Schall JI, Leonard MB, Zemel BS. Vitamin D insufficiency in children, adolescents, and young adults with cystic fibrosis despite routine oral supplementation. Am J Clin Nutr. 2007;86(6):1694-9. [PubMed ID: 18065588]. https://doi.org/10.1093/ajcn/86.5.1694.
-
30.
Queiroz DJM, Silva AS, Silva Junior CCD, Persuhn DC, Diniz ADS, Lima R, et al. Vitamin D levels and their association with oxidative stress and inflammation markers in patients with cystic fibrosis. Nutr Hosp. 2023;40(2):280-5. [PubMed ID: 36719006]. https://doi.org/10.20960/nh.04253.
-
31.
Aris RM, Merkel PA, Bachrach LK, Borowitz DS, Boyle MP, Elkin SL, et al. Guide to bone health and disease in cystic fibrosis. J Clin Endocrinol Metab. 2005;90(3):1888-96. [PubMed ID: 15613415]. https://doi.org/10.1210/jc.2004-1629.
-
32.
Bertolaso C, Groleau V, Schall JI, Maqbool A, Mascarenhas M, Latham NE, et al. Fat-soluble vitamins in cystic fibrosis and pancreatic insufficiency: efficacy of a nutrition intervention. J Pediatr Gastroenterol Nutr. 2014;58(4):443-8. [PubMed ID: 24345827]. [PubMed Central ID: PMC4212898]. https://doi.org/10.1097/MPG.0000000000000272.
-
33.
Norton L, Page S, Sheehan M, Mazurak V, Brunet-Wood K, Larsen B. Prevalence of inadequate vitamin d status and associated factors in children with cystic fibrosis. Nutr Clin Pract. 2015;30(1):111-6. [PubMed ID: 25550329]. https://doi.org/10.1177/0884533614562839.
-
34.
Lai HJ, Song J, Lu Q, Murali SG, Gajapathy M, Wilk BM, et al. Genetic factors help explain the variable responses of young children with cystic fibrosis to vitamin D supplements. Clin Nutr ESPEN. 2022;51:367-76. [PubMed ID: 36184229]. https://doi.org/10.1016/j.clnesp.2022.07.018.
-
35.
Grossmann RE, Zughaier SM, Kumari M, Seydafkan S, Lyles RH, Liu S, et al. Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: A randomized, controlled trial. Dermatoendocrinol. 2012;4(2):191-7. [PubMed ID: 22928076]. [PubMed Central ID: PMC3427199]. https://doi.org/10.4161/derm.20332.
-
36.
Iniesta RR, Cook S, Oversby G, Koufaki P, Van der Linden ML, Vlachopoulos D, et al. Systematic review and meta-analysis: Associations of vitamin D with pulmonary function in children and young people with cystic fibrosis. Clin Nutr ESPEN. 2023;54:349-73. [PubMed ID: 36963882]. https://doi.org/10.1016/j.clnesp.2023.02.006.
-
37.
Dediu M, Ciuca IM, Pop LL, Iacob D. The Relation between Vitamin D Level and Lung Clearance Index in Cystic Fibrosis-A Pilot Study. Children (Basel). 2022;9(3):329. [PubMed ID: 35327701]. [PubMed Central ID: PMC8947157]. https://doi.org/10.3390/children9030329.
-
38.
Dehghani SM, Javaherizadeh H, Heidary M, Honar N, Ataollahi M, Ilkanipour H, et al. Stunting, wasting, and mid upper arm circumference status among children admitted to Nemazee Teaching Hospital. Nutr Hosp. 2018;35(1):33-7. [PubMed ID: 29565146]. https://doi.org/10.20960/nh.1143.