Cystic fibrosis

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.

• 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.

• 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. ^[5]
• 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.

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

• General considerations
  • 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) ^[6][7]
• 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 ^[8]

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
  • Pancreatitis
  • Exocrine pancreatic insufficiency
    • Foul-smelling steatorrhea (fatty stools) may occur.
    • Malabsorption
    • Abdominal distention
    • Diarrhea
    • Hypoproteinemia
    • Deficiency of fat-soluble vitamins
• CF-related diabetes mellitus (CFRD) ^[9]
• Liver and bile duct abnormalities
  • Cholecystolithiasis, cholestasis
  • Fatty metamorphosis of the liver, eventually progressing to liver cirrhosis
  • Biliary cirrhosis; with portal hypertension, jaundice, and/or esophageal varices
• Intestinal obstruction; : abdominal distention, pain, and a palpable mass
• Rectal prolapse (rare)

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:

• 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: can lead to cepacia syndrome, a severe necrotizing pneumonia that is often accompanied by rapid respiratory decline and can progress to sepsis ^[10]
    • 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) ^[11]
    • 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
• Hemoptysis
• Signs of chronic respiratory insufficiency: digital clubbing associated with chronic hypoxia

Sweat glands

• Particularly salty sweat
• Possible electrolyte wasting

Musculoskeletal

• Frequent fractures due to osteopenia
• Kyphoscoliosis

Urogenital

• Urinary
  • Nephrolithiasis, nephrocalcinosis
  • Frequent urinary tract infections
• Genital
  • Men: usually infertile
    • Obstructive azoospermia is common; , spermatogenesis may be intact
    • The vas deferens may be absent.
    • Undescended testicle
  • Women: reduced fertility
    • Viscous cervical mucus can obstruct fertilization.
    • Menstrual abnormalities (e.g., amenorrhea)
  • Delayed development of secondary sexual characteristics

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 ^[12]

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 ^[12][13]

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

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

CF screening is routinely performed in the US.

Laboratory tests ^[14]

• 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
  • Prenatal
    • Indication: both parents are carriers of a CFTR mutation
    • Specimen collected via chorionic villus sampling or amniocentesis
  • Postnatal/adult analysis: may be required if the sweat test is negative or intermediate range in a patient with suspected CF
• 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

• Blood: Contraction alkalosis and hypokalemia may occur.
  • Increased NaCl and H₂O loss via the sweat →; contraction of the extracellular fluid (ECF) volume → RAAS activation → increased renal reabsorption of NaCl and H₂O and excretion of H⁺ and K⁺ → alkalosis and hypokalemia (See “Physiology of the kidney”)
  • Effects on ECF are comparable to those of loop diuretics.
• Stool: ↓ chymotrypsin and pancreatic elastase
• Imaging
  • X-ray/CT chest shows:
    • Hyperinflation
    • Reticulonodular pattern
  • CT of the head may show opacification of sinuses
  • Ultrasound: increased liver echogenicity (fatty liver)
• Pulmonary function tests:
  • ↓ FEV1:FVC ratio and ↑ residual volume (RV) and total lung capacity (TLC) ratio
  • Findings are similar to those in obstructive pulmonary diseases (see “Spirometry”).

Gastrointestinal

• 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)
    • Bilious vomiting
    • Abdominal distention
    • No passing of meconium or stool
  • Diagnostics
    • X-ray abdomen (with contrast agent) ^[15]
      • 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 ^[16]
      • 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 (e.g., intestinal perforation, volvulus)
• 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 ^[17]
  • Highest prevalence in the second and third decades of life
  • Tends to occur in individuals with pancreatic insufficiency
  • Clinical manifestations include abdominal pain and distention, a palpable cecal mass, and flatulence.

Respiratory

• Allergic bronchopulmonary aspergillosis (ABPA): ∼ 10% of individuals with CF develop this condition. ^[18][19]
• Pulmonary emphysema
  • Pneumothorax
  • Cor pulmonale

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

• Median life expectancy: 39 years ^[20]
• 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 ^[21]
• 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 ”Immunization schedule”)
• Palivizumab: antibody against respiratory syncytial virus (RSV) for infants < 24 months
• Long-term treatment with azithromycin may be used to prevent recurrent pulmonary infections.

Symptomatic management

• Respiratory
  • The following agents are used to increase mucociliary clearance and to reduce the viscosity of mucus in the airways.
    • Aerosolized dornase alpha: a recombinant form of human DNAse that breaks down extracellular DNA in sputum and thereby functions as a mucolytic.
    • Hypertonic saline nebulization
  • Bronchodilator therapy (e.g., albuterol)
  • Chest physiotherapy (e.g., postural drainage with percussion)
  • In chronic rhinosinusitis: intranasal glucocorticoids (see “Sinusitis”)
  • 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
    • Lung transplantation is a treatment option for patients with end-stage lung disease who are physically fit for surgery.
• Diet
  • Additional sodium chloride intake
  • High-energy diet to compensate for increased demand
  • Pancreatic enzyme supplements
  • Oral supplementation of fat-soluble vitamins

CFTR modulators ^{[22] [23]}

• 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 ^[24][25]

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