We reviewed the evidence regarding the effect of regular vitamin A or vitamin A-like (carotenes or other retinoids) supplements in children and adults with cystic fibrosis.
In people with cystic fibrosis only a small proportion of some vitamins, such as vitamin A, may be absorbed by the body and lead to problems caused by vitamin deficiency. A lack of vitamin A (vitamin A deficiency) can cause eye and skin problems and is associated with poorer general and respiratory health. Therefore, people with cystic fibrosis are usually supplemented with regular vitamin A preparations from a very young age. However, too much vitamin A can cause bone and liver problems. Excessive carotene levels are known to cause carotenaemia, a harmless, reversible yellowing of the skin, whilst a lack of carotene is not known to cause adverse manifestations in individuals with normal vitamin A levels.
The evidence is current to: 01 June 2018.
No studies comparing vitamin A or other retinoid supplements to placebo (dummy drug containing no vitamin A) were included, but we did find one study comparing beta-carotene supplementation (a precursor of vitamin A) to placebo. A total of 24 people with cystic fibrosis (aged 6.7 to 27.7 years) were put into groups at random and treated either with β-carotene capsules (at a high dose for three months followed by a low dose for a further three months) or with placebo (for six months).
No studies on vitamin A supplementation were included in this review.
The single included study revealed that high-dose beta-carotene supplementation for three months led to fewer days on which people with CF required antibiotics compared to placebo, but this was not the case in the following three-month section of the study when low-dose beta-carotene supplementation was compared to placebo. Other clinical outcome measures (growth, nutritional status and lung function) showed no statistical significant differences between treatment and placebo groups. No side effects were observed. The other outcomes in this review, such as vitamin A deficiency symptoms, mortality, toxicity and quality of life, were not reported.
Quality of the evidence
We could only include one study in this review and that study had several limitations. This is reflected in the assessment of low-quality evidence, judged using the specific evidence grading system (GRADE). So, we feel that the strength of evidence is low. Not all outcome measures were reported after each supplementation dose and results should be viewed with some caution as some beta-carotene from the high-dose period was probably still present in the blood during the low-dose supplementation period.
Since no studies on vitamin A supplementation were included in the review, no conclusions can be drawn regarding the routine use of vitamin A supplements. Due to limitations of the included study of beta-carotene supplementation, no definitive conclusions regarding its use can be drawn either. Until further evidence is available, local guidelines should be followed regarding supplementation.
Since no randomised or quasi-randomised controlled studies on retinoid supplementation were identified, no conclusion on the supplementation of vitamin A in people with CF can be drawn. Additionally, due to methodological limitations in the included study, also reflected in the low-quality evidence judged following the specific evidence grading system (GRADE), no clear conclusions on β-carotene supplementation can be drawn. Until further data are available, country- or region-specific guidelines regarding these practices should be followed.
People with cystic fibrosis (CF) and pancreatic insufficiency are at risk of a deficiency in fat-soluble vitamins, including vitamin A. Vitamin A deficiency predominantly causes eye and skin problems, while excessive levels of vitamin A can harm the respiratory and skeletal systems in children and interfere with the metabolism of other fat-soluble vitamins. Most CF centres administer vitamin A as supplements to reduce the frequency of vitamin A deficiency in people with CF and to improve clinical outcomes such as growth, although the recommended dose varies between different guidelines. Thus, a systematic review on vitamin A and vitamin A-like supplementation (carotenes or other retinoids) in people with CF would help guide clinical practice. This is an update of an earlier Cochrane Review.
To determine if supplementation with vitamin A, carotenes or other retinoid supplements in children and adults with CF reduces the frequency of vitamin A deficiency disorders, improves general and respiratory health and affects the frequency of vitamin A toxicity.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Cystic Fibrosis Trials Register compiled from electronic database searches and handsearching of journals and conference abstract books. Additionally we searched several ongoing trials registries, including ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform and the International Standard Randomised Controlled Trial Number Registry.
Most recent database searches: 01 June 2018.
All randomised or quasi-randomised controlled studies comparing all preparations of oral vitamin A, carotenes or retinoids (or in combination), used as a supplement compared to placebo at any dose, for at least three months, in people with CF (diagnosed by sweat tests or genetic testing) with and without pancreatic insufficiency.
Two authors individually assessed study quality and extracted data on outcome measures. The authors assessed the quality of the evidence using the GRADE system. Investigators were contacted to retrieve missing quantitative data.
No studies of vitamin A or other retinoid supplementation were eligible for inclusion. However, one randomised study of beta (β)-carotene supplementation involving 24 people with CF who were receiving pancreatic enzyme substitution was included. The study compared successive β-carotene supplementation periods (high dose followed by low dose) compared to placebo. The results for the low-dose supplementation period should be interpreted with caution, due to the lack of a wash-out period after the high-dose supplementation.
The included study did not report on two of the review's primary outcomes (vitamin A deficiency disorders and mortality); results for our third primary outcome of growth and nutritional status (reported as z score for height) showed no difference between supplementation and placebo, mean difference (MD) -0.23 (95% confidence interval (CI) -0.89 to 0.43) (low-quality evidence). With regards to secondary outcomes, supplementation with high-dose β-carotene for three months led to significantly fewer days of systemic antibiotics required to treat pulmonary exacerbations, compared to controls, MD -15 days (95% CI -27.60 to -2.40); however, this was not maintained in the second three-month section of the study when the level of β-carotene supplementation was reduced, MD -8 days (95% CI -18.80 to 2.80) (low-quality evidence). There were no statistically significant effects between groups in lung function (low-quality evidence) and no adverse events were observed (low-quality evidence). Supplementation affected levels of β-carotene in plasma, but not vitamin A levels. The study did not report on quality of life or toxicity.