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Cystic fibrosis — the disease

Cystic fibrosis (CF) is an inherited disorder that causes widespread dysfunction of the exocrine glands, resulting in chronic lung disease and pancreatic insufficiency. It is one of the most common genetic disorders in the UK. The incidence of CF in Caucasians is approximately one in 2,500 live births and 4 per cent of the population are carriers.1 The incidence in non-Caucasians is much lower, however, and is estimated to be around one in 20,000 in ethnic African populations and one in 100,000 in Oriental populations. In the UK, there are approximately 8,000 patients with CF, more than half of whom are children.

Prognosis

Although there is no cure for the disease, advances in clinical management in the form of physiotherapy, antibiotic treatment and attention to nutrition have led to a considerable improvement in life expectancy with most patients nowadays living beyond the age of 30 years.2 The prognosis continues to improve, and it is projected that a newborn infant with CF in the UK is likely to have a life expectancy well in excess of 40 years — double that of 20 years ago.3 In patients with adequate pancreatic function, life expectancy could be more than 50 years.

Genetics

CF is caused by mutations in a single gene in the middle of chromosome 7, (see: www.genet.sickkids.on.ca/cftr). The condition is inherited as an autosomal recessive condition, which means that a sufferer must inherit two copies of the changed gene — one from each parent. Carriers of the disease have a change in one copy of the CF transmembrane regulator (CFTR) gene.

CFTR functions as a vital chloride channel in epithelial membranes. It also helps to regulate the transport of sodium and other ions. The overall function of CFTR is to prevent the accumulation of sodium chloride inside mucus-producing cells, which is necessary to produce mucus of the correct consistency.

Almost 1,000 mutations have been identified in the CF gene, but a few common mutations cause disease in most patients. Mutations have been divided into six classes based mainly on the molecular fate of CFTR:4

  • Class I — CFTR is not synthesised
  • Class II — CFTR is synthesised, but in an abnormal form, which fails to escape from the cellular endoplasmic reticulum
  • Class III — CFTR is synthesised and is transported within the cell, but there is disruption in its activation and regulation at the cell membrane
  • Class IV — CFTR is synthesised and expressed at the cell membrane but chloride conductance is reduced
  • Class V — CFTR synthesis or processing is partly defective
  • Class VI — CFTR is synthesised but there is defective conductance of other ions (other than chloride)


The most common mutations are class I to III while class IV to VI mutations are rarer. Worldwide, the most common mutation is class II in which there is a deletion of phenylalanine at position 508 in the amino acid sequence of CFTR (DF508). However, its frequency varies between ethnic groups, accounting for 70 per cent of mutations in the white populations of Britain and the US but under 50 per cent in southern European populations.

CFTR mutations are correlated with disease severity.5 Thus, patients with class I to III mutations generally have more severe disease than patients with class IV to VI mutations. Correlations are strongest for pancreatic insufficiency and sweat chloride concentrations. Class I to III mutations are associated with pancreatic insufficiency, while class IV to VI mutations are not. However, CFTR mutation does not correlate well with lung function. Almost all patients have lung disease, but there is wide variability between patients and types of mutation. Such differences suggest that other genes or environmental factors, or both, modify the development, severity and progression of the disease.

Mutations of CFTR are also associated with conditions other than CF. For example, chronic pancreatitis, particularly in the absence of a history of excessive alcohol intake, is associated with an increased frequency of CFTR mutations. Other conditions associated with CFTR include asthma, allergic bronchopulmonary aspergillosis in individuals with asthma, congenital bilateral absence of the vas deferens, disseminated bronchiectasis (abnormal and permanent dilation of the bronchus), neonatal transitory hypertrypsinaemia and diffuse panbronchiolitis. Increasingly, these conditions are labelled “CFTR-related disease”.

Respiratory function

The lungs are the most affected organs in CF and respiratory symptoms the most usual presenting feature. CF is the most common cause of recurrent bronchopulmonary infection in children. Although the lungs of babies born with CF are structurally normal at birth, the genetic defect causes chronic pulmonary infection in the presence of only a few bacterial pathogens. The most common pathogen is Pseudomonas aeruginosa, followed by Staphylococcus aureus, Haemophilus influenzae and Stenotrophomonas maltophilia.6 Burkholderia cepacia complex is another organism that can cause infections. In recent years, non-tuberculous mycobacterium, methicillin-resistant Staphylococcus aureus and the fungus Aspergillus fumigatus have also raised concern.

How mutations in CFTR lead to the development of these infections is unclear and several ideas have been put forward and reviewed.4 One hypothesis is that inflammation is present in the airways of a baby with CF during the first few months of life, and that this predisposes to infection. However, not all experts agree with this, saying that inflammation follows infection. Another suggestion is that normal CFTR is able to bind and kill respiratory pathogens while defective CTFR cannot do this, leaving bacteria free to multiply in the airways. A third hypothesis is that epithelial cells in the airways of patients with CF behave like sweat glands and have high salt concentrations. This reduces bacterial defence with the result that bacteria can multiply on respiratory surfaces, leading to infection. Another proposal is that abnormal sodium and chloride transport in the airway lumen lead to fluid depletion and increased mucus viscosity. Bacteria invading the lung are trapped in this viscous mucus layer in which they encounter favourable growth conditions.

Evidence for all these hypotheses is conflicting and none of them explains all the infections that can occur. What is certain, however, is that the inflammatory response to bacterial and viral infections is exaggerated and extended in patients with CF. Inflammation is present in all patients with lung disease, even in those who are clinically stable and is believed to prejudice the course of the disease. Monitoring of airways inflammation and the effect of anti-inflammatory treatment is, therefore, important, but is difficult because of a lack of reliable non-invasive markers for airways inflammation.

Gastrointestinal function

About 95 per cent of patients with CF have exocrine pancreatic insufficiency. The volume of pancreatic secretion is reduced, leading to the retention and premature activation of digestive enzymes in the pancreatic ducts. This results in significant malabsorption, often characterised by severe steatorrhoea. Malabsorption is exacerbated by pancreatic bicarbonate deficiency. This deficiency reduces the ability to buffer gastric acid reaching the duodenum and also causes pancreatic enzyme inactivation and bile salt precipitation.

During the first few years of the patient’s life the islets of Langerhans are spared from damage with the result that diabetes mellitus is rare during the first decade. However, progressive pancreatic damage leads to an increasing risk of CF-related diabetes with age. Most of these patients have a combination of reduced and delayed insulin secretion with insulin resistance.

CFTR is expressed in cells throughout the gastrointestinal tract. Children can be born with meconium ileus because of the viscosity of meconium in CF. Later in life they may develop distal intestinal obstruction syndrome. This condition develops when viscous secretions result in intestinal obstruction and was formerly known as the meconium ileus equivalent  syndrome. This is an important cause of small intestinal obstruction unique to CF. Other gastrointestinal disorders associated with CF include increased gastro-oesophageal reflux, peptic ulcer, rectal prolapse and gastrointestinal malignancy. Intestinal mucosal transport abnormalities and increased motility of the small intestine may also occur.

About one third of patients with CF have abnormal results of liver function tests with fatty infiltration occurring in about 70 per cent of older patients. Infiltration may progress to biliary cirrhosis with bile duct dilatation, inflammation and fibrosis. Changes in liver and bile salt metabolism may cause cholecystitis (inflammation of the gall bladder) or liver failure or both. Up to a third of patients have a poorly functioning gallbladder and gallstones occur increasingly  with age.

Other dysfunction

Sweat gland function CF results in abnormally high concentrations of sodium and chloride in sweat. This is a diagnostic feature of the disease.

Reproductive function

Puberty is delayed in most patients with CF. Most men are infertile owing to failure of development of the vas deferens and epididymis. Sexual potency and spermatogenesis are normal, and men have become fathers using artificial insemination. In women, fertility tends to be reduced by the presence of thickened mucus in the cervix, but this does not necessarily preclude the possibility of pregnancy. Secondary amenorrhoea may develop as the disease progresses.

Bones and joints

Bones and joints can be affected by CF. Chronic malabsorption increases the risk of osteoporosis, osteopenia and arthropathy.

Nutritional status

The risk of nutritional inadequacy in patients with CF is high. This is because of:

  • Reduced absorption. Pancreatic enzyme insufficiency leads to impaired absorption of fat, nitrogen and fat-soluble vitamins, compromising energy (calorie) balance and nutritional status.
  • Poor appetite. Chronic chest infection causes loss of appetite. Periods of poor food intake increase the risk of energy and nutrient intakes not being met.
  • Increased energy (calorie) requirements. The lung disease associated with CF increases energy requirements because of the increased energy cost involved in breathing and frequent lung infections. Resting energy expenditure increases with the severity of the lung infection. There may also be an increase in energy expenditure resulting from a genetic defect of the disease itself.

Children can be underweight and poor growth can occur, but malnutrition should not be regarded as inevitable. With appropriate management, the effects of malnutrition can be minimised. In older patients, there may be additional nutritional implications as a result of diabetes, liver disease, bone disease, pregnancy or heart-lung transplantation.

Screening

Genetic screening is available for the most common CFTR mutations and this identifies 85–95 per cent of carriers. The chance of detecting a mutation in both members of a couple who are carriers is about 80 per cent. To be affected, a child must inherit a CFTR mutation from both parents. Most couples where one partner is related to someone with CF want to be tested before trying to conceive. Genetic testing is considered to be appropriate if one or both of the prospective parents, or a relative, is a carrier or has the disease.

A programme to screen all newborn babies was introduced in 2004 in the UK, and this programme will be fully implemented in 2006. There is evidence that neonatal diagnosis is linked to improved nutrition and hence increased weight gain, early growth and better prognosis.

Diagnosis

Following the introduction of the neonatal screening programme in the UK, most (but not all) children will be diagnosed shortly after birth.

Clinical signs for diagnosis of CF are shown in the Panel 1. Symptoms usually become apparent in infancy, but with milder mutations now being identified, diagnosis may not be made until later in life. The diagnosis of CF in older children and adults may be difficult. A family history of the disease, recurrent chest infections, the passage of large, pale, greasy, offensive-smelling stools, meconium ileus and failure to thrive in children or undernutrition in adults are suggestive of cystic fibrosis. Other diagnostic features include:7

  • A high sweat sodium concentration (over 60 mmol/L). Results from this test can be difficult to interpret, with false negatives and false positives. Repeated analysis and meticulous analytical technique are essential.
  • A gene defect as identified by blood DNA analysis. However, the CFTR gene is large so a complete analysis of the whole sequence is rarely practical. Indications for this test include a child with a borderline or positive sweat test.
  • Changes in the sinuses and lungs as identified by radiology.
  • Reduced faecal concentration of chymotrypsin or pancrease-specific elastase, which can confirm pancreatic insufficiency.
  • Presence of bacterial pathogens typical for CF (eg, Pseudomonas aeruginosa) which can be detected by analysis of sputum or throat swab samples.
  • Absence of vas deferens and epididymis. However, this can occur without other clinical signs of CF.

Treatment

CF is a life-long illness and requires the care of a multidisciplinary team. In the UK care is provided through a network of specialist centres. Patients should be reviewed every two to three months by a hospital paediatrician with an interest in CF and at least once a year in a specialist tertiary CF centre. A number of different therapies are usually prescribed. Only non-drug therapy will be described here.

Gene therapy

The only potential cure for CF lies in restoration of CFTR function through gene therapy. Since the identification of CFTR in 1989, efforts have been made to deliver copies of the normal CFTR gene, as though it were a drug, to the lungs, which are the most affected yet accessible organs. Both viral vectors and lipid complexes have been used to deliver the gene. Early reports of CFTR transfer both in vitro and in vivo appeared in the early 1990s and confirmed that it is possible to achieve some functional restoration of the defects in ion transport by transgene expression.8

However, an adequate level of gene transfer for disease treatment has not so far been achieved. There are several reasons for this. First, the thick mucus in patients’ lungs forms an effective natural barrier to gene therapy. Secondly, repeat administration of virus vectors leads to formation of specific antibodies. Thirdly, lipid carriers may not specifically target cells that express CFTR. A variety of new technologies, including delivery systems to bypass the mucus and enhancement of vector binding mechanisms are under investigation.8 Progress in this area is slow. Gene therapy is not yet a clinically effective treatment for lung disease in CF, although it remains the most promising possibility for curative rather than symptomatic therapy.

Attention has also been given to ways of bypassing the CFTR protein. The CFTR protein channel is not the only way that cells regulate fluid movement across epithelial surfaces. An alternative chloride channel, normally quiescent in humans, has been identified. This has led to the development of a new class of compounds — P2Y2 receptor agonists — which stimulate this channel in humans by mimicking the activity of adenosine triphosphate (ATP).

Results of studies suggest that these compounds inhibit sodium absorption, restore chloride transport, rehydrate the surface of the airways and increase mucus clearance. Most recently, denufosol tetrasodium (INS37217), a metabolically stable and potent P2Y2 agonist, has been developed and been shown to be well tolerated when given by inhalation.9 This compound may enhance mucus clearance more effectively than previously investigated P2Y2 agonists and a phase II safety and efficacy trial in  patients with mild CF has recently been completed.


Physiotherapy Chest physiotherapy is an integral part of the management of CF. On diagnosis, patients usually begin physiotherapy twice a day. Different techniques are used depending on the patient’s age. The technique needs to be reviewed regularly by a paediatric physiotherapist. Clinical guidelines for the physiotherapy management of CF are available on the CF Trust website (www.cftrust.org.uk)


Oxygen Patients with advanced lung disease and persistently low oxygen saturation may require oxygen therapy. Patients who do not need oxyen at home may need it if travelling by air due to the pressurised cabin environment and subsequent effects. Travellers with CF should check their requirement for oxygen and its availability during the journey and at the destination.


Lung transplantation Lung or heart-lung transplantation should be considered for patients with CF and end-stage lung disease. When to put a patient on the transplant list is difficult to identify. However, a forced expiratory volume in one second (FEV1) below 30 per cent of predicted in a patient receiving maximum medical treatment is considered to be a good indicator for assessment for lung transplantation.4 Overall survival of patients following lung transplant is less than for those with transplants of other organs. In patients with CF, three-year survival is about 60 per cent. Survival is generally better for adults than for children, although survival rates for children are improving.


    Nutritional management


Attention to nutrition is vital in patients with CF. This requires good dietetic management. Nutritional requirements should be carefully assessed and a dietary strategy devised to meet the individual’s nutritional needs and their food preferences. Achievement and maintenance of good nutritional status improves prognosis, helps to realise the potential for growth, reduces the risk of pulmonary infection and optimises lung function. The effectiveness of the diet should be monitored regularly. Monitoring should include assessment of food intake and appetite, adherence to dietary guidance, use of vitamin supplements and oral food supplements, measurement of body weight and, in children, growth parameters. Guidelines on the nutritional management of CF have been produced by the CF Trust (www.cftrust.org.uk)


Energy In patients with CF, dietary energy requirements are usually higher than normal because of the increased energy expenditure arising from malabsorption and lung disease. In the UK, it is recommended that the diet contains 20–50 per cent more than the estimated average requirement (EAR) for energy. For example, the EAR for a boy aged 7–10 years is 8.24 MJ (1,970 kcal)/day. In CF, this could therefore increase to between 9.2 MJ (2,200 kcal) and 10.5 MJ (2,500 kcal)/day. In addition, individual needs will vary. Patients with pancreatic sufficiency may be able to meet their energy needs for growth on the EAR, while those with advanced lung disease and severe malabsorption are likely to need considerably more.


Fat intake Fat intake was at one time restricted as a means of reducing steatorrhoea. However, restricting fat compromises intake of energy and fat-soluble vitamins. Moreover, with the advent of more effective pancreatic enzyme replacement therapy, it is not thought to be necessary. It is usually recommended that the 35–40 per cent of dietary energy comes from fat, but in practice intakes of 30–35 per cent are likely to be achieved.

Now that patients with CF are living longer, care should also be taken in the type of fat consumed and its implications for long-term health. A relatively high-fat diet does not have to contain excessive saturated fat. Foods such as high-fat milk, cream and cheese may be recommended, but fat spreads and oils, for example, can be derived from monounsaturated sources.


Vitamins Vitamin supplements are routinely prescribed for CF patients with pancreatic insufficiency, although the amounts used vary widely. CF does not generally influence the absorption of water-soluble vitamins so routine supplementation is not necessary. However, all CF patients with pancreatic insufficiency are at risk from deficiencies of fat-soluble vitamins and supplements should be taken from diagnosis onwards.

Optimal doses have not been adequately established. It has been suggested that compensatory mechanisms may result in relatively good absorption of vitamins A and E so high doses may not be necessary. Requirements are likely to be highest in those with poorly controlled malabsorption. General guidance on dosage for fat-soluble vitamins is shown in Panel 2. However, requirements will vary according to the degree of pancreatic sufficiency and fat-soluble vitamin status.

No single preparation provides fat-soluble vitamins in appropriate quantities, so regimens must contain a combination of products (eg, vitamin A and D capsules with an additional vitamin E supplement). Whether vitamin K supplements should be given is debatable. Older recommendations suggest not, but many CF patients with pancreatic insufficiency or liver disease have vitamin K deficiency.11,12 In addition, vitamin K has a role in bone metabolism, and osteoporosis and osteopenia are increasingly reported in patients with CF. If vitamin K is to be supplemented, the water-soluble form menadiol should be used as fat-soluble phytomenadione may not be adequately absorbed.

Fully comprehensive multivitamin supplements are unnecessary and may not provide sufficient quantities of individual fat-soluble vitamins. Intake of fat-soluble vitamins from oral nutritional supplements (eg, sip feeds and enteral feeds) should also be considered. Monitoring of plasma levels is advisable.


Minerals and trace elements CF results in abnormally high concentration of sodium in the sweat. Sodium loss will increase further in hot temperatures or during physical exertion. However, salt depletion is only a risk in heatwaves or hot climates. In these circumstances, extra salt or salt supplements may be necessary, but normally there is no need to encourage the consumption of salty food or liberal use of the salt pot.

Serum iron concentrations are often low in patients with CF. Patients should be advised to emphasise iron-rich foods in the diet. Iron supplements are not routinely recommended.


Additional nutritional support Patients are not always able to achieve their dietary energy requirements and supplementary forms of nutrition may be needed. General strategies can be employed to improve poor food intake (eg, increasing meal frequency, choosing calorie dense foods). However, if food intake remains poor, oral supplements (eg, glucose powders or glucose polymer liquids, products containing fat and carbohydrate or sip feeds) may be appropriate, but emphasis should be placed on the use of normal foods rather than supplements.

If energy intake remains continuously inadequate, artificial nutritional support can be provided via nasogastric or gastrostomy/jejunostomy feeding. This is often given overnight and administration may need to be long term (ie, for a period of months or even years).

Enteral feeding usually aims to provide up to 50 per cent of the total energy requirements. However, if daytime food intake is particularly poor, an increased amount of enteral feed is necessary. Adults are usually given whole protein enteral feeds of high energy density (1.5–2 kcal/ml), while children can be given paediatric whole protein feeds providing 1.5kcal/ml. Occasionally, one of the specialist high-fat feeds formulated for people with pulmonary disease may be used. Pancreatic enzymes may be administered at the beginning and end of the feed, but there seems to be wide variation in UK practice regarding administration and assessment of the required dose during enteral feeding.

Low-fat elemental feeds have been favoured because it is thought that they are better absorbed than whole protein feeds. However, they are expensive and tend to have a lower energy density. Some CF centres favour elemental feeds with a high proportion of fat from medium chain triglycerides, and these have been shown to improve weight gain even in patients with advanced lung disease.13 Elemental feeds may be given without pancreatic enzyme replacement because their absorption may be equivalent to that of whole protein formula plus enzyme replacement.11 However, this strategy is controversial.

Parenteral nutrition is usually only indicated in special circumstances, and usually only on a short-term basis, when enteral feeding is contraindicated (eg, in meconium ileus or severe respiratory problems).


Fatty acid supplements Patients with CF have altered plasma levels of fatty acids. Recent research has shown abnormalities in the proportions of arachidonic and docosahexaenoic acids.14 Restoring the balance of these fatty acids has been found to inhibit inflammatory processes and may be beneficial in patients with CF.15,16 However, a recent review concluded that evidence is insufficient to draw firm conclusions.17


    Summary


CF is a common genetic disorder in the UK that causes chronic lung disease and pancreatic dysfunction. The risk of nutritional inadequacy is high. Better management has improved life expectancy, but the disease continues to be associated with considerable morbidity and mortality. Gene therapy offers hope for a cure, but formulations are not yet effective enough to be a viable treatment option. Attention to nutrition is vital and requires good dietetic management.

Citation: Hospital Pharmacist URI: 11091423

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