Ep 223 – Cystic fibrosis

In this episode, Dr Roger Henderson explores cystic fibrosis, a condition that has undergone one of the most remarkable transformations in modern medicine. Once considered almost exclusively a life-limiting childhood disease, cystic fibrosis is now increasingly recognised as a chronic condition extending well into adult life, thanks to major advances in diagnosis, multidisciplinary care and targeted therapies. The episode covers the underlying genetics and pathophysiology, the multisystem nature of the disease and key features of diagnosis and management, along with the revolutionary impact of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. It also considers the continuing importance of holistic, multidisciplinary care and what the future may hold for patients living with cystic fibrosis.

Key take-home points

• Cystic fibrosis is a multisystem autosomal recessive disorder caused by mutations in the CFTR gene, not simply a respiratory disease. Defective CFTR function affects the lungs, pancreas, liver, gastrointestinal tract, sinuses, reproductive system and sweat glands.
• Abnormal CFTR function leads to dehydrated, thick secretions that obstruct ducts and airways. This underlies the characteristic problems of chronic infection, inflammation and progressive organ damage.
• More than 2,000 CFTR mutations have been identified, producing a wide spectrum of disease severity. The commonest mutation, F508del, causes abnormal protein folding and failure of the protein to reach the cell surface.
• The lungs are structurally normal at birth, but disease develops because impaired mucociliary clearance allows thick mucus to accumulate. A vicious cycle of mucus retention, infection and neutrophilic inflammation eventually leads to bronchiectasis and respiratory failure.
• Chronic infection with organisms such as Pseudomonas aeruginosa remains a major determinant of long-term prognosis.
• Pancreatic insufficiency is common and results in malabsorption, poor nutrition and fat-soluble vitamin deficiencies. Progressive pancreatic damage may also lead to cystic fibrosis-related diabetes, which requires specialist management.
• Cystic fibrosis commonly affects other organ systems. Patients may develop meconium ileus, distal intestinal obstruction syndrome, chronic rhinosinusitis, nasal polyps, hepatobiliary disease and reduced fertility.
• Excessive sodium and chloride loss in sweat produces the characteristic salty sweat. This also increases the risk of dehydration and electrolyte imbalance, particularly during exercise or hot weather.
• Newborn screening has transformed early diagnosis and allows treatment to begin before significant organ damage develops. However, clinicians should still recognise later presentations such as recurrent chest infections, bronchiectasis, chronic sinus disease, pancreatic insufficiency or unexplained male infertility.
• Diagnosis is confirmed by demonstrating CFTR dysfunction, with the sweat chloride test remaining the cornerstone of diagnosis. Genetic testing confirms the causative mutations and identifies eligibility for mutation-specific therapies.
• Regular monitoring includes spirometry, imaging and sputum microbiology. Pulmonary exacerbations require prompt treatment with targeted antibiotics, optimisation of airway clearance and supportive respiratory care.
• Comprehensive management extends well beyond drug therapy. Chest physiotherapy, inhaled therapies, pancreatic enzyme replacement, nutritional support, vitamin supplementation and regular exercise all remain fundamental to long-term care.
• CFTR modulators have transformed the treatment of eligible patients by targeting the underlying molecular defect. They improve lung function, reduce pulmonary exacerbations, enhance nutritional status and represent one of the clearest examples of precision medicine in clinical practice.
• Although outcomes have improved dramatically, cystic fibrosis is not cured by current therapies. Lifelong multidisciplinary care remains essential, with lung transplantation reserved for selected patients with advanced respiratory failure.

Key references

1. NICE. 2017. https://www.nice.org.uk/guidance/ng78.
2. Kulkarni H, et al. J Postgrad Med. 2019;65(4):193-196. doi: 10.4103/jpgm.JPGM_263_18.
3. Corriveau S, et al. Curr Opin Pulm Med. 2018;24(6):574-578. doi: 10.1097/MCP.0000000000000520.
4. Conway S, et al. J Cyst Fibros. 2014;13 Suppl 1:S3-22. doi: 10.1016/j.jcf.2014.03.009.
5. Heneghan M, et al. Cochrane Database Syst Rev. 2023;11(11):CD010966. doi: 10.1002/14651858.CD010966.pub4.
6. Somaraju URR, Solis-Moya A. Cochrane Database Syst Rev. 2020;8(8):CD008227. doi: 10.1002/14651858.CD008227.pub4.