• Clinical science

Cystic fibrosis

Abstract

Cystic fibrosis (CF) is an autosomal recessive disorder caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The mutation leads to the production of defective chloride channels in cell membranes of the exocrine glands. Symptoms are associated with the production of abnormally hyperviscous secretions of exocrine glands. 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, susceptibility to 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 life expectancy of patients with cystic fibrosis remains low. Complications of chronic lung disease are the leading cause of death in patients with CF.

Epidemiology

  • Second most common hereditary metabolic disorder among 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![1]

References:[1]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[2][3]

Pathophysiology

  • Mutated CFTR gene misfolded protein → retained protein in RER that is unable to reach the cell membrane defective chloride channel → inability to transport intracellular chloride ions across the membrane exocrine glands (e.g., sweat, mammary, salivary glands) produce hyperviscous secretions accumulation of secretions and blockage of exocrine glands → chronic inflammation → organ damage
  • Elevated levels of NaCl in sweat → gold standard diagnostic tool (see “Diagnostics” below)

References:[4][5][6]

Clinical features

Gastrointestinal

Respiratory

Sweat glands

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

Musculoskeletal

Urogenital

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

Diagnostics

General

  • Diagnosis of CF begins with identifying certain indications for further evaluation (i.e., clinical symptoms suggesting CF, a positive newborn screen, or a sibling with CF).
  • Best initial test is the sweat chloride test.
    • Abnormal or borderline results warrant DNA testing to identify two CFTR mutations that confirm the diagnosis.
    • If only one or no CFTR mutations are identified, an expanded DNA analysis or second sweat test should be performed; if either one of these are positive, the diagnosis is confirmed.

Diagnostic criteria

  • Typical clinical manifestations of CF
  • AND evidence of CFTR dysfunction
    • Sweat chloride ≥ 60 mmol/L on two occasions
    • OR CFTR gene mutation
    • OR abnormal nasal potential difference test

Neonatal screening

  • ↑ Immunoreactive trypsinogen (IRT)
    • Usually the first screening assay performed on neonates
    • Detects elevated levels of IRT in heel-prick blood
  • DNA assay
    • Either primary screening test or confirmation of CF after abnormal IRT result
    • Identification of common CFTR mutations

All neonates are screened for CF in the US!

Laboratory tests

  • Quantitative pilocarpine iontophoresis (sweat test) is the gold standard.
    • Chloride levels > 60 mmol/L on two or more occasions are consistent with CF.
    • The test should be conducted in patients > 2 weeks of age and > 2 kg in weight (more accurate).
  • DNA analysis
  • Nasal potential difference test
    • Indication: unclear findings in sweat chloride and DNA tests despite CF-like disease in an organ system
    • 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 a chloride-free solution is administered)

Supportive tests

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

Treatment

Symptomatic management

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

Treatment of pulmonary infections

Pathogen Antibiotic therapy
Infants
Adults
  • Stenotrophomonas maltophilia

Preventive measures

References:[12][1][13][14][15][16][17][18]

Complications

Gastrointestinal

  • Meconium ileus
    • Definition: failure to pass the first stool in neonates (meconium usually passes in the first 24–48 hours after birth)
    • Etiology: Cystic fibrosis is the leading cause in (> 90%) of cases.
    • Clinical findings: signs of a distal small bowel obstruction
      • Bilious vomiting
      • Abdominal distention
      • No passing of meconium or stool
    • Diagnostics: abdominal x-ray (with contrast agent)
      • Dilated small bowel loops, microcolon, Neuhauser sign ("soap bubbles" effect)
      • Air-fluid levels are uncommon because of the viscous consistency of meconium
  • Differential diagnosis: → see differential diagnosis of intestinal obstruction in neonates
  • Treatment
    • Enema with a contrast agent
    • Surgery is required in complicated cases: intestinal perforation or volvulus
  • Small bowel obstruction may also occur in older children and adults.

Respiratory

References:[7][19][20][21][22]

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

Prognosis

  • Progress in the medical and psychological management of patients with cystic fibrosis has lead to a significant improvement in survival in recent years. Successful pregnancies are now possible.
  • The severity of pulmonary disease is the main determinant of life expectancy.
    • Chronic respiratory infections and mucus plugging → bronchiectasis (irreversible) → progressive respiratory failure → death
  • Median life expectancy: ∼ 39 years

References:[23]