Jim Littlewood. April, 2002. The historical development of nutritional and dietetic management of cystic fibrowsis [online]. Based on paper delivered at the XIIIth International Cystic Fibrosis Congress, Stockholm, Sweden. June 2000. Available from http://www.cysticfibrosismedicine.com.
The late Dr. Crozier of the Toronto clinic, described cystic fibrosis (CF) as "an intricate, vexatious disease involving the whole patient" (1). Although initially considered to be primarily a nutritional disorder it is important to consider nutritional treatment as one part of the general management - particularly in relation to the state of the chest. Malnutrition adversely affects respiratory function by diminishing respiratory muscle strength in both chronic obstructive pulmonary disease (COPD) and CF, altering ventilatory capacity and impairing immune function. Conversely, respiratory problems, particularly infection, have an adverse effect on the nutritional state of patients with more advanced cystic fibrosis.
The Thirties - the first clear description of cystic fibrosis
Dorothy Andersen's detailed description of the autopsy findings of 49 patients with 'fibrocystic disease of the pancreas' identified the condition as a distinct clinical entity and differentiated CF from coeliac disease (2). She likened the epithelial changes seen in CF to those found in vitamin A deficiency, which, for some years, she believed was involved in the pathogenesis (3).
The Forties - CF a generalised genetic disorder
In the Forties CF was recognised as being a generalised disorder and described as "mucoviscidosis" (4). Also the familial incidence was recognised as indicating a recessive mode of inheritance (5). However, it was still considered that full expression of the genetic defect required an additional factor, believed to be vitamin A deficiency (5). The presence of infection is one of the more obvious conditioning factors, which initiates the deterioration of respiratory function and worsens the effect of the genetic mutation.
Early recognition of the importance of early nutrition
The dietary treatment recommended for CF in the Forties was predominantly a high protein diet, large doses of vitamin A, and crude pancreatic extract with meals. Pancreatic extracts had been available since the early 1930s and Andersen reviewed their use in patients with congenital pancreatic deficiency (6). She advised "a low fat, high protein diet with a liberal allowance of vegetables, fruits and sugar and moderate restriction of starch. Supplementary vitamin A is essential and pancreatin and vitamin B complex are given" (7). Another important message was Andersen's observation that dietary therapy should be started early - "the effectiveness of treatment depends on the degree and type of the respiratory tract infection present when dietary treatment is begun" and "when it is begun after the onset of suppurative bronchitis, it may prolong life somewhat but will not alter the prognosis". With regard to the malabsorption, Andersen noted, "patients excreted half the protein and half the fat fed and 15% of the carbohydrate. Good growth had been obtained with 6-8 g/kg/day protein of which casein hydrolysate forms 1-1.5g. Because fat is poorly absorbed carbohydrate is used as the main source of calories. One or two eggs and fish liver oil is taken daily to provide fat-soluble essential substances. Skimmed milk is given and fried foods are forbidden. Supplements of vitamins A and B are given and 1-2 g of pancreatin with every meal" (8). In the same year, 1949, Andersen still considered that "persistent bronchitis complicating fibrocystic disease is the result of failure of absorption of vitamin A, and presumably other fat-soluble specific substances which, in turn, results from the inability of the diseased pancreas to secrete enzymes necessary for absorption of fat" (8).
CF considered be a generalised epithelial secretory disorder
By the late 1940s, the importance of vitamin A deficiency was increasingly questioned and the possibility of an abnormal epithelial secretion (i.e. mucoviscidosis) was becoming a more popular theory of causation (8). Discussing the suggestion that the disease may be a more generalised secretory defect, the lungs being affected with the same abnormality as the pancreas, she notes (as others have done subsequently) that the lungs of children who die in the neonatal period appeared to be normal or show only evidence of aspiration; also no abnormality had been demonstrated in the secretions; also the mucus in the CF lungs more resembled that found in other lung disorders than the secretions in the pancreatic duct. In the same paper, Andersen presents evidence suggesting that the maintenance of adequate nutrition is protective to the bronchi if started early. She described 22 patients with no evidence of respiratory infection most of whom had been treated with good diets before cough had been present as long as two months. Another leading clinician and researcher during the 1940s was Paul di Sant'Agnese, who also considered nutrition to be a central component of the treatment package. He believed the improved prognosis, which had occurred during the decade, was due to "An appropriate diet began promptly and continued consistently, use of sulphadiazine during the stage of chronic cough and the use of (nebulised) penicillin" (9). Reviewing experience with 134 patients from Boston, Lowe noted that "those who tended to survive longest had good gains in weight before the first symptoms and fair gains after" (10). Thus, in the decade following the description of CF, the nutritional aspects of the disease were regarded as of major importance, even to possibly being involved in the pathogenesis. Early diagnosis and treatment after neonatal screening would protect against the known deficiencies of vitamins, essential fatty acids and other essential nutrients, which are known to occur within weeks of birth (11). The nutritional advantages of early diagnosis after neonatal screening are currently the strongest evidence for neonatal screening and early treatment (12).
During the Fifties the outlook was still regarded as hopeless by most people. The diagnosis still relied on clinical symptoms and signs supported by some evidence of pancreatic insufficiency. Unfortunately the progressive downhill clinical course and early death usually confirmed the diagnosis.
Abnormal sweat electrolytes described
During a heat wave in 1951 seven of twelve infants admitted with heat prostration to a New York hospital were already known to have CF (13). di Sant'Agnese and colleagues showed these infants had an abnormally high level of sodium, chloride, and to a lesser extent potassium, in their sweat (14). In the late 1950s, Harry Shwachman described a detailed method of management based on early diagnosis, active early treatment of chest infection and attention to nutrition. The nutritional management he recommended was "providing a liberal diet in which a relatively high protein intake was emphasised, and an effort made to reduce the total fat intake. Water miscible multivitamin preparations were given in twice the usual dosage. Vitamin B complex was used liberally (15). Their paper was notable for the introduction of the Shwachman-Kulczycki clinical score that is still widely used.
Pancreatin shown to improve intestinal malabsorption
Although pancreatin had been available since the Thirties, Norman and colleagues from London published some of the first objective evidence that pancreatic enzyme therapy was effective in children with CF by showing treatment resulted in considerable improvement in both fat and nitrogen absorption (16).
The outlook remained very poor, most children dying in childhood from suppurative lung disease, progressive malnutrition being an inevitable association (17, 18). There was, as yet, less emphasis on the relationship between nutrition, the immunological state and survival. Two important investigations, which clearly permitted differentiation between coeliac disease and cystic fibrosis, became more generally available during the Sixties - the pilocarpine iontophoresis sweat test (19) and the jejunal biopsy in children (20).
During the decade there were other approaches used to combat the nutritional consequences of severe chest infections. Large doses of anabolic steroids in a terminally ill patient with CF had been noted to have an impressive beneficial effect and a similar effect in 6 further patients (21). Anabolic steroids remained part of the nutritional management in many clinics for some years, despite their obvious side effects, as they appeared to improve the quality of life of many patients (22).
Improved survival of infants with meconium ileus
In the Fifties the mortality for CF infants with meconium ileus was still over 50% but in 1957 Bishop & Koop described their ileostomy, which reduced the surgical interference required and greatly improved the survival (23). These were early days for neonatal surgery; anesthesia and intensive nutritional support and the results for many other neonatal surgical conditions were very poor. In the Sixties there was further improvement in the non-operative management of meconium ileus by the use of gastrografin enemas (24, 25).
Specialised CF clinics develop in North America and Europe
A number of specialist CF clinics published impressive comprehensive treatment regimes e.g. "in an effort to alter the progressive course of the disease all available therapeutic measures were considered" (26). Matthews and colleagues from the Cleveland clinic directed their efforts against "the obstructive pulmonary lesion, the secondary pulmonary infections and the pancreatic exocrine insufficiency and the nutritional aspects". They stressed that - "The frequent observation, critical evaluation and close supervision of the patient by physicians experienced in the treatment of this disease are essential". How wise this advice - and how slowly heeded by some paediatricians! Their nutritional advice included "a low fat, high protein formula for infants who should be started on solids including meat at 2 months. Formulas of equal parts skimmed milk and evaporated milk formula is used or Nutramigen. A tablespoon of casein hydrolysate and simple sugars could be added". Water soluble vitamin supplements were prescribed in twice the usual dosage at all ages also vitamin E, 50 mg for infants and 100 mg for older patients and vitamin K, 5 mg twice weekly for infants on broad-spectrum antibiotics. Older children had the standard high protein, low fat diet in vogue at the time. A more refined pancreatic enzyme, Cotazyme 1-3 per feeding, was regarded as a "breakthrough" over Viokase and Panteric granules (27).
The Seventies was characterised by increasing interest in the extent and severity of the nutritional problems as survival steadily improved. The weight and height of children with CF at the time showed an initial 'catch up' phase following diagnosis and treatment. Thereafter the weights were around 1.0 SD below normal for age throughout childhood but then fell off severely during adolescence (17,18). Typical nutritional advice at the time for infants and children with CF was that "the general attitude should be liberal rather than restrictive and rigid. The aim should be for an acceptable compromise between troublesome steatorrhoea and severe restriction of dietary fat". Older children with CF were said to tolerate 30-40 g of fat daily, should be well supplied with calories, some 200 Kcal/kg/day and 4-5 g of protein/kg/day (28).
The "Allan Diet" to improve absorption
As the pancreatic enzyme supplements in the Seventies were still relatively inefficient, attempts were made to improve absorption and nutrition by modifying the type of food taken. It had been shown previously that children with CF achieved better nitrogen absorption with casein hydrolysate than with whole protein (29). Also substitution of medium chain triglyceride (MCT) for long chain fats had been shown to be beneficial in improving abdominal symptoms and absorption in patients with CF even if there was no significant effect on growth (30,31). Thus, in an attempt to improve absorption by dietary manipulation, Dr. Allan, a general paediatrician from Macclesfield in England, used a nutritional supplement consisting of beef serum protein hydrolysate, a glucose polymer and medium chain triglycerides - the so called "Allan diet" (32,33). Seventeen patients with CF were treated for 3-31 months. In 7 of 11 patients, where the supplement provided 100% of the protein and calorie needs and in those with a poor initial nutritional state, there were increased rates of weight gain. The effect was less pronounced when the supplement was taken with ordinary food and provided only 50% of the dietary needs. A subsequent study from Cincinnati treating 15 of the most nutritionally compromised patients with the diet showed significant gains in weight (>0.5SD) and improvement in biochemical parameters over a year, lending further support to the beneficial effect of the "Allan Diet" (18). A subsequent controlled trial of the Allan diet confirmed the improvement in 28 treated patients receiving the diet for 12 months (34). Although the group as a whole had some improvement in growth and nutrition, only 10 (36%) had significant improvement in weight, height or both (>0.5 SD) the greatest improvements being in young, mildly affected patients. The authors' conclusions were that "such an unpleasant and expensive diet should be restricted to a few selected cases, rather than given as routine treatment" (34). Subsequently most clinicians found that patient acceptance of a monotonous and relatively unpalatable formula presented the greatest challenge; also the new acid resistant enzymes were soon to become available permitting a normal fat intake in most patients.
Crozier in Toronto abandoned the traditional low fat diet
Undoubtedly, restriction of dietary fat was a major reason for the poor energy intake. Dr Crozier, in Toronto, would appear to have laid the foundations of the nutritional philosophy of the Toronto clinic, later considered to be a major factor in the exceptional survival of their patients (35). From the early Seventies Crozier abandoned the traditional low fat diet believing that "to deprive the child with cystic fibrosis, who usually has very little subcutaneous fat, of this important nutrient seems ridiculous". Thus, as early as 1972, he changed his patients to a high saturated fat diet of whole milk, butter, eggs, and animal fats. This new regimen resulted in improved body weight and an increase in cholesterol (by 11%) and triglycerides (by 12%). However, the increased fat intake did require the patients to take 60 -100 Cotazym capsules per day (1). There was considerable discussion on the influence of nutritional state on the state of the chest and prognosis and comparison between the series of Lapey where more modest doses of enzymes were used - 3 capsules per meal (36).
Many patients had inadequate energy intakes when measured
A number of important studies measured the actual energy intake CF patients. Contrary to the traditional impression that people with CF had voracious appetites, these studies confirmed that many children consumed less energy than recommended for unaffected children of their age (37, 38,39). More recent studies continued to show many people with CF had suboptimal energy intakes (40). Towards the end of the Seventies an important paper supported the suggestion that a good nutritional state was associated with a better prognosis (41). Also pancreatic sufficient patients, who were better nourished, had better lung function than those who were pancreatic insufficient (42). In October 1977, we started our first nutritional study of Leeds children with CF (43) primarily looking at the vitamin status in 36 treated patients. The results of our first nutritional study of these treated patients revealed low fat-soluble vitamin levels in many despite supplements. Many still had a severe degree of fat malabsorption (10 excreted more than 100 mmol (24.8 g)/day and 17 more than 50 mmol (14.2 g)/day). These results prompted us to start regular Comprehensive Assessments, which have continued to the present day as Annual Assessments (44,45,46). Sydney Gellis, commenting on our nutritional study (43) in the 1983 Year Book of Pediatrics observed "The lesson to be learned from this study seems to be that despite treatment patients with cystic fibrosis can be expected to have serious problems with malnutrition." This certainly described the situation in the UK in the early Eighties.
The Eighties - a "scientific roller coaster"
The Eighties was a decade of impressive scientific progress culminating in the identification of the CF gene in 1989. The recognition of epithelial electrolyte transport abnormalities (47) was followed by the demonstration of chloride impermeability of the sweat glands48, localisation of the gene to chromosome 7 in 1985 and eventual identification of the gene by Lap Chi Tsui, Riordan and Collins in 1989 (49,50,51).
Increasing involvement of dietitians experienced in CF
A major factor in improving nutrition in the UK was the increasing involvement of professional dietitians/nutritionists in the teams at the few CF Centres caring for people with CF. With their involvement, there was more accurate measurement of the quantitative and qualitative aspects of the dietary intake. When the qualitative aspects of the intake were analysed, it was apparent that patients who had a normal fat intake clearly had a higher energy intake, better growth and nutritional state than those with a restricted fat intake (52). The dietitian was also able to recommend the most appropriate method of increasing the energy intake for a particular patient, having assessed the general family situation and the patient's likes and dislikes. This was beyond the practical abilities of most CF clinicians. Even a single review by a dietitian experienced in CF, at the time of an annual assessment, resulted in an improved energy intake when this was measured a year later (53).
Increasing attention to improving the dietary energy
Intake As the reports of inadequate energy intake became generally appreciated more attention was given to areas where this could be improved. The relaxation of fat restriction, a major advance made possible by the availability of the new acid resistant enzymes, was only slowly implemented in the UK. In the early Eighties, the usual diet recommended for a person with CF was still high in calories, protein and carbohydrate, with moderate fat restriction. In 1985 Goodchild recommended an increased energy intake and a normal fat intake for CF patients (54); but progress was very gradual and some experienced CF clinicians considered that "steatorrhoea is seldom controlled by pancreatin alone and reduction of fat in the diet is necessary" (55). However, after using the new acid-resistant enzymes (Pancrease since 1983 and Creon from 1985), it was clear to us in Leeds that "many patients were having their energy intake severely compromised by the traditional prescription of a low fat diet. Fat restriction is seldom required now if adequate doses of pancreatic extracts are given" (56,57).
Enteral and parenteral nutrition
In some patients increasing the intake of food and fat, even with the help of an experienced dietitian, failed to achieve an energy intake, which would achieve adequate weight gain and growth. Intravenous nutrition could circumvent both the problems of intake and absorption and provide a satisfactory short-term solution. Twelve CF patients were given intravenous nutrition for 3 weeks with Intralipid, amino acids and glucose. There was significant weight gain, which persisted for over 6 months, fewer pulmonary infections, improved clinical scores and pulmonary function tests (58). But the intravenous route was obviously inconvenient and therefore various methods of enteral feeding were tried. At the 1984 9th International CF Congress in Brighton, supplementary enteral feeding of various types was a major topic. However, it was a general gastroenterologist from Leeds, who first reported nocturnal elemental enteral feeding in a 13-year-old girl with CF (59). Enteral feeding, both nasogastric and by gastrostomy, became more widely used and it was obvious that such methods could rehabilitate patients with severe nutritional problems where oral methods had failed (60, 61,62,63,64). Enteral feeding is now established practice in most large CF units (62, 65,64). Fine bore nasogastric feeds are an alternative to gastrostomy (66, 67). As the more mechanical aspects of nutritional management were improved the behavioral aspects of nutrition received increasing attention.
As the condition of the chest deteriorated, the increasing energy requirement, adversely affected efforts to improve the net energy balance. Undernourished older patients with CF were shown to have increased energy requirements 25-80% higher than in healthy individuals (68). Indirect calorimetry in 71 stable CF patients aged 8.9 to 35.5 years showed the resting energy expenditure (REE) to be raised in most to 95 to 153% of the predicted value even in patients with mild chest disease (69). The REE was also raised in infants (70). Subsequent studies confirmed these findings but all showed a considerable variation in REE between patients (71,72,73) and also before and after antibiotic treatment in the same patient (74, 75). Some authors suggested that the increased REE was related to the presence of the CF mutation itself (76), a factor that was independent of inflammatory activity (73); although not all studies have confirmed this relationship (77). More recent studies in adults with CF emphasise the important contribution of the oxygen cost of breathing in CF but, in contrast to chronic obstructive pulmonary disease, this does not appear to be the main reason for the increased energy expenditure (78). While these studies explain the increased energy requirements necessary to maintain energy balance in some patients, particularly those with severe chest involvement, each patient still requires individual assessment of intake, output and the state of the chest. The adequacy of their energy intake will be ultimately be measured by evaluation of their nutritional state and, in children, their rate of growth (79).
Measures to improve function of older enzyme preparations
In the early 1980s, before the obvious superiority of the new acid resistant enzymes was widely appreciated, there was considerable interest in, and some success with, measures to preserve the activity of the exogenous enzymes by reduction of gastric acid with agents such as bicarbonate, cimetidine and ranitidine (80, 81,82). However, in the early Eighties, the new acid resistant enzymes were increasingly used and, as they were quite obviously so much better than the older preparations, most clinicians lost interest in measures designed to augment the activity of the older preparations. However, more recently, with the advent of fibrosing colonopathy in 1993 (83), and the Committee on the Safety of Medicine's recommendation to avoid high doses of pancreatic enzymes, there has been renewed interest in acid reduction using more effective agents such as omeprazole and lansoprazole as a means of reducing the dose of enzymes (84).
Acid resistant pancreatic enzymes - a major advance
Pancreatic enzymes up to the end of the Seventies were crude, impure and inefficient and were regarded more as a food supplement than a drug. The modest effect of these early preparations was, in part, explained by the fact that 90% of their enzyme activity was destroyed by the gastric acid (85). The increasing doses of the older pancreatic enzymes recommended by some clinics, although improving absorption, raised concerns about hyperuricaemia and hyperuricosuria (86). Fortunately the reduction in enzyme dose achieved with the new acid resistant enzymes solved the problem. Another reason for suboptimal response to exogenous pancreatic enzymes was the bile salt abnormalities described in CF (87). Subsequent duodenal intubation studies in 13 children with CF and controls confirmed low total bile salt concentrations, abnormal glycine/taurine ratios and percentage of dihydroxy bile salts in patients with pancreatic insufficiency. The findings were considered consistent with a broken enterohepatic circulation, which could contribute to lipid malabsorption (88). Although these studies were done prior to the use of more efficient acid resistant enzymes, even with more effective enzymes the excretion of bile acids is still twice normal (89). Towards the end of the Seventies the acid resistant microspheres (Pancrease) became available in North America and the results were presented at the North American CF Club (90, 91,92,93) and published (94). These new enzymes were undoubtedly a major advance in nutritional management. Later studies confirmed the marked superiority of the new acid resistant preparations (95, 96). Certainly, through the Eighties there was a noticeable improvement in the treatment and nutritional state the patients from around the UK as judged by their condition at the time of first referral to our unit for comprehensive assessment (45,46).
The considerable nutritional interest in the early nineties was somewhat overshadowed by the identification of the CF gene in 1989 and the obvious potential for gene replacement therapy. The general principles of nutritional management were by this time reasonably well established (97, 98). It was a time for attention to "fine tuning" and dealing with the minority of patients who still had nutritional problems despite appropriate dietary advice and a reasonable dose of acid resistant enzymes taken in a correct manner. Also it was important to ensure that all patients were benefiting from the significant nutritional advances of the Eighties.
High strength enzymes - a welcome advance
Many patients, when taking a normal fat intake, did require a large number of enzyme capsules (average 30 per day in our paediatric clinic) to control their intestinal malabsorption. It was not surprising that these patients, and their professional advisors, welcomed the introduction of the new "high lipase enzymes" in 1992 (Creon 25,000, Pancrease HL and Nutrizym 22). Studies showed these preparations to be effective as the standard strength enzymes on a lipase for lipase basis thus permitting a reduction in the number of capsules taken to achieve the same lipase intake and degree of control (99, 100,101.102,103,84). However, others and we found that, in practice, although a considerable and welcome reduction in capsule numbers was possible, to achieve adequate absorption in some patients the actual intake of lipase increased considerably when using the new high strength enzymes (unpublished data). As a result, the enzyme intake and lipase intake of many patients increased considerably although the number of capsules required was about halved.
Fibrosing colonopathy
In 1993 a new complication, fibrosing colonopathy (FC), was observed in Liverpool. Five CF children with unusual strictures of the ascending colon, four of whom had FC, were reported from Liverpool83. Studies in the UK (104) and the US (105) showed a relationship with the very high dose of lipase achieved with the new enzymes. An epidemiological study of 14 cases detected in the UK showed they had been taking 46,200 IU lipase/kg/day (range 15,250-84,560) compared with the controls' 21,500 (range 0-85,870). In the UK study, there was also an association with enzyme preparations that contained the copolymer Eudragit L30 D55 in their covering (104). A case controlled study of 29 confirmed cases in the USA confirmed the association with the high lipase intake (mean 50,046 IU lipase/kg/day compared to controls' 18,985 IU). Subsequent studies have added further support to the role of copolymer as one important factor in the pathogenesis (106, 107,108); however, its role in the pathogenesis not generally accepted Although only 17 patients in the UK have developed FC since its first recognition in 1993, the condition has had a major influence on attitudes to pancreatic enzyme treatment.
Pancreatic enzymes since 1994
Although there is lack of agreement on the role of copolymer, all agree that high doses of lipase are relevant in the aetiology of FC. In the UK, the Committee on the Safety of Medicines has advised "avoidance of the high strength enzymes Pancrease HL and Nutrizym 22 in children aged 15 and under. Restriction of dose to less than 10,000 IU lipase/kg/day regardless of the preparation used". Most clinicians in the UK now avoid copolymer containing enzymes and use standard Pancrease, Creon 10,000 or Creon 25,000, which do not contain copolymer and have not been associated with fibrosing colonopathy (84). It is interesting that the only 3 cases of fibrosing colonopathy in the UK since the CSM's advice have all been taking high doses of Nutrizym GR - the only standard strength enzyme which still contains copolymer in the covering. The increased caution with which enzymes are used has led to a considerable reduction in dose in many clinics without adverse effects on absorption or nutrition (109). Most people with CF can be well controlled (fat absorption over 85%) with doses of less than or only slightly in excess of 10,000 IU lipase/kg/day (84). Also, the need to avoid high enzyme doses has renewed interest in methods of reducing enzyme dose e.g. acid reduction with ranitidine (110) omeprazole(111), lansoprazole (112) and even adding bicarbonate to the microsphere preparation (113).
With increasing survival CFRDM affects over 30% of adults with CF and during the Nineties there has been greater attention to CFRDM. An important observation was that the gradual onset of glucose intolerance (in contrast to clinical diabetes mellitus) as judged by glucose tolerance tests, was associated with a worse clinical course (114, 115). As survival improves, as it certainly will, an increasing proportion of the CF population, perhaps the majority will be affected by CFRDM or glucose intolerance. The increasing use of dietary energy supplements, particularly enteral feeds, and the use of oral corticosteroids are both recognised as important precipitating factors.
CF related liver disease
The recognition and treatment of CF related liver disease (CFRLD) is an increasingly relevant clinical issue (116). Focal biliary cirrhosis was present in 70% of older patients at autopsy (117) and 2-5% of patients have serious multilobular cirrhosis. When severe uncontrolled malabsorption was more common, fatty infiltration was seen and was reversible by more appropriate treatment. Thus, it is not surprising that the definition and prevalence of CFRLD varies with time and between CF clinics. Undoubtedly the introduction of ursodeoxycholic acid treatment (URSO) for CF liver disease by Colombo in the late 1980s was a major advance in nutritional management (118, 119).
Osteoporosis
Although osteoporosis was described as a complication of CF in the Seventies (120), there has been a great increase in interest during the last decade. Although some patients with advanced disease had obvious X-ray changes of osteoporosis with kyphosis, vertebral collapse and an increased frequency of fractures (121), the availability of Dual Energy X-ray Absorptiometry (DEXA) scanning has allowed more accurate recognition in a greater proportion of CF patients. Severity of disease and nutritional factors has been identified as important in a number of studies (122). Some 75% of transplant patients have severe osteoporosis worsened by their postoperative inactivity and steroid therapy (121, 123). Better nutrition in childhood, more effective enzymes to improve intestinal absorption and attention to energy, calcium and vitamin D intake and regular monitoring of intestinal absorption and plasma vitamin D levels should reduce the incidence and severity of osteoporosis in adolescents and adults (124, 125). Drug therapy with the biphosphonate family of drugs is under investigation in a number of centres for those with established osteoporosis.
Pregnancy
New challenges beyond imagination of the early CF clinicians include the management of pregnancy in women with CF- indeed the importance of preconceptual nutrition is recognised as particularly important.
Essential fatty acids and cystic fibrosis
Abnormal fatty acid (EFA) composition of serum chylomicrons and adipose tissue of children with CF was described first in 1962 and in subsequent publications (126,127,128,129,130,131). There is also a relative EFA deficiency in heterozygotes. There has been considerable discussion as the whether the EFA abnormalities are a primary metabolic abnormality or merely secondary to the intestinal malabsorption. Even if not a primary defect it has been suggested that the abnormal EFA status may affect the severity of organ disease. This was first suggested by the unusual course of child with CF treated with IV infusions of soya oil emulsion, which contains mainly linoleic acid (132). Following the initial case report, a further 7 children with CF were treated for at least a year with infusions of Intralipid. The authors suggested that the course of the treated children was "remarkably better" than that of unsupplemented children with CF in Auckland at the time. A partial correction of an error of prostaglandin metabolism was postulated (133). Rosenlund also reported some fall of sweat sodium levels (129). Chase & Dupont (131) reported low levels of linoleic acid in 12 children with CF and a higher production of prostaglandin F2 than controls. Oral supplementation with 10-g linoleic acid in 6 children increased the linoleic acid levels and reduced prostaglandin F2 production. They postulated that over-production of prostaglandins might be causally related to the chronic pulmonary disease.
The first double blind nutritional intervention study in CF
In a subsequent controlled trial, 10 children were given either infusions of 20 ml/kg of 10% Intralipid or the calorific equivalent infusions of 10% glucose on alternate weeks for a year (134). The children given Intralipid or glucose gained similar amount of weight - more than either had gained in the previous year. Height gain was just significantly better in the test children (4.8+-1.3 cm and 6.4+-1.3 cm (P>. 05) during the trial year but they did not gain significantly more weight and height than during the previous year. "Cumulative analysis" showed a greater improvement in the test group although numbers seemed hardly adequate. This is said to be the first double blind study of nutritional intervention in cystic fibrosis. A subsequent trial of Intralipid failed to produce a fall in sweat electrolytes (135). Paradoxical effects of essential fatty acid supplementation with primrose oil on lipid profiles and sweat electrolytes were reported in 16 patients (136). There was a significant fall in sweat sodium concentrations after 6 weeks, but sweat chloride was unchanged - effects on membrane function or Na+ pump activity were suggested (136). The foregoing selection of studies are described in some detail in view of the recent renewal of interest in essential fatty acids following the suggestion that a membrane lipid imbalance plays a role in the phenotypic expression of CF in cftr-/-mice. In cftr-/- mice there is a marked imbalance with increase in phospholipid-bound arachidonic acid (AA) and reduction in docosahexanoic acid (DHA) in organs affected by cystic fibrosis and was not secondary to intestinal malabsorption of reduced hepatic synthesis. Oral administration of DHA to the mice corrected the lipid imbalance and prevented the early pathological changes observed in the pancreas (137). It was suggested that certain phenotypic manifestations might result from remediable alterations in phospholipid-bound arachidonic acid and DHA levels. The results of clinical trials are awaited with interest.
The relevant fat-soluble vitamins A, D and E had been discovered in the earlier part of the century. Deficiencies of fat-soluble vitamins in CF patients were described in the Sixties and Seventies. Biochemical deficiencies were common even in patients receiving regular vitamin supplements of A, D and E in doses considered reasonable at the time (43). However, there have only been occasional reports of clinical deficiency syndromes.
Vitamin A.
Shortly after the original description, Andersen reported evidence of vitamin A deficiency in 10/49 patients. Vitamin A deficiency keratinises the bronchial epithelium, changes she considered predisposed to the pulmonary disease (3). The plasma level usually correlates with the retinol binding protein (138). Clinical deficiency syndromes described included xerophthalmia and night blindness (139,140) and intracranial hypertension (141). Compliance, excessive faecal losses over and above the degree of fat malabsorption (142) and metabolic abnormalities have been suggested as reasons for persisting deficiencies despite supplements. However, in practice, with appropriate supplements to maintain a normal plasma level, and close monitoring, most patients are vitamin A replete and have normal visual function (143). In our experience correction of vitamin A deficiency is associated with an improved clinical course (144), which is interesting considering the previous suggestions as to its importance in the pathogenesis (3). Nowadays the antioxidant role is considered to be of importance.
Vitamin D
Although rickets145 and osteomalacia (146) are rarely reported even in older people with CF, osteoporosis, osteopenia and low levels of vitamin D metabolites are being increasingly recognised both in children and adults with CF (147, 148,149). Although normal levels were reported by some in patients supplemented with 800 IU daily (150) our early studies, even in supplemented people with CF suggested that subclinical vitamin D deficiency was not uncommon (43); others had similar experience (151). In older unsupplemented patients 75% had levels below the normal range (152) and not all recovered with 800 IU vitamin D daily emphasising the need for regular monitoring and dose adjustment. The increasing interest in osteoporosis has revived an interest in both calcium and vitamin D levels.
Vitamin E
The first report of vitamin E deficiency in CF involved an infant with necrotic muscle changes (153). Farrell reviewed the subject. Vitamin E levels vary with the severity of the steatorrhoea and are also related to the plasma lipid levels; unsupplemented CF patients have very low plasma levels (154). Deficiency may be associated with neurological problems (155, 156), increasing haemolysis and at times frank haemolytic anaemia (157). Correction reduces red cell fragility and improves haemoglobin levels (158). All studies show levels can be normalised with 5-10 times the EAR 40 IU of a water or fat-soluble preparation of alpha-tocopherol (159, 160).
Vitamin K
Vitamin K deficiency, causing hypoproteinaemia and bleeding, was described in a number of CF infants during the 1970s, initially presumed to be due to vitamin K deficiency (161); at times there has been confusion with child abuse (162). A later study showed no association of increase in prothrombin time with vitamin K1 and similar levels in CF and controls although no infants were included (163). More recently subclinical vitamin K levels, as shown by elevated PIVKA II levels) are almost universal in pancreatic insufficient patients (164, 165). As vitamin K is required for the formation of osteocalcin, the role of subclinical deficiency in osteopenia and osteoporosis is of increasing importance although, as yet, there is no convincing evidence correlating vitamin K deficiency and bone disease (166, 167). Intestinal malabsorption and the use of antibiotics affecting gut flora could both aggravate the tendency to vitamin K deficiency in CF patients (168). Present studies are investigating the need and dose for long-term supplementation (169). There is no doubt that patients with CF who have liver disease and those having surgery should receive vitamin K supplements.
Water-soluble vitamins
No deficiencies were found in one study of 36 patients - normal levels of B1, B2, B6, C, and folic acid (43). Recent work, while confirming normal levels of vitamin C, does show some association of vitamin C levels and indices of inflammation (160).
Essential element nutritional status
Minerals and trace elements have tended to be normal (170) although there are isolated reports of deficiencies even when taking pancreatic enzymes (171). Our results suggested that in the vast majority of patients with cystic fibrosis, essential element status, apart from iron, is adequate (copper, zinc, calcium, magnesium) and it is unlikely that supplementation of these elements is required (170). Although recent suggestions that zinc deficiency may be more common than generally appreciated, particularly in patients with liver disease, but absorption seems to be adequate with enzymes (172) and a supplemental study failed to show any advantage in one series of treated patients (173). Iron has received attention ever since Andersen noted hemosiderosis in 13 of 49 patients reported in her original paper (2). In 127 patients 41 (32%) had low serum ferritin levels but the iron state did not correlate with the clinical score, radiological score or sputum cultures and there was no evidence the patients with low iron levels differed from the rest (174) More recently 44/71 (62%) adult patients who had a lower haemoglobin concentration and 10 were anaemic. The cause was not dietary but their condition was worse and chronic inflammation was considered to be the main cause in these adults. 15 patients completed a 3-month course of iron with no clinical effect or change in haemoglobin (175). Most recently of 40 adult CF patients the mean transferrin was reduced in 16% and 63% were iron deficient (transferrin saturation < 16%), 36% had low serum ferritin but the study did not add to understanding the cause (176). The situation regarding iron is still not clear.
Sodium chloride
Chronic salt depletion is now recognised as an important reason for failing to thrive. The characteristically low plasma electrolytes with raised renin and aldosterone are appropriately termed the pseudo-Bartter syndrome (177). The occurrence of seven cases in five years during the summer months may have been related to a reduction in the electrolyte content of proprietary baby milks (178).
The steady improvements in management of nutrition that have occurred, particularly over the past 20 years, are impressive. Optimal treatment of the chest infection will minimize the increased energy requirements and contribute to achieving and maintaining a better nutritional state. Although many children will pass through adolescence normally, national data from many countries still shows that there is a tendency for the median values for both height and weight to fall below normal particularly during adolescence. However, with present knowledge, with early diagnosis and modern management, and regular input from a dietitian experienced in CF, there should be only a few patients who cannot achieve normal nutritional state and normal growth. Experience shows that regular dietetic input is essential; also regular monitoring by clinical and laboratory assessments. Gastrointestinal problems should be investigated at an early stage, including assessment of the degree of malabsorption, rather than merely increasing the enzyme dose. Regular monitoring of plasma vitamin levels and adjustment of doses when indicated should achieve normal levels in most patients. The recent suggestion that nutritional factors may determine the severity of the phenotypic expression of the CF mutation has again renewed interest in the quantitative and qualitative aspects of CF nutrition and may lend further support for the need for early diagnosis and treatment to avoid preventable dietary deficiencies and malnutrition.
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Acknowledgments
The author is grateful to the many colleagues who have contributed to the nutritional management of people with cystic fibrosis, and also to the patients and their families who have so willingly taken part in the clinical research studies at St James University Hospital & Seacroft Hospital in Leeds.
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