Cystic Fibrosis

Epidemiology

• Synonyms: mucoviscidosis, fibrosa cystica
• Incidence differs significantly among ethnicities:
  • Caucasians: 1 in 3,000–4,000 live births
  • Latin Americans: 1 in 4,000–10,000 live births
  • African Americans: 1 in 15,000–20,000 live births
  • Asian Americans: 1 in 100,000 live births
• Most common autosomal recessive disease in white populations
• Incidence in the United States: 1 in 3,400 live births
• Cystic fibrosis (CF) screening is part of the newborn screening in many countries with a high prevalence of the condition.
• More than 75% of people with CF are diagnosed by the age of 2.

Etiology and Pathophysiology

Etiology

• Autosomal recessive inheritance 
• Over 1,500 causative mutations have been identified.
• The most common mutation in Central Europe and North America is the delta F508 mutation on chromosome 7. This deletion causes the loss of phenylalanine in position 508.

• The type of mutation is crucial in determining the severity of the disease.
  There are 4 distinct classes:
  1. No gene expression of CFTR
  2. The CFTR channel can be constructed, but cannot be built into the membrane or be located (applies to the delta F508 mutation).
  3. The channel is expressed and built-in, but cannot open due to the mutation.
  4. The protein does not fold correctly, and therefore the channel does not open properly.
• CFTR encodes an important component of ATP-gated chloride channel in cell membranes.
  • Usually found in epithelial cells throughout the body (e.g., gastrointestinal and respiratory epithelia, sweat glands, exocrine pancreas, exocrine glands of reproductive organs)

Pathophysiology

• Mutated CFTR → absent or dysfunctional chloride channel → dysfunctional transport of chloride → abnormal secondary transport of sodium and water
• In sweat glands: inability to reabsorb chloride from the lumen → reduced reabsorption of sodium and water → sweat with elevated levels of sodium chloride + excessive loss of salt
• In rest of exocrine glands: inability to secrete chloride into the lumen → accumulation of intracellular chloride → increased sodium and water reabsorption → formation of hyperviscous mucus → accumulation of secretions → blockage of small passages → chronic inflammation → multiple organ damage

Impact on organ systems

• Lung
  • Ineffective mucociliary clearance; obstruction of the alveoli/bronchioles with an increased risk of infection 
  • Destruction of the lung and reformation into a honeycomb parenchymal pattern due to chronic inflammation
• Pancreas
  • Blockage of the exocrine gland’s secretion outlets
  • Fibrotic and cystic mutation
  • Loss of exocrine function
• Gallbladder
  • Obstruction of bile drainage
  • Development of biliary cirrhosis
• Intestines
  • Obstipation

Clinical Presentation

Respiratory system

• Chronic/recurrent sinus infections, nasal polyps
• Recurrent pulmonary infections, especially with Pseudomonas aeruginosa 
  • Increasing lung insufficiency leads to exertional dyspnea, anoxia, and bronchiectasis
  • Clubbing of fingers and nails
  • 10%–50 % of patients develop polyposis nasi and chronic pansinusitis 
  • Expiratory wheezing and barrel chest

Gastrointestinal system

Reproductive system

• Males 
  • Infertility and delayed secondary sexual development due to:
    • Obstructive azoospermia due to bilateral aplasia/atresia of the deferent duct
    • Undescended testicle; 15 times more likely than in the general population 
• Females
  • Reduced fertility due to:
    • Viscous cervical mucus 
    • Amenorrhea

Urinary system

• Nephrolithiasis
• Stress incontinence (frequent coughing)

Mnemonic device

To recall the most common clinical features of cystic fibrosis, remember the acronym CF PANCREAS:

• C: Chronic cough
• F: Failure to thrive
• P: Pancreatic insufficiency (exocrine)
• A: Alkalosis and hypotonic dehydration
• N: Nasal polyps, neonatal dehydration
• C: Clubbing of fingers (Hippocratic fingers and nails)
• R: Rectal prolapse
• E: Electrolyte elevation (sweat)
• A: Atresia, absence of vas deferens
• S: Sputum with Staphlococcus aureus or Pseudomonas

Complications

Diagnosis

Newborn screening

• CF testing is part of the newborn screening in most high-prevalence countries (North America, Australia, many European countries).
• Involves multiple steps of testing on dried blood spots
• Measurement of immunoreactive trypsinogen, if positive → mutation analysis of CFTR
• If results indicate CF, the next step is a sweat chloride test when the infant is at least 2 weeks of age and weighs over 2 kg.

Sweat chloride test: gold-standard of diagnosis 

•  Pilocarpine iontophoresis used to determine sweat chloride concentration
•  > 60 mmol/L in 2 tests: diagnosis of CF

Further testing

If the diagnosis remains unclear, further testing can be done.

Nasal potential difference

• Specialized test only at CF centers; further evaluates CFTR dysfunction
• Electrodes are placed in the nasal cavity, which is then bathed in a series of solutions with different salts designed to change ion flow across the membrane in predictable ways.
• Patients with CF have a more negative baseline difference and react differently to the other salts because of defective chloride transport.

Fecal elastase

Pancreatic insufficiency can be detected when screening the stool for pancreatic elastase-1, which is absent in 80% of people with CF.

Imaging

• Sinus CT: panopacification, nasal polyps
• Chest CT: bronchiectasis typically in upper lobes, may progress to be visible on radiographs

Airway culture

• Persistent detection of the following bacteria in respiratory secretion and sputum
• 80% grow S. aureus or Pseudomonas aeruginosa
• Haemophilus influenzae, Burkholderia cepacia, Stenotrophomonas maltophilia
  • All (except S. aureus) would be unusual in healthy people without CF

Treatment

Management of CF should be multidisciplinary and include specialized physicians, physiotherapists, dieticians, and/or psychological support.

Prognosis

• With optimal treatment, CF patients have a median life expectancy of 45 years.
• 50% of patients die before the age of 18 from respiratory failure.
• The prognosis depends on several factors:
  • Age 
  • Female sex
  • Gene variant 
  • Colonization by multi-drug resistant pathogens 
  • Lung function
  • Complications
  • Access to medical care 

Differential Diagnosis

The following conditions are related to cystic fibrosis:

• Bronchiectasis: a chronic condition in which the bronchi walls thicken as a result of inflammation and infection. This condition is characterized by the permanent enlargement of sections of the airways within the lungs. Patients often have flare-ups of breathing difficulties, displaying chronic cough with mucus production.
• Pneumonia: acute or chronic inflammation of lung tissue caused by infection with bacteria, viruses, or fungi. Pneumonia can be also due to toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy.
• Malabsorption: a disorder involving the inability to absorb nutrients from food, such as carbohydrates, fats, minerals, proteins, or vitamins. Lactose intolerance and celiac disease are related to malabsorption.
• Failure to thrive: children who are gaining weight or height more slowly compared with other children of similar age or sex. Usually, they present with underdevelopment of motor skills gained in early childhood, such as rolling over, standing, and walking.
• Dehydration: a condition caused by excessive loss of body fluids. Water is lost out of the individual cells of the body, leading to a net decrease in the total volume of water in the body.
• Rectal prolapse: a condition in which the rectum loses its normal attachments inside the body, thereby turning itself inside-out through the anus. Definitive treatment requires surgery.
• Allergic bronchopulmonary aspergillosis: a hypersensitivity response to the fungus Aspergillus. Patients most often affected are those with asthma or cystic fibrosis.
• Biliary cirrhosis: a chronic disease in which bile ducts are slowly degraded. With the backup of bile in the liver, patients often suffer from cirrhosis.
• Asthma: a chronic inflammatory condition characterized by reversible obstruction to airflow in the lower airways. Patients present with intermittent or persistent wheezing, cough, and dyspnea. Diagnosis is usually confirmed with pulmonary function testing that shows a reversible obstructive pattern. Treatment varies based on the severity and includes bronchodilators and inhaled corticosteroids for control of inflammation.
• Primary ciliary dyskinesia (PCD): a rare autosomal-recessive genetic disorder leading to dysfunction of the ciliated epithelium. Patients present early in childhood with recurring rhinosinusitis, otitis, respiratory infections, and eventual bronchiectasis. PCD is often associated with situs inversus and infertility.