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Carol White is a 10-year-old with cystic fibrosis that was diagnosed soon after birth by the paediatrician performing a sweat test, which was found to contain a high amount of sodium chloride. Genetic analysis confirmed this result. She has had recurrent problems with chest infections despite her regime of physiotherapy, inhaled drugs, special diet and courses of antibiotic when infections occur. She is monitored to ensure that the appropriate anti-microbial drug is given. She is managed by the local CF Paediatric Unit, where the specialist multidisciplinary team is based. Their energetic treatment of her infections aims to minimise lung damage, which is monitored by means of regular CT scans.
Her mother is expecting another child and Carol wonders if her new brother or sister will have CF. Her parents had been to see a genetic counsellor who suggested prenatal diagnosis.Carol's classmates don't understand why she coughs so much and doesn't play and run around with them, and she feels 'left out'. She often worries about how long she will live and whether she will ever have children of her own.
What is Cystic Fibrosis?
What are the causes of Cystic Fibrosis?
What are the symptoms of Cystic Fibrosis?
How is Cystic Fibrosis diagnosed?
What treatments are available for Cystic Fibrosis?
How is Cystic Fibrosis prevented?
What are the psychosocial aspects associated with Cystic Fibrosis?
Cystic Fibrosis (CF) is a lethal autosomal recessive disease; the most common amongst the Caucasian population (Kumar & Clark, 2009). It causes abnormal salt and water movement across mucosal epithelia, rendering mucus secretions abnormally viscous. A multisystem disorder; CF affects numerous organs. However, it is characterised by the primary clinical manifestations of recurrent endobronchial infections, chronic pulmonary obstruction and pancreatic dysfunction. There is no cure for CF, and sufferers have a median survival of approximately 37 years.
Genetics of CF
CF is caused by a faulty gene that encodes the cystic fibrosis transmembrane regulator (CFTR) protein. The pattern of inheritance is described in Figure 1:
Figure 1: The inheritance pattern of cystic fibrosis
Cystic Fibrosis gene
The CFTR gene is located on the long arm of chromosome 7; region 7q31.2, and consists of 27 exons (Kumar & Clark, 2009). The amino acid sequence and its resultant structural features, places CFTR in the ATP-binding cassette transporters gene superfamily (Gadsby et al, 2006). The structure is shown in Figure 2:
Figure 2: Structure of CFTR
The CFTR consists of 1480 amino acids, creating a single polypeptide chain with 5 functional domains. It contains 2 nucleotide-binding domains (NBD1 & 2) for ATP hydrolysis, which are responsible for channel gating. 12 membrane-spanning alpha helices (grouped into 2 transmembrane domains), contribute to creating the CL conductance pore. An intracellular regulatory domain (R-domain) provides the site for phosphorylation, thus regulating activation of CFTR (Rowe et al, 2005).
Inserted within the plasma membrane; CFTR acts as a critical chloride ion (Cl-) channel, controlling the bi-directional flow of Cl-. Given this, CFTR modulates transport of salt and water (by osmotic diffusion) across epithelial membranes. In addition to regulating Cl- conductance, CFTR exhibits roles in regulation of Na+ transport via the epithelial sodium channel (ENaC), calcium activated chloride channels (CACC), potassium channels (ROMK1) and the chloride/bicarbonate exchanger (Rowe et al, 2005).
More than 1500 CFTR mutations have been shown to cause CF; most being substitutions or deletions of DNA bases. Mutations can be classified into 6 groups, according to their effects on CFTR (Fig. 3):
Figure 3: 6 classes of mutation of CFTR
Class I: Defective protein synthesis (truncated translation); Class II: Abnormal processing & trafficking (leading to premature degradation); Class III: Defective activation / regulation (e.g. reduced ATP hydrolysis); Class IV: Decreased conductance/gating; Class V: Reduced surface expression of CFTR (due to abnormal promoter/splicing); Class VI: Reduced membrane residence time (due to C-terminus abnormalities) (Rowe et al, 2005; Sloane & Rowe, 2010)
The most common mutation causing CF (approximately 70% in UK), is the deletion of 3 base pairs encoding the amino acid: phenylalanine. This occurs at position 508 in the AA sequence, and is therefore denoted âˆ†F508. This causes the CFTR protein to fold aberrantly, preventing maturation in the ER and initiating premature degradation (Class II). The CFTR therefore fails to reach the plasma membrane. Those who are homozygous for the âˆ†F508 mutation exhibit the most severe form of CF, as there is significantly defective absence of epithelial Cl- conductance.
Pathophysiology of CF
The location of the CFTR determines where symptoms occur. The primary sites of pathogenesis are as follows:
Skin - Sweat Gland
The mechanism of normal salt reabsorption in sweat glands, and the pathophysiology associated with CF is shown in Figure 4.
Figure 4: Sodium chloride reabsorption in the normal and CF sweat gland
In the normal sweat gland (B), sweat is transported to the skin surface via ducts (exocrine). Na+ and Cl- are reabsorbed at the distal end of the duct, passing through the ENaC and CFTR in the apical epithelial membrane respectively. It is important to note that the CFTR has a stimulatory effect on ENaC in sweat glands. Therefore, movement of Cl- intracellularly is closely followed by inward movement of Na+ in order to maintain electrical equilibrium. However, in the CF sweat gland (C) the CFTR is defective. Cl- transport is significantly reduced in combination with a down-regulation of ENaC, which virtually eliminates Na+ absorption. Ultimately, the reabsorption of NaCl is ineffective, leading to a high sweat salt content in CF patients (Rowe et al, 2005).
Precise regulation of the volume of liquid on airway surfaces is critically important. In the respiratory tract, cilia are surrounded by airway surface liquid (ASL) which comprises a periciliary liquid layer (PCL) and an overlying mucus layer. PCL provides a low viscosity environment for cilial beating (thus mucus propulsion), while the mucus layer traps inhaled pathogenic material (Donaldson & Boucher, 2007). Hydration status is vitally important for efficient mucociliary and cough clearance (Knowles & Boucher, 2002). Given that CFTR and ENaC regulate salt (and water) movement across the epithelial membrane, these channels are responsible for regulation of PCL and mucus layer hydration.
The mechanism of salt movement across normal and CF airway epithelium is shown in Figure 5:
Normal Airway Epithelium
CF Airway Eptihelium
Alt. Cl- channel
Figure 5: Chloride and Sodium movement across the normal and CF airway epithelium
In the normal airway, there is a balance between Na+ absorption through ENaC and Cl- secretion through CFTR (and alternative CL- channels). This maintains the ASL volume and hydration status. In CF, the majority of Cl- secretion across the airway epithelium is lost to due to defective CFTR. The defective CFTR is also unable to down-regulate ENaC. Consequently, Na+ transport out of the ASL proceeds at an unregulated rate, with concomitant osmotic diffusion of water. This results in a decreased ASL volume and mucus dehydration, which increases the viscosity of mucus and adversely affects airway clearance.
Similarly as in the lungs, absence of the normal CFTR causes mucus dehydration and resultant obstruction in pancreatic ducts. Moreover, the CL/HCO3 exchanger experiences a loss of function due to the defective CFTR (as it has a regulatory role), therefore reducing bicarbonate secretion.
What are the symptoms of CF?
Upper respiratory tract symptoms include sinusitis and nasal polyps. However, pulmonary problems are the principal factor in causing disability and death in CF patients.
Recurrent bronchopulmonary infections are common. Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia and Haemophilus influenza are particularly prevalent, due to static airway secretions (Rowe et al, 2005). Pseudomonas aeruginosa is the primary bacteria responsible for causing lung tissue injury. It causes increased production of mucin, providing nutrients for the bacterium and further clogging the airways (Marieb & Hoehn, 2010).It also forms large colonies (biofilms); preventing destruction by neutrophils, and produces large amounts of alginate matrix; permitting adhesion to damaged epithelial surfaces. These features make it particularly difficult to eradicate (Kumar & Clark, 2009).
Inflammation is also responsible for compromised lung function and facilitates bacterial infection. Neutrophils in mucus release lysosomes to digest bacteria, however, neutrophil elastase (a lysosome component) causes significant damage to lung tissue. Such damage is accompanied by an increase in mucus secretion, ciliary dyskinesia, and increased binding of Pseudomonas aeruginosa to airway epithelium (Rowe et al, 2005; Kumar & Clark, 2009). Inflammatory mediators are also released, promoting damage and scarring. Chronic inflammation and mucus obstruction leads to bronchiecstasis; chronic permanent dilation of the bronchioles.
As damage progresses, patients may suffer from chronic hypoxia, dyspnoea, haemoptysis, and eventually complete respiratory failure.
More than 85% of CF sufferers have pancreatic dysfunction due to mucus impaction and viscous secretions, which cause chronic fibrosis and pancreatitis (Rowe et al, 2005).Consequent inability to produce pancreatic enzymes render malabsorption and maldigestion common, causing 'failure to thrive' in children, poor weight gain and fat soluble vitamin deficiency. CF sufferers also often present with steattorrhoea (high levels of faecal fat) and meconium ileus at birth. Reduced fat emulsification results in an increased level of circulating cholesterol, increasing the prevalence of cholesterol gallstones. Sufferers may also experience liver cirrhosis (due to chronic obstruction of bile canaliculi) and gastrointestinal malignancy.
Additional symptoms may include; CF-related diabetes, male infertility (obstructive azoospermia) due to deterioration of the vas deferens and epididymis in utero, amenorrhea (no periods) in females, cor pulmonale, diabetes mellitus, decreased bone mineral density and delayed puberty and skeletal maturity (Kumar & Clark, 2009).
How is CF diagnosed?
Diagnosis of CF is based primarily on clinical presentation and familial history. However, this is supported by CFTR function tests, genetic analysis and radiological imaging (Castellani et al, 2008). The key tools for diagnosing CF are:
CFTR mutation analysis
The CF gene mutation panel tests the most common CFTR gene mutations, and is routine for evaluation of CF or carrier status. Ethnicity must be considered when selecting the mutation range, as there are population differences in mutation detection and mutation frequencies (Mishra et al, 2005).
Prenatal diagnosis may be used to help inform reproductive decisions. This is based on CFTR mutation analysis, and may be performed by chorionic villus sampling in the first trimester or amniocentesis in the second/third trimester (Mishra et al, 2005).
Usually by the heelstick method, a blood sample is taken from the newborn for analysis using the Immunoreactive Trypsinogen (IRT) test. Elevated levels of trypsinogen, the precursor of the pancreatic enzyme trypsin, indicates CF. However, this may be due to pancreatitis or pancreatic cancer (false positive), therefore verification is required (Kumar & Clark, 2009).
This test is regarded as the 'gold standard' in confirmation of CF diagnosis (Taylor et al, 2009). Pilocarpine is used to stimulate localised sweating in the flexor of the forearm, allowing sample collection for analysis. This may be difficult in newborns, as an adequate sweat sample must be provided for reliable diagnosis (Mishra et al, 2005; Kumar & Clark, 2009). The reference ranges for CF diagnosis are shown below in Table 1:
Table 1: Sweat chloride concentration ranges (Mishra et al, 2005)
Computed tomography (CT) scanning provides a detailed cross-sectional picture of the body, and is particularly useful for visualising organs and tissues. Chest CT scans look for hallmark signs of bronchiecstasis and airway obstruction, while sinus CT scans indicate mucus filled sinuses and nasal polyps (Kumar & Clark, 2009).
X-Rays of the lungs can be used to visualise hyperinflation, areas of pulmonary collapse, and consolidation associated with infection. Ultrasonography may be used to detect foetal echogenic bowel, which indicates meconium ileus (Mishra et al, 2005).
This test is used for detection and identification of bacterial infection in the respiratory tract and lungs. Approximately 80% of CF patients show a positive result for Pseudomonas aeruginosa (Kumar & Clark, 2009).
What treatments are available for CF?
CF requires comprehensive multidisciplinary management, and patients are often referred to specialised CF centres for medical and psychosocial therapy.
The current medical treatments available for CF are extensive, and are summarised in Table 2:
Table 2: Summary of medical treatments currently used for Cystic Fibrosis patients
Mode of administration
Kills S. aureus & P. aeruginosa
Kills Staphylococcus aureus
Kills Pseudomonas aerugniosa
Oral, Inhaled, Intravenous (for severe exacerbations & P. aeruginosa infection)
Dornase alfa (Pulmozyme)
Recombinant human DNase hydrolyses DNA in mucus/sputum, reducing viscosity and facilitating clearance
Î²2-agonists e.g. Salbutamol
Relieves bronchospasm by dilating bronchi and bronchioles, reducing airway resistance and facilitating airflow
Anti-inflammatory: reduces symptoms of bronchiolitis, bronchospasm, & paranasal sinus inflammation
Oral, Inhaled, Topical
Pancreatic Enzyme Supplements
Enteric-coated enzymes e.g. Pancrelipase
Counter-acts the effects of pancreatic dysfunction: malabsorption and maldigestion.
Chest Physical Therapy
CF patients are encouraged to perform chest physical therapy (CPT) for 20-40 minutes, at least twice daily. CPT involves a range of techniques for facilitating airway clearance, performed by a trained physiotherapist, carer or patients themselves. The techniques used are postural drainage and percussion/vibration.
Postural drainage involves placing the body in a position whereby gravity aids clearance of airway secretions from the lungs (see Figure 6). Percussion can be achieved by 'chest clapping', using a cupped hand on designated positions on the thorax (Figure 6). Vibration is achieved manually, or by mechanical device (e.g. high frequency chest wall oscillation device). The latter two techniques help to loosen and mobilise mucus in the airways. Figure 6 shows recommended CPT positions:
Figure 6: Chest Physical Therapy positions (uwhealth.org)
Patients require a high number of calories and an increased protein and fat intake as part of their diet (30-50% more than normal). Meal enhancement and supplemental IV feeding are common. This promotes normal growth patterns and weight gain. Moreover, due to the reduced secretion of pancreatic lipase, supplemental fat-soluble vitamins (A, D, E, K) are required to prevent deficiency.
Social Implications of living with CF
Living with a chronic illness is challenging, both physically and emotionally. Patients may experience feelings of isolation, depression, and stress. Stigma associated with progressive, incurable, and poorly understood diseases may exacerbate such feelings. Children are particularly vulnerable, especially without appropriate education of peers about CF.
In addition, rigorous daily treatment regimens may cause issues with compliance, especially in adolescents. Such time commitment and emotional investment may also be detrimental for families living with CF, for example siblings may feel that parental attention is unequally distributed.
Certainly, reproductive decisions for those who are carriers of CF or with a familial history have particularly important implications. Such individuals should be referred to a genetic counsellor in order to be presented with accurate facts about the disease, its heritability, and the types of genetic tests available/appropriate. Pre and post-test genetic counselling, psychosocial evaluation, and follow-up are all integral to the process.
Conclusion & Future Implications
CF is a chronic multisystem disease that severely impacts patients' lives. Symptoms are myriad and range in severity, primarily affecting the respiratory tissue and gastrointestinal tract. Current treatment is extensive, including medical intervention, physical therapy, and tailored nutrition. These are not mutually exclusive; patients are often required to adhere to a strict daily regimen including all treatments. These factors often impact the psychosocial state of patients and their families. In order to effectively manage CF and all of its biopsychosocial elements, there should be comprehensive reciprocal involvement of the MDT, the patient, and support networks.
Currently, there are a number of studies exploring treatment strategies to facilitate mucociliary clearance by restoring ASL and hydrating mucus secretions, while bypassing the mutated CFTR (Sloane & Rowe, 2010). These include activating alternative Cl- channels, inhibiting ENaC hyperabsorption of Na+, and replacement of the faulty CFTR gene using gene therapy (Davies & Alton 2010; Sloane & Rowe, 2010). In combination with improving CF care, such therapeutic advances may provide a brighter future for the CF patient.