Etiology

CF is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel found in the apical membrane of epithelial cells. More than 2000 CF-causing CFTR mutations have been found, the most common of which is F508del, a class II mutation found in up to 80% to 90% of patients.[1]​

Patients may be either homozygous or heterozygous with respect to CFTR mutations. Carriers of one CFTR mutation and one normal CFTR allele usually do not demonstrate disease.

Pathophysiology

Mutations in CFTR result in abnormal salt transport by epithelial cells, resulting in thick, sticky secretions in the:[16][17][18][19][20][21][22][23][24][25]

  • Pancreas, leading to blockage of exocrine ducts, early activation of pancreatic enzymes, and eventual autodestruction of the exocrine pancreas. Most patients require supplemental pancreatic enzymes.

  • Intestine, where the resulting bulky stools can lead to intestinal blockage.

  • Respiratory system, where the absence of CFTR results in mucus retention, chronic infection, and inflammation that eventually destroy lung tissue.

Lung disease is the most common cause of morbidity and mortality. There are multiple hypotheses regarding the pathogenesis of lung disease

Classification

According to clinical phenotype

With pancreatic insufficiency

  • Patients require supplemental pancreatic enzymes to maintain normal digestion.

With pancreatic sufficiency

  • Patients do not require supplemental pancreatic enzymes.

According to genotype

Patients are also classified by their CFTR mutations, which inform treatment options with CFTR modulators:[1]

  • Class I: no functional CFTR protein is made (e.g., G542X)

  • Class II: CFTR protein is made but it is misfolded (e.g., F508del)

  • Class III: CFTR protein is formed into a channel but it does not open properly (e.g., G551D)

  • Class IV: CFTR protein is formed into a channel but chloride ions do not cross the channel properly (e.g., R347P)

  • Class V: CFTR protein is not made in sufficient quantities (e.g., A455E)

  • Class VI: CFTR protein with decreased cell surface stability (e.g., 120del123).

More than 2000 CF-causing CFTR mutations have been found, the most common of which is F508del, a class II mutation found in up to 80% to 90% of patients.[1]

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