Cystic Fibrosis

Cystic Fibrosis is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles

Definition

CF is an autosomal recessive disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR), located on chromosome 7, which results in multisystem exocrine organ dysfunction.

Epidemiology

  • In the United States, approximately 30,000 people are affected by CF, and about 1000 new cases are diagnosed every year.1
  • CF is the most common life-shortening genetic disease in Caucasians; however, the diagnosis should be considered in patients of diverse ethnic backgrounds as well.
  • Patients are typically diagnosed via newborn screening or during childhood, but there is increasing recognition of milder variants that may not present until later in life.
  • In 2016, approximately 50% of patients with CF were ≥18 years old.

Etiology

  • CF is caused by mutations in the CFTR gene, a cyclic adenosine monophosphate (cAMP)–regulated chloride channel, which normally maintains hydration of exocrine organ secretions.
  • Abnormal CFTR causes decreased chloride secretion and increased sodium absorption on the surface of epithelial cells with resulting thickened secretions in the airways, sinuses, pancreatic ducts, biliary tree, intestines, and reproductive tract.
  • CFTR mutations are categorized into five classes: (1) defective synthesis, (2) defective processing and maturation, (3) defective regulation, (4) defective conductance, and (5) reduced function/synthesis.
  • The most common mutation is F508del, a class II mutation resulting from the deletion of DNA coding for phenylalanine (F) amino acid at position 508. The majority of the resultant misfolded protein is destroyed intracellularly and does not reach the cell surface. Over 85% of patients in the United States have at least one copy of this mutation.1
  • G551D and R117H mutations, present in 3%–5% of the patients, are class III mutations in which the defective regulation of the CFTR protein results in impaired opening of the channel.
  • >2000 other potentially causative mutations in the CFTR gene have been identified.1

Pathophysiology

  • CFTR normally regulates transport of chloride ions across the epithelium.
  • The primary pulmonary manifestations of disease are related to the malfunction of chloride transport across the airway epithelium, resulting in diminished airway surface liquid and impaired mucociliary clearance.
  • Poor mucociliary clearance results in an impaired ability to clear infection. Recurrent infection begets an inflammatory cascade that results in bronchiectasis, chronic infection, and, ultimately, respiratory failure and premature death.
  • Similarly, thickened secretions in the pancreatic and biliary ducts lead to maldigestion, malabsorption, and, occasionally, liver disease and diabetes.2

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