22nd February 2024

Cystic Fibrosis

Background

Cystic fibrosis (CF) is a genetic multi-organ disorder. It predominantly affects the lungs in the earlier stages, with subsequent involvement of further organs such as the spleen, pancreas, liver, and intestines. 

Cystic fibrosis is an autosomal recessive inherited disorder with a carrier frequency of 1:22 in the Caucasian population. There are more than >1900 genetic mutations for cyst transmembrane conductor regulator (CFTR) which is the critical culprit protein involved in the pathophysiology and subsequent sequalae of cystic fibrosis.

Pathophysiology

The genetic mutation for CFTR is located on the long arm of chromosome 7 in the region of 7q31.2.  The most common genetic abnormality is deletion of position 508 in the amino acid sequence which results in a defective CFTR protein. CFTR is a channel protein in membranes of cells which produce mucus, sweat, saliva, tears, and the digestive system. The channel is responsible for the transportation of chloride ions across cell membranes.  The mutation alters the secondary and tertiary structure of proteins, leading to a failure of the opening of chloride ion channels in response to elevated cyclic AMP in epithelial cells. This results in decreased excretion of chloride ions, increased absorption of sodium ions and subsequently increased water retention in epithelial cells. Thus, intraluminal secretions have increased viscosity and tenacity. This subsequently leads to chronic bacterial colonisation, causing more repeated episodes of infection. Each infection episode produces more inflammatory cytokines, causing organ parenchymal damage.

References

• Thibodeau PH, Richardson JM 3rd, Wang W, Millen L, Watson J, Mendoza JL, Du K, Fischman S, Senderowitz H, Lukacs GL, Kirk K, Thomas PJ. The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis. J Biol Chem. 2010 Nov 12;285(46):35825-35. doi: 10.1074/jbc.M110.131623. Epub 2010 Jul 28.
• Farrell PM, White TB, Ren CL, et al. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr 2017; 181S:S4.

Presentation

Clinical Features

Respiratory symptoms

Frequent respiratory tract infections are a hallmark of cystic fibrosis patients. CF is the most common cause of bronchopulmonary infection in childhood and a major cause in early adult life. Sinusitis and nasal polyps are common manifestations. Shortness of breath, reduced exercise tolerance, fatigue, chronic productive cough and haemoptysis occur later once airway flow limitation and bronchiectasis develop. Spontaneous and secondary pneumothorax may also occur. Respiratory failure, cor-pulmonale and use of long-term oxygen eventually develop.

Gastrointestinal symptoms

Multiple gastrointestinal organs contain CFTR epithelial channels.

Common gastrointestinal associations with CF:

• Steatorrhea
• Development of diabetes mellitus
• Meconium ileus
• Pancreatitis 
• Fatty liver which can lead to liver cirrhosis
• Chronic malabsorption and maldigestion
• Meconium ileus and bowel obstruction

Other features 

Males are more likely to be affected by infertility due to failure of development of the vas deferens and the epididymis. Females can conceive but are likely to develop secondary amenorrhea as the disease progresses. Osteoporosis can also be found due to skeletal maturity delay and arthropathy can occur later during disease.

CF patients are at increased risk of anaemia. Mechanisms can include dysregulation of iron stores, anaemia associated with chronic disease, increased risk of haemoptysis and potential marrow suppression from immunosuppressives in post-lung transplant patients. CF can also be linked with autoimmune conditions such as rheumatoid arthritis. 

References

• Uijterschout L, Nuijsink M, Hendriks D, et al. Iron deficiency occurs frequently in children with cystic fibrosis. Pediatr Pulmonol 2014; 49:458.
• Grey V, Atkinson S, Drury D, et al. Prevalence of low bone mass and deficiencies of vitamins D and K in pediatric patients with cystic fibrosis from 3 Canadian centers. Pediatrics 2008; 122:1014.
• Merkel PA. Rheumatic disease and cystic fibrosis. Arthritis Rheum 1999; 42:1563.

Diagnosis 

Cystic fibrosis is diagnosed from clinical history and a combination of the following:

• Family history of cystic fibrosis
• Sweat sodium concentration >60mmol/l
• Serum DNA analysis
• Absence of vas deferens and epididymis

Laboratory evidence 

Sweat testing remains the main diagnostic testing for confirmation of CF. DNA analysis can also be undertaken if there is an intermediate sweat test result. The test involves the collection of sweat after pilocarpine inotrophesis and the chemical determination of chloride concentration. 

Radiological evidence 

Patients with CF will commonly present with features of bronchiectasis on a chest x-ray and CT. Areas of consolidation, hyperinflated lung fields, lymph node enlargement and pneumothorax are features of CF which can be seen on CXR. Mucus plugging, bronchial dilatation and pulmonary arterial enlargement secondary to pulmonary hypertension are features which can be visualised on CT. 

References

• Stern RC. The diagnosis of cystic fibrosis. N Engl J Med 1997; 336:487
• Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. Cystic Fibrosis Foundation Consensus Panel. J Pediatr 1998; 132:589.
• Farrell PM, White TB, Ren CL, et al. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr 2017; 181S:S4

Management

Cystic fibrosis management incorporates an array of different strategies. These include conservative management, disease education, regular physiotherapy, antibiotic therapies for exacerbation to direct CFTR modulator therapy and lung transplantation.

CF patients should have an annual pneumococcal, seasonal flu and COVID 19 vaccination to reduce the risk of viral exacerbation. Regular chest physiotherapy, including postural drainage, helps with mucus expectoration. Regular prescription of beta 2 agonists and inhaled corticosteroids provide symptomatic relief and reduce the propensity for future exacerbations. Regular antibiotic therapy such as azithromycin has been shown to be effective against particular bacterial colonisation such as Pseudomonas Aeruginosa. 

Regular input from multidisciplinary teams is essential in the management of CF patients. Dietitians work closely to reduce growth impedance by addressing nutritional deficiencies due to secondary organ involvement, i.e. pancreatic insufficiency, reduced gut motility, etc. Physiotherapists and occupational therapists work closely to ensure mobility optimisation and aids which help with adaptation at home. 

Psychologist and psychiatry input is paramount as CF patients are oftentimes young with chronic long term sequalae, affecting multiple organs and reducing the negative impact from a psychological perspective. 

Patients with severe disease are considered for the lung/liver transplantation register provided there are no significant contraindications such as solid organ/ haematological malignancies, raised BMI (>35), advanced dysfunction of any other major, lifestyle risk factors including excessive alcohol consumption, smoking or use of illicit substances or non-compliance with medication therapies. Relative contraindication considers age above 60, end organ damage including chronic kidney disease, heart failure, diabetes and need for mechanical ventilation support.  Overall outcomes for lung/liver transplantation are encouraging with 5-year survival >60% and 10-year survival >50%.

References

• Meachery G, De Soyza A, Nicholson A, et al. Outcomes of lung transplantation for cystic fibrosis in a large UK cohort Thorax 2008;63:725-731.
• Weill D. Lung transplantation: indications and contraindications. J Thorac Dis. 2018 Jul;10(7):4574-4587. doi: 10.21037/jtd.2018.06.141.