Cystic fibrosis (CF) is the most common recessively inherited life limiting disease in the UK. Incidence rates are around 1 in 2500 live births and approximately 1 in 25 of the population is a carrier for the disease . There are approximately 9000 patients currently in the UK . CF mostly affects Caucasian populations; however, there are a significant number of cases amongst families from the Indian subcontinent and the Middle East. It is rare in Chinese, South East Asian and African-Caribbean ethnic groups.
The outlook for patients with CF has steadily improved over the years as a result of early diagnosis; more aggressive treatment; agreed standards of care which define assessment, monitoring, detection and treatment of complications; and the recommendation that care is delivered in specialist centres by a multidisciplinary team of trained health professionals experienced in the management of the condition . The proportion of adults with CF has increased dramatically and currently stands at 56% of the CF population . Median survival is 41.4 years and is predicted to be 50 years of age for infants born in 2000 .
CF is caused by a mutation of the cystic fibrosis transmembrane conductance regulator gene (CFTR). This results in dysfunction in the regulation of salt and water across the cell membranes of secretory epithelial cells and in thickened secretions in all organs with epithelial cells; hence CF is a multi-organ condition. Approximately 1500 different genetic mutations have been identified. The most common genotype which accounts for around 52% of cases is homozygote ΔF508, with F508 plus one other genotype accounting for approximately 39% of cases. Class I, II and III mutations are the most severe giving rise to more typical presentations of CF. Class IV and V mutations give rise to milder or atypical CF.
The clinical consequences include
- recurrent respiratory infection, inflammation, bronchial damage, bronchiectasis resulting ultimately in respiratory failure
- exocrine pancreatic dysfunction with approximately 85% of patients suffering from insufficiency in pancreatic enzyme production, malabsorption and, if not adequately controlled, malnutrition
- bowel obstruction with approximately 15% of infants suffering from meconium ileus at birth, and recurrent bowel blockages in older patients due to distal intestinal obstruction syndrome
- impaired glucose tolerance or CF related diabetes
- liver disease and portal hypertension
- reduced bone mineral density
- gut motility problems
- infertility in most males
- CF arthropathy
- behavioural and psychological problems as a result of severe life limiting disease
- reduced bone mineral density
Newborn screening for CF was introduced across the UK in October 2007. All infants born since this date are offered screening for CF on day 5 of life. There are best practice guidelines defining the protocol for screening and diagnosis, and guidelines for management of infants picked up through screening [5, 6]. The majority of CF diagnoses are made through this programme and should be confirmed by sweat test and/or genetic mutation analysis by 4 weeks of age. Early diagnosis through newborn screening has been shown to confer significant benefits, especially in terms of growth and nutrition [7, 8].
The majority of cases picked up through screening have typical CF; however, the nature of the screening programme will result in some cases where diagnosis is uncertain because of anomalies in the genotype, phenotype or sweat test result. These cases should still be managed in a CF specialist centre.
Some cases of CF will not be picked up through the screening programme, either because they were born before October 2007, were born outside of the UK, or missed the screening process. A clinical diagnosis will be made in these patients, confirmed through sweat test and genetic mutation analysis.
Chronic respiratory disease
The lungs are normal at birth but may become affected early in life [5, 6]. Due to the abnormal secretions there is obstruction of the small airways, with secondary infection and inflammation. Recurrent infection with organisms such as Staphylococcus aureus, Haemophilus influenzae and Pseudomonas sp. leads to damage of the bronchial wall, bronchiectasis and abscess formation.
The major objective of chest treatment is to prevent infection, remove secretions and thereby delay the rate of lung damage and maintain respiratory function. This is done by:
- regular surveillance of secretions and prompt and aggressive treatment of infection with antibiotic therapy, either oral, aerosol or intravenous
- oral prophylactic antibiotic therapy in younger children
- regular chest physiotherapy to aid removal of bronchial secretions
- use of bronchodilators and oral steroids to open the airways and reduce inflammation
- encouragement of an active lifestyle and physical exercise
Pancreatic insufficiency (PI) is the most common gastrointestinal defect in CF affecting approximately 95% of patients in northern Europe . Approximately 92% of infants will be pancreatic insufficient by the age of 12 months , although the introduction of newborn screening and early identification of patients with milder mutations may result in the proportion of patients with known pancreatic sufficiency increasing in the future.
PI develops when more than 90% of acinar function is lost. Damage begins in utero and there is ongoing destruction of acini and replacement with fibrous and fatty tissue. Consequently the secretion of digestive enzymes and bicarbonate is reduced or absent, resulting in malabsorption of fat, protein, bile, fat soluble vitamins and vitamin B12. Treatment is with the use of pancreatic enzyme replacement therapy (PERT).
Diagnosis of PI is made by faecal elastase measurement. In the 10%−15% who are defined as having normal pancreatic function at diagnosis, enzyme secretion may be diminished. However, it may be sufficient for digestion of nutrients without the need for PERT . A proportion of those with normal faecal elastase will go on to develop PI; faecal elastase should be rechecked periodically and if symptoms of malabsorption develop.
Meconium ileus is the presenting feature in up to 25% of infants with CF. It becomes apparent within the first days of life and often before the result of newborn screening is available. It is caused by a blockage of the terminal ileum with thick meconium and develops in utero. Management of meconium ileus may be conservative; however, some patients will require surgical intervention, with or without intestinal resection and stoma formation.
Distal intestinal obstruction syndrome
Distal intestinal obstruction syndrome (DIOS) is a common complication in CF and estimates suggest a prevalence of 5−12 episodes per 1000 patients per year in children . It is characterised by frequent abdominal pain, accompanied by complete or partial intestinal obstruction. Faecal material and mucus gathers in the distal ileum and there is often a palpable mass in the right lower abdomen.
DIOS is more common in older patients, in those with PI (although it can be seen in pancreatic sufficient patients) and in those who have had previous gastrointestinal surgery. It usually responds to medical management including rehydration combined with stool softening laxatives or gut lavage. In extreme cases surgical intervention may be necessary.
Gastro-oesophageal reflux (GOR) has been reported in approximately 20% of infants with CF , although in a review of screened infants at one UK centre incidence was as high as 43% . The mechanisms are unclear; however, it is considered to be mainly due to inappropriate relaxation of the gastro-oesophageal sphincter. GOR is most prevalent in young children with CF and improves with age. GOR may result in poor weight gain, feeding disturbances, abdominal pain, and respiratory symptoms including wheeze and reflex bronchospasm. Treatment includes thickening feeds and the use of anti-reflux medication .
Abdominal pain has been reported in approximately 30% of patients . It is particularly common in children with poorly controlled malabsorption or constipation, but may be due to other disorders including intussusception, appendicitis, Crohn’s disease and cow’s milk protein enteropathy. Abdominal pain may negatively impact on nutritional intake and nutritional status.
Other gastrointestinal problems
Other problems include rectal prolapse, acute pancreatitis, coeliac disease and Crohn’s disease.
Other clinical problems
CF related diabetes
CF related diabetes (CFRD) is the most common comorbidity affecting approximately 19% of adolescents and up to 50% of adults . The prevalence is increasing with the increased survival of people with CF. It is a distinct type of diabetes with features of both type 1 and type 2 diabetes. There is progressive fibrous and fatty infiltration of the exocrine pancreas resulting in destruction of the islet cells, leading to loss of endocrine cells and reduced insulin production. In addition there may be insulin resistance.
The development of CFRD is often gradual, preceded by worsening of nutritional status and decline in lung function. Regular screening and prompt treatment is essential to prevent clinical deterioration. The development of CFRD has a negative impact on growth in adolescents  and on nutritional status, respiratory function and survival [17, 19–21]. It is more common in females than males [22–24].
Treatment aims are to eradicate hyperglycaemia and to maintain good nutrition and lung function. Clinical improvement and reversal of decline in pulmonary function and nutritional status has been documented when the diabetes is treated with insulin [25, 26].
Diagnosis and screening
Annual screening for CFRD is recommended through random blood glucose level monitoring; in some situations detailed assessment may be required in between annual reviews. The incidence of CFRD increases after 10 years of age by approximately 5% annually.
International consensus is yet to be established; however, UK CF Trust and American Diabetes Association guidance [27, 28] recommends that all patients over the age of 12 years should be screened annually by performing a standard oral glucose tolerance test (OGTT, T0, T120 75 g). A diabetic OGTT does not necessarily mean that the individual has CFRD, but shows that at the time of the assessment the patient had abnormal handling of glucose which may revert to normal. The result of the OGTT should be considered alongside the clinical picture at the time. An abnormal OGTT or impaired OGTT indicates a higher risk for developing CFRD. HbA1c is not considered sensitive enough for detecting CFRD, possibly because hyperglycaemia may be transient or because red blood cell turnover is elevated due to chronic inflammation in CF.
Assessment of glycaemic control in between annual assessments should be considered in the following circumstances:
- symptoms of hyperglycaemia or hypoglycaemia
- unexplained decline in nutritional status
- unexplained decline in lung function
- on commencement of continuous enteral feeding; mid and immediate post feeding blood glucose levels should be measured and repeated monthly at home
- during infective exacerbations or corticosteroid use
Possible action to be taken on the results of routine OGTT are given in Table 11.1.
Table 11.1 Possible action to be taken on the results of routine oral glucose tolerance test (OGTT)
|Normal OGTT||Repeat in 1 year|
|Impaired OGTT||Repeat in 1 year or sooner if clinical parameters worsen|
|Diabetes OGTT without symptoms||Home blood glucose monitoring. If normal repeat in 6 months|
|Diabetes OGTT with symptoms||Start treatment|
Whilst OGTT remains the gold standard for the diagnosis of CFRD, continuous glucose monitoring is increasingly being used to aid diagnosis and treatment [29–31]. Dobson et al.  describe a ‘pre diabetic phase’ in the development of CFRD which may be clinically significant. This phase may present up to 4 years prior to diagnosis of CFRD using OGTT, and is characterised by deterioration in lung function, poor growth and weight gain. This raises concern regarding the sensitivity of the standard OGTT as a diagnostic tool and a continuous glucose monitoring system (CGMS) may be more sensitive in detecting this early stage [33, 34].
CGMS may be particularly useful for patients receiving overnight enteral nutrition, when the overnight glucose loading may predispose to nocturnal hyperglycaemia and home monitoring may be practically difficult.
Medical management and treatment
Patients should be referred to a diabetologist, ideally one who has an interest in CF and works alongside the CF team, seeing patients where possible in joint CF/diabetes clinics.
Insulin is the mainstay of treatment of CFRD [28, 35] and the aim of treatment is to eradicate symptoms of hyperglycaemia, maintain nutritional status and pulmonary function, and reduce the risk of long term microvascular complications. Insulin has a potent anabolic effect which may be of additional benefit for children and young people with growth and nutritional difficulties.
Optimal control may be difficult to achieve in the adolescent age group due to difficulties with compliance, variable food intake, exercise and growth. Insulin regimens need regular review and adjustment and should be individualised to take into account the eating habits and lifestyle of the child or adolescent. Once or twice daily mixed insulin injections may be used; however, better control may be obtained with multiple daily injections of short acting insulin given with meals. The advantage of this is that the dose may be adjusted for differing intake of food. Multiple daily injections, however, increase the burden of treatment and carry a risk of hypoglycaemia. Recent uncontrolled trials suggest that once daily injections of intermediate or long acting insulin improve weight and lung function and are useful in CFRD and early insulin deficiency .
Experience in the use of insulin pumps for the treatment of CFRD is in its infancy; however, initial studies suggest improvements in blood glucose control, body weight and lean body mass .
Cystic fibrosis associated liver disease
Approximately 5%−10% of patients develop multilobular cirrhosis during the first decade of life. Most patients later develop signs of portal hypertension with complications such as variceal bleeding. Liver failure develops later usually in adult life, but is not inevitable. Cystic fibrosis associated liver disease (CFLD) is associated with more severe CF phenotypes .
Annual screening for liver disease is important to detect pre symptomatic signs; the bile acid ursodeoxycholic acid, which may halt progression of liver disease, should be commenced. Liver disease should be considered if the patient has two of the following: persistently abnormal liver function tests, abnormal physical examination or abnormal liver ultrasound. A liver biopsy should be performed if there is doubt over the diagnosis. Patients should have annual assessment of liver function.
The development of liver disease has a negative impact on nutritional status , often as a result of worsening fat absorption, and aggressive nutritional management is important to reverse this trend . Liver transplantation remains the only option for those who develop end stage liver disease and is considered to be effective, initially stabilising the decline in pulmonary function which is a feature of the development of CFLD. One year survival post transplant is estimated at 92.3% and 84.1% after 5 years . Studies suggest, however, that nutritional status does not improve post liver transplant and pre transplant body mass index (BMI) does not alter survival .
Reduced bone mineral density (BMD) was first described in CF in 1979, but the full extent of the problem was not apparent until the 1990s when detailed studies were performed. Patients may develop low BMD through either osteoporosis or vitamin D deficiency osteomalacia. Studies suggest that BMD is normal in well nourished CF children with well preserved lung function, but many patients fail to gain bone mass normally and/or experience premature bone loss in adolescence or early adult life; 23.5% of adults are reported to have osteoporosis  and up to 38% of patients assessed in one centre demonstrated evidence of reduced bone mineral mass . The premature bone loss is preceded by reduced peak bone mass accrual in adolescence [44, 45].
The aetiology of low BMD is multifactorial and major risk factors include [46, 47]
- overall disease severity, including links to FEV1 (forced expiratory volume in 1 second)
- the frequency and duration of intravenous antibiotic therapy
- corticosteroid use
- exercise tolerance and levels of physical activity
- DF508 genotype
- delayed puberty
Peak growth velocity is associated with high bone mass accrual. In healthy populations, peak bone mass accrual occurs at 11.7 years in girls and 13.4 years in boys. Puberty may be delayed in CF and this is associated with a reduction in bone age and delay in peak height velocity by 9−14 months .
There are also nutritional factors:
- nutritional status and lean body mass
- vitamin D status may result in impaired bone mineralisation and increased loss
- vitamin K deficiency may contribute by altering the balance of bone formation and resorption
- calcium intake
Diagnosis of low BMD
CF Trust guidelines  recommend that BMD should be measured in the lumbar spine from around 10 years of age. These scans (DXA scans) should ideally be done in a centre with a clinical team experienced in performing and interpreting bone densitometry in children. DXA scans should be repeated every 1−5 years; serial measurements will allow for identification of peak bone mass and this may influence treatment options if premature bone loss occurs.
Recommendations to optimise bone health
Low BMD in adults has its origins in childhood and factors to optimise bone health should be considered in paediatric care. Dietary factors play a significant role and it is important that patients are regularly reviewed by an experienced paediatric dietitian with the aim of achieving normal weight, height, body composition, optimal vitamin D and K status and adequate calcium intake.
Weight bearing physical exercise should be encouraged. Children and adolescents should be encouraged to exercise for 20−30 minutes three times per week and exercises should include high impact weight bearing exercises.
Glucocorticosteroid use should be minimised and CF pulmonary exacerbations should be promptly treated to minimise the systemic inflammatory effect on bone. Pubertal delay should be recognised and treated.
The malnutrition seen in CF is multifactorial and is determined by three main features: energy loss, increased energy expenditure and anorexia.
Pancreatic insufficiency in the majority of patients with CF results in pancreatic exocrine secretions containing fewer enzymes and bicarbonate; pancreatic secretions have a lower pH and are a smaller volume than in those with pancreatic sufficiency. The consequence, when untreated, is foul smelling frequent loose stools. Malabsorption of fat and nitrogen is severe in untreated patients; however, carbohydrate malabsorption is minimal. Malabsorption can be controlled with the use of PERT although, even when treated, many patients still have a degree of fat malabsorption. Estimates suggest that stool energy losses account for up to 11% of gross energy intake .
Pancreatic bicarbonate deficiency results in reduced buffering of gastric acid in the duodenum, resulting in decreased efficiency of pancreatic enzymes. Mucosal ion transport abnormalities affect water and electrolyte transport and there may be impaired mucosal uptake of nutrients. Altered motility may affect intestinal transit time and impact on absorption of nutrients.
Energy losses may be further exacerbated by previous gastrointestinal surgery for meconium ileus which may result in shortening of the bowel, strictures at the site of anastomoses, malrotation and adhesions. Energy may be lost due to vomiting following coughing and GOR. Untreated CFRD will cause energy loss through glycosuria. CFLD may increase malabsorption.
Increased energy expenditure
Many investigators describe an increase in resting energy expenditure (REE) in patients with CF, with a large range of requirements. Impaired lung function significantly increases REE and can double REE above that of controls . Increased REE is closely associated with declining pulmonary function and subclinical infection [51–54].
Continuous injury to the lungs leads to progressive fibrosis and airway obstruction, with increased work of breathing. Data are conflicting on total energy expenditure, with evidence that patients with moderate lung impairment adapt to increased REE by reducing activity levels, thereby maintaining their energy expenditure levels . The variability in energy requirements between patients emphasises the need for individual assessment.
Anorexia and low energy intakes
Poor dietary intake can contribute to malnutrition in children with CF. Appetite is often reduced during pulmonary exacerbations. This leads to a familiar pattern of weight gain between exacerbations and weight loss during, thus impairing long term nutritional status. Dietary assessments in CF children demonstrate that energy intake is higher than in controls, but rarely exceeds 111% [56–58].
Behavioural feeding difficulties and poor child−parent interactions at mealtimes can be a problem and mealtimes are often reported to be a time of conflict. Abnormal eating behaviours include excessively long mealtimes, delay tactics, food refusal and spitting out food [59, 60].
There has been evidence of strong links between improved nutritional status and survival for over 30 years. A study compared patients in two North American clinics: one treated patients with the low fat diet which was the gold standard treatment at the time; the other clinic treated patients with a high fat diet. Those receiving the high fat diet were found to be taller and heavier and to have improved survival . The improvement in nutritional status was considered to be the main difference for the increased survival seen between the two clinics.
Other studies have shown the effect of nutrition on prognosis. Growth failure and wasting are both independent prognostic indicators in survival. Patients with height <5th percentile at 5 years of age have a significantly increased risk of death; this increase persists at 7 years of age . Patients with ideal body weight >85% have a better prognosis at 5 years of age than those with body weight <85% . Good nutritional status is also positively correlated with lung function . Malnutrition results in poor height growth, impaired respiratory muscle function, immunological impairment and increased susceptibility to infection [65, 66].
Regular and accurate nutritional assessment is vital so that decline in nutritional status is picked up and treated promptly. European , UK  and North American guidelines  give guidance on frequency and methods of assessment and interpretation of results.
Weight, height and head circumference
Sequential measurements of height and weight (and head circumference in children <2 years of age) should be carried out at every clinic visit so that malnutrition is prevented or at least detected early and interventions are put in place promptly. Measurements should be carried out by appropriately trained staff following national and local guidelines and plotted on appropriate centile charts so that comparison may be made with standards .
Delayed puberty in adolescents with CF should be taken into account when interpreting growth as there may be an overestimation of malnutrition, as height velocity slows prior to the pubertal growth spurt. Assessment and consideration of pubertal stage is therefore important when considering nutritional status in this age group [67, 68].
Body mass index
BMI is a measure of body fatness or thinness and is a calculation of weight (kg) ÷ height (m)2. There are BMI centile charts for age and sex (UK 1990 data). Care should be taken in the interpretation of BMI, as inaccurate assessments can be made in children whose height has been impacted by chronic malnutrition or delayed puberty. An expert consensus group of the Royal College of Paediatrics and Child Health (2009) recommended that BMI be used in children as a measure of thinness or fatness in children over 2 years of age, when height can be measured accurately . For children <2 years, when height/length is more difficult to measure, BMI measurements should be interpreted with caution and used in combination with other measures. BMI centile may pick up nutritional failure in children >2 years of age more accurately than height for age percentile, weight for age percentile and percentage ideal body weight .
Percentage weight for age, height for age and percentage weight for height
Percentage weight for height (%wt/ht) is often used in CF centres as a measure of nutritional status and is calculated by weight (kg) × 100/weight (kg) equivalent to current height centile.
Serial measurements of %wt/age and %ht/age are also useful to track progress of individual patients. %wt/ht, like BMI, assesses weight in proportion to height, but does not assess stunting or the impact of delayed puberty. Serial measurements of %wt/age and %ht/age must be considered together. Although the calculation is simple to do, a high degree of inaccuracy has been reported in clinical practice . Since no single method provides an accurate assessment of nutritional status, a variety of the above measures should be used, and any changes over time used to inform nutritional management.
Skinfold thickness and mid upper arm circumference
Measurement of skinfold thickness uses subcutaneous fat to determine total body fatness; however, reliability of this as a proxy for body fatness is poor  so skinfold thickness measurements are not used routinely in clinical practice.
Mid upper arm circumference gives an estimation of lean body mass and may be a useful measure of nutritional status in patients with significant organomegaly or fluid retention, as may be seen in patients with advanced CFLD. There are normal data to compare individual patient data against so that trends can be monitored .
Bone age and bone mineral density
Bone age should be assessed in any child with stunting (%ht/age <90%, or height <0.4th centile) or with pubertal delay.
Bone mineral density should be measured in a specialist CF centre in all children >10 years of age and repeated every 1−5 years, depending on the degree of reduced BMD observed.
Consensus reports and UK CF Trust guidelines define malnutrition in children and young people up to the age of 18 years as follows.