Cystic Fibrosis Detailed

Cystic Fibrosis (CF) – Detailed Overview 1. Introduction Cystic Fibrosis (CF) is a hereditary disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. - Autosomal recessive single-gene disorder. - Two copies of the mutated gene required for disease manifestation. 2. Genetics • Chromosome: 7 • Inheritance: Autosomal recessive • Mutation Classes: • Class 1: Premature stop codon → no protein. • Class 2: Misfolded protein → abnormal processing. • Class 3: Impaired regulatory function → defective channel gating. • Class 4: Impaired conducting function. • Class 5: Reduced protein quantity. • Class 6: Unstable CFTR protein. 3. CFTR Structure & Function • Structure: ABC transporter, 5 domains (Regulatory, 2 Transmembrane, 2 Nucleotide-binding) • Location: Apical membranes of epithelial cells • Function: Chloride transport, regulation of secretions • Sodium Role: ENaC channels work with CFTR; CFTR defect → dehydrated mucus 4. Pathophysiology 1. CFTR dysfunction → thick mucus 2. Mucus retention → obstruction 3. Bacterial colonization → chronic infection 4. Immune response → neutrophils → tissue damage → bronchiectasis Triangle of CF: Obstruction – Infection – Inflammation 5. Organ Systems Affected 5.1 Gastrointestinal & Pancreas • Thick mucus blocks pancreatic secretions • Symptoms: poor growth, bloating, constipation/diarrhea • Complications: DIOS, GORD • Treatments: pancreatic enzymes, laxatives, antacids, proton pump inhibitors 1 5.2 Lungs • Sticky mucus traps bacteria • Symptoms: cough, wheezing, SOB, infections • Mucus composition: mucins, lipids, proteins, DNA • Mucociliary clearance impaired Common Microbes: - Early: Staph aureus, H. influenzae, Strep pneumoniae - Later: Pseudomonas aeruginosa, Burkholderia cepacia - Fast-decline: MRSA, Mycobacterium spp. Biofilm Formation: protects bacteria → chronic infection 5.3 Other Organs • Sweat glands → salty sweat • Reproductive system → male infertility • Liver → biliary plugging, hepatomegaly (ursodeoxycholic acid treatment) • Pancreas → CF-related diabetes (insulin) 6. Diagnosis • Carrier testing, antenatal testing, newborn screening (IRT heel prick) • Confirmation: genetic testing, sweat test • Clinical signs: meconium ileus, recurrent cough, steatorrhea • Early detection: limits lung damage, improves nutrition • Downsides: false positives, ethical issues 7. Management & Treatments 7.1 Respiratory • Prophylactic antibiotics: • Step 1 (G+ Staph aureus): Flucloxacillin, Trimethoprim • Step 2 (G- H. influenzae): Amoxicillin, Cefaclor • Step 3 (G- P. aeruginosa): Nebulised colistin/tobramycin • Acute infection: oral/IV antibiotics based on sensitivity • Nebulised therapy: bronchodilators, hypertonic saline 7%, recombinant DNase 7.2 Gastrointestinal & Nutritional • High-calorie diet, enzyme supplements, fat-soluble vitamins (A, D, E, K) • Salt supplements for hyponatremia 7.3 Pancreatic Complications • Pancreatic enzymes (Creon) 2 7.4 Liver Complications • Ursodeoxycholic acid 7.5 CFTR Modulators • Ivacaftor: potentiator → enhances CFTR function • Orkambi (Lumacaftor/Ivacaftor): corrector + potentiator 7.6 Diabetes • CF-related diabetes → insulin therapy 7.7 Allergic Bronchopulmonary Aspergillosis • Diagnosis: symptoms, IgE, sputum culture • Treatment: prednisolone ± itraconazole 8. Summary of Pathophysiology 1. CFTR mutation → impaired chloride transport 2. Thick, dehydrated mucus → obstruction 3. Impaired clearance → bacterial infection 4. Immune response → inflammation → lung damage 5. Progressive complications in GI, liver, pancreas, reproductive system 3