- Clinical science
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.
Second most common hereditary metabolic disorder in white populations
- Most common lethal genetic disorder in white populations
- Non-Hispanic whites: ∼1/3300
- Heterozygote frequency among non-Hispanic whites: 1/25
Children of heterozygous parents have a 25% chance of developing cystic fibrosis!
Epidemiological data refers to the US, unless otherwise specified.
Hereditary autosomal recessive disorder
- Defective CFTR (cystic fibrosis transmembrane conductance regulator) protein due to mutation in CFTR gene
- 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).
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)
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).
- in newborns
- Failure to thrive due to malabsorption
- Gastrointestinal symptoms are common in infancy.
- Pancreatic disease
- Liver and bile duct abnormalities
- Intestinal obstruction; : abdominal distention, pain, and a palpable mass
- Rectal prolapse (rare)
- Respiratory symptoms are common in adulthood.
- Obstructive lung disease with bronchiectasis
- Chronic sinusitis; may eventually develop
Recurrent or chronic productive cough and pulmonary infections with characteristic microorganisms
- S. aureus is the most common cause of recurrent pulmonary infection in infancy and childhood.
- P. aeruginosa is the most common cause of recurrent pulmonary infections in adulthood.
- Dangerous bacteria (especially Pseudomonas aeruginosa) are easily transmitted to patients with CF → rapid decline in pulmonary function and increased risk of death (multiple antibiotic courses in their lifetime → high resistance to commonly used antibiotics!)
- Expiratory wheezing (obstruction), barrel chest , moist rales (indicate pneumonia), hyperresonance to percussion
- Signs of chronic respiratory insufficiency: digital clubbing associated with chronic hypoxia
- Airway hyperreactivity (e.g., wheezing)
- Especially salty-tasting sweat → electrolyte wasting
- Hyperhidrosis does not occur.
- The following factors may compromise the fertility of patients or cause them to be completely infertile:
- Delayed secondary sexual development in both sexes
- 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.
- Typical clinical manifestations of CF: chronic sinopulmonary disease, gastrointestinal and nutritional irregularities, syndromes of salt loss, obstructive azoospermia
- AND evidence of CFTR dysfunction
- ↑ Immunoreactive trypsinogen (IRT)
- DNA assay
All neonates are screened for CF in the US!
Quantitative pilocarpine iontophoresis (sweat test) is the best initial test.
- 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).
- Other blood tests
- Contraction alkalosis and hypokalemia may occur (due to excessive loss of H2O and NaCl via the sweat glands and renal H+/K+ wasting)
- Stool: ↓ chymotrypsin and pancreatic elastase
- Chest x-ray/CT: hyperinflation
Pulmonary function tests: ↓ FEV1:FVC ratio and ↑ residual volume (RV) and total lung capacity (TLC) ratio
- Findings are consistent with an ; see .
- Ultrasound: increased liver echogenicity (fatty liver)
Ideally, management should be supervised by specialists in cystic fibrosis centers.
- Hypertonic saline nebulization or aerosolized dornase alpha (recombinant DNAse that is a specific mucolytic agent that breaks down extracellular DNA in sputum)
- Bronchodilator therapy (e.g., albuterol)
- Chest physiotherapy
- In chronic rhinosinusitis: intranasal glucocorticoids (see )
- Mucolytics (e.g., N-acetylcysteine)
- High-dose ibuprofen has been shown to reduce respiratory disease progression.
- In chronic respiratory insufficiency
- Long-term oxygen inhalation therapy
- Treatment of last resort: lung transplantation
CFTR modulators 
- 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.
- Ivacaftor: improves Cl- transport by increasing the likelihood that the Cl- channel is open at the cell surface.
- 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
- Tezacaftor: increases the amount of mature CFTR protein on the cell surface by improving intracellular processing and trafficking of the CFTR protein
Treatment of pulmonary infections
- Annual influenza vaccine for all CF patients > 6 months with inactivated influenza vaccine (IIV)
- Pneumococcal vaccine (see the )
- Palivizumab: antibody against respiratory syncytial virus (RSV) for infants < 24 months
- Long-term treatment with azithromycin may be used to prevent recurrent pulmonary infections.
- 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)
- Differential diagnosis: : See .
- Enema with a contrast agent
- Surgery is required in complicated cases: intestinal perforation or volvulus
- Small bowel obstruction can also occur in older children and adults.
We list the most important complications. The selection is not exhaustive.
- 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