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Home , Vitamin C, Vitamin E, Vitamin E deficiency, Vitamin K

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 A deficiency Dorothy Anderson1 described deficiency. During increases the number of secreting cells whilst decreasing the following 60 years the involvement of 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 -soluble vitamins because it is this group that is deficiency15. malabsorbed by the pancreatic insufficient people with CF. A role for 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 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 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 sources such as , 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 . 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 , and . Beta- ( 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 present in the intestine and elsewhere .The vitamin A level (5258 mmol/L) predicted a forced carotenoids are present in and vegetables and like expiratory volume in 1 s (FEV1)of550% with an odds vitamin A are fat-soluble and absorbed from the . 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 linked in visual pigment, and retinoic , an intracellular in its defensive role with the other 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 can be a highly reactive species that can cause mutagenesis, cell found. Studies in show that advanced vitamin A damage and death if left unchecked. Both 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 levels lead to reduced calcification of and measurement of the stored form, retinyl ester in ; in growing this leads to and in mature conjunction with retinol binding may be more bone to . 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 of osteoporosis35 with associated osteomalacia36 are A have not been confirmed in a liver biopsy study that becoming more apparent in adult patients. The 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 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: 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 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 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, . Cholecalciferol is hydroxylated in the liver to muscle weakness and . Chronic toxicity can lead to 25-OHD3 (25-hydroxy vitamin D) and then again in the nephrocalcinosis and vascular calcification. to 1,25 (OH2)D3 (). Calcitriol acts as a hormone to stimulate the synthesis of a 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- 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 play a more important role than or fat- ( peroxidation). In stopping it forms malabsorption32. Thirty-five per cent of infants with CF a less potent , 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 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 oils, nuts fortified did not show any increased risk of fracture during margarines, eggs, wholemeal cereals and . 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 deficiency in CF relate to discovery in 1922 in experiments where it was found to presentation following haemorrhagic episodes56,57. be a fat-soluble ‘factor’ in diet necessary to allow normal of this fat-soluble vitamin was thought to reproduction39. Deficiency has an effect on the central be the primary cause. However, the production of vitamin nervous system leading to muscle weakness, and K by bacteria in the gut is likely to be an important source decreased reflexes. Neurological consequences of vitamin E in CF. Recent discussions have alluded to the role of deficiency have been described in CF40,41. Prolonged or antibiotics in destroying gut bacteria resulting in low severe deficiency can lead to , blindness and vitamin K levels58 and reports of haemorrhage in CF cardiac abnormalities42. patients59. The role of constant courses of antibiotics on Thirty-eight per cent of infants with CF, diagnosed by vitamin K levels in CF patients is not understood, although neonatal screening, have low vitamin E6. This deficiency a correlation between antibiotic usage and increase in may extend throughout life43 even with vitamin E PIVKA-II (protein induced vitamin K absence—II) has been supplementation24. There is some suggestion that this shown58. deficiency is not as severe when vitamin E is expressed in Vitamin K is not routinely supplemented in patients relation to lipids44 (increased concentrations of serum with cystic fibrosis and as yet there is no consensus on the appear to cause tocopherol to partition out of cellular role of routine supplementation60. There are reports of membranes in the circulation). However, vitamin E excess levels of vitamin K in CF patients routinely deficient CF patients show impaired resistance to oxidation supplemented61, although toxicity of vitamin K is not well of their low density lipoproteins. This can be improved with reported, except in neonates. A dosage of 5 mg per week effective vitamin E supplementation45. has been shown to be sufficient to improve both vitamin K Improvement in vitamin E levels after supplementation levels and in CF62. with 50 mg of vitamin E in patients with CF was not found Monitoring of vitamin K status is hard; most clinics will to be related to fat malabsorption46. Supplementation can use the annual review63 to measure as a also lead to improved haemoglobin levels in cystic fibrosis guide to vitamin K deficiency. It is possible to measure 46 children , and deficiency is known to cause haemolytic vitamin K1 and PIVKA-II in the laboratory but these are still anaemia47. Vitamin E supplements can be taken in either mainly used as research tools58,61 rather than routine. fat-soluble or -soluble forms48. Excessive vitamin E (41000 iu/day) may exacerbate the coagulopathy associated with vitamin K deficiency. Reports suggest daily dosage VITAMIN C with 400 iu (267 mg) of vitamin E is safe and will achieve Vitamin C or ascorbic acid is a major water-soluble normalization of vitamin E levels49. antioxidant in the body. It is for this reason and the fact that levels may be low in CF64 that it is the only water soluble vitamin reviewed in this article. As discussed in the vitamin VITAMIN K E section, antioxidants are a recent area of research in Vitamin K was originally described by Dam as the CF38,65. is the best known result of vitamin C vitamin in 1935. It is found mainly in green vegetables deficiency as confirmed by Lind on HMS Salisbury back in (K1—) but is also produced by bacteria 1747, when he prevented scurvy in seamen by feeding them 30 (K2—menaquinones). The best known role of vitamin K is in oranges and . Other fruits and vegetables the synthesis of prothrombin and several other blood contain vitamin C. It is easily denatured by prolonged coagulation factors. It acts as a for an that heating. catalyses glutamate residues to g-carboxyglutamyl residues50. A common perception is that vitamin C has a role in containing g-carboxyglutamyl, in particular osteo- shortening or even preventing the . A review calcin, have been found to play a role in bone metabolism51 of 31 controlled trials by Truswell suggests that there is no opening a whole new area of interest for the role of significant preventive effect66. However, renewed interest vitamin K. on the effects of diet on pulmonary health have lead to A recent large epidemiological study of vitamin K intake epidemiological studies suggesting that a higher intake of 16 and hip fractures in 72 327 nurses has suggested an vitamin C is related to better pulmonary function and JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Supplement No. 38 Volume 93 2000

Table 1 Recommendations for vitamin supplementation in cystic CURRENT RECOMMENDATIONS FOR VITAMIN fibrosis SUPPLEMENTATION It is with some hesitation that the reader is referred to Table Daily UK USA requirements 1 for the current recommendations for supplementation for (Refs 71,72) (Ref 73) in health vitamins in CF for both the UK71,72 and the USA73. Many papers are accumulating to show that fat-soluble vitamin Vitamin A 1 mg levels are invariably at the lower end of the normal Infant 4000 iu (1200 mg) 5000 iu spectrum in patients with CF despite supplementa- 2–8 years 5000 iu (1500 mg) 5000 iu tion37,64,74. With the vast wealth of literature on the 8+ years 8000 iu (2400 mg) 5–1 0000 iu detrimental effects of sub-optimal vitamin levels there must Vitamin D 3 mg now be scope for aiming at higher levels. This does not 0–8 years 400 iu (10 mg) 400 iu necessarily mean an across the board increase in 48 years 800 iu (42 years) 800 iu recommended dosage, but more an individually tailored Vitamin E 10 mg approach, aiming to push each individual’s levels into the Infant 75 iu (50 mg) 25–100 iu higher end of the normal range. The recommendations for 2–8 years 150 iu (100 mg) 100–200 iu vitamin supplementation are currently under review by the 10+years 300 iu (200 mg) 200–400 iu Interest Group of The British Dietetic Vitamin K 100 mg Association. 51 year 2.5 mg/week 41 year 5–10 mg/day 5 mg62/week DISCUSSION Vitamin C 30 mg (UK) 60 mg (USA) The roles of the discussed vitamins and their relationship to morbidity in CF are shown in Table 2. It must be remembered that there are many contributory factors to the eventual vitamin levels measured in plasma. Vitamin E status was found to be significantly lower in patients with Table 2 Some specific roles of vitamins in relation to cystic 75 fibrosis liver disease . Low vitamin A is associated with worse clinical status scores64. This has been confirmed again more Vitamin Role recently with a study looking at treatment of acute respiratory exacerbations in CF; a depressed value when Vitamin A Immunity unwell at the beginning of treatment improved significantly Respiratory epithelium integrity at the end of 2 weeks of intravenous antibiotics27. This must Provitamin A (b-carotene) Antioxidant defence always be taken into account when interpreting low vitamin

Vitamin D Bone A levels. Adherence to prescribed treatments is invariably worse Vitamin E Antioxidant defence than professionals anticipate76,77. This can especially be Vitamin K Coagulation predicted from vitamin E and A levels. Liver disease can Bone metabolism add to a patient’s malabsorption and ursodeoxycholic acid Vitamin C Antioxidant defence supplementation has been shown to improve absorption of vitamin A and E78–80, but not taurine81.

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