Evaluation of the Efficacy of a Nanomicellar Formulation of Fat-Soluble Vitamins in Patients with Cystic Fibrosis: a Randomized Controlled Trial

Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)

Papilledema and hypervitaminosis A after elexacaftor/tezacaftor/ivacaftor for cystic fibrosis

Selection bias and vitamin E status in cystic fibrosis

Joining the Crowd: Cystic Fibrosis and Cardiovascular Disease Risk Factors

Fat-soluble vitamin deficiency in children with cystic fibrosis in NSW

The first clear description of ‘fibrocystic disease of the pancreas’ or Cystic Fibrosis (CF) came in the late 1930s1 and evidence of vitamin A deficiency was reported in 10 of 49 patients as early as 1939.2 Indeed, this paper recommended ‘generous dosages’ of vitamin A for these patients. Biochemical evidence of fat-soluble vitamin deficiency occurs early in infants diagnosed with CF by newborn screening.3–6 Sokol et al. reported the fat-soluble vitamin status of 36 infants diagnosed by newborn screening between 1984 and 1987 with the initial evaluation being undertaken at around seven weeks of age. There was an inverse correlation between three-day faecal fat excretion and serum α-tocopherol levels (vitamin E). Twenty-one percent of patients had low vitamin A levels, 35% low vitamin D, 38% low vitamin E and vitamin E:lipid ratio though none had an elevated PIVKA-II (protein induced by vitamin K absence or antagonism) – one indicator of vitamin K deficiency. Introduction of pancreatic enzyme replacement therapy, and standard fat-soluble vitamin supplementation corrected vitamin A and D status at 6 and 12 months of age. However, 10% of patients remained vitamin E deficient.3 Feranchak et al. reported that 44 of 96 (45.8%) infants diagnosed by newborn screening between 1984 and 1997 had a deficiency of one or more of the fat-soluble vitamins by 4–8 weeks of age. Vitamin A deficiency occurred in 29% of patients, vitamin D deficiency in 22.5% and vitamin E deficiency in 22.8%.4 Bines et al. reported low serum retinol in 20 out of 39 (51%) infants and low α-tocopherol in nine of 38 (24%) infants diagnosed by newborn screening between 1991 and 1994.5 These studies are supported by more contemporaneous data. Neville and Ranganathan reported 58 infants diagnosed by newborn screening between 2001 and 2006. Median age of diagnosis was 1 month (range 0–3 months). Vitamin D deficiency was described in 11 of 30 infants (37%), vitamin E deficiency in seven of 45 (16%) and vitamin A deficiency 27 of 45 (60%). Vitamin A and E levels were significantly lower in pancreatic insufficient patients. Vitamin A and E status was significantly correlated with pancreatic status though there was no significant correlation with pancreatic status and vitamin D deficiency.6 Why bother to take vitamins? Firstly, because at the time of diagnosis of CF there is clear biochemical evidence of vitamin A deficiency in up to 60% of infants6 and vitamin D and E deficiency in up to 37%6 and 38%,3 respectively. Untreated, the incidence of biochemical and later clinical vitamin deficiencies will increase. Most people with CF are at risk of fat-soluble vitamin deficiencies due to fat malabsorption and maldigestion as a consequence of pancreatic insufficiency and bile salt deficiency. Patients treated with pancreatic enzyme replacement therapy may still experience refractory steatorrhoea due to enzyme inactivation as a consequence of high intestinal pH, small bowel bacterial overgrowth,7 the presence of a mucus barrier lining the intestine, short gut syndrome due to previous bowel resection and CF-related liver disease. Adherence rates are difficult to assess8 but non-adherence to pancreatic enzyme replacement is commonly reported9,10 and contributes to malabsorption. We know that some patients do not bother to take their prescribed vitamins as adherence rates in people with CF of 47% of the recommended vitamin prescription have been reported.9,11 Modi et al. compared different methods of assessing adherence to vitamin therapy. Adherence was variable and ranged from 22% when recorded in a diet diary to 94% for self-report by children.10 Non-adherence to therapy, poor dietary intake either due to anorexia or poor dietary sources of vitamins can also contribute to fat-soluble vitamin deficiency in CF. All of these factors put people with CF at high risk of vitamin deficiencies and in addition there are vitamin-specific risk factors detailed below. Advances in the clinical and medical management of people with CF have led to improved life expectancy and new and emerging co-morbidities. The introduction of newborn screening allowing for earlier and more aggressive intervention together with improved pancreatic enzyme replacement therapy, the early introduction of appropriate fat soluble vitamin supplementation and an overall improvement in nutritional status together with advances in our understanding of fat-soluble vitamin metabolism12 mean we need to consider fat-soluble vitamin status in the context of modern disease. The emphasis of how vitamin status is defined has shifted. Traditionally vitamin status was discussed in terms of overt deficiency resulting in the classically recognized deficiency symptoms such as night blindness and xeropthalmia in vitamin A deficiency. Now vitamin status is also considered in terms of subclinical deficiencies which are defined as low serum, tissue or airway surface liquid vitamin levels with no visible signs or symptoms of deficiency. It is increasingly recognized that subclinical deficiencies in CF may play a significant role. Vitamin status may now be considered in the context of health outcomes rather than overt deficiency12 with levels being described as deficient, insufficient, adequate, optimal and toxic.

Letters to the Editor

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. 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.

Cystic fibrosis and alpha 1 antitrypsin deficiency are two important autosomal recessive multi organ diseases They are complex and severe diseases that involve various organs including pancreas Pancreatic disease in cystic fibrosis varies from complete loss of exocrine and endocrine functions to nearly normal pancreatic function A strong correlation between genotype and phenotype is recognized Pancreatic involvement is characterized by malabsorption of fat and protein and growth failure Fat malabsorption leads to special problems with the fat soluble vitamins Enzyme and fat soluble vitamin replacements are the milestones of the malabsorption treatment Gene therapy offers the best hope for a cure of cystic fibrosis Although an association between alpha1 antitrypsin deficiency and chronic pancreatitis has been reported in several case reports in prospective studies it has been shown that pancreatitis prevalence in patients with alpha1 antitrypsin deficiency was not different from that of healthy controls Thus it was concluded that alpha 1 antitrypsin deficiency was not related to the pathogenesis of idiopathic or hereditary chronic pancreatitis However protective role of alpha 1 antitrypsin against pancreatic auto digestion suggests that the deficiency of that protein may worsen the pancreatic disease rather than causing it Early detection and management of pancreatic insufficiency is essential to optimize health and outcomes in cystic fibrosis and alpha 1 antitrypsin deficiency patients Turk Arch Ped 2009; 44: 7 11 Key words: Alfa 1 antitripsin deficinecy cystic fibrosis pancreas

Rationale: Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leads to impaired pancreatic function and therefore reduced intestinal absorption of lipids and fat-soluble vitamins especially in patients with CF developing pancreatic insufficiency (PI). Previous studies showed that CFTR modulator therapy with lumacaftor-ivacaftor (LUM/IVA) in Phe508del-homozygous patients with CF results in improvement of pulmonary disease and thriving. However, the effects of LUM/IVA on plasma concentration of the lipid soluble vitamins A and E remain unknown. Objectives: To investigate the course of plasma vitamin A and E in patients with CF under LUM/IVA therapy. Methods: Data from annual follow-up examinations of patients with CF were obtained to assess clinical outcomes including pulmonary function status, body mass index (BMI), and clinical chemistry as well as fat-soluble vitamins in Phe508del-homozygous CF patients before initiation and during LUM/IVA therapy. Results: Patients with CF receiving LUM/IVA improved substantially, including improvement in pulmonary inflammation, associated with a decrease in blood immunoglobulin G (IgG) from 9.4 to 8.2 g/L after two years (p < 0.001). During the same time, plasma vitamin A increased significantly from 1.2 to 1.6 µmol/L (p < 0.05), however, levels above the upper limit of normal were not detected in any of the patients. In contrast, plasma vitamin E as vitamin E/cholesterol ratio decreased moderately over the same time from 6.2 to 5.5 µmol/L (p < 0.01). Conclusions: CFTR modulator therapy with LUM/IVA alters concentrations of vitamins A and vitamin E in plasma. The increase of vitamin A must be monitored critically to avoid hypervitaminosis A in patients with CF.

People with cystic fibrosis are at an increased risk of fat-soluble vitamin deficiency including vitamin E. Vitamin E deficiency can cause a host of conditions such as haemolytic anaemia, cerebellar ataxia and cognitive difficulties. Vitamin E supplementation is widely recommended in cystic fibrosis and aims to ameliorate this deficiency. To determine the effects of any level of vitamin E supplementation on the frequency of vitamin E deficiency disorders in people with cystic fibrosis. We searched the Cochrane Group's Cystic Fibrosis Trials Register and also searched international trial registers for any ongoing clinical trials that were not identified during our register search.Date of last search of the Register: 10 February 2014. Date of last search of international trial registers: 30 August 2014. Randomised controlled trials and quasi-randomised controlled trials comparing any preparation of vitamin E supplementation to placebo or no supplement, regardless of dosage or duration. Two authors extracted outcome data from each study (published information) and assessed the risk of bias of each included study. Four studies with a total of 141 participants were included in the review, two of these were in children (aged six months to 14.5 years), and the other two did not specify participants' age. All studies used different formulations and doses of vitamin E for various durations of treatment (10 days to six months). Two studies compared the supplementation of fat-soluble as well as water-soluble formulations to no supplementation in different arms of the same study. A third study compared a water-soluble formulation to a placebo; and in the fourth study a fat-soluble formulation of vitamin E was assessed against placebo.At one month, three months and six months, water-soluble vitamin E significantly improved serum vitamin E levels compared with control: at one month, two studies, mean difference 17.66 (95% confidence interval 10.59 to 24.74); at three months, one study, mean difference 11.61 (95% confidence interval 4.77 to 18.45); and at six months, one study, mean difference 19.74 (95% confidence interval 13.48 to 26.00). At one month fat-soluble vitamin E significantly improved serum vitamin E levels compared with control: one month, two studies, mean difference 13.59 (95% CI 9.52 to 17.66). The findings at three months were imprecise; one study; mean difference 6.40 (95% CI -1.45 to 14.25).None of the studies report the review's primary outcomes of vitamin E total lipid ratio or the incidence of vitamin E-specific deficiency disorders, or the secondary outcomes lung function or quality of life. Only one study, comparing water-soluble vitamin E with placebo, reported the secondary outcome of growth and nutritional status (weight), but the results are uncertain due to imprecision around the effect estimate.There was limited detail about randomisation and blinding in the included studies which compromises the quality of the evidence base for the review. The heterogeneous mix of the formulations with differing biovailabilities among these studies also limits the generalisability of the data to the wider cystic fibrosis population. Vitamin E supplementation led to an improvement in vitamin E levels in people with cystic fibrosis, although the studies may have been at risk of bias. No data on other outcomes of interest were available to allow conclusions about any other benefits of this therapy.In future, larger studies are needed, especially in people already being treated with enteric-coated pancreatic enzymes and supplemented with vitamin E, to look at more specific outcome measures such as vitamin E status, lung function and nutritional status. Future studies could also look at the optimal dose of vitamin E required to achieve maximal clinical effectiveness.

People with cystic fibrosis are at an increased risk of fat-soluble vitamin deficiency, including vitamin E. Vitamin E deficiency can cause a host of conditions such as haemolytic anaemia, cerebellar ataxia and cognitive difficulties. Vitamin E supplementation is widely recommended for people with cystic fibrosis and aims to ameliorate this deficiency. This is an updated version of the review. To determine the effects of any level of vitamin E supplementation on the frequency of vitamin E deficiency disorders in people with cystic fibrosis. We searched the Cochrane Group's Cystic Fibrosis Trials Register and also searched international online trial registries for any ongoing clinical trials that were not identified during our register search. Date of last search of the Register: 11 August 2020. Date of last search of international online trial registries: 20 July 2020. Randomised controlled trials and quasi-randomised controlled trials comparing any preparation of vitamin E supplementation to placebo or no supplement, regardless of dosage or duration. Two authors extracted outcome data from each study (published information) and assessed the risk of bias of each included study. They assessed the quality of the evidence using GRADE. Four studies with a total of 141 participants were included in the review, two of these were in children (aged six months to 14.5 years), and two did not specify participants' age. All studies used different formulations and doses of vitamin E for various durations of treatment (10 days to six months). Two studies compared the supplementation of fat-soluble as well as water-soluble formulations to no supplementation in different arms of the same study. A third study compared a water-soluble formulation to a placebo; and in the fourth study a fat-soluble formulation of vitamin E was assessed against placebo. There was limited detail about randomisation and blinding in the included studies which compromises the quality of the evidence base for the review. The heterogeneous mix of the formulations with differing biovailabilities among these studies also limits the generalisability of the data to the wider cystic fibrosis population. None of the studies in either comparison report the review's primary outcomes of vitamin E total lipid ratio or the incidence of vitamin E-specific deficiency disorders, or the secondary outcomes lung function or quality of life. Water-soluble vitamin E Water-soluble vitamin E may improve serum vitamin E levels compared with control at six months, one study (45 participants), mean difference (MD) 19.74 umol/L (95% confidence interval (CI) 13.48 to 26.00) (low-quality evidence). Similar results were also seen at one month, two studies (32 participants), MD 17.66 umol/L (95% CI 10.59 to 24.74) and at three months, one study (45 participants), MD 11.61 umol/L (95% CI 4.77 to 18.45). Only one study (45 participants) reported weight (secondary outcome of growth and nutritional status) at one and six months, but showed no difference between treatment and control at either time point. Fat-soluble vitamin E Two studies (36 participants) reported higher levels of serum vitamin E at one month with fat-soluble vitamin E compared with control, MD 13.59 umol/L (95% CI 9.52 to 17.66); however, at three months one study (36 participants) showed no difference between treatment and control. No studies in this comparison reported on growth or nutritional status. Vitamin E supplementation may lead to an improvement in vitamin E levels in people with cystic fibrosis, although evidence we assessed was low quality. No data on other outcomes of interest were available to allow conclusions about any other benefits of this therapy. In future, larger studies are needed, especially in people already being treated with enteric-coated pancreatic enzymes and supplemented with vitamin E, to look at more specific outcome measures such as vitamin E status, lung function and nutritional status. Future studies could also look at the optimal dose of vitamin E required to achieve maximal clinical effectiveness.

People with cystic fibrosis and pancreatic insufficiency are at risk of fat soluble vitamin deficiency as these vitamins (A, D, E and K) are co-absorbed with fat. Thus, some cystic fibrosis centres routinely administer these vitamins as supplements but the centres vary in their approach of addressing the possible development of deficiencies in these vitamins. Vitamin A deficiency causes predominantly eye and skin problems while supplementation of vitamin A to excessive levels may cause harm to the respiratory and skeletal systems in children. Thus a systematic review on vitamin A supplementation in people with cystic fibrosis would help guide clinical practice. To determine if vitamin A supplementation in children and adults with cystic fibrosis:1. reduces the frequency of vitamin A deficiency disorders;2. improves general and respiratory health;3. increases the frequency of vitamin A toxicity. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Cystic Fibrosis Trials Register: 07 April 2014. All randomised or quasi-randomised controlled trials comparing all preparations of oral vitamin A used as a supplement compared to either no supplementation (or placebo) at any dose and for any duration, in children or adults with cystic fibrosis (defined by sweat tests or genetic testing) with and without pancreatic insufficiency. No relevant studies for inclusion were identified in the search. No studies were included in this review. As there were no randomised or quasi-randomised controlled trials identified, we cannot draw any conclusions on the benefits (or otherwise) of regular administration of vitamin A in people with cystic fibrosis. Until further data are available, country or region specific guidelines on the use of vitamin A in people with cystic fibrosis should be followed.

Cystic fibrosis (CF) is the most common genetic disease that causes respiratory failure within the Caucasian population. The life span of patients with CF has gradually increased from a median of 2 years of age to >30 years. Concurrent with this increased lifespan, a variety of other nutritional, endocrine and bone issues have been recognised. Decreased absorption of fat-soluble vitamins (D and K in particular) because of pancreatic insufficiency, altered sex hormone production, chronic inflammation, a lack of physical activity, glucocorticoid treatment and an intrinsic hyper-resorptive bone physiology are some of the factors that contribute to the prominence of bone disease within the CF population. In some series, three-quarters of adult patients with CF have osteopenia or osteoporosis. Lung transplantation is one viable treatment for patients with end-stage CF, which requires a lifetime of antirejection medication. Immunosuppressant therapies have a detrimental effect on bone mineral density (BMD). To combat the multifactorial nature of CF-related bone disease, advances in nutritional and vitamin supplementation, and anti-resorptive and anabolic therapies have evolved. Chronic vitamin D depletion contributes to bone disease in the CF population. The isoform of vitamin D that is the best and safest supplement, with the lowest cost, has yet to be identified. However, it is clear that many patients with CF who receive the standard of care (i.e. two daily combination vitamin A, D, E and K tablets [ADEKs]) may still be vitamin D-deficient. More aggressive supplementation needs to be individualised, with close monitoring of serum 25-hydroxyvitamin D levels. Similarly, routine calcium supplementation may be important, and evidence is accumulating that vitamin K also plays an important role in maximising and maintaining BMD. Early recognition and treatment of delayed puberty in adolescents and hypogonadism in adults with hormone replacement therapy is recommended to maintain BMD in patients with CF. Bisphosphonates, including pamidronic acid, etidronic acid and alendronic acid, reduce bone resorption by inhibiting the recruitment and function of osteoclasts. Pamidronic acid is beneficial in improving BMD in CF patients before and after transplantation. Bisphosphonate therapy and minimisation of glucocorticoid dosage have been shown to be efficacious in glucocorticoid-induced osteoporosis. Teriparatide is the first US FDA-approved anabolic growth agent for bone, and has been shown to increase BMD and decrease fracture incidence in postmenopausal women. Teriparatide may offer a new avenue for treating bone disease in CF since many patients may have poor bone formation as well as accelerated bone breakdown. Numerous clinical trials are underway to optimise treatment of CF osteoporosis.

The LC–MS method for the simultaneous analysis of selected fat-soluble vitamins and their metabolites in serum samples obtained from pediatric patients with cystic fibrosis