U01.01.049 Cystic fibrosis

1. Genetics

CFTR Function: Encodes an ATP-gated chloride (Cl⁻) channel:
- Secretes Cl⁻: In lungs and gastrointestinal (GI) tract.
- Reabsorbs Cl⁻: In sweat glands.
Common Mutation: Misfolded CFTR protein, retained in the Rough Endoplasmic Reticulum (RER) and not transported to the cell membrane.
- Leads to decreased Cl⁻ secretion and increased intracellular Cl⁻.
- Compensatory increased sodium (Na⁺) reabsorption via epithelial Na⁺ channels (ENaC) → Increased water reabsorption → Thick, viscous mucus in lungs and GI tract.
- Increased Na⁺ reabsorption → Negative transepithelial potential difference.

Sweat Test: Elevated Cl⁻ concentration in pilocarpine-induced sweat test is diagnostic.
Associated Findings:
- Contraction alkalosis and hypokalemia (similar to loop diuretic effects).
- Elevated immunoreactive trypsinogen (newborn screening).

Age Group	Infections
Infancy/Early Childhood	Staphylococcus aureus
Adulthood	Pseudomonas aeruginosa
Any Age	Allergic bronchopulmonary aspergillosis (ABPA)

Chronic bronchitis and bronchiectasis → Reticulonodular pattern on chest X-ray (CXR).
Sinus Issues: Sinus opacification.

Manifestations	Complications
Pancreatic insufficiency	Malabsorption with steatorrhea, fat-soluble vitamin deficiencies (A, D, E, K).
Meconium ileus (in newborns)	Intestinal obstruction.
Biliary cirrhosis and liver disease	Hepatic failure.

Sex	Manifestations
Men	Infertility due to absence of vas deferens (spermatogenesis unaffected).
Women	Subfertility due to thick cervical mucus or amenorrhea.

Therapy Type	Treatment Options
Mucus Clearance	Chest physiotherapy, albuterol, aerosolized dornase alfa (DNase), hypertonic saline.
Anti-inflammatory	Azithromycin and ibuprofen (slows disease progression).
Nutritional Support	Pancreatic enzyme replacement therapy.
Targeted Therapy	Combination of lumacaftor (corrects protein misfolding) and ivacaftor (opens Cl⁻ channels).

CFTR Defect: Causes thick mucus leading to recurrent infections, respiratory compromise, and GI malabsorption.
Sweat Test: Gold standard diagnostic tool.
Complications: Affect multiple organ systems, including lungs, pancreas, liver, and reproductive organs.
Treatment: Multifactorial approach including symptom management, enzyme replacement, and CFTR-modulating therapies.