Cystic Fibrosis — CFTR Gene, Symptoms, Trikafta Modulators & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene on chromosome 7. The CFTR protein is a chloride ion channel in the apical membranes of epithelial cells lining the airways, gut, pancreas, liver, and sweat glands. Defective or absent CFTR function leads to dehydrated, thick mucus accumulating in the airways and other organ lumens. This sticky mucus causes recurrent bacterial infections and progressive lung damage, exocrine pancreatic insufficiency, CF-related diabetes, hepatobiliary disease, male infertility (absent vas deferens), and salt loss (salty sweat). Over 2,000 CFTR mutations are known; the most common is F508del (Phe508del) — a deletion present in approximately 85% of CF patients in at least one allele.

Cystic fibrosis is caused by inheriting two pathogenic mutations in the CFTR gene — one from each parent (autosomal recessive inheritance). If both parents carry one mutation, each pregnancy has a 25% chance of CF, 50% chance of being a carrier (asymptomatic), and 25% chance of being unaffected. CF carrier frequency in Northern European populations is approximately 1 in 25 — making CF affecting 1 in 2,500 births. CFTR mutations are classified by functional consequence: Class I (nonsense mutations — no CFTR protein produced); Class II (most common — F508del — misfolded protein degraded before reaching cell surface); Class III (gating mutations — protein reaches cell surface but channel does not open — responsive to ivacaftor); Class IV-VI (partial function). The specific mutation class determines which CFTR modulator therapy will be effective. Family history of CF or being a known CF carrier increases carrier risk.

Newborns: detected by newborn blood spot screening (immunoreactive trypsinogen/IRT test) before symptoms develop. Infants: meconium ileus (10-15% — bowel obstruction at birth); faltering growth; salty-tasting skin; malabsorption and steatorrhoea (greasy, foul-smelling stools) from pancreatic exocrine insufficiency. Children and adults — pulmonary: chronic cough with purulent sputum; recurrent chest infections (initially Staphylococcus aureus, then Pseudomonas aeruginosa colonisation — progressive); bronchiectasis; haemoptysis; progressively deteriorating FEV1 (lung function); respiratory failure. Gastrointestinal: malabsorption; fat-soluble vitamin deficiencies (A, D, E, K); distal intestinal obstruction syndrome (DIOS); CF-related liver disease (cirrhosis in 5-10%). CF-related diabetes (CFRD): affects 40-50% of adults with CF — associated with accelerated lung function decline. Male infertility: bilateral absence of vas deferens (azoospermia) in almost all CF males.

Newborn screening: immunoreactive trypsinogen (IRT) test on blood spot sample (Guthrie card) at day 5 of life — positive results lead to DNA analysis for CFTR mutations; confirmed by sweat test. Sweat chloride test (pilocarpine iontophoresis): gold standard diagnostic test — sweat chloride above 60 mmol/L is diagnostic of CF; 30-59 mmol/L is borderline (requires CFTR mutation analysis); below 30 mmol/L is normal. CFTR mutation analysis: genetic panel testing for common CFTR mutations; full CFTR gene sequencing for atypical cases. Diagnosis in older children and adults with atypical presentation: symptoms of CF plus positive sweat test and/or two CFTR mutations. Lung function (spirometry): FEV1 and FVC — annual monitoring of lung function decline is critical. Sputum microbiology: identify colonising pathogens (Pseudomonas aeruginosa, Burkholderia cepacia complex, Stenotrophomonas maltophilia, Achromobacter — guide antibiotic selection). CT chest: documents bronchiectasis distribution and progression.

CFTR modulator therapy — the greatest advance in CF treatment: Trikafta (elexacaftor/tezacaftor/ivacaftor, brand name Kaftrio in Europe) — approved for CF patients aged 2 and above with at least one F508del allele (85% of CF patients); reduces sweat chloride to near-normal, improves FEV1 by 14-15 percentage points, reduces pulmonary exacerbations by 63%, and dramatically improves quality of life and life expectancy. Ivacaftor (Kalydeco) alone — for Class III gating mutations (G551D and others; approximately 5% of CF patients). Airway clearance (chest physiotherapy): twice daily — active cycle of breathing technique (ACBT), oscillating PEP devices (Aerobika, Acapella), Flutter device, autogenic drainage — loosens and clears mucus. Nebulised mucolytics: dornase alfa (Pulmozyme — cleaves extracellular DNA from dead neutrophils, reducing mucus viscosity); hypertonic saline (7%) — draws water into airways, improves mucociliary clearance. Inhaled tobramycin or azithromycin (long-term suppressive antibiotic therapy for Pseudomonas-colonised patients). IV antibiotics for pulmonary exacerbations (2-week courses). Pancreatic enzyme replacement therapy (PERT — Creon capsules with every meal and snack — titrated to stool consistency). Fat-soluble vitamin supplementation (A, D, E, K); high-calorie, high-protein diet. CF-related diabetes: insulin therapy (oral hypoglycaemics generally ineffective). Lung transplantation: considered when FEV1 falls below 30% or rapid decline — bilateral sequential lung transplantation; 5-year post-transplant survival 50-60%.

Without treatment, CF leads to rapid progression of bronchiectasis, respiratory failure, and death in early childhood — prior to the era of modern treatment, most CF patients died before adulthood. Even with treatment, progressive lung disease causes the major morbidity and mortality. Pseudomonas aeruginosa chronic colonisation accelerates lung function decline; Burkholderia cepacia complex infection (particularly B. gladioli and B. cenocepacia) carries significantly worse prognosis and is a relative contraindication to lung transplant. CF-related diabetes causes accelerated pulmonary decline if poorly controlled. Pneumothorax and massive haemoptysis are acute life-threatening complications in adults with advanced CF. Meconium ileus, DIOS (distal intestinal obstruction syndrome), and intussusception require urgent surgical management. With Trikafta, the prognosis for those eligible (F508del) has been dramatically transformed — many are living into their 50s and beyond.

CF cannot be prevented in an affected individual (genetic condition) — but genetic counselling and carrier testing allow families to make informed reproductive decisions. Preimplantation genetic diagnosis (PGD) during IVF allows selection of unaffected embryos. Prenatal diagnosis (chorionic villus sampling or amniocentesis) is available to known CF carrier couples. Optimal daily management for CF patients: twice-daily airway clearance (even when well) — the most important daily self-care activity; take all medications as prescribed (inhalers before physiotherapy, Pulmozyme 30 minutes before); adhere to PERT with every meal; maintain excellent nutrition (high calorie, high protein); exercise regularly — physical activity improves mucociliary clearance and lung health; annual comprehensive CF centre review (lung function, sputum, nutrition, CFRD screening, bone density). Infection control: CF patients should not meet each other (risk of cross-infection with Pseudomonas, B. cepacia); avoid communal CF events; practice strict hand hygiene.

CF is usually diagnosed at birth through newborn screening in the UK and most high-income countries — parents receive prompt referral to a specialist CF centre. See a GP for: unexplained recurrent chest infections in a child (particularly in the first years of life), persistent productive cough not responding to routine treatment, faltering growth or malabsorption, or salty-tasting skin in an infant — these may indicate CF missed by newborn screening or diagnosed in an older child. Seek emergency care for: acute haemoptysis (coughing blood — can be life-threatening in advanced CF), acute respiratory failure or worsening breathlessness, meconium ileus or distal intestinal obstruction syndrome (severe abdominal pain, constipation, and vomiting), and sudden unexpected deterioration. CF patients already receiving specialist care should contact their CF team at the first sign of a pulmonary exacerbation (increased cough, worsening sputum colour/quantity, reduced lung function, fever) — early IV antibiotic treatment prevents further lung damage.