Cystic Fibrosis: CFTR Molecular Pathophysiology
One misfolded chloride channel, a dozen organ-system consequences
CFTR: gene, protein and inheritance
The channel. Cystic fibrosis is an autosomal recessive disease caused by loss of CFTR, the cystic fibrosis transmembrane conductance regulator, encoded on chromosome 7q31. CFTR belongs to the ATP-binding cassette (ABC) transporter family but works as an apical anion channel for Cl− and HCO3−. Opening needs two signals: cAMP-activated protein kinase A phosphorylates its regulatory (R) domain, and ATP binds its two nucleotide-binding domains to gate the pore. CFTR also restrains the epithelial sodium channel (ENaC).
Population genetics. About 1 in 25 people of Northern European ancestry are carriers, making CF the most common lethal autosomal recessive disease in that population. Hardy-Weinberg ties the numbers together: a carrier frequency (2pq) near 1/25 implies an allele frequency (q) near 1/50 and a disease frequency (q²) near 1 in 2,500 births, the same answer as 1/25 × 1/25 × 1/4 for two random partners. Two carriers face a 1 in 4 risk with each pregnancy, and an unaffected sibling of a patient has a 2/3 chance of being a carrier.
Mutation classes
F508del. The most common variant is an in-frame deletion of three nucleotides that removes phenylalanine 508. The protein misfolds, ER quality control retains it, and it is ubiquitinated and degraded by the proteasome, so very little CFTR reaches the apical membrane; any that is rescued also gates poorly. About 85–90% of US patients carry at least one F508del allele.
| Class | Defect | Example | Therapeutic angle |
|---|---|---|---|
| I | No functional protein (nonsense, frameshift, splice) | G542X | Nothing for modulators to act on |
| II | Misfolding, ER retention, degradation | F508del | Correctors plus potentiator |
| III | Reaches the surface but rarely opens (gating) | G551D | Potentiator (ivacaftor) |
| IV | Open pore conducts poorly | R117H | Residual function; often milder |
| V | Too little normal protein | Splicing or promoter variants | Residual function; often milder |
Ion transport pathophysiology
Airways, pancreas and intestine. In these epithelia CFTR secretes Cl− and HCO3− into the lumen and water follows. When CFTR is lost, anion secretion fails while ENaC, no longer restrained, absorbs Na+ excessively and water follows it out of the lumen. The airway surface liquid shrinks, mucus becomes dehydrated and sticky, cilia cannot clear it, and a cycle of chronic infection and neutrophil-driven inflammation begins. The nasal transepithelial potential difference is more negative than normal, reflecting this Na+ hyperabsorption. In the pancreas and gut, missing HCO3− leaves secretions acidic and protein-rich, so they precipitate and plug ducts.
Sweat duct. Here the direction is reversed. Sweat is made isotonic in the secretory coil, and the duct reabsorbs Cl− through CFTR while Na+ follows through ENaC, leaving hypotonic sweat. Without CFTR, chloride cannot be reclaimed and sodium reabsorption falls with it, so sweat stays salty and parents may notice the child tastes salty.
| Tissue | Normal CFTR role | Consequence of loss |
|---|---|---|
| Airway | Cl− and HCO3− secretion; restrains ENaC | Na+ hyperabsorption, dehydrated mucus, bronchiectasis |
| Pancreas | HCO3−-rich fluid flushes enzymes out | Duct plugging, autodigestion, fibrosis, insufficiency |
| Intestine | Hydrates luminal contents | Meconium ileus, distal intestinal obstruction |
| Biliary tree | Dilutes and alkalinizes bile | Inspissated bile, focal biliary cirrhosis |
| Sweat duct | Reabsorbs Cl− (Na+ follows) | Salty sweat, salt depletion |
Diagnosis
- Newborn blood-spot screenelevated immunoreactive trypsinogen (IRT) leaked from obstructed pancreatic ducts
- Second tierCFTR variant panel and/or repeat IRT, depending on the program
- Sweat chloride testpilocarpine iontophoresis: ≥60 mmol/L consistent with CF; 30–59 intermediate; ≤29 unlikely
- Confirmsweat chloride ≥60 mmol/L or two disease-causing CFTR variants, plus a positive screen, family history or compatible features
Screening has made most diagnoses presymptomatic, but older children and adults still present with recurrent sinopulmonary infection, nasal polyps, pancreatitis or male infertility. A child with nasal polyps and a newborn with meconium ileus should both be tested for CF.
Clinical manifestations
Gastrointestinal, endocrine and hepatobiliary
- Meconium ileus in ~15–20% of affected newborns: thick meconium obstructs the terminal ileum, with no meconium passed in the first 48 hours, distension, bilious vomiting and a microcolon on contrast enema. Older patients develop distal intestinal obstruction syndrome (DIOS); toddlers may have rectal prolapse.
- Exocrine pancreatic insufficiency in ~85%: steatorrhea, failure to thrive despite a large appetite, low fecal elastase, and deficiency of vitamins A (night blindness), D (rickets, low bone density), E (hemolytic anemia, neuropathy) and K (bleeding with a prolonged PT). The disease is named for the cysts and fibrosis it leaves in the pancreas.
- CF-related diabetes: islets are destroyed within the fibrotic pancreas, causing insulin deficiency with some resistance in roughly 40–50% of adults; ketoacidosis is uncommon, and annual oral glucose tolerance testing begins at age 10.
- Liver and gallbladder: inspissated bile causes focal biliary cirrhosis, the characteristic lesion, which can progress to multilobular cirrhosis with portal hypertension and varices; neonatal cholestasis and gallstones also occur.
Respiratory
Airways and sinuses. Chronic infection produces upper-lobe-predominant bronchiectasis with daily productive cough, hemoptysis, pneumothorax, digital clubbing and progressive obstructive lung disease; respiratory failure is the leading cause of death. Pansinusitis and nasal polyps are common.
Microbiology. Staphylococcus aureus and nontypeable Haemophilus influenzae predominate in early childhood. Pseudomonas aeruginosa is acquired in adolescence and, once it switches to a mucoid, alginate-producing biofilm, is nearly impossible to eradicate; it is the dominant adult pathogen. Burkholderia cepacia complex spreads between patients, can cause rapid decline with necrotizing pneumonia and bacteremia (cepacia syndrome) and complicates transplant candidacy. Nontuberculous mycobacteria such as M. abscessus also matter.
ABPA. Allergic bronchopulmonary aspergillosis is a hypersensitivity reaction to colonizing Aspergillus fumigatus, not invasive infection: new wheeze, falling FEV1, central bronchiectasis with mucus plugs, eosinophilia, total IgE usually above 1,000 IU/mL and Aspergillus-specific IgE. Treat with systemic corticosteroids, often plus itraconazole.
Mimic. Primary ciliary dyskinesia (e.g., DNAH5 variants, absent dynein arms) also causes bronchiectasis, sinusitis and male infertility, but the sweat test is normal, the vasa are present and sperm are immotile rather than absent.
Electrolytes and reproduction
Salt depletion. Sweat losses of NaCl, especially in infants in hot weather, cause volume depletion with hyponatremia, hypochloremia, hypokalemia and metabolic alkalosis (a pseudo-Bartter picture); routine salt supplementation prevents it.
Fertility. About 98% of men with CF have congenital bilateral absence of the vas deferens (CBAVD): a low-volume, acidic, fructose-poor ejaculate with azoospermia but normal spermatogenesis, so surgical sperm retrieval with ICSI allows biological fatherhood. Milder CFTR variants cause isolated CBAVD in otherwise healthy men, whose partners are offered carrier testing before IVF. Women have thick cervical mucus and reduced fertility.
Treatment
| Therapy | Mechanism | Notes |
|---|---|---|
| Elexacaftor, tezacaftor | Correctors: improve folding and trafficking of F508del CFTR | Always paired with ivacaftor |
| Ivacaftor | Potentiator: raises open probability of CFTR at the membrane | First used for G551D; sweat chloride falls with response |
| Elexacaftor/tezacaftor/ivacaftor | Triple modulator combination | For ≥1 F508del allele; large FEV1 gains; monitor liver enzymes and pediatric lens opacities |
| Dornase alfa | Recombinant human DNase I cleaves extracellular neutrophil DNA | Lowers sputum viscosity |
| Hypertonic saline (7%) | Osmotically rehydrates airway surface liquid | Improves mucociliary clearance |
| Inhaled tobramycin or aztreonam; azithromycin | Suppress chronic Pseudomonas; azithromycin is also anti-inflammatory | Long-term maintenance |
| Pancreatic enzymes, ADEK, salt, high-calorie diet | Replace lost digestive function and electrolytes | Good nutrition tracks with better lung function |
Daily airway clearance (chest physiotherapy, oscillating devices, exercise) underpins care, and lung transplantation is the option for end-stage disease. N-acetylcysteine, which breaks mucin disulfide bonds, is not a standard CF therapy.
Sweat chloride is both the diagnostic test and the biomarker of modulator response: it falls sharply once functional CFTR returns to the sweat duct.
CFTR modulators are CYP3A substrates: strong inducers such as rifampin markedly lower their levels and should be avoided, and strong inhibitors require dose reduction.