Cystic fibrosis
Description
- Autosomal recessive multisystem exocrinopathy from CFTR dysfunction (chr 7q31)
- CFTR = cAMP-regulated chloride/bicarbonate channel on apical epithelium
- Loss -> dehydrated, acidic, viscid secretions -> obstruction, infection, fibrosis of every ducted organ
Classic vs non-classic
| Classic | Non-classic | |
|---|---|---|
| Sweat Cl | >60 mmol/L | Intermediate (30-59) or normal |
| Pancreas | Insufficient (~85%) | Sufficient; pancreatitis 5-20% |
| Lung | Obstructive from infancy | Variable, later onset |
| Other | Meconium ileus 15-20%, liver disease 5-10%, CBAVD | CBAVD, sinusitis |
- CFTR-related disorders - single-organ phenotypes without full CF: isolated CBAVD, recurrent pancreatitis, disseminated bronchiectasis
Mutation classes - determine which modulator works
| Class | Defect | Example | Modulator |
|---|---|---|---|
| I | No protein (nonsense/frameshift) | G542X, W1282X | None - no protein to modulate |
| II | Misfolded, degraded | F508del (~70% of alleles) | Corrector + potentiator |
| III | Gating | G551D | Potentiator (ivacaftor) |
| IV | Reduced conductance | R117H | Potentiator |
| V | Reduced quantity | 3849+10kbC>T | Potentiator +/- corrector |
| VI | Reduced stability | 4326delTC | Stabiliser |
- I-III = "minimal function", severe, pancreatic insufficient. IV-VI = residual function, milder, often pancreatic sufficient
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