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The diet in cystic fibrosis: why is it important?
Current Paediatrics (2000) 10, 155–161 © 2000 Harcourt Publishers Ltd doi:10.1054/ cupe.2000.0102, available online at http://www.idealibrary.com on
Symposium: Allergic and respiratory disease
The diet in cystic fibrosis: why is it important?
A. MacDonald
and aggressive nutritional management and they present exciting challenges to the CF care team.
KEY POINTS
• • • •
•
Chronic malnutrition and poor growth is common in cystic fibrosis (CF) Malabsorption, increased energy expenditure, anorexia, behavioural feeding difficulties, diabetes, liver disease, and gastro-oesophageal reflux (GOR) all contribute to malnutrition Nutritional requirements are high, but individual energy requirements depend on clinical state, age and activity levels All patients need generous quantities of energy rich foods. Nutritional supplements and enteral feeds are necessary only if a high energy, nutrient rich diet does not produce acceptable growth Pancreatic enzymes are necessary with all meals and snacks in patients with pancreatic insufficiency. Maximum lipase dosage recommended is 10 000 units/kg/day
EFFECT OF MALNUTRITION Chronic malnutrition with significant weight retardation and linear growth failure has long been recognized as a general problem amongst most CF populations. Patients have poor height and delayed puberty, and the eventual weight/size of those surviving to adulthood is commonly below average. Bone age and onset of menarche may be delayed and pubertal delay can occur despite good clinical state. In a cross-sectional study on growth from UK CF clinics, the mean body weight in boys was between –0.25 and –0.5 SD until the age of 10 years, and in girls was –0.5 SD below the population mean during the same period, with body mass index (BMI) decreasing from the age of 5 years. Postpubertal stature and weight maintenance in the CF population show substantial deficit. Malnutrition also causes increased depletion of lean body mass, increased susceptibility to infection, decreased muscle force, reduced exercise tolerance and altered pulmonary function. Specific deficits of essential fatty acids, fat-soluble vitamins and micronutrients have been demonstrated, and problems such as reduced bone mineral density and osteoporosis are prevalent in adult patients.1 In addition, sodium depletion has been commonly reported in young infants.
INTRODUCTION Dietary support plays a key role in CF. It improves nutritional status, growth, and helps minimize the progressive decline in pulmonary function commonly seen in CF. The nutritional status of patients with CF is directly correlated with their mortality and morbidity. Pancreatic exocrine insufficiency, declining pulmonary function, increased survival, and complications such as liver disease and diabetes have led to the development of a number of complex and new nutritional problems. All of these demand attentive
CAUSES OF MALNUTRITION A variety of complex organic and psychological factors contribute to malnutrition in CF and will vary considerably between patients depending on their
Anita MacDonald, Dietetic Department, The Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK. Correspondence to AMCD.
155
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disease expression, clinical state, age and sex.2 These include malabsorption, increased energy requirements, anorexia associated with pulmonary infection, behavioural feeding difficulties, concurrent diseases such as diabetes, liver disease, GOR, eating disorders and poor compliance with treatment regimens. Malabsorption It is estimated that up to 90% of CF patients have pancreatic insufficiency. As pancreatic exocrine secretions contain less enzymes and bicarbonate, have a lower pH and are of a smaller volume, the physical properties of proteins and mucus within the lumen are affected. This results in obstruction to the small ducts and secondary damage to pancreatic digestive enzyme secretions, causing malabsorption.3 Other problems such as gastric hypersecretion, reduced duodenal bicarbonate concentration and pH, disorders of bile salt metabolism, disordered intestinal motility and permeability, liver disease, and short bowel syndrome after intestinal resection in the neonatal period may all contribute to malabsorption. The severity of malabsorption is variable and there can be significant malabsorption of protein and fat-soluble vitamins despite adequate use of enzyme supplements. Stool energy losses account for 11% of gross energy intake in CF patients: three times higher than normal. Other losses Nitrogen losses in the sputum can reach 10 g/day during severe acute pulmonary exacerbation, especially from Pseudomonas aeruginosa. Sputum is particularly rich in amino acids. Increased energy expenditure Resting energy expenditure (REE), an estimate of basal metabolic rate, is 10–20% greater than in healthy controls and may contribute to energy imbalance. Increased REE appears to be closely associated with declining pulmonary function and subclinical infection. Bronchial sepsis leads to local release of leukotrienes, free oxygen radicals and cytokines including tumour necrosis factor-alpha (TNF-α). Antibiotics have been shown to reduce energy requirements of moderately ill patients with chronic Pseudomonas aeruginosa.
a number of hepatic and biliary abnormalities, of which chronic cholestatic liver disease is by far the most relevant. The prevalence of liver disease ranges between 9 and 37%, depending on the definition of liver disease; it peaks during adolescence and is associated with a 3.4% mortality rate. It has been suggested that liver involvement predisposes CF patients to malnutrition and patients with severe liver disease need even more intensive nutritional therapy. A further complication associated with vomiting and therefore energy loss is GOR. It has been estimated that as many as one in five newly diagnosed infants with CF have GOR. Low energy intake Although dietary assessments in CF children demonstrate that energy intake is greater than controls, it rarely exceeds 110% of requirements. Healthy controls tend to underreport their dietary intake, whereas CF patients often overestimate theirs to be in agreement with the nutritional advice they are usually receiving. Factors associated with a reduced appetite include: chronic respiratory infection and other complications of CF such as distal ileal obstruction syndrome (DIOS); abdominal pain; GOR resulting in oesophagitis, pain and vomiting; media pressure to eat a healthy low fat, low sugar diet; inappropriate concepts regarding body image; depression, eating disorders in teenagers; poor use of dietary supplements; dislike of high energy foods and poverty. Behaviour feeding difficulties and poor child–parent interactions at mealtimes are a particular problem and have received much attention. Mealtimes are the most frequently reported area of difficulty for parents of preschool children. Abnormal eating behaviours in toddlers and school children include excessively long meals, delay tactics, food refusal and spitting out food. Toddlers with more feeding difficulties have lower energy intake. AIMS OF NUTRITIONAL MANAGEMENT There are three main aims of nutritional management: • to achieve optimal nutritional status • to achieve normal growth and development • to maintain normal feeding behaviour.
NUTRITIONAL REQUIREMENTS Concurrent disorders If undiagnosed or poorly controlled, diabetes mellitus may increase energy losses due to glycosuria. The prevalence of impaired glucose intolerance and diabetes is high, ranging from 14 to 36%. It increases with age, and an insidious decline in overall clinical status often occurs before diagnosis of diabetes is made.4 In addition, CF is increasingly associated with
Energy The heterogeneity of these patients, including the presence of respiratory infection, activity and nutritional status, make it difficult to give universal recommendations for energy requirements.5 Each individual’s energy requirements will vary depending upon clinical condition and activity levels. The only
The diet in cystic fibrosis practical method to gauge adequate nutrition is by closely monitoring weight gain, growth and overall nutritional status. Some children will grow normally by consuming no more than the estimated average requirement (EAR) for energy, whereas those with advanced pulmonary disease may need 50–60% more energy than normal. A useful guideline to follow is to assess the existing energy intake and increase this value by a further 20–30% if weight gain or growth is poor. It is generally recommended that protein provides 15%; fat 35–40%; and carbohydrate 45–50% of the total energy intake. Protein Exact protein requirements are unclear; it is generally accepted that protein intake should be increased to compensate for excessive loss of nitrogen in the faeces and sputum, and increased protein turnover in malnourished patients.
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clinical features such as night blindness, conjunctival and corneal xerosis, dry thickened skin and abnormalities of bronchial mucosal epithelialization. Vitamin A status is difficult to assess, owing to lack of a reliable marker, and serum levels of retinol do not adequately mirror the concentration of vitamin A in the liver. Vitamin E A neuropathy due to vitamin E deficiency has been widely reported in adult CF patients. Symptoms and signs include absent deep tendon reflexes, loss of position sense and vibration sense in lower limbs, dysarthria, tremor, ataxia and decreased visual activity. Vitamin E may also be important in controlling the progression of lung disease in CF. The antioxidant function of vitamin E and the scavenger role of both vitamins A and E may protect the lungs from oxygen-radical damage during the inflammatory response to infection. Vitamin D
Fibre The traditional high fat, high sugar diet for children with CF is low in dietary fibre. Reports of fibre intake confirm this and there is evidence that children with low intake of fibre suffer from more abdominal pain and take higher doses of pancreatic enzymes.6 It is possible that lack of fibre may compromise colonic function, causing statis of substrate, constipation and abdominal pain. Furthermore, fatty acids derived from unabsorbed fibre provide the colon with its major source of nutrition. A malnourished colon may be at greater risk of developing complications such as DIOS and fibrosing colonopathy.7 Further work is needed on the role of fibre in CF. Vitamins Fat-soluble vitamin requirements are high. This is attributed to fat malabsorption, but correction of fat malabsorption with pancreatic enzymes does not correct low serum concentrations of fat-soluble vitamins. There is no universally agreed standard dosage of vitamin supplementation in CF, but for many years in our clinic it has been practice to recommend 8000 IU (2400 µg) daily vitamin A; 800 IU (20 µg) daily vitamin D; and for vitamin E the usual recommended daily doses are 50 mg in infancy, 100 mg in 1–10-year-old children and 200 mg for teenagers and adults. Patients particularly at risk are those with poorly controlled malabsorption, liver disease, poor compliance with prescribed supplements, small bowel resection and late diagnosis of CF. Vitamin A Low serum vitamin A levels are commonly reported in CF, and case reports of vitamin A deficiency document
Osteoporosis, fractures and low bone mineral density is commonly reported in adults with CF. This has been associated with low vitamin D stores but may also be related to malnutrition, delayed puberty, hypogonadism, diabetes, physical inactivity, smaller skeletal size, glucocorticoid therapy and cyclosporin therapy.1,8 Vitamin K The true prevalence of vitamin K deficiency is unknown and there is no consensus on routine vitamin K supplementation. There is now a suggestion that routine vitamin K supplementation should be considered in all patients with pancreatic insufficiency and particularly when there is severe noncholestatic and cholestatic liver disease, major small bowel resection and following prolonged antibiotic treatment.9 Essential fatty acids Essential fatty acid deficiency is frequently reported in CF, but particularly in infancy before a diagnosis is made. Clinical features include increased water permeability of the skin, increased susceptibility to infection, impaired wound healing, growth retardation, thrombocytopenia and reduced platelet aggregation. It is characterized by a deficiency of linoleic acid with either low or normal arachidonic acid concentrations and increased concentrations of saturates and monounsaturates (such as palmitic, palmitoleic acid, eicosatrienoic acid). The cause of essential fatty acid deficiency is debatable and has been demonstrated in both well-nourished young CF patients and undernourished patients. It has been linked to both underlying defects of fatty acid metabolism, low fat diets and increased metabolic
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Table 1 Useful dietary supplements in CF suitable for 1–16-year-olds Energy
Protein
Fibre
kcal
kJ
g
g
Fortified milkshakes (per 100 ml) Paediasure * (Ross) Paediasure with fibre * (Ross) Fresubin (Fresenius) Clinutren 1.5 (Nestle) Clinutren ISO (Nestle) Complan (Farleys) Fortisip (Nutricia) Resource Shake (Novartis) Entera (Fresenius)
101 100 100 150 100 108 150 170 150
424 420 420 630 420 454 630 714 630
2.5 2.5 2.5 5.6 3.8 3.8 5.0 5.1 5.6
– 0.5 – – – – – – –
Fortified juice drinks (per 100 ml) Enlive (Ross) Fortijuce (Nutricia) Provide Xtra (Fresenius)
125 125 125
525 525 525
4.0 4.0 3.75
Fortified semi-solid and solid supplements (per 100 g) Formance (Ross) Ensure Bars (Ross)†
176 373
739 1566
4.8 17.1
Unfortified milkshake powders (per 100 g dry powder) Scandishake (SHS)
200
840
4.7
Glucose polymer powders (per 100 g) Super soluble Maxijul (SHS) Caloreen (Nestle) Polycal (Nutricia) Vitajoule (Vitaflo)
380 400 380 380
1596 1680 1596 1596
– – – –
– – – –
Glucose polymer drinks (per 100 ml) Liquid Polycal (Nutricia) Liquid Maxijul (SHS)
247 200
1037 840
– –
– –
Glucose/fat powders (100 g) Duocal (SHS) Quickcal (Vitaflo)
492 780
2061 3276
– 4.6
– –
– – –
–
* Specifically for 1–6-year-old children. † Mean analysis of two flavours.
usage in undernourished patients. Possible causes include increased lipid turnover in cell membranes, defects in desaturase activity, increased oxidation of fatty acids for energy source, increased production of eicosanoids, increased peroxidation of polyunsaturated fatty acids or disorders of lipoprotein metabolism. Although linoleic acid supplements have been shown to be beneficial in CF and for children with recurrent respiratory infection, routine supplementation is not advocated at present. NUTRITIONAL SUPPORT High energy/high protein diet A high energy, nutritionally rich diet from normal food should always be encouraged as the first stage in nutritional support. A good variety of energy rich foods should be encouraged, such as full cream milk, cheese, meat, full cream yoghurt, milk puddings, cakes and biscuits. Extra butter or margarine can be added to bread, potatoes and vegetables. Frying foods or basting in oil will increase energy density. Extra milk or cream can be added to soups, cereal, desserts,
mashed potatoes and used to top tinned or fresh fruit. Regular snacks are important. Malnourished children achieve higher energy intake when more frequent meals are offered. However, it is necessary that parents establish a good routine for meals and snacks and do not permit children to substitute sweets and chocolate for savoury food at mealtimes. Although this advice is simple, dietetic input should be intensive, dietary goals must be achievable and agreed in consultation with the child and parents at each clinic visit. Attention should be given to psychological, social, behavioural and developmental aspects of feeding. A meta-analysis of differing treatment interventions to promote weight gain in CF demonstrated that a behavioural approach was just as effective in promoting weight gain than invasive medical procedures.10
DIETARY SUPPLEMENFTS Dietary supplements should be reserved for weight loss, decline in height or weight z score (providing
The diet in cystic fibrosis weight z score is no more than 1 SD above height), nutrient intake below dietary reference values and acute chest infections. There are surprisingly little data to support efficacy of dietary supplements in CF. However, any benefit appears to directly relate to acceptability and patient compliance. There are now numerous types of Advisory Committee for Borderline Substances (ACBS) prescribable dietary supplements available. Some useful supplements are summarized in Table 1. The range, packaging and composition are constantly improving and supplements have now been designed specifically for 1–6-year-old children with a lower protein and micronutrient composition. No more than 20% of the EAR for energy should be given as dietary supplements except during an acute infection or if a patient is being considered for enteral feeding. Excessive supplementation will impair appetite and decrease nutrient intake from normal foods. Guidelines for the quantity of energy to give specific age groups from dietary supplements is given in Table 2.
ENTERAL FEEDING Approximately 5% of CF patients require enteral feeding; the majority of these are teenagers, reflecting the deterioration in nutritional status which occurs in adolescence. Enteral feeding should be considered if expected weight for height is persistently less than 85%, there is failure to gain weight over a 3–6-month period, and height and weight are below the second percentile. Enteral feeding is associated with improvements in body fat, height, lean body mass and muscle mass, increased total body nitrogen, improved strength and development of secondary sexual characteristics. Improvement in weight precedes improvement in height. If pulmonary function is poor (i.e. FEV1 <40% predicted) at the start of enteral feeding, there may be little improvement in nutritional status. However some studies have documented stabilization or improvement in pulmonary function in CF with enteral feeding. To produce lasting benefit, numerous studies have demonstrated that enteral feeding should be continued in the long term. Type of enteral feed Polymeric feeds are the first feed of choice in most CF centres and are tolerated by most patients with CF. Patients over 1 year old will usually tolerate a 1.5 kcal/ml (6.3 kJ/ml) paediatric or adult (dependent on age or weight) standard feed. They have several advantages: they are cheap, prescribable (ACBS), have a low osmolality and are available in ready-to-hang packs. No difference in fat malabsorption, nitrogen absorption and weight gain has been observed when polymeric feeds together with enzyme replacement
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Table 2 Guidelines for the quantity of daily dietary energy of dietary supplements in CF at different age groups Age 1–3 years 4–5 years 6–11 years Over 12 years
Daily energy 200 kcal (840 kJ) 400 kcal (1680 kJ) 600 kcal (2520 kJ) 800 kcal (3360 kJ)
therapy, and semi-elemental feeds have been compared. High fat polymeric feeds have not been shown to have any beneficial effect on nutritional status or VCO2 in non-oxygen-dependent children and adolescents with CF.
Administration of feed The route used for feed will be influenced by the duration of feeding and by the preference of the patient, relatives and physician. Percutaneous endoscopic gastrostomy (PEG) is now probably the preferred channel in children for long-term feeding. It has been made more acceptable by the development of the gastrostomy button. Gastrostomy feeding is associated with less loss of feeding time due to complications. Problems associated with the nasogastric route include problems of inserting the tube, particularly with nasal polyps, nasal irritation, tube displacement with coughing or vomiting and the potential risk of aspiration. Other complications include nasopharyngeal sepsis and oesophageal erosion. It is common practice to give enteral feeding for 8–10 h overnight with a 1 or 2 h break before the first physiotherapy session in the morning. Allowing teenagers to have one or two nights off the feed each week helps compliance. At least 40–50% of the estimated energy requirement is usually given via the tube, with weight and growth being regularly reviewed. Hyperglycaemia is a potential problem and blood glucose should be monitored on feeding. It is not known how to best give pancreatic enzymes with tube feeds and practices vary widely. There is some suggestion it may be better to give them at the beginning of the feed and just before the patient goes to sleep. Dosage of pancreatic enzymes with enteral feeds is arbitrary, but can be estimated by using the amount of pancreatic enzymes required for a normal meal and adjusting the quantity in accordance with the fat composition of the feed.
PANCREATIC ENZYME REPLACEMENT THERAPY Most CF centres predominantly use enteric-coated microspheres for all infants and children, either administered as granules or in a gelatine capsule. The
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most common preparations include Creon 10 000 (Solvay) and Pancrease (Cilag). These comprise pHsensitive enteric-coated microspheres contained within a capsule. The enteric coating protects the enzymes from stomach acid inactivation, disintegrating to release the enzyme only when pH rises above 5.5 in the duodenum.11 The administration of entericcoated microspheres should achieve at least 90% fat absorption if given in appropriate dosages. Several studies have demonstrated that enteric-coated microspheres are more effective then conventional pancreatic powder and enteric-coated capsules. The recent introduction of the newer, smaller Creon 10 000 capsules are popular and effective with children. Pancreatic enzymes should be administered with all meals and protein- and fat-containing snacks. There is evidence that pancreatic enzymes should be spread throughout the meal to optimize mixing and minimize partitioning of the pancreatin with the liquid phase of the meal, which empties more rapidly than the solid phase. Young children should be encouraged to swallow the whole capsules as soon as possible, usually from 4–5 years of age. Until then, there is little option but to give the granules out of the capsule. In 1993, the UK Committee on Safety of Medicines (CSM) recommended that Pancrease HL, Nutrizym 22 and Panzytrat 25 000 were contraindicated in CF for children aged 15 years and under.12 Most high lipase pancreatic enzymes containing 22 000–25 000 units of lipase/capsule are associated with the development of fibrosing colonopathy, although its precise aetiology remains uncertain. As a result of concerns about fibrosing colonopathy, the CSM also recommend that a maximum of 10 000 units lipase/kg/day is given from pancreatic enzyme preparations, irrespective of formulation. The dosage depends upon residual pancreatic function, enzyme supplement properties, amount of fat and protein consumed and pathophysiological factors.11 Dosage is often determined by stool output (frequency/colour/consistency), presence of abdominal pain and by faecal fat studies. Before the recommendations by the CSM, it was not uncommon for many patients to be on much higher dosages of pancreatic enzymes. However, it has been demonstrated that dosage can be reduced to acceptable intakes for many patients without deterioration in growth and acceptable coefficient of fat absorption.
INFANT FEEDING Feeding infants with cystic fibrosis should be relatively straightforward, but screened and non-screened infants have been reported to have nutritional problems at diagnosis. Failure to thrive, anaemia, salt depletion, tocopherol deficiency, hypoalbuminaemia and even kwashiorkor are seen in unscreened infants. Delayed catch-up growth following diagnosis has
been seen in screened and non-screened infants. Most infants with pancreatic insufficiency will thrive on a normal energy intake of 100–130 kcal (420–540 kJ) in conjunction with pancreatic enzymes. Breast milk in conjunction with pancreatic enzyme supplements is widely advocated for the baby with CF. Growth and weight gain has been shown to be satisfactory and with near zero z scores. Breast milk has several theoretical advantages over formula: it provides immunological protection against infection, it contains long chain polyunsaturated fatty acids, taurine, optimal essential amino acids and breast feeding is better psychologically for the mother. The distress and anxiety associated with the diagnosis may lead to initial difficulties in production of breast milk. However, with good advice, encouragement and patience from health professionals, these will usually be resolved. Alternatively, infants with CF have been shown to thrive satisfactorily on normal infant whey or casein-based formula with pancreatic enzyme supplements. Breast and normal infant formula are low in sodium, reports of electrolyte depletion are common and routine sodium supplementation is recommended for all babies with CF. If weight gain is less than expected or if a meconium ileus has resulted in surgery and bowel resection, the energy requirements may be as high as 150– 200 kcal (630–836 kJ) kg/day. The feed of choice is then one of the new high-energy infant formulas i.e. Infatrini (Nutricia), SMA High Energy (SMA Nutrition), containing 90–100 kcal/100 ml. They are preferable to giving energy supplemented normal formulas for infants with FTT as they have a better energy/protein ratio, a more concentrated micronutrient profile and are associated with improved growth. Protein hydrolysate formulas should only be used in CF if an infant develops temporary disaccharide intolerance after surgery for meconium ileus as there are few advantages for their use in the routine care of newly diagnosed infants with CF. They are also less palatable, more expensive and still need pancreatic enzymes administered with them.
DIETARY MANAGEMENT OF DIABETES The main aim of management is to achieve normoglycaemia, as the reporting of serious secondary complications such as microangiopathy and nephropathy is increasing. However, the provision of optimal nutrition is still of paramount importance and any dietary restriction should be minimized. All dietary advice should be tailored according to clinical status as well as individual lifestyles and food preferences. Ideally, complex carbohydrates should be encouraged at each meal and at bedtime. Fat should not be restricted. Sugar-containing foods can be eaten, but preferably following complex carbohydrates. It is probably better to give sugar-free squashes and substitute glucose
The diet in cystic fibrosis polymer powders for milk-containing supplements. Regular snacks should continue to be encouraged. Poor diabetic control should be improved by alterations in insulin therapy rather than imposing dietary restrictions that may adversely affect nutritional status. CONCLUSION Nutritional management is an integral part of good CF care. Regular attendance at CF centres has been shown to improve nutritional and clinical status. A dietitian is the key player in the assessment of nutritional status, evaluation of dietary nutritional adequacy, dietary counselling, appropriate dosage of pancreatic enzymes, vitamin supplementation, monitoring and regular follow-up of progress. However, continued support and positive encouragement by all CF team members will help motivate and inspire individuals to comply with their nutritional treatment regimens and improve overall nutritional status. REFERENCES 1. Haworth CS, Selby PL, Webb AK, Dodd ME, Musson H, McL Niven R, Economou G, Horrocks AW, Freemont AJ, Mawer EB, Adams JE. Low bone mineral density in adults with cystic fibrosis. Thorax 1999; 54: 961–967.
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2. Anthony H, Paxton S, Catto-Smith A, Phelan P. Physiological and psychological contributors to malnutrition in children with cystic fibrosis: review. Clinical Nutrition 1999; 18: 327–335. 3. Turck D, Michaud L. Cystic fibrosis: nutritional consequences and management. Baillière’s Clin Gastr 1998; 12: 805–822. 4. Lanng S, Thorsteinsson B, Nerup J, Koch C. Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis. Eur J Pediat 1992; 151: 684–687. 5. Ramsey BW, Farrell PM, Pancharz P and the Consensus Committee. Nutritional assessment and management in cystic fibrosis. Am J Clin Nutr 1992; 55: 108–116. 6. Gavin J, Ellis J, Dewar AL, Roles CJ, Connett GJ. Dietary fibre and the occurrence of gut symptoms in cystic fibrosis. Arch Dis Child 1997; 76: 35–37. 7. Dodge JA. The aetiology of fibrosing colonopathy. Postgrad Med J 1996; 72 (Suppl 2): S52–S55. 8. Donovan DS, Jr, Papdopoulos A, Staron RB, Addesso V, Schulman L, McGregor C, Cosman F, Lindsay RL, Shane E. Bone mass and vitamin D deficiency in adults with advanced cystic fibrosis lung disease. Am J Respir Crit Care Med 1998; 157: 1892–1899. 9. Rashid M, Durie P, Andrew M, Kalnins D, Shin J, Corey M, Tullis E, Pencharz PB. Prevalence of vitamin K deficiency in cystic fibrosis. Am J Clin Nutr 1999; 70: 378–382. 10. Jelalaian E, Stark LJ, Reynolds L, Seifer R. Nutrition intervention for weight gain in cystic fibrosis: a meta analysis. J Pediatr 1998; 132: 486–492. 11. Leonard CH, Knox AJ. Pancreatic enzyme supplements and vitamins in cystic fibrosis. J Hum Nutr Dietetics 1997; 10: 3–16. 12. Committee on the Safety of Medicines. Report of the Pancreatic Enzymes Working Party. London: Committee on the Safety of Medicines, Medicines Control Agency; 1998.
Symposium: Allergic and respiratory disease
The diet in cystic fibrosis: why is it important?
A. MacDonald
and aggressive nutritional management and they present exciting challenges to the CF care team.
KEY POINTS
• • • •
•
Chronic malnutrition and poor growth is common in cystic fibrosis (CF) Malabsorption, increased energy expenditure, anorexia, behavioural feeding difficulties, diabetes, liver disease, and gastro-oesophageal reflux (GOR) all contribute to malnutrition Nutritional requirements are high, but individual energy requirements depend on clinical state, age and activity levels All patients need generous quantities of energy rich foods. Nutritional supplements and enteral feeds are necessary only if a high energy, nutrient rich diet does not produce acceptable growth Pancreatic enzymes are necessary with all meals and snacks in patients with pancreatic insufficiency. Maximum lipase dosage recommended is 10 000 units/kg/day
EFFECT OF MALNUTRITION Chronic malnutrition with significant weight retardation and linear growth failure has long been recognized as a general problem amongst most CF populations. Patients have poor height and delayed puberty, and the eventual weight/size of those surviving to adulthood is commonly below average. Bone age and onset of menarche may be delayed and pubertal delay can occur despite good clinical state. In a cross-sectional study on growth from UK CF clinics, the mean body weight in boys was between –0.25 and –0.5 SD until the age of 10 years, and in girls was –0.5 SD below the population mean during the same period, with body mass index (BMI) decreasing from the age of 5 years. Postpubertal stature and weight maintenance in the CF population show substantial deficit. Malnutrition also causes increased depletion of lean body mass, increased susceptibility to infection, decreased muscle force, reduced exercise tolerance and altered pulmonary function. Specific deficits of essential fatty acids, fat-soluble vitamins and micronutrients have been demonstrated, and problems such as reduced bone mineral density and osteoporosis are prevalent in adult patients.1 In addition, sodium depletion has been commonly reported in young infants.
INTRODUCTION Dietary support plays a key role in CF. It improves nutritional status, growth, and helps minimize the progressive decline in pulmonary function commonly seen in CF. The nutritional status of patients with CF is directly correlated with their mortality and morbidity. Pancreatic exocrine insufficiency, declining pulmonary function, increased survival, and complications such as liver disease and diabetes have led to the development of a number of complex and new nutritional problems. All of these demand attentive
CAUSES OF MALNUTRITION A variety of complex organic and psychological factors contribute to malnutrition in CF and will vary considerably between patients depending on their
Anita MacDonald, Dietetic Department, The Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK. Correspondence to AMCD.
155
156
Current Paediatrics
disease expression, clinical state, age and sex.2 These include malabsorption, increased energy requirements, anorexia associated with pulmonary infection, behavioural feeding difficulties, concurrent diseases such as diabetes, liver disease, GOR, eating disorders and poor compliance with treatment regimens. Malabsorption It is estimated that up to 90% of CF patients have pancreatic insufficiency. As pancreatic exocrine secretions contain less enzymes and bicarbonate, have a lower pH and are of a smaller volume, the physical properties of proteins and mucus within the lumen are affected. This results in obstruction to the small ducts and secondary damage to pancreatic digestive enzyme secretions, causing malabsorption.3 Other problems such as gastric hypersecretion, reduced duodenal bicarbonate concentration and pH, disorders of bile salt metabolism, disordered intestinal motility and permeability, liver disease, and short bowel syndrome after intestinal resection in the neonatal period may all contribute to malabsorption. The severity of malabsorption is variable and there can be significant malabsorption of protein and fat-soluble vitamins despite adequate use of enzyme supplements. Stool energy losses account for 11% of gross energy intake in CF patients: three times higher than normal. Other losses Nitrogen losses in the sputum can reach 10 g/day during severe acute pulmonary exacerbation, especially from Pseudomonas aeruginosa. Sputum is particularly rich in amino acids. Increased energy expenditure Resting energy expenditure (REE), an estimate of basal metabolic rate, is 10–20% greater than in healthy controls and may contribute to energy imbalance. Increased REE appears to be closely associated with declining pulmonary function and subclinical infection. Bronchial sepsis leads to local release of leukotrienes, free oxygen radicals and cytokines including tumour necrosis factor-alpha (TNF-α). Antibiotics have been shown to reduce energy requirements of moderately ill patients with chronic Pseudomonas aeruginosa.
a number of hepatic and biliary abnormalities, of which chronic cholestatic liver disease is by far the most relevant. The prevalence of liver disease ranges between 9 and 37%, depending on the definition of liver disease; it peaks during adolescence and is associated with a 3.4% mortality rate. It has been suggested that liver involvement predisposes CF patients to malnutrition and patients with severe liver disease need even more intensive nutritional therapy. A further complication associated with vomiting and therefore energy loss is GOR. It has been estimated that as many as one in five newly diagnosed infants with CF have GOR. Low energy intake Although dietary assessments in CF children demonstrate that energy intake is greater than controls, it rarely exceeds 110% of requirements. Healthy controls tend to underreport their dietary intake, whereas CF patients often overestimate theirs to be in agreement with the nutritional advice they are usually receiving. Factors associated with a reduced appetite include: chronic respiratory infection and other complications of CF such as distal ileal obstruction syndrome (DIOS); abdominal pain; GOR resulting in oesophagitis, pain and vomiting; media pressure to eat a healthy low fat, low sugar diet; inappropriate concepts regarding body image; depression, eating disorders in teenagers; poor use of dietary supplements; dislike of high energy foods and poverty. Behaviour feeding difficulties and poor child–parent interactions at mealtimes are a particular problem and have received much attention. Mealtimes are the most frequently reported area of difficulty for parents of preschool children. Abnormal eating behaviours in toddlers and school children include excessively long meals, delay tactics, food refusal and spitting out food. Toddlers with more feeding difficulties have lower energy intake. AIMS OF NUTRITIONAL MANAGEMENT There are three main aims of nutritional management: • to achieve optimal nutritional status • to achieve normal growth and development • to maintain normal feeding behaviour.
NUTRITIONAL REQUIREMENTS Concurrent disorders If undiagnosed or poorly controlled, diabetes mellitus may increase energy losses due to glycosuria. The prevalence of impaired glucose intolerance and diabetes is high, ranging from 14 to 36%. It increases with age, and an insidious decline in overall clinical status often occurs before diagnosis of diabetes is made.4 In addition, CF is increasingly associated with
Energy The heterogeneity of these patients, including the presence of respiratory infection, activity and nutritional status, make it difficult to give universal recommendations for energy requirements.5 Each individual’s energy requirements will vary depending upon clinical condition and activity levels. The only
The diet in cystic fibrosis practical method to gauge adequate nutrition is by closely monitoring weight gain, growth and overall nutritional status. Some children will grow normally by consuming no more than the estimated average requirement (EAR) for energy, whereas those with advanced pulmonary disease may need 50–60% more energy than normal. A useful guideline to follow is to assess the existing energy intake and increase this value by a further 20–30% if weight gain or growth is poor. It is generally recommended that protein provides 15%; fat 35–40%; and carbohydrate 45–50% of the total energy intake. Protein Exact protein requirements are unclear; it is generally accepted that protein intake should be increased to compensate for excessive loss of nitrogen in the faeces and sputum, and increased protein turnover in malnourished patients.
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clinical features such as night blindness, conjunctival and corneal xerosis, dry thickened skin and abnormalities of bronchial mucosal epithelialization. Vitamin A status is difficult to assess, owing to lack of a reliable marker, and serum levels of retinol do not adequately mirror the concentration of vitamin A in the liver. Vitamin E A neuropathy due to vitamin E deficiency has been widely reported in adult CF patients. Symptoms and signs include absent deep tendon reflexes, loss of position sense and vibration sense in lower limbs, dysarthria, tremor, ataxia and decreased visual activity. Vitamin E may also be important in controlling the progression of lung disease in CF. The antioxidant function of vitamin E and the scavenger role of both vitamins A and E may protect the lungs from oxygen-radical damage during the inflammatory response to infection. Vitamin D
Fibre The traditional high fat, high sugar diet for children with CF is low in dietary fibre. Reports of fibre intake confirm this and there is evidence that children with low intake of fibre suffer from more abdominal pain and take higher doses of pancreatic enzymes.6 It is possible that lack of fibre may compromise colonic function, causing statis of substrate, constipation and abdominal pain. Furthermore, fatty acids derived from unabsorbed fibre provide the colon with its major source of nutrition. A malnourished colon may be at greater risk of developing complications such as DIOS and fibrosing colonopathy.7 Further work is needed on the role of fibre in CF. Vitamins Fat-soluble vitamin requirements are high. This is attributed to fat malabsorption, but correction of fat malabsorption with pancreatic enzymes does not correct low serum concentrations of fat-soluble vitamins. There is no universally agreed standard dosage of vitamin supplementation in CF, but for many years in our clinic it has been practice to recommend 8000 IU (2400 µg) daily vitamin A; 800 IU (20 µg) daily vitamin D; and for vitamin E the usual recommended daily doses are 50 mg in infancy, 100 mg in 1–10-year-old children and 200 mg for teenagers and adults. Patients particularly at risk are those with poorly controlled malabsorption, liver disease, poor compliance with prescribed supplements, small bowel resection and late diagnosis of CF. Vitamin A Low serum vitamin A levels are commonly reported in CF, and case reports of vitamin A deficiency document
Osteoporosis, fractures and low bone mineral density is commonly reported in adults with CF. This has been associated with low vitamin D stores but may also be related to malnutrition, delayed puberty, hypogonadism, diabetes, physical inactivity, smaller skeletal size, glucocorticoid therapy and cyclosporin therapy.1,8 Vitamin K The true prevalence of vitamin K deficiency is unknown and there is no consensus on routine vitamin K supplementation. There is now a suggestion that routine vitamin K supplementation should be considered in all patients with pancreatic insufficiency and particularly when there is severe noncholestatic and cholestatic liver disease, major small bowel resection and following prolonged antibiotic treatment.9 Essential fatty acids Essential fatty acid deficiency is frequently reported in CF, but particularly in infancy before a diagnosis is made. Clinical features include increased water permeability of the skin, increased susceptibility to infection, impaired wound healing, growth retardation, thrombocytopenia and reduced platelet aggregation. It is characterized by a deficiency of linoleic acid with either low or normal arachidonic acid concentrations and increased concentrations of saturates and monounsaturates (such as palmitic, palmitoleic acid, eicosatrienoic acid). The cause of essential fatty acid deficiency is debatable and has been demonstrated in both well-nourished young CF patients and undernourished patients. It has been linked to both underlying defects of fatty acid metabolism, low fat diets and increased metabolic
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Table 1 Useful dietary supplements in CF suitable for 1–16-year-olds Energy
Protein
Fibre
kcal
kJ
g
g
Fortified milkshakes (per 100 ml) Paediasure * (Ross) Paediasure with fibre * (Ross) Fresubin (Fresenius) Clinutren 1.5 (Nestle) Clinutren ISO (Nestle) Complan (Farleys) Fortisip (Nutricia) Resource Shake (Novartis) Entera (Fresenius)
101 100 100 150 100 108 150 170 150
424 420 420 630 420 454 630 714 630
2.5 2.5 2.5 5.6 3.8 3.8 5.0 5.1 5.6
– 0.5 – – – – – – –
Fortified juice drinks (per 100 ml) Enlive (Ross) Fortijuce (Nutricia) Provide Xtra (Fresenius)
125 125 125
525 525 525
4.0 4.0 3.75
Fortified semi-solid and solid supplements (per 100 g) Formance (Ross) Ensure Bars (Ross)†
176 373
739 1566
4.8 17.1
Unfortified milkshake powders (per 100 g dry powder) Scandishake (SHS)
200
840
4.7
Glucose polymer powders (per 100 g) Super soluble Maxijul (SHS) Caloreen (Nestle) Polycal (Nutricia) Vitajoule (Vitaflo)
380 400 380 380
1596 1680 1596 1596
– – – –
– – – –
Glucose polymer drinks (per 100 ml) Liquid Polycal (Nutricia) Liquid Maxijul (SHS)
247 200
1037 840
– –
– –
Glucose/fat powders (100 g) Duocal (SHS) Quickcal (Vitaflo)
492 780
2061 3276
– 4.6
– –
– – –
–
* Specifically for 1–6-year-old children. † Mean analysis of two flavours.
usage in undernourished patients. Possible causes include increased lipid turnover in cell membranes, defects in desaturase activity, increased oxidation of fatty acids for energy source, increased production of eicosanoids, increased peroxidation of polyunsaturated fatty acids or disorders of lipoprotein metabolism. Although linoleic acid supplements have been shown to be beneficial in CF and for children with recurrent respiratory infection, routine supplementation is not advocated at present. NUTRITIONAL SUPPORT High energy/high protein diet A high energy, nutritionally rich diet from normal food should always be encouraged as the first stage in nutritional support. A good variety of energy rich foods should be encouraged, such as full cream milk, cheese, meat, full cream yoghurt, milk puddings, cakes and biscuits. Extra butter or margarine can be added to bread, potatoes and vegetables. Frying foods or basting in oil will increase energy density. Extra milk or cream can be added to soups, cereal, desserts,
mashed potatoes and used to top tinned or fresh fruit. Regular snacks are important. Malnourished children achieve higher energy intake when more frequent meals are offered. However, it is necessary that parents establish a good routine for meals and snacks and do not permit children to substitute sweets and chocolate for savoury food at mealtimes. Although this advice is simple, dietetic input should be intensive, dietary goals must be achievable and agreed in consultation with the child and parents at each clinic visit. Attention should be given to psychological, social, behavioural and developmental aspects of feeding. A meta-analysis of differing treatment interventions to promote weight gain in CF demonstrated that a behavioural approach was just as effective in promoting weight gain than invasive medical procedures.10
DIETARY SUPPLEMENFTS Dietary supplements should be reserved for weight loss, decline in height or weight z score (providing
The diet in cystic fibrosis weight z score is no more than 1 SD above height), nutrient intake below dietary reference values and acute chest infections. There are surprisingly little data to support efficacy of dietary supplements in CF. However, any benefit appears to directly relate to acceptability and patient compliance. There are now numerous types of Advisory Committee for Borderline Substances (ACBS) prescribable dietary supplements available. Some useful supplements are summarized in Table 1. The range, packaging and composition are constantly improving and supplements have now been designed specifically for 1–6-year-old children with a lower protein and micronutrient composition. No more than 20% of the EAR for energy should be given as dietary supplements except during an acute infection or if a patient is being considered for enteral feeding. Excessive supplementation will impair appetite and decrease nutrient intake from normal foods. Guidelines for the quantity of energy to give specific age groups from dietary supplements is given in Table 2.
ENTERAL FEEDING Approximately 5% of CF patients require enteral feeding; the majority of these are teenagers, reflecting the deterioration in nutritional status which occurs in adolescence. Enteral feeding should be considered if expected weight for height is persistently less than 85%, there is failure to gain weight over a 3–6-month period, and height and weight are below the second percentile. Enteral feeding is associated with improvements in body fat, height, lean body mass and muscle mass, increased total body nitrogen, improved strength and development of secondary sexual characteristics. Improvement in weight precedes improvement in height. If pulmonary function is poor (i.e. FEV1 <40% predicted) at the start of enteral feeding, there may be little improvement in nutritional status. However some studies have documented stabilization or improvement in pulmonary function in CF with enteral feeding. To produce lasting benefit, numerous studies have demonstrated that enteral feeding should be continued in the long term. Type of enteral feed Polymeric feeds are the first feed of choice in most CF centres and are tolerated by most patients with CF. Patients over 1 year old will usually tolerate a 1.5 kcal/ml (6.3 kJ/ml) paediatric or adult (dependent on age or weight) standard feed. They have several advantages: they are cheap, prescribable (ACBS), have a low osmolality and are available in ready-to-hang packs. No difference in fat malabsorption, nitrogen absorption and weight gain has been observed when polymeric feeds together with enzyme replacement
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Table 2 Guidelines for the quantity of daily dietary energy of dietary supplements in CF at different age groups Age 1–3 years 4–5 years 6–11 years Over 12 years
Daily energy 200 kcal (840 kJ) 400 kcal (1680 kJ) 600 kcal (2520 kJ) 800 kcal (3360 kJ)
therapy, and semi-elemental feeds have been compared. High fat polymeric feeds have not been shown to have any beneficial effect on nutritional status or VCO2 in non-oxygen-dependent children and adolescents with CF.
Administration of feed The route used for feed will be influenced by the duration of feeding and by the preference of the patient, relatives and physician. Percutaneous endoscopic gastrostomy (PEG) is now probably the preferred channel in children for long-term feeding. It has been made more acceptable by the development of the gastrostomy button. Gastrostomy feeding is associated with less loss of feeding time due to complications. Problems associated with the nasogastric route include problems of inserting the tube, particularly with nasal polyps, nasal irritation, tube displacement with coughing or vomiting and the potential risk of aspiration. Other complications include nasopharyngeal sepsis and oesophageal erosion. It is common practice to give enteral feeding for 8–10 h overnight with a 1 or 2 h break before the first physiotherapy session in the morning. Allowing teenagers to have one or two nights off the feed each week helps compliance. At least 40–50% of the estimated energy requirement is usually given via the tube, with weight and growth being regularly reviewed. Hyperglycaemia is a potential problem and blood glucose should be monitored on feeding. It is not known how to best give pancreatic enzymes with tube feeds and practices vary widely. There is some suggestion it may be better to give them at the beginning of the feed and just before the patient goes to sleep. Dosage of pancreatic enzymes with enteral feeds is arbitrary, but can be estimated by using the amount of pancreatic enzymes required for a normal meal and adjusting the quantity in accordance with the fat composition of the feed.
PANCREATIC ENZYME REPLACEMENT THERAPY Most CF centres predominantly use enteric-coated microspheres for all infants and children, either administered as granules or in a gelatine capsule. The
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most common preparations include Creon 10 000 (Solvay) and Pancrease (Cilag). These comprise pHsensitive enteric-coated microspheres contained within a capsule. The enteric coating protects the enzymes from stomach acid inactivation, disintegrating to release the enzyme only when pH rises above 5.5 in the duodenum.11 The administration of entericcoated microspheres should achieve at least 90% fat absorption if given in appropriate dosages. Several studies have demonstrated that enteric-coated microspheres are more effective then conventional pancreatic powder and enteric-coated capsules. The recent introduction of the newer, smaller Creon 10 000 capsules are popular and effective with children. Pancreatic enzymes should be administered with all meals and protein- and fat-containing snacks. There is evidence that pancreatic enzymes should be spread throughout the meal to optimize mixing and minimize partitioning of the pancreatin with the liquid phase of the meal, which empties more rapidly than the solid phase. Young children should be encouraged to swallow the whole capsules as soon as possible, usually from 4–5 years of age. Until then, there is little option but to give the granules out of the capsule. In 1993, the UK Committee on Safety of Medicines (CSM) recommended that Pancrease HL, Nutrizym 22 and Panzytrat 25 000 were contraindicated in CF for children aged 15 years and under.12 Most high lipase pancreatic enzymes containing 22 000–25 000 units of lipase/capsule are associated with the development of fibrosing colonopathy, although its precise aetiology remains uncertain. As a result of concerns about fibrosing colonopathy, the CSM also recommend that a maximum of 10 000 units lipase/kg/day is given from pancreatic enzyme preparations, irrespective of formulation. The dosage depends upon residual pancreatic function, enzyme supplement properties, amount of fat and protein consumed and pathophysiological factors.11 Dosage is often determined by stool output (frequency/colour/consistency), presence of abdominal pain and by faecal fat studies. Before the recommendations by the CSM, it was not uncommon for many patients to be on much higher dosages of pancreatic enzymes. However, it has been demonstrated that dosage can be reduced to acceptable intakes for many patients without deterioration in growth and acceptable coefficient of fat absorption.
INFANT FEEDING Feeding infants with cystic fibrosis should be relatively straightforward, but screened and non-screened infants have been reported to have nutritional problems at diagnosis. Failure to thrive, anaemia, salt depletion, tocopherol deficiency, hypoalbuminaemia and even kwashiorkor are seen in unscreened infants. Delayed catch-up growth following diagnosis has
been seen in screened and non-screened infants. Most infants with pancreatic insufficiency will thrive on a normal energy intake of 100–130 kcal (420–540 kJ) in conjunction with pancreatic enzymes. Breast milk in conjunction with pancreatic enzyme supplements is widely advocated for the baby with CF. Growth and weight gain has been shown to be satisfactory and with near zero z scores. Breast milk has several theoretical advantages over formula: it provides immunological protection against infection, it contains long chain polyunsaturated fatty acids, taurine, optimal essential amino acids and breast feeding is better psychologically for the mother. The distress and anxiety associated with the diagnosis may lead to initial difficulties in production of breast milk. However, with good advice, encouragement and patience from health professionals, these will usually be resolved. Alternatively, infants with CF have been shown to thrive satisfactorily on normal infant whey or casein-based formula with pancreatic enzyme supplements. Breast and normal infant formula are low in sodium, reports of electrolyte depletion are common and routine sodium supplementation is recommended for all babies with CF. If weight gain is less than expected or if a meconium ileus has resulted in surgery and bowel resection, the energy requirements may be as high as 150– 200 kcal (630–836 kJ) kg/day. The feed of choice is then one of the new high-energy infant formulas i.e. Infatrini (Nutricia), SMA High Energy (SMA Nutrition), containing 90–100 kcal/100 ml. They are preferable to giving energy supplemented normal formulas for infants with FTT as they have a better energy/protein ratio, a more concentrated micronutrient profile and are associated with improved growth. Protein hydrolysate formulas should only be used in CF if an infant develops temporary disaccharide intolerance after surgery for meconium ileus as there are few advantages for their use in the routine care of newly diagnosed infants with CF. They are also less palatable, more expensive and still need pancreatic enzymes administered with them.
DIETARY MANAGEMENT OF DIABETES The main aim of management is to achieve normoglycaemia, as the reporting of serious secondary complications such as microangiopathy and nephropathy is increasing. However, the provision of optimal nutrition is still of paramount importance and any dietary restriction should be minimized. All dietary advice should be tailored according to clinical status as well as individual lifestyles and food preferences. Ideally, complex carbohydrates should be encouraged at each meal and at bedtime. Fat should not be restricted. Sugar-containing foods can be eaten, but preferably following complex carbohydrates. It is probably better to give sugar-free squashes and substitute glucose
The diet in cystic fibrosis polymer powders for milk-containing supplements. Regular snacks should continue to be encouraged. Poor diabetic control should be improved by alterations in insulin therapy rather than imposing dietary restrictions that may adversely affect nutritional status. CONCLUSION Nutritional management is an integral part of good CF care. Regular attendance at CF centres has been shown to improve nutritional and clinical status. A dietitian is the key player in the assessment of nutritional status, evaluation of dietary nutritional adequacy, dietary counselling, appropriate dosage of pancreatic enzymes, vitamin supplementation, monitoring and regular follow-up of progress. However, continued support and positive encouragement by all CF team members will help motivate and inspire individuals to comply with their nutritional treatment regimens and improve overall nutritional status. REFERENCES 1. Haworth CS, Selby PL, Webb AK, Dodd ME, Musson H, McL Niven R, Economou G, Horrocks AW, Freemont AJ, Mawer EB, Adams JE. Low bone mineral density in adults with cystic fibrosis. Thorax 1999; 54: 961–967.
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2. Anthony H, Paxton S, Catto-Smith A, Phelan P. Physiological and psychological contributors to malnutrition in children with cystic fibrosis: review. Clinical Nutrition 1999; 18: 327–335. 3. Turck D, Michaud L. Cystic fibrosis: nutritional consequences and management. Baillière’s Clin Gastr 1998; 12: 805–822. 4. Lanng S, Thorsteinsson B, Nerup J, Koch C. Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis. Eur J Pediat 1992; 151: 684–687. 5. Ramsey BW, Farrell PM, Pancharz P and the Consensus Committee. Nutritional assessment and management in cystic fibrosis. Am J Clin Nutr 1992; 55: 108–116. 6. Gavin J, Ellis J, Dewar AL, Roles CJ, Connett GJ. Dietary fibre and the occurrence of gut symptoms in cystic fibrosis. Arch Dis Child 1997; 76: 35–37. 7. Dodge JA. The aetiology of fibrosing colonopathy. Postgrad Med J 1996; 72 (Suppl 2): S52–S55. 8. Donovan DS, Jr, Papdopoulos A, Staron RB, Addesso V, Schulman L, McGregor C, Cosman F, Lindsay RL, Shane E. Bone mass and vitamin D deficiency in adults with advanced cystic fibrosis lung disease. Am J Respir Crit Care Med 1998; 157: 1892–1899. 9. Rashid M, Durie P, Andrew M, Kalnins D, Shin J, Corey M, Tullis E, Pencharz PB. Prevalence of vitamin K deficiency in cystic fibrosis. Am J Clin Nutr 1999; 70: 378–382. 10. Jelalaian E, Stark LJ, Reynolds L, Seifer R. Nutrition intervention for weight gain in cystic fibrosis: a meta analysis. J Pediatr 1998; 132: 486–492. 11. Leonard CH, Knox AJ. Pancreatic enzyme supplements and vitamins in cystic fibrosis. J Hum Nutr Dietetics 1997; 10: 3–16. 12. Committee on the Safety of Medicines. Report of the Pancreatic Enzymes Working Party. London: Committee on the Safety of Medicines, Medicines Control Agency; 1998.