• 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 affected individuals 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. More recently, however, the development of CFTR-modulators has provided a causal approach for individuals with certain specific mutations. The median life expectancy is 39 years. Complications of chronic lung disease are the leading cause of death.

Epidemiology

  • Second most common genetic metabolic disorder; after hemochromatosis in individuals of Northern European descent. [1][2][3]
  • Incidence: approx. 1:3,500 in the US [4]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Children whose parents are both heterozygous carriers of cystic fibrosis have a 25% chance of being affected by the condition.

Pathophysiology

  • General considerations
  • 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 (e.g., in the GI tract or lungs)
    • 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- and H2O → 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)
    • ↑ Na+ reabsorption → transepithelial potential difference between interstitial fluid and the epithelial surface increases; (i.e., negative charge increases; e.g., from normal -13 mv to abnormal -25 mv)

Clinical features

Gastrointestinal [8]

Gastrointestinal symptoms are common in children. The presence of these features during infancy should raise suspicion for CF.

In almost all cases of meconium ileus, cystic fibrosis is the underlying disease.

Respiratory [8]

Respiratory symptoms are common in adulthood. CF should be considered in individuals with the following features:

Sweat glands

  • Particularly salty sweat
  • Possible electrolyte wasting

Musculoskeletal

Urogenital

Diagnostics

General

  • CF should be suspected in the presence of clinical features, positive newborn screening, or positive family history.
  • Neonatal screening is routinely performed in all US states.
  • 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 for either one of these tests confirms the diagnosis.
  • Carrier screening is recommended in women with a family history of CF who wish to conceive.

Diagnostic criteria [11]

The criteria for diagnosing CF are: .

Neonatal screening [11][12]

A positive NBS test result alone does not confirm CF diagnosis and should quickly be followed by further diagnostics.

CF screening is routinely performed in the US.

Laboratory tests [13]

  • Sweat test (quantitative pilocarpine iontophoresis): best initial test
    • Method: The chloride concentration in the sweat is measured following chemical stimulation of the sweat glands with pilocarpine.
    • Interpretation
      • A chloride concentration ≥ 60 mmol/L indicates a likely diagnosis of cystic fibrosis.
      • Chloride concentrations between 30–59 mmol/L are considered intermediate range and require genetic analysis to either rule out or confirm CF diagnosis.
      • A chloride concentration < 30 mmol/L implies that CF is unlikely.
    • The test should be conducted in patients > 2 weeks of age and > 2 kg in weight.
  • DNA analysis
  • Nasal potential difference test
    • Indication: unclear findings in sweat and DNA tests despite the presence of typical clinical features of CF
    • Voltage measurements before and after the nose is perfused with different solutions show abnormal epithelial secretion of chloride (e.g., more negative baseline potential difference and no difference in nasal potential difference after administration of a chloride-free solution).

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.

Supportive tests

Treatment

Symptomatic management

CFTR modulators [14] [15]

  • Mechanism of action: CFTR modulators partially restore function of the CFTR protein.
  • Indication: Approved for patients with CF with certain mutations (e.g., the ΔF508 mutation in the CFTR gene)
  • Combination therapy: CFTR modulators act synergistically with each other to increase both the quantity and function of the CFTR protein on the cell surface, resulting in enhanced chloride transport.
  • Drugs
    • Ivacaftor
      • Increases the likelihood of the Cl- channel at the cell surface being open and thus improves Cl- transport.
      • Monotherapy for patients > 6 months of age with a G551D mutation
      • Combination therapy with either tezacaftor or lumacaftor
      • Triple-combination therapy with tezacaftor and elexacaftor
    • Lumacaftor
      • Improves the conformational stability of the defective CFTR protein, which leads to increased intracellular processing and transport of functional CFTR protein to the cell surface
      • Used in combination with ivacaftor for patients > 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 transport of the CFTR protein
      • Used in combination with ivacaftor for patients ≥ 6 years who are homozygous for the delta F508 mutation or a CFTR mutation responsive to the drugs
    • Elexacaftor: increases the amount of mature CFTR protein on the cell surface by improving intracellular processing and transport of the CFTR protein, works at an alternate binding site than tezacaftor on the CFTR protein

Ivacaftor increases the activity of CFTR and thereby improves Cl- transport.

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

Treatment of pulmonary infections [16][17]

Population Pathogen Antibiotic therapy
Children
Adults
  • Aspergillus
  • Stenotrophomonas maltophilia

Complications

Gastrointestinal

Respiratory

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

Prognosis

  • Median life expectancy: 39 years [23]
  • Individuals with CF who have pancreatic sufficiency tend to present with mainly pulmonary symptoms in late childhood/early adulthood and generally have a milder course of disease [24]
  • The main determinant of life expectancy is the severity of pulmonary disease: chronic respiratory infections and mucus plugging → bronchiectasis (irreversible) → progressive respiratory failure → death

Prevention