CYSTIC FIBROSIS

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  1. Typical Presentations

    1. Persistent pulmonary infection, failure to thrive, pancreatic insufficiency, meconium ileus in newborns

  2. Epidemiology

    1. Most common lethal genetic disease in Caucasians

    2. 1 in 2500 Caucasians births; 1 in 17,000 African-American births


  1. Genetics

    1. Autosomal Recessive

    2. Mutation in cystic fibrosis transmembrane regulator (CFTR) protein

      1. CFTR protein = Chloride channel

      2. Mutation associated with defective ion transport in epithelial cells

        1. Causes thick, viscous secretions in lungs, pancreas, liver, intestine, and reproductive tract

      3. Delta F508 is the most common mutation - single phenylalanine deletion at amino acid 508 on long arm of chromosome 7

  1. Manifestions: Pulmonary Disease

    1. Persistent, productive cough; Hyperinflation on CXR; Pulmonary function tests consistent with obstructive airway disease; Bronchiectasis; Digital clubbing

    2. Colonization

      1. Pseudomonas aeruginosa

        1. Heavy, slime producing mucoid variant unique to CF patients

        2. Once colonized, almost impossible to eradicate

      2. Burkholderia cepacia complex

        1. Associated with shortened survival and progressive disease acceleration

      3. Staphylococcus aureus and haemophilus influenzae infections common during early childhood


Chest xray: Hyperinflation and bilateral infiltrates in CF patient Chest CT: Bronchiectasis in CF


  1. Manifestations: Other Affected Organs

    1. Gastrointestinal tract

      1. Meconium ileus in newborns: pathognomonic

      2. Meconium ileus equivalent in older children and adults: distal ileal obstruction

    2. Sinuses

      1. Chronic nasal congestion, Nasal polyps, Sinusitis


    1. Pancreas

      1. Pancreatic insufficency: Steatorrhea, Deficiency of fat soluble vitamins (A, D, E, and K), Failure to thrive

      2. Chronic pancreatitis

      3. Exocrine deficiency: Diabetes Mellitus

l Atrophy, fatty infiltration, and fibrosis of pancreatic exocrine glands

    1. Reproductive tract

      1. Male infertility: Defect in sperm transport, affecting more than 95%

      2. Female infertility: Related to production of abnormally tenacious cervical mucus, affecting up to 20%

    1. Biliary tree

      1. Focal biliary cirrhosis or fatty liver infiltration

      2. Cholelithiasis

Focal biliary Cirrhosis

    1. Musculoskeletal

      1. Low bone mineral density: Higher risk of fracture

      2. Hypertrophic osteoarthropathy: Periosteal new bone formation

      3. CF associated arthropathy: Short episodes of pain and swelling in the joints

  1. Diagnosis

    1. Sweat testing (Pilocarpine Iontophoresis) – gold standard

    2. Molecular Diagnosis: Genotyping – 30 of 1250 most common mutations now screened

    3. Nasal potential difference - after perfusion with amiloride and chloride-free solution

  1. Treatment

    1. Antibiotics: Tobramycin with an anti-pseudomonal penicillin or 3rd generation cephalosporin

    2. Mucolytics: DNAse, N-acetylcysteine, Hypertonic saline

    3. Bronchodilators: b2 – agonists, Anti-cholinergics, Anti-leukotrienes

    4. Anti-inflammatory agents: Corticosteroids, Ibuprofen

    5. Other: Physiotherapy, Airway clearance devices, Exercise, Supplemental oxygen, Lung transplantation

    6. Nutrition: pancreatic enzymes, vitamin supplements, nocturnal feeds (G tubes, NG tubes)

VIII. Future Directions

    1. Gene therapy: Under-study, in – vivo manipulation is promising

    2. Gentamicin: Allows read-through of premature stop codons and allows synthesis of complete CFTR gene

    3. Improved antibiotics: Defensins - cationic peptides that have antimicrobial properties



References:

1. Rowe, SM, Miller, S, Sorscher, EJ. Cystic fibrosis. N Engl J Med 2005; 352:1992.

2. Ratjen, F, Doring, G. Cystic fibrosis. Lancet 2003; 361:681

3. Gibson, RL, Burns, JL, Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. Am J Respir Crit Care Med 2003; 168:918.

4. DiSant'Agnese, PA, Hubbard, VS. The pancreas. In: Cystic Fibrosis, Taussig, LM (Ed), Thieme-Stratton, New York, 1984, p.230.

5. DiSant'Agnese, PA, Hubbard, VS. The gastrointestinal tract. In: Cystic Fibrosis, Taussig, LM (Ed), Thieme-Stratton, New York, 1984, p. 296.

6. Stern, RC. The diagnosis of cystic fibrosis. N Engl J Med 1997; 336:487.

Category: Medicine Notes , Pathology Notes

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