Pathophys
What is the inheritance pattern and most common mutation (including chromosome!) of CF?
AR, deltaF508, codon deletion on chromosome 7 (trinucleotide deletion means non frameshift)
How does the sweat chloride test work?
Pilocarpine induces sweating, chloride in sweat is measured and > 60mmol/L is a positive result indicative of CF
Sweat glands: unable to reabsorb Cl-
What is one non-pharmacological approach to CF treatment?
physiotherapy
What is the biggest pulmonary complication of CF?
Recurrent infections
S aureus [infancy and early childhood], P aeruginosa [adulthood], allergic bronchopulmonary aspergillosis [ABPA]), chronic bronchitis
What causes the mucousy secretions seen in CF?
Most common mutation --> misfolded protein --> protein retained in RER and not transported to cell membrane --> decreased Cl− (and H2O) secretion --> increased intracellular Cl− results in compensatory Na+ reabsorption via epithelial Na+ channels (ENaC) --> increased H2O reabsorption --> abnormally thick mucus secreted into lungs and GI tract
What is a newborn screening tool used to diagnose CF?
Trypsinogen: immunoreactive trypsinogen
Trypsinogen is a pancreatic enzyme precursor found in the blood that is elevated in most of those with CF at birth, regardless of whether their mutation is pancreatic sufficient or insufficient. The concentration of IRT is elevated in babies with CF since pancreatic ducts are partially blocked leading to abnormal enzyme drainage
How do ivacaftor and lumacaftor work?
ivacaftor: increase CFTR Cl- channel gate opening and conductance and improve Cl- transport
lumacaftor: improve protein folding, protein stability, and the transport of functional CFTR protein to the cellsurface
What GI complications can be seen in CF?
Pancreatic insufficiency, malabsorption with steatorrhea, fat-soluble vitamin deficiencies (A, D, E, K), biliary cirrhosis, liver disease. Meconium ileus in newborns
Do we see increased or decreased consumption of ATP in CF?
Decreased: the Cl- channel uses ATP to move Cl- outside the cell. With the channel mutated, less ATP is consumed.
If there are inconclusive results (sweat test, trypsinogen, genetic testing), what test is performed and how does it work?
Nasal potential difference measurements - abnormal results with clinical symptoms sufficient to diagnose
Placing electrodes in the nasal cavity and measuring voltage in the basal state, after:
1. nasal perfusion with amiloride to block sodium transport
2. nasal perfusion with a chloride-free solution containing a cAMP agonist, such as isoproterenol, to stimulate CFTR-dependent chloride transport
Patients with CFTR dysfunction have a high potential difference in the basal state, a greater decline than controls following amiloride, and minimal response to low chloride-isoproterenol perfusion
What are some pharmacological treatments for CF other than CTFR modulators?
High-dose ibuprofen: can slow the progression of lung disease
Bronchodilators: SABA (e.g., albuterol)
Mucolytics
What are some tidbits of information that can suggest CF (other than pulmonary and GI manifestations)?
Nasal polyps, nail clubbing, infertility in males (absence of vas deferens, spermatogenesis may be unaffected)/subfertility in women (amenorrhea, abnormally thick cervical mucus)