- 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 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.
- CF is a hereditary autosomal recessive disorder caused by defective CFTR (cystic fibrosis transmembrane conductance regulator) protein due to mutation in the CFTR gene located on the long arm of chromosome 7. 
- The most common mutation causing CF is delta F508 (ΔF508), a nucleotide deletion that leads to the absence of phenylalanine (F) in position 508 of the CFTR protein.
- The CFTR gene encodes the CFTR protein, which is an important component of the ATP-gated chloride channel in cell membranes.
- Mutated CFTR gene → misfolded protein → retention for degradation of the defective protein in the rough endoplasmic reticulum (rER) → absence of ATP-gated chloride channel 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 (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)
Gastrointestinal symptoms are common in children. The presence of these features during infancy should raise suspicion for CF.
- Meconium ileus (in newborns)
- Failure to thrive (due to malabsorption)
- Pancreatic disease
- CF-related diabetes mellitus (CFRD) 
- Liver and bile duct abnormalities
- Intestinal obstruction; : abdominal distention, pain, and a palpable mass
- Rectal prolapse (rare)
Respiratory symptoms are common in adulthood. CF should be considered in individuals with the following features:
- COPD with bronchiectasis
- Chronic sinusitis: nasal polyps may eventually develop
Recurrent or chronic productive cough and pulmonary infections
- 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.
- Other commonly involved bacteria: Burkholderia cepacia, S. pneumoniae, H. influenzae
- Increased susceptibility of individuals with CF to opportunistic, potentially life-threatening pathogens (e.g., Pseudomonas aeruginosa, Aspergillus)
- Infections with Pseudomonas aeruginosa → rapid decline in pulmonary function (patients with CF go through multiple antibiotic courses in their lifetime → increasing resistance of Pseudomonas aeruginosa to commonly used antibiotics) 
- A chronic infection with Aspergillus species may lead to allergic bronchopulmonary aspergillosis (see “Complications” below)
- Pulmonary obstruction and airway hyperreactivity may manifest with expiratory wheezing; and/or dyspnea.
- Barrel chest , moist rales (indicate pneumonia), hyperresonance to percussion
- Signs of chronic respiratory insufficiency: digital clubbing associated with chronic hypoxia
- Particularly salty sweat
- Possible electrolyte wasting
- Men: usually infertile
- Women: reduced fertility
- Delayed development of secondary sexual characteristics
- 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 
The criteria for diagnosing CF are: .
- Positive newborn screening (NBS), a positive family history, or presence of typical features (e.g., chronic sinopulmonary disease, gastrointestinal and nutritional irregularities, syndromes of salt loss, obstructive azoospermia) PLUS one of the following:
- Sweat chloride testing with a chloride value ≥ 60 mmol/L
- Evidence of two CF-causing CFTR gene mutations and a sweat chloride test result ≥ 30 mmol/L
- Positive physiologic CTFR testing with abnormal nasal potential difference test or intestinal current measurement
Neonatal screening 
A positive NBS test result alone does not confirm CF diagnosis and should quickly be followed by further diagnostics.
- Immunoreactive trypsinogen (IRT)
- DNA assay
CF screening is routinely performed in the US.
Laboratory tests 
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.
- 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.
- Blood: hypokalemia may occur. and
- Stool: ↓ chymotrypsin and pancreatic elastase
- Pulmonary function tests:
- The following agents are used to increase mucociliary clearance and to reduce the viscosity of mucus in the airways.
- Bronchodilator therapy (e.g., albuterol)
- Chest physiotherapy (e.g., postural drainage with percussion)
- 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
- Additional sodium chloride intake
- High-energy diet to compensate for increased demand
- Pancreatic enzyme supplements
- Oral supplementation of
CFTR modulators  
- 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.
- 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
Treatment of pulmonary infections 
Meconium ileus: failure to pass the first stool in neonates (meconium usually passes within the first 24–48 hours after birth)
- Etiology: Cystic fibrosis is the cause in > 90% of cases.
- Clinical findings: signs of a distal small bowel obstruction (thick meconium plugs the distal ileum)
X-ray abdomen (with contrast agent) 
- Dilated small bowel loops
- Microcolon: narrow caliber of the colon, as it is still unused (meconium has not been passed through yet)
- Neuhauser sign (soap bubble appearance): a mottled or bubble-like appearance in the distal ileum and/or cecum as a result of meconium mixing with swallowed air 
- Air-fluid levels are uncommon because of the viscous consistency of meconium.
- X-ray abdomen (with contrast agent) 
- Differential diagnosis: See “.”
- Small bowel obstruction: can also occur in older children and adults
- Distal intestinal obstruction syndrome (DIOS) : blockage of the small intestines by thickened stool in the distal ileum and right colon 
We list the most important complications. The selection is not exhaustive.
- Median life expectancy: 39 years 
- 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 
- The main determinant of life expectancy is the severity of pulmonary disease: chronic respiratory infections and mucus plugging → bronchiectasis (irreversible) → progressive respiratory failure → death
- Annual influenza vaccine for all affected individuals > 6 months with inactivated influenza vaccine
- Pneumococcal vaccine (see ” ”)
- Palivizumab: antibody against respiratory syncytial virus (RSV) for infants < 24 months
- Long-term treatment with azithromycin may be used to prevent recurrent pulmonary infections.