Cystic fibrosis Study Guide

📖 Core Concepts Autosomal recessive inheritance – two defective CFTR alleles are required for disease. CFTR protein – a chloride channel on epithelial cells; its loss reduces Cl⁻ secretion and water movement, leading to thick mucus. Mutation classes I: no protein (nonsense/frameshift) II: misfolded protein, degraded (e.g., ΔF508) III: gating defect – protein reaches membrane but won’t open IV: reduced conductance V: reduced synthesis Key organ effects – dehydrated airway surface liquid → poor mucociliary clearance → chronic lung infection; pancreatic duct blockage → exocrine insufficiency; salty sweat (Cl⁻ > 60 mEq/L). CFTR modulators – potentiators (increase channel opening) and correctors (help protein reach the membrane). Mainstay of care – airway clearance, infection control, nutrition, and organ‑specific therapy. --- 📌 Must Remember ΔF508 accounts for 70 % of cases worldwide (≈90 % in the U.S.). Sweat chloride diagnostic threshold: > 60 mEq/L (pilocarpine iontophoresis). Carrier risk: 25 % chance of an affected child when both parents are carriers. Life expectancy: median 40–50 years in developed countries; trending toward 59 years in the U.S. Antibiotic indications: any pulmonary exacerbation or documented decline in FEV₁. CFTR modulators efficacy: Ivacaftor → ≈10 % ↑ FEV₁ in responsive mutations. Lumacaftor/ivacaftor, tezacaftor/ivacaftor → improve ΔF508 processing. Elexacaftor/tezacaftor/ivacaftor (Trikafta) → treats ≈90 % of patients, ↓ exacerbations 63 %, ↓ sweat Cl⁻ 41.8 mmol/L. Pancreatic insufficiency occurs in 85–90 % of patients with severe (Class I–II) mutations. Male infertility: ≥97 % have congenital bilateral absence of the vas deferens (CBAVD). --- 🔄 Key Processes Defective ion transport Loss of CFTR → ↓ Cl⁻ secretion → water stays in cells. Unopposed ENaC ↑ Na⁺ reabsorption → water pulled from airway surface liquid (ASL). Mucus dehydration cycle ↓ ASL → thick mucus → impaired ciliary beating → bacterial colonization → inflammation → further mucus production. Pancreatic duct obstruction Thick secretions block ducts → ↓ bicarbonate + enzymes → malabsorption (steatorrhea, fat‑soluble vitamin loss). Sweat gland failure CFTR normally reabsorbs Cl⁻; its loss → high Cl⁻ in sweat → salty skin. --- 🔍 Key Comparisons Class I vs. Class II – No protein produced vs. misfolded protein degraded. ΔF508 (Class II) vs. Gating mutations (Class III) – Misfolding vs. functional protein that won’t open. Inhaled vs. Intravenous antibiotics – Inhaled → high airway concentrations, lower systemic toxicity; IV → needed for severe exacerbations or organisms not cleared by inhaled agents. Ivacaftor vs. Lumacaftor/ivacaftor – Potentiator (opens channel) vs. corrector + potentiator (helps ΔF508 reach membrane then open). --- ⚠️ Common Misunderstandings “CF is a lung disease only.” – It is multisystem; pancreas, liver, sinuses, sweat glands, and reproductive organs are all affected. “All patients benefit from any CFTR modulator.” – Efficacy depends on mutation class; e.g., ivacaftor works only on gating mutations. “Positive sputum culture = always treat.” – Chronic colonization may be suppressed rather than eradicated; treatment decisions rely on clinical decline and culture results. “High‑dose pancreatic enzymes cure malabsorption.” – Enzyme timing with meals and adequate acid suppression are also essential. --- 🧠 Mental Models / Intuition “Water‑Salt‑Mucus” triangle: Think of CF as a balance sheet where loss of CFTR (salt) leads to water loss from the airway surface → thick, sticky mucus → infection. Restoring any side (salt transport, water, mucus clearance) improves the whole system. “Mutation‑Specific Prescription” – Match the drug class to the mutation class (potentiator → Class III, corrector → Class II). --- 🚩 Exceptions & Edge Cases Rare mutations – May be missed by standard panels; full sequencing required when phenotype strongly suggests CF. Burkholderia cepacia complex – No proven benefit from antibiotics; infection control is critical. Cystic fibrosis–related diabetes – Presents with features of both type 1 and type 2; insulin is preferred over oral agents. CFTR modulators + CYP3A inducers – Carbamazepine reduces plasma levels → avoid concomitant use. --- 📍 When to Use Which Airway clearance: Baseline: Chest physiotherapy + oscillatory device. If sputum is thick: Add hypertonic saline (3–7 %). If sputum viscosity persists: Add dornase alfa. Antibiotics: New exacerbation: Obtain sputum culture → start IV antibiotics (based on sensitivities). Chronic P. aeruginosa: Long‑term inhaled tobramycin or aztreonam. MRSA: Early oral/IV therapy; consider inhaled options. CFTR modulators: Class III gating mutation: Ivacaftor alone. ΔF508 (homozygous): Lumacaftor/ivacaftor or tezacaftor/ivacaftor; consider triple therapy if ≥1 ΔF508 allele. Pancreatic insufficiency: All patients with steatorrhea: Start pancreatic enzyme replacement with each meal. If vitamins low: Supplement A, D, E, K. --- 👀 Patterns to Recognize Early lung pathogens → age: <10 y → Staph aureus / H. influenzae; >10 y → Pseudomonas aeruginosa dominance. Sweat chloride > 60 mEq/L consistently across repeat tests → diagnostic of CF (unless secondary causes). Recurrent sinus infections + nasal polyps → clue to underlying CF in adolescents/adults. Failure to thrive + bulky, foul stools in infants → pancreatic insufficiency. --- 🗂️ Exam Traps “CF is autosomal dominant” – Wrong; it is recessive. “All CF patients have pancreatic insufficiency.” – Not true; milder mutations (Class IV‑V) may retain some function. “Elevated sweat chloride alone confirms CF.” – Must be ≥60 mEq/L on two occasions; borderline values need genetic confirmation. “Inhaled antibiotics eradicate P. aeruginosa.” – They suppress colonization; eradication requires aggressive early therapy, often combined with oral agents. “CFTR modulators cure CF.” – They improve function but do not correct the underlying genetic defect. ---