• Clinical science

Cystic fibrosis

Summary

Cystic fibrosis (CF) is an autosomal recessive disorder caused by a mutation in the CFTR gene, which encodes for the cystic fibrosis transmembrane conductance regulator protein. The mutation leads to the production of defective chloride channels in cell membranes of the exocrine glands, and symptoms are caused by these glands producing abnormally hyperviscous secretions. Failure to pass meconium (meconium ileus) is often the first clinical sign of cystic fibrosis. Later, the lungs, digestive system, and sweat glands are commonly affected. Bronchial accumulation of hyperviscous mucus and impaired ciliary clearance predispose patients to chronic respiratory infection, pulmonary colonization with multiresistant bacteria, and long-term complications such as emphysema. Impaired secretion of pancreatic and biliary juices leads to digestive problems and chronic organ damage. The sweat test (pilocarpine iontophoresis) is considered the gold standard for detecting elevated levels of chloride in sweat, which is a characteristic sign of cystic fibrosis. The mainstay of treatment is symptomatic management. The median life expectancy is 39 years. Complications of chronic lung disease are the leading cause of death.

Epidemiology

  • Second most common hereditary metabolic disorder in white populations
    • Most common lethal genetic disorder in white populations
  • Incidence
    • Non-Hispanic whites: ∼1/3300
    • Hispanics: ∼1/8000 to 9000
    • African Americans: ∼1/15,300
    • Asian Americans: ∼1/32,100
  • Heterozygote frequency among non-Hispanic whites: 1/25

Children of heterozygous parents have a 25% chance of developing cystic fibrosis!

References:[1]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[2][3]

Pathophysiology

  • The CFTR gene, which is located on the long arm of chromosome 7, encodes the CFTR protein, which is an important component of the ATP-gated chloride channel in cell membranes.
  • Mutated CFTR gene (ΔF508 mutation) → misfolded protein → defective protein is retained in the rough endoplasmic reticulum (rER) for degradation → ATP-gated chloride channel is absent on the cell surface of epithelial cells throughout the body (e.g., intestinal and respiratory epithelia, sweat glands, exocrine pancreas, exocrine glands of reproductive organs)
    • In sweat glands: The chloride channel is responsible for transporting Cl- from the lumen into the cell (reabsorption).
      • Defective ATP-gated chloride channel inability to reabsorb Cl- from the lumen of the sweat glands → reduced reabsorption of Na+ and H2O → excessive loss of salt and elevated levels of NaCl in sweat
    • In all other exocrine glands: The chloride channel is responsible for transporting Cl- from the cell into the lumen (secretion).
      • Defective ATP-gated chloride channel → inability to transport intracellular Cl- across the cell membrane → reduced secretion of Cl- → accumulation of intracellular Cl- → ↑ Na+ reabsorption (via ENaC); ↑ H2O reabsorption formation of hyperviscous mucus → accumulation of secretions and blockage of small passages of affected organs → chronic inflammation and remodeling → organ damage; (see “Clinical features” below for details)
      • ↑ Na+ reabsorption → transepithelial potential difference between interstitial fluid and the epithelial surface increases (i.e., becomes more negative: e.g., from normal -13 mv to abnormal -25 mv)
        • This characteristic pattern of bioelectric properties can be used for diagnosis

In all exocrine glands, the Cl- channel is responsible for transporting intracellular Cl- across the cell membrane. However, in sweat glands, the Cl- channel is responsible for transporting Cl- from the lumen into the cell. The sweat test relies on the inability of the sweat glands to reabsorb salt, which results in elevated NaCl levels in sweat (see “Diagnostics” below).

References:[4][5][6]

Clinical features

Gastrointestinal

Respiratory

  • Respiratory symptoms are common in adulthood.
  • Obstructive lung disease with bronchiectasis
  • Chronic sinusitis; nasal polyps may eventually develop
  • Recurrent or chronic productive cough and pulmonary infections with characteristic microorganisms
  • Airway hyperreactivity (e.g., wheezing)

Sweat glands

  • Especially salty-tasting sweat → electrolyte wasting
  • Hyperhidrosis does not occur.

Musculoskeletal

Urogenital

References:[7][1][8][9][10]

Diagnostics

General

  • In most cases, CF is suspected based on clinical features, a positive newborn screen, or a sibling with CF.
  • Best initial test is the sweat chloride test.
    • If results are abnormal or borderline, DNA testing for the two CFTR mutations is indicated to confirm the diagnosis.
    • If only one or no CFTR mutations are identified, an expanded DNA analysis or second sweat test should be performed; a positive result on either one of these confirms the diagnosis.

Diagnostic criteria

Neonatal screening

All neonates are screened for CF in the US!

Laboratory tests

Supportive tests

References:[7][1][11][8]

Treatment

Symptomatic management

Ideally, management should be supervised by specialists in cystic fibrosis centers.

CFTR modulators [12]

  • Indication: patients with CF who are homozygous for the delta F508 mutation in the CFTR gene
  • Mechanism of action: These drugs modulate the expression of the defective CFTR protein by improving the production, intracellular processing, and function of the defective protein.
  • Combination therapy: The drugs work synergistically to increase both the quantity and function of the CFTR protein on the cell surface, resulting in enhanced chloride transport.
  • Drugs
    • Ivacaftor: improves Cl- transport by increasing the likelihood that the Cl- channel is open at the cell surface.
      • Monotherapy for patients > 6 months of age with a G551D mutation
      • Combination therapy with; either tezacaftor or lumacaftor (see below)
    • Lumacaftor: improves the conformational stability of the defective CFTR protein, which leads to increased intracellular processing and trafficking of functional CFTR protein to the cell surface
      • Combination therapy with ivacaftor for patient > 6 years old who are homozygous for the delta F508 mutation
    • Tezacaftor: increases the amount of mature CFTR protein on the cell surface by improving intracellular processing and trafficking of the CFTR protein
      • Combination therapy with ivacaftor for patients ≥ 6 years who are homozygous for the delta F508 mutation or a CFTR mutation responsive to the drugs

Because CFTR modulators are only effective in patients with certain CFTR mutations, it is essential to perform CFTR genotyping prior to initiating treatment.

Treatment of pulmonary infections

Pathogen Antibiotic therapy
Infants
Adults
  • Stenotrophomonas maltophilia

Preventive measures

References:[13][1][14][15][16][17][18][19]

Complications

Gastrointestinal

Respiratory

References:[7][20][21][22][23]

We list the most important complications. The selection is not exhaustive.

Prognosis

  • Median life expectancy: ∼ 39 years
  • The main determinant of life expectancy is the severity of pulmonary disease: chronic respiratory infections and mucus plugging → bronchiectasis (irreversible) → progressive respiratory failure → death
  • Progress in the medical and psychological management of patients with CF has lead to:
    • Significant improvement in survival in recent years
    • Successful pregnancies

References:[24]