JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Supplement No. 38 Volume 93 2000 Theroleofvitaminsincysticfibrosis Siobha´ nBCarr1 MRCPCH MSc Jennifer McBratney2 BSc(Hon) J R Soc Med 2000;93(Suppl. 38):14–19 SECTION OF PAEDIATRICS & CHILD HEALTH, 23 NOVEMBER 1999 INTRODUCTION by replacing the mucus-secreting ciliated epithelium with In one of the first descriptions of cystic fibrosis (CF), squamous epithelium. Even mild vitamin A deficiency Dorothy Anderson1 described vitamin A deficiency. During increases the number of secreting cells whilst decreasing the following 60 years the involvement of vitamins has ciliated cells, leading to impairment of the cilia-mediated continued to be discussed2–5. From the beginning of life6 to cleaning action of the lung13,14. Also relevant to CF is the the terminal stages7 vitamin deficiency has been shown to fact that adhesion of Staphylococcus aureus to nasal respiratory play a role. The focus has quite rightly been on the role of epithelial cells is increased in states of vitamin A fat-soluble vitamins because it is this group that is deficiency15. malabsorbed by the pancreatic insufficient people with CF. A role for retinol in immunity has been suggested since We shall inform the reader about the availability of these the 1920s16. Various mechanisms have been discussed: T-cell vitamins from diet and supplements, discuss their role in subset depressions; cell differentiation; phagocyte stimu- the body and describe the effects of excess and deficiency, lation; and cytokine modulation17–19. Over the last two and review some of the available literature specific to CF. decades large population studies in developing countries The fat soluble vitamins (A,D,E,K) will be covered with a have suggested that mortality and morbidity is increased in brief mention of vitamin C. vitamin A deficient children20. A decrease in morbidity and mortality after vitamin A supplementation has been shown 21,22 Vitamin A though there have been some conflicting results . Studies to confirm this relationship in CF are technically Vitamin A, also known as retinol, is present only in animal difficult because of the multi-factorial basis of respiratory food sources such as liver, fish oils and dairy products. It infections. However, looking at a population of 78 children can also be formed from some 50 of the 600 known with CF in their first year of vitamin A screening, a positive 8 carotenoids . These account for one-third to two-thirds of correlation between low vitamin A status and lung function our dietary vitamin A intake and are found mainly in yellow was found (Figure 1). Multiple regression analysis showed a fruit, vegetables and carrots. Beta-carotene (provitamin A), multiple R value of 0.62, with age, vitamin A and clinical perhaps the best known can be converted to vitamin A by score all having a significant effect on lung function. A low 9 an oxygenase present in the intestine and elsewhere .The vitamin A level (5258 mmol/L) predicted a forced carotenoids are present in fruits and vegetables and like expiratory volume in 1 s (FEV1)of550% with an odds vitamin A are fat-soluble and absorbed from the ileum. Two ratio of 5 (95% CI 1.7–14.4)23. of its main active metabolites are retinol, which is involved Provitamin A (b-carotene) is a potent antioxidant linked in visual pigment, and retinoic acid, an intracellular in its defensive role with the other antioxidants vitamin E messenger involved in cell differentiation. and vitamin C. This is especially relevant when related to Visual morbidity in relation to vitamin A deficiency has the defence of the lungs in CF. Antioxidants are the body’s 10,11 been reported in CF although not in supplemented natural defence system against oxygen free radicals 12 patients with normal vitamin A levels . Xerophlamia and (oxidants). Oxidants refer to any molecular species capable subsequent blindness secondary to vitamin A deficiency are of independent existence that contain one or more unpaired related to its role in maintenance of mucus secreting electron. They are continually produced by the body in epithelia. This role is also crucially important for the both health and disease—CF is no exception. Oxidants are respiratory epithelia, where stores of retinyl ester can be a highly reactive species that can cause mutagenesis, cell found. Studies in rats show that advanced vitamin A damage and death if left unchecked. Both bacteria such as deficiency alters the structure of the respiratory epithelium Pseudomonas aeruginosa and neutrophils release oxidants and are thought to contribute to the lung damage in CF. Departments of 1Paediatric Respiratory Medicine and 2Dietetics, Barts and The Increased oxidation and decreased antioxidants together London CF Centre, Queen Elizabeth Children’s Services, Royal London Hospital, Whitechapel, London E1 1BB, UK lead to the oxidant/antioxidant imbalance found in CF. Correspondence to: Dr Siobha´ n Carr, 2nd Floor Fielden House, Royal London Toxicity with vitamin A overdose has been reported in 25,26 Hospital, Whitechapel, London E1 1BB, UK CF after supplementation . Measurement of plasma 14 E-mail: [email protected] retinol may be unreliable, especially with its variability JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Supplement No. 38 Volume 93 2000 FEV1 (% predicted for height and sex) Figure 1 The relationship between vitamin A and forced expiratory volume in 1 s (FEV1 ) in 78 steady-state CF Vitamin A (mmol/L) children. ~ Female; & male during acute exacerbation27. Retinol is stored in the liver Low vitamin D levels lead to reduced calcification of and measurement of the stored form, retinyl ester in bones; in growing bone this leads to rickets and in mature conjunction with retinol binding protein may be more bone to osteomalacia. Reports of rickets in CF individuals appropriate28. Fears that patients with CF on long-term date back to 197733. With increased survival34 the problems supplementation may be at risk of chronic hypervitaminosis of osteoporosis35 with associated osteomalacia36 are A have not been confirmed in a liver biopsy study that becoming more apparent in adult patients. The osteoporosis suggested liver stores actually decrease with age29. present is likely to be multi-factorial in origin; vitamin D playing a role along with the use of steroids and reduced VITAMIN D exercise, secondary to ill health. There is a particular problem in patients post-transplant7 compounded by the There are two main forms of vitamin D: ergocalciferol immunosuppressive regimens used. (vitamin D2), which is artificially produced and cholecalci- Dosage with 20 mg/day (800 iu, the recommended ferol (vitamin D3). The majority of cholecalciferol is formed dose) of vitamin D in 20 adolescents and adults with CF was naturally by the action of ultraviolet light. There is a non- insufficient to raise the plasma 25-OHD3 to normal levels in enzymatic reaction in the dermis of the skin causing 40% of patients37. This paper was written in 1985 and yet conversion of the steroid 7-dehydrocholesterol to pre- we are still recommending this dosage, possibly for fear of vitamin D then to cholecalciferol. Cholecalciferol does vitamin toxicity. Overdose with vitamin D is possible, occur in food substances such as fatty fish and fortified leading to hypercalcaemia associated with thirst, polyuria, margarines. Cholecalciferol is hydroxylated in the liver to muscle weakness and anorexia. Chronic toxicity can lead to 25-OHD3 (25-hydroxy vitamin D) and then again in the nephrocalcinosis and vascular calcification. kidney to 1,25 (OH2)D3 (calcitriol). Calcitriol acts as a hormone to stimulate the synthesis of a calcium transport protein in the small intestine30. VITAMIN E Monitoring of plasma vitamin D concentration in its 25- There are eight similar compounds with vitamin E activity; OHD3 form is the most accessible, although measurement a-tocopherol is the most active of these, the one measured of 1,25-(OH2)D3 is also possible. Studies in CF show levels in plasma and the one referred to when listed in fortified to be low or marginally low in children with CF compared food contents. Vitamin E is present in all cell membranes with controls, despite supplementation31. Vitamin D levels and acts as a very important antioxidant by reducing the vary with season (sun-light exposure), and this appears to effects of free oxygen radicals on unsaturated fatty acids play a more important role than liver disease or fat- (lipid peroxidation). In stopping lipid peroxidation it forms malabsorption32. Thirty-five per cent of infants with CF a less potent radical, hence vitamin E is consumed. Lipid picked up by newborn screening already had low vitamin D peroxidation has been shown to be increased in CF24. This levels6. consumption of vitamin E is postulated to be one of the 15 JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Supplement No. 38 Volume 93 2000 reasons for low levels of vitamin E in CF patients38, along increased risk of hip fracture in women with a low intake with the increased oxidative stress of both bacterial of vitamin K52. Our own review of fracture rates in a group infection and chronic inflammation. of 121 children with CF when compared with their siblings Vitamin E is found in vegetable oils, nuts fortified did not show any increased risk of fracture during margarines, eggs, wholemeal cereals and broccoli. The childhood53. Most reports of fracture and osteoporosis in word ‘tocopherol’ is derived from the Greek words tokos the literature54,55 relate to adults with CF. (childbirth) and phero (to bring forth) relating to its Early reports of vitamin K deficiency in CF relate to discovery in 1922 in rat experiments where it was found to presentation following haemorrhagic episodes56,57. be a fat-soluble ‘factor’ in diet necessary to allow normal Malabsorption of this fat-soluble vitamin was thought to reproduction39.