309.3 🏥 內科專科考前版

309.3.1 Mechanistic Deep Dive

309.3.1.1 CFTR Structure + Function

  • Membrane-spanning protein
  • Two transmembrane domains
  • Two nucleotide-binding domains (NBD1, NBD2)
  • Regulatory R domain
  • ATP-driven Cl- channel + indirect HCO3- regulation
  • Regulates other channels (ENaC inhibition, ORCC)

309.3.1.2 Mucus Pathology

  • Dehydrated airway surface liquid (ASL)
  • Impaired ciliary function
  • Mucus plug formation
  • Bacterial trapping
  • Chronic inflammation

309.3.1.3 Inflammation in CF

  • Even before infection — primary inflammatory state
  • Neutrophil-dominant
  • NF-κB pathway hyperactivation
  • IL-8 secretion
  • Persistent + dysregulated

309.3.2 Recent Trials & Updates

309.3.2.1 VX-661-103, VX-440-103 (ETI Trials, 2019)

  • Phase 3 trials
  • F508del homozygous + heterozygous + multiple genotypes
  • Improved FEV1 (10-15%)
  • Reduced exacerbations (60%)
  • FDA approval 2019

309.3.2.2 ETI Expanded Indications (2023-2024)

  • Younger ages (2-5 yo)
  • Broader mutation panel
  • Reduced age criteria

309.3.2.3 CFRD GLP-1 + SGLT2i Trials

  • Limited data
  • Mostly insulin
  • Future role unclear

309.3.2.4 Gene Therapy CF

  • AAV-based, lentivirus
  • Multiple trials
  • Limited durability
  • Continued investigation

309.3.2.5 CRISPR CFTR Repair

  • Preclinical / early phase
  • Ex-vivo edits possible
  • In-vivo lung delivery challenging

309.3.2.6 Organoid-Based Therapy Selection

  • Intestinal organoids from rectal biopsy
  • Test CFTR modulator response
  • Personalize therapy
  • Especially for rare mutations

309.3.3 High-Yield Specialist Points

309.3.3.1 Sweat Test (Pilocarpine Iontophoresis)

  • ≥ 60 mmol/L: positive
  • 30-59 mmol/L: borderline (repeat + further workup)
  • < 30 mmol/L: CF unlikely (note: < 40 in children, < 30 in adults)
  • Adequate sweat volume needed (≥ 75 mg)
  • Specialized lab

309.3.3.2 Atypical CF Presentations

  • Recurrent pancreatitis (CFTR-related)
  • Idiopathic bronchiectasis adult
  • Male infertility (CBAVD)
  • Chronic rhinosinusitis without lung disease
  • Sweat chloride may be intermediate
  • Single CFTR mutation + clinical features

309.3.3.3 Adult CF Care

  • Separate adult center
  • CFRD screening annual
  • Liver disease surveillance
  • Bone health
  • Cancer surveillance (colon)

309.3.3.4 CF Pulmonary Exacerbation Treatment

  • IV antibiotics 2-3 weeks
  • Based on prior cultures
  • Pseudomonas: combination β-lactam + aminoglycoside
  • Tobramycin once-daily preferred
  • Cefepime, pip-tazo, ceftolozane-tazobactam
  • Avoid aminoglycoside in severe ototoxicity history

309.3.3.5 Vest Therapy (HFCWO)

  • Mainstay airway clearance
  • 2-3x daily
  • Insurance-covered in US for CF

309.3.3.6 Dornase Alfa (Pulmozyme)

  • Recombinant DNase
  • Reduces sputum viscosity
  • Daily nebulized
  • Improved FEV1

309.3.3.7 Hypertonic Saline 7%

  • Restores airway hydration
  • ↓ Exacerbations
  • BID nebulized

309.3.3.8 Mannitol (Bronchitol)

  • Osmotic agent
  • Alternative airway clearance
  • Less common in US

309.3.3.9 Lung Transplantation

  • BMI > 17, FEV1 < 30%, hypoxia, hypercapnia, hospitalizations
  • 5-year survival 60-70%
  • B. cepacia complex exclusion at many centers
  • Bilateral lung transplant

309.3.3.10 Future Directions

  • ETI universal? Or replacement gene therapy?
  • mRNA therapy
  • Pulmonary microbiome modulation
  • Anti-inflammatory beyond modulators

309.3.4 Pearls

  • CF: autosomal recessive, CFTR mutation; F508del most common
  • Multi-organ disease: lung + pancreas + GI + liver + sweat + reproductive
  • Diagnosis: sweat chloride ≥ 60 + clinical + genetic
  • CFTR modulators revolutionary: ETI (Trikafta/Kaftrio) covers ~ 90%
  • Pediatric pathogens: S. aureus → adolescent Pseudomonas → adult Pseudomonas + NTM
  • B. cepacia worst — may exclude from transplant
  • Survival: ≥ 60 for newborns now (vs 30s pre-modulator era)
  • CFRD: combined insulin deficiency + resistance; CGM; insulin