Cystic Fibrosis
Overview
Autosomal recessive that results from the inheritance of two mutant alleles at the locus encoding the cystic fibrosis transmembrane conductance regulator (CFTR) on chromosome 17
Epidemiology: Most lethal inherited disease in the caucasian pop – heterozygote carrier frequency of 1 in 20
Incidence: 1 in 2000 births
Etiology: Mutation in the 250 kilobase CFTR gene. Altered structure/function of CFTR leads to altered ion transport and through unknown mechanisms altered mucus and chronic infection and inflammation.
- >600 different mutations. Most common (75%): 3 base pair deletion resulting in an absent phenylalanine at position 508 in CFTR molecule
- Different CF mutations are associated with different phenotypes (F508 Þ pancreatic insufficiency)
- 80% of adults >26 yo chronically infected with Pseudomoas aeruginosa: reason not completely explained by alterations in ion transport at the plasma membrane
CFTR: 1480 amino acid integral membrane glycoprotein which functions as a cAMP regulated chloride channel.
- Ion flow regulation: binding of ATP to two cytoplasmic nucleotide binding domains and the PKA mediated phosphorylation of serine and threonine residues in a cytoplsmic regulatory domain
- Function
: allows the epithelium to control the fluid and electrolyte content of its extracellular milieu by transporting chloride ions across the plasma membrane while water passively follows. Involved in:
- secretion of fluid in the respiratory and GI tracts,
- hydration and appropriate glycosylatoinof mucusglycproteins,
- maintenance of an alkaline milieu in small bowel,
- resorption of electrolytes in the sweat ducts
- maintaining the patency of the developing vas deferns
Pathophysiology
Inflammatory response to endobronchial pathogens (P. aeruginosa) is a crucial determinant of disease progression
- Inflammation: dominated by polymorphonuclear leukocytes and their proteolytic enzymes
- Protease-anti-protease imbalance contributes to airway destruction
Skin latered Na/Cl concentrations in sweat
Genito-urinary: reproductive altered cervical mucus, azoospermia, infertility
Respiratory: upper airways (sinusitis) lower airway (cystic bronchiectasis)
GI: Pancreas: exocrine and endocrine insufficiency (pancreas is replaced by fibrous tissue) Þ diabetes
- Liver: biliary cirrhosis
- Bowel: obstruction, meconium ileus
Symptoms and signs
Heat prostration
Infertility
Nasal polyposis
cough
recurrent pneumonia
hemoptysis, pneumothorax, repiratory insufficiency (from airway destruction)
Fat malabsorption/steatorrheaÞ malnutrition
abdominal pain
pancreatitis
diabetes
prolapsed rectum
Patient evaluation
based on clinical criteria
Requires the presence of characteristic abnormalities in at least 2 organ systems including:
- abnormal sweat chloride concentration
- obstructive ventilatory defect associated with chronic infection
- pancreatic insufficiency
- azoospermia or a family history of classic cystic fibrosis.
Lab findings
Sweat Cl- > 60-80 mEq/L by pilocarpine ionophoresis: excellent discriminating power
Obstructive azoospermia on semen analysis
Sputum culture with mucoid pseudomonas aeruginosa
CXR: cystic bronchiectatic changes predominantly in the upper lobes
PFT: obstructive defect
Stool fat, serum iso-amylase, beta-carotene
Therapies
Most therapies are symptomatic improved survival is credited to comprehensive treatment programs
Maintenance therapy
Pulmonary: slow progression of lung damage by:
- (1) Improving mucus clearance: mechanical treatment to remove secretions (percussion, posturaldrainage) drugs (recombinant human DNAse alters the visco-elastic properties of secretions)
- (2) Restraining infection: cannot eradicate lung pathogens but can delay colonization with oral floroquinolones, and aerosol colisthmethane
- (3) Controling inflammation: prednisone, NSAID’s
- (4) Maintaining airflow and gas exchange: bronchodilation, inhaled beta agonists, inhaled anti-cholinergics
GI: Pancreatic enzyme and vitamin (A,D,E,K) supplements