Fia

Cystic fibrosis

Normal

Heterozygotes (carriers - clinically normal)

Figure 1 Mode of inheritance of CF: a Mendelian inherited recessive characteristic.

Prognosis

The median age of survival has dramatically risen from approximately 2 years in the 1940s to around 30 years in the 1990s. A current survival estimation following diagnosis is approximately 40 years. This improved prognosis can be attributed to a combination of factors including aggressive management of infections, effective antibiotics, improved nutritional management, modern physiotherapy techniques, and the centralization of treatment in specialist centers. The survival age for females with CF would appear to be less than that for males. This may be related to poorer nutritional status amongst female CF patients. Expert management started immediately after an early diagnosis of CF by neonatal screening results in an important beneficial effect on outcome and may be critical to the clinical course of the condition and long-term prognosis. Even though optimized nutrition, antibiotics, and chest physiotherapy remain the mainstay of CF management, new approaches to treatment are being developed that may add to the traditional medical therapy for CF. As prognosis and survival improves nutritional related issues become more prevalent including the effective management of pregnancy, diabetes, osteoporosis, and transplantation.

Clinical Features

The clinical features of CF are listed in Table 1. Pathogenesis of Lung Disease

Pulmonary disease can be demonstrated within the first few months of life. Bacterial infection is characterized by high levels of neutrophils and mediators of infection in the form of interleukin 1, 8 and elastases. Mucous glands become dilated leading to obstruction, secondary infection, and progressive lung damage. Frequent periods of respiratory infection and exacerbation are common in CF with increased cough, increased sputum production, and shortness of breath. The immune response appears

Table 1 Clinical features of CF

Respiratory features of cystic fibrosis

Atelectasis Incomplete expansion of a lung or part of a lung due to airlessness or collapse

Bronchiectasis Chronic dilatation of the bronchi associated with coughing and expectoration of purulent mucus Bronchitis Inflammation of one or more bronchi

Pneumonia Inflammation of the lungs with air spaces becoming filled with exudates

Pneumothorax An accumulation of air in the pleural space

Gastrointestinal features of cystic fibrosis

Cholelithiasis The presence or formation of gallstones

Cirrhosis Liver disease characterized by loss of normal liver tissue and fibrosis Distal intestinal Blockage of the bowel with feces, obstruction mucus, and undigested food syndrome

Gastroparesis Paralysis of the stomach or delayed gastric emptying Malabsorption Impaired intestinal absorption of nutrients

Maldigestion Impaired intestinal digestion of nutrients

Meconium ileus Blockage of the bowel with meconium

Osteoporosis/ Reduction in bone mass

Osteopenia

Pancreatic Reduction of enzyme production from insufficiency the pancreas

Portal hypertension High pressure in the portahepatic artery

Rectal prolapse Protrusion of the rectal mucous membrane through the anus Splenomegaly Enlargement of the spleen to be of great significance. Chronic inflammation has been cited as the cause of so much of the lung damage seen in CF. Steroidal anti-inflammatory drugs have been shown to be beneficial but have nutritional side effects such as hyperglycemia and osteoporosis. Nonsteroidal anti-inflammatory drugs such as ibuprofen have been used in some centers with positive results but their long-term effect on renal function is not yet known. The impact of malnutrition on lung disease and respiratory muscle function has been extensively studied in patients with CF. Malnutrition and deterioration of lung function are interdependent. Prevention of malnutrition from the time of diagnosis is associated with better lung function and improved survival.

Gastrointestinal Complications

Individuals with CF can develop a variety of gastrointestinal (GI) disorders related to the pathophysiological changes associated with CF. Pancreatic insufficiency, which is present in the majority of CF patients leads to many of the GI manifestations of CF including steatorrhea, abdominal pain, distal intestinal obstruction syndrome (DIOS), and rectal prolapse. Gastroesophageal reflux (GOR) occurs frequently in CF due to decreased lower esophageal sphincter pressure and is usually treated by proton pump inhibitors. In patients with advanced lung disease vomiting is common after strenuous bouts of coughing and this over time may lead to decline in nutritional status. Peptic ulcer disease, pancreatitis, and intussusception also occur to varying degrees in patients with CF. Crohn's disease and celiac disease occur more frequently in the CF population than in controls and gastrointestinal tumors, although rare, have an increased incidence in CF.

Meconium ileus is the presenting complaint in up to 15% of infants with CF. This is a condition in which the small intestine is blocked with tenacious meconium and surgical intervention is required to correct it. Excessive mucus in the small bowel of patients with CF can provide a physical barrier to the absorptive surface. Undigested or unabsorbed food in association with this mucus, and possibly a reduced gut motility, can lead to a partial or complete obstruction of the GI tract in older children and adults known as meconium ileus equivalent, or more accurately distal intestinal obstruction syndrome (DIOS). This is a condition specific to CF. The usual clinical presentation is one of abdominal pain, abdominal distension, and constipation. It can be precipitated by dehydration, change in eating habits, change in enzyme brand or dose, or immobility. DIOS is treated with a laxative regime and should have a diet and enzyme review.

CF-Related Diabetes Mellitus (CFRD)

Diabetes requiring insulin is the most common comorbidity in CF. The islets of Langerhan are the last cells to be damaged in the process of fibrosis of the pancreas. The incidence of diabetes in CF has been reported to be 8-15% but this may be underestimated due to lack of screening. It is estimated that 50% of patients over 30 years will have some degree of glucose intolerance. The primary cause of CFRD is insulin deficiency secondary to pancreatic fibrosis. Diagnostic criteria for CFRD are the same as for non-CF-related diabetes. Glucose metabolism is also affected by many factors including infection, malabsorption, abnormal intestinal transit time, and steroid use, all features of CF. While CFRD shares many of the characteristics of both type 1 and type 2

diabetes, it is itself a distinct clinical condition. Hyperglycemia may adversely influence weight and pulmonary function and as the age of survival increases may lead to the development of microvas-cular complications. Retrospective studies have shown in those presenting with overt diabetes melli-tus, deterioration in weight and respiratory status for 2 years before diagnosis are reversed once insulin therapy is instituted. A program of multiple daily insulin injections and self-monitoring of blood glucose with the aim of normoglycemia is the preferred treatment with regular follow-up with the Endocrinology team. All patients with CF should be screened annually for CFRD using the oral glucose tolerance test. Minimal dietary restrictions are imposed on this group of patients in an attempt to maximize nutritional intake. See section on dietary management of CF.

Liver Disease

Another complication associated with increased longevity in CF is liver disease, which affects between 2 and 37% of adults with CF. The development of liver disease in CF has been attributed to the blockage of small bile ductules with thick secretions, and the subsequent development of progressive cholestasis, biliary fibrosis, and eventually biliary cirrhosis and portal hypertension. The persisting acidic conditions in the upper small bowel lead to bile salt precipitation and defective lipid emulsification. Unhydrolyzed fat and other products of maldigestion may interfere with bile acid reabsorption in the terminal ileum, thereby reducing the total bile salt pool. Fecal losses of primary and secondary bile acids leads to an imbalance of bile salts, which further increases the viscosity of the already tenacious bile. Treatment with urso-deoxycholic acid has led to an improvement in bile excretion and liver function tests. Complications of liver disease including ascites, gastro and esophageal varices may further exacerbate a patient's nutritional status. In a small number of patients liver failure may require liver transplantation. See section on dietary management of CF.

Nutritional Management

Aggressive nutritional management of patients with CF is key in their overall management. Nutritional management of CF involves maximizing dietary intake, minimizing malabsorption and maldigestion, monitoring vitamin intakes and serum levels, and adapting eating patterns in the event of diabetes, osteoporosis, DIOS, or liver disease. Nutritional support in the form of nocturnal gastrostomy feeding may be necessary if nutritional failure persists (BMI < 18.5 kg/m2). It is well recognized that the malnutrition seen in CF is due to an energy imbalance caused by three main factors: decreased dietary intake, increased energy requirements, and increased energy losses. There appears to be a direct association between the degree of malnutrition and the severity of pulmonary disease, affecting overall prognosis. Many patients are capable of balancing these factors effectively and have a normal growth velocity and good nutritional status. However, as lung function deteriorates, energy requirement increases and appetite decreases leading to a loss of energy stores and lean tissue further contributing to progressive deterioration of lung function (see Figure 2).

Decreased Dietary Intake

People with CF are advised to consume a diet high in energy with no fat restriction. Prior to the development of enteric-coated enzymes in the mid 1980s, patients with CF were advised to follow a low-fat diet in an attempt to minimize fat malabsorption and steatorrhea. Unfortunately, older patients continue this practice as they have developed an aversion to fatty foods after many years of avoiding them. Decreased dietary intake secondary to anorexia is common in CF and can become more of a problem during recurrent chest infections. There have also been an increased number of reports of eating disorders and abnormal eating behavior in the CF population. In addition polypharmacy, repeated exacerbations of CF, organomegaly, gastrointestinal problems, food intolerance, and poor social circumstances can reduce oral intake.

Increased Energy Requirements

Energy requirements are increased during periods of infection by catabolism and fever and continue to increase with advanced pulmonary disease. It has been estimated that CF patients require 120-150% of the estimated average requirement for energy. As pulmonary function deteriorates, mobility also decreases and overall energy expenditure is reduced as a result. Owing to the heterogenicity of CF the energy requirements of individuals will vary and should be assessed on an individual basis. Energy losses through sputum may also be significant in a patient with a marginal energy intake. Salbutamol, often used as a bronchodilator in CF, can increase basal metabolic rate.

Increased Energy Losses

Pancreatic changes are caused by the obstruction of small ducts with thick secretions and cell debris.

Figure 2 Interdependent factors that may give rise to progressive energy deficit as lung function deteriorates.

Functional tissue becomes replaced with fibrotic tissue leading to pancreatic exocrine insufficiency when more than 90% of the normal structure of the pancreas is lost. Pancreatic insufficiency is the most common gastrointestinal manifestation in CF, occurring in at least 95% of patients. The production of pancreatic secretions including enzymes and bicarbonate is reduced, necessitating pancreatic enzyme replacement therapy (PERT). PERT is supplied in the form of gelatin capsules containing microspheres, which are swallowed whole with food. The capsule dissolves within the stomach and releases the microspheres, which are protected from the gastric acid by an enteric coating. Enzymes should be taken immediately before or during a meal to maximize their efficacy. The microspheres mix with the stomach contents and pass through the pylorus into the duodenum where they become activated. Microspheres should be less than 1.5 mm in diameter to ensure they leave the stomach with food. Fibrosis of the pancreas tends to be a progressive process so increasing amounts of oral enzyme supplements are often required as patients get older. All people with CF have some level of pancreatic dysfunction but requirements of enzymes are variable and must be assessed individually. Clinically, the aim of PERT is to correct symptomatic steator-rhea, relieve any abdominal pain, reduce the mass and frequency of stool passed, and achieve weight gain within normal limits.

The enteric coating on enzyme supplements is designed to dissolve at a pH of 6, the optimal pH for pancreatic enzymatic action. Owing to the reduced production of bicarbonate and the resulting lower pH of the duodenum in patients with CF, the enteric coating of the enzyme may fail to dissolve so that the enzyme does not become activated at the absorptive surface of the small bowel. Increasing the duodenal pH by taking proton pump inhibitors may improve absorption. Changing the brand of enzyme may also improve absorption as dissolution characteristics of the enteric coating and proportions of enzymes contained within the microspheres vary. Patients should be dissuaded from chewing enzymes as this breaks the enteric coating and leads to deac-tivation in the acid medium of the stomach. Even with maximal PERT it has been estimated that between 10 and 20% of ingested fat will be malab-sorbed. Colonic strictures known as fibrosing colonopathy (FC) in CF populations receiving high-potency enzymes with a more concentrated dose of lipase and protease per capsule have been reported The etiology of this FC remains unclear. Recently, it has been suggested that FC may be related to the presence of methacrylic acid copolymer (MAC) coating present in some preparations rather than actual enzyme strength. Some adult patients continue to take high-dose enzymes and are advised to do so within recommended levels. The working group on PERT use recommends that no more than 10 000 units of lipase per kilogram body weight be taken per day.

Dietary Management of CF

Patients with CF are encouraged to consume a diet providing 150% of the recommended intake for age and sex. However, this is only a guideline, since in practice the energy requirement for a patient with CF is that which maintains their ideal body weight when malabsorption has been controlled. Maximizing energy intake from everyday foods should be the initial step in the promotion of a high-energy diet. As fat is the most concentrated source of energy in the diet, liberal use of fat should be encouraged; this can best be achieved by recommending frequent consumption of high-fat meals and snacks including confectionery, desserts, and cakes. PERT should be dosed accordingly.

Dietary Supplements

The energy intake of many patients with CF is commonly suboptimal. Many patients find it difficult to eat sufficient food daily to attain or maintain their ideal body weight. During a respiratory exacerbation of CF, energy requirements are at a maximum, but appetite is often reduced. Dietary supplements in the form of sip feeds can be a useful adjunct to a high-energy diet. Care should be taken to ensure that supplements are used in addition to a diet and not as a substitute for normal foods.

Enteral Feeding

When diet and oral dietary supplements are undesirable or ineffective and nutritional failure persists, i.e., BMI <18.5 kg/m2, enteral feeding should be considered. Research has demonstrated a sustained weight gain and a slowing decline in respiratory function associated with supplemental enteral feeding. Artificial nutritional support can be provided via nasogastric or gastrostomy tube depending on patient preference. Gastrostomy feeding is becoming more popular, whether passed endoscopically or under fluoroscopic guidance. The introduction of low-profile gastrostomy feeding tubes or 'button' tubes have made this method of nutritional support more acceptable of patients. The type of feed used and the PERT given with it, varies between centers. Feeds are usually administered overnight in an attempt to provide 30-50% of energy requirements and to allow for maximal oral intake during the day. Gastrostomy feeds can be used over longer periods during periods of acute pulmonary infection, loss of appetite, or in the severely malnourished patient. Patients with a previous poor intake should be monitored for refeeding syndrome.

Specific Dietary Considerations

There are some medical complications of CF that warrant particular nutritional attention.

Liver Disease

Patients with liver disease as a complication of their CF may have ascites, gastric, or esophageal varices, all of which may affect nutritional status and options for nutritional support. Dietary management of the patient with CF and liver disease centers on maximizing energy intake and is best achieved by encouraging small, frequent, energy-dense meals, snacks, and drinks. Suboptimal oral intake can arise in patients with hepatomegaly or splenomegaly, who often have a feeling of fullness after eating referred to as the 'small stomach syndrome.' The benefits of gastrostomy insertion should be carefully weighed in the patient with gastric varices or splenomegaly due to risk of bleeding. A moderate sodium restriction may alleviate ascites. If coagulation is impaired, supplementation with vitamin K may be indicated.

Treatment of liver disease in CF is with urso-deoxycholic acid, which has a positive effect on liver enzymes. Whether this improvement is associated with improvement in nutritional status is unknown.

Cystic Fibrosis-Related Diabetes (CFRD)

The dietary treatment of CF-related diabetes varies from standard diabetic dietary advice. The principle of the diet centers on maintaining caloric intake whilst ensuring glycemic control. The treatment of CFRD should enhance rather than impair a patient's nutritional status. This is done by encouraging a high-fat diet and confining the intake of refined carbohydrate to mealtimes. Insulin doses should be increased so as to maximize the flexibility of the diet, particularly in those patients who are already nutritionally compromised Patients taking oral nutritional supplements and/or overnight gastro-stomy feeds need to have their insulin doses carefully monitored and adjusted accordingly.

Bone Disease in CF

Osteopenia and osteoporosis are now widely recognized in the CF population. There are a number of contributing factors to this early development of bone disease including steroid usage, malabsorption of calcium and, more importantly, vitamin D, poor nutritional status, decreased levels of physical activity, and a reduced peak bone mass in CF patients compared to healthy individuals. Assessment of bone health is by dual energy X-ray absorptiometry (DXA) scanning and there are a variety of treatment options available depending on the severity of disease ranging from dietary calcium and vitamin D supplementation to the use of bisphosphonate drugs, which aim to halt the progression of bone loss and promote bone formation.

Fertility Issues

As the number of people with CF of a reproductive age increases, so does the incidence of pregnancy in this group. Although almost all males with CF are infertile owing to the absence of the vas deferens, most females are fertile. Pregnancy in women with CF requires special nutritional attention with regular monitoring, particularly with respect to adequate weight gain, and vitamin and mineral status.

Body Composition Studies in CF

Studies of body composition in CF patients have shown deficits in total body mass, lean body mass, and body fat, which affect body density. As skinfold thickness percentiles are derived from body density, it has been suggested that the assessment of the body fat content of children with CF using, or derived from, body density such as skinfold thickness is invalid. Muscle function indices have been shown to respond to refeeding in malnourished patients with CF before body composition or biochemical indices of protein status improved, and so appear to be sensitive markers of nutritional status.

Assessment of Nutritional Status

Malnutrition in CF remains a major clinical problem. Growth and nutritional status should be monitored at each clinic visit to ensure early detection of any deterioration, and to prompt appropriate nutritional intervention. The many factors that complicate nutritional status in CF are shown in Table 2.

When weight falls to a BMI of less than 18.5 kg/m2 nocturnal enteral feeding should be considered. At diagnosis and when the patient shows clinical deterioration the following should be determined:

Table 2 Factors affecting nutritional status

• Variation in gene mutation

• Frequency of pulmonary exacerbations

• Gastroesophageal reflux

• Distal intestinal obstruction syndrome

• Pancreatitis

• Liver disease

• Diabetes mellitus

• Dietary dislikes and misconceptions

• Psychological problems/eating disorders

• Transplantation electrolytes, serum albumin and other liver function tests, oral glucose tolerance test, full blood count, serum retinol, and alpha tocopherol. If there is any evidence of iron deficiency, iron status should be assessed. Other medical disorders should be considered in the evaluation of nutritional failure. These include diabetes mellitus, liver disease, Crohn's disease, celiac disease, chronic abdominal pain, DIOS, and esophagitis.

Vitamin Status in CF

At least 85% of CF patients have some level of pancreatic insufficiency leading to a degree of fat malabsorption. For this reason, unless supplemented, most patients are at risk of developing either clinical or subclinical deficiencies of the fat-soluble vitamins, vitamin A, D, E, and K. Those most at risk appear to be individuals with poorly controlled malabsorption, poor adherence to treatment, liver disease, bowel resection, or following a late diagnosis.

Vitamin A

Vitamin A should be supplemented at a dose of 4000-10 000IU per day. However, low serum levels of retinol have been noted even at this dose. If retinol levels are persistently low despite adequate supplementation, an assessment of compliance, reti-nol-binding protein (RBP), and zinc levels should be checked. Special care should be given to vitamin A supplementation during pregnancy as high levels are reported to be teratogenic.

It is important to consider hepatotoxicity with large supplemental doses of vitamin A in a patient who may store vitamin A in the liver, yet shows low serum levels of retinol, and who may display ocular signs of deficiency. The free alcohol retinol is almost entirely attached to RBP, which is synthesized in the liver. Decreased levels of RBP, which may occur in up to 25% of patients with CF, may be due to an abnormality in its production by the liver, zinc deficiency, or protein energy malnutrition. Even with adequate vitamin supplementation and pancreatic enzyme replacement treatment, up to 20% of patients may have ocular signs of deficiency of reti-nol. Xerosis may improve by increasing the dose of vitamin A alone, or combined with zinc. It has been suggested that there may exist a specific defect in the handling of retinol in the GI tract of people with CF unrelated to the level of fat malabsorption. A correlation has been demonstrated between low levels of vitamin A and poor lung function.

Beta-Carotene

Beta-carotene is one of the carotinoids present in plasma and a precursor of vitamin A. It is effective as an antioxidant at lower oxygen saturation states than vitamin E. It has a biological role as a lipid-soluble chain-breaking antioxidant in biomembranes. Routine supplementation with beta-carotene could diminish lipid peroxidation and improve essential fatty acid status.

Vitamin D

Vitamin D deficiency may be caused by malabsorption, underexposure to sunlight or defects in metabolism due to liver disease. Even though skin exposure to sunlight is the major source of vitamin D, serum concentrations will vary between individuals depending on endogenous production in the skin. Rickets as a result of vitamin D deficiency is rare but has been described in CF. Osteopenia and retarded bone maturation have been reported in a number of CF patients, even with supplementation to recommended levels. Bone density has been shown to be significantly decreased in all sites compared with that of normal young adults. Other variables such as activity levels and nutritional status have not been adequately researched, although the incidence of osteoporosis was found to be higher in those patients with severe respiratory disease. To attain and maintain normal serum levels a daily dose of 400-2000IU is generally required in adults.

Vitamin E

Cholestasis and a reduced enterohepatic circulation of bile acids contribute to the malabsorption of fat-soluble vitamins from the small intestine. Vitamin E is highly lipophilic and deficiency correlates with degree of fat malabsorption. Subclinical neuro-electrophysiological abnormalities are already present in about 40% of patients by 2 months of age. Neurological signs of vitamin E deficiency are responsive to supplementation if initiated early but are irreversible if treatment starts after the neurological lesions are present. As circulating alpha tocopherol is transported in the blood attached to lipid it is should be expressed as a ratio to total lipid to be correctly interpreted. Current recommendations are to monitor serum vitamin E levels annually and adjust supplementation accordingly. A daily dose of 400 IU per day should achieve normal serum levels in adults.

Vitamin K

A review of the literature provides conflicting opinions in the area of routine supplementation of vitamin K as the prevalence of vitamin K deficiency has not been established. Theoretically, the risk factors for patients developing vitamin K deficiency are pancreatic insufficiency, severe liver disease, extensive small bowel resection, and chronic broad-spectrum antibiotic use. Monitoring the coagulation system is advised, as vitamin K estimations are not generally routinely available. It seems prudent to prescribe vitamin K supplements to patients with the above risk factors. Vitamin K has recently been shown to play an important role in bone health. There are no specific guidelines on supplementation, but doses of 5-10 mg appear to be a prudent guide. Annual monitoring of fat-soluble vitamin levels should be carried out and doses of vitamins altered as appropriate.

Water-Soluble Vitamins

Supplementation with water-soluble vitamins is, in general, thought to be unnecessary in CF. In cases where dietary intake is poor or unbalanced, supplementation of vitamin C is advised. Supplementation with other water soluble vitamins is not routinely recommended.

Mineral Status in CF

Fat malabsorption can lead to the formation of insoluble fatty acid complexes with minerals in the gut, leading to a reduction in their absorption. CF may also be associated with intestinal mucosal defects, which may further retard the absorption of nutrients. Suboptimal levels of zinc, selenium, manganese, and iron have all been described in CF. Routine iron supplementation is not recommended as it has been suggested that Pseudomonas aerugi-nosa grows in tissues with a high concentration of iron. In addition, levels of iron may be suppressed as a normal body response in times of infection, and attempting to correct this is potentially harmful. Sodium and chloride do not need to be supplemented unless in very hot climates or during excessive exercise.

The Oxidant/Antioxidant Imbalance in CF

Patients with CF frequently exhibit increased oxygen free radical generation from activated neutrophils due to chronic lung inflammation. This, coupled with antioxidant deficiencies due to exocrine pancreatic insufficiency, results in an oxidant/antioxi-dant imbalance. Consequently, free radical attack on unsaturated fatty acids of lipid structures occurs leading to lipid peroxidation. An efficient antioxi-dant supply is suggested to control tissue damage by restoring the oxidant/antioxidant balance.

Conclusions

There is a complex relationship between physiological, environmental, and genetic variables leading to a great variability in energy requirements among individuals with CF. Despite advances in the treatment of CF the need for good nutritional strategies in CF will continue. Individually tailored nutritional advice for each patient with CF by a dietitian experienced in the area of CF is essential.

See also: Diabetes Mellitus: Etiology and Epidemiology; Classification and Chemical Pathology; Dietary Management. Eating Disorders: Anorexia Nervosa; Bulimia Nervosa. Liver Disorders. Malnutrition: Primary, Causes Epidemiology and Prevention; Secondary, Diagnosis and Management. Nutritional

Assessment: Anthropometry; Biochemical Indices; Clinical Examination. Nutritional Support: Adults, Enteral; Adults, Parenteral; Infants and Children, Parenteral. Vitamin A: Physiology; Biochemistry and Physiological Role; Deficiency and Interventions. Vitamin D: Physiology, Dietary Sources and Requirements; Rickets and Osteomalacia. Vitamin K.

Further Reading

Borowitz DS, Grand RJ, and Durie PR, and the Consensus Committee (1995) Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Journal of Paediatrics 127: 681-684.

Dodge JA (1992) Nutrition in cystic fibrosis: a historical overview. Proceedings of the Nutrition Society 51: 225-235.

McDonald A, Holden C, and Harris G (1991) Nutritional strategies in cystic fibrosis: current issues. Journal of the Royal Society of Medicine 84(supplement 18): 28-35.

Moran A, Hardin D, Rodman D, and Allen HF, and the consensus committee (1999) Diagnosis screening and management of cystic fibrosis related diabetes mellitus: A consensus conference report. Diabetes Research and Clinical Practice 45: 57-68.

Ramsey BW, Farrell PM, and Pencharz P, and the Consensus Committee (1992) Nutritional assessment and management in cystic fibrosis: a consensus report American Journal of Clinical Nutrition 55: 108-116

Rosenstein et al. (1998) The diagnosis of cystic fibrosis: A consensus statement. Journal of Pediatrics 132(4): 589-595.

Sinaasappel M, Stern M, Litttlewood J, Wolfe S, Steinkamp G, Harry, Heijerman HGM, Robberecht E, and Döring G (2002) Nutrition in patients with cystic fibrosis: a European Consensus. Journal of Cystic Fibrosis 1: 51-75.

Warner J (ed.) (1992) Cystic fibrosis. British Medical Bulletin 48(4): 717-978.

Zentler-Munro PI (1987) Cystic fibrosis: a gastroenterological cornucopia. Gut 28: 1531-1547.

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