- Clinical science
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.
- Second most common hereditary metabolic disorder among white populations
- 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
- Calculation of heterozygote frequency with the
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
- Mutated CFTR gene → misfolded protein → retained protein in RER that is unable to reach the cell membrane: → defective ATP-gated 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
- Defective chloride channel → chloride remains in the lumen → sodium moves along from the lumen into the cells → creates an extremely positive gradient → further transport of sodium is inhibited → sodium and chloride are trapped → elevated levels of NaCl in sweat (see “Diagnostics” below)
- Gastrointestinal symptoms are frequent in infancy
- Failure to thrive
- Exocrine pancreatic insufficiency
- CF-related diabetes mellitus (CFRD)
- Liver and bile duct abnormalities
- Abdominal distention, pain, and a palpable mass
- Rectal prolapse (rare)
- Respiratory symptoms are frequent in adulthood
- Obstructive lung disease with bronchiectasis
- Chronic sinusitis; may eventually develop
Recurrent or chronic productive cough and pulmonary infections with characteristic microorganisms
- 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
- 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.
- Typical clinical manifestations of CF
- AND evidence of CFTR dysfunction
↑ Immunoreactive trypsinogen (IRT)
- Usually the first screening assay performed on neonates
- Detects elevated levels of IRT in heel-prick blood
- DNA assay
All neonates are screened for CF in the US!
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)
- Other blood tests
- Hypochloremic alkalosis may occur (due to NaCl wasting).
- ↑ Serum bicarbonate levels
- 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 (in keeping with an obstructive pattern) → see
- Ultrasound: increased liver echogenicity (fatty liver)
- Ideally, management should be supervised by specialists in cystic fibrosis centers.
- Hypertonic saline nebulization or dornase alpha
- Bronchodilator therapy (e.g., albuterol)
- Chest physiotherapy (e.g., postural drainage with percussion)
- In chronic rhinosinusitis: intranasal glucocorticoids (→ see )
- Mucolytics (e.g., N-acetylcysteine)
- In chronic respiratory insufficiency
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
- 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 may also occur in older children and adults.
We list the most important complications. The selection is not exhaustive.
- 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