Cystic Fibrosis

Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. The gold standard for diagnosis is the sweat chloride test, which can be complemented by genetic testing. Cystic fibrosis ultimately leads to chronic inflammation and multisystem organ failure. Management includes CFTR modulator therapy and system-specific strategies for supportive care. Prognosis varies depending on treatment and complications. With optimal medical care, patients can live into their mid-40s.

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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.
Type of mutation on cystic fibrosis

Types of mutation in cystic fibrosis

Image by Lecturio.
  • 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

Small intestineThick secretions impair absorption, increasing the risk of obstruction.
  • Fails to pass meconium within 48 hrs of life in newborn
  • Constipation, abdominal pain
  • Bowel obstruction, unable to pass gas, abdominal distention, nausea, vomiting
Large intestineIncompletely digested macronutrients lead to thick stool, predisposing patient to impaction, obstruction, intussusception.
Pancreas
  • Thick secretions block pancreatic duct and impair fat absorption, leading to a deficiency of fat-soluble vitamins A, D, E, and K.
  • Decreased bicarbonate damages digestive lining and impairs absorption.
  • Pancreatic enzymes slowly destroy pancreas, leading to fibrosis and impaired endocrine function (diabetes).
Abdominal pain; abdominal cramping; bloating; frequent bulky, oily stools; weight loss; flatulence
Hepatobiliary
  • Bile is dehydrated, leading to gallstones.
  • Chronic cholestasis leads to inflammation and fibrosis, which results in cirrhosis and portal hypertension.
Right upper quadrant pain after large, fatty meals; nausea; vomiting; jaundice

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

Exacerbation of pulmonary disease
  • No single set criteria; defined as an acute change in pulmonary status
    • New or increased cough or sputum production, decreased exercise tolerance, increased respiratory rate
  • Can include loss of appetite, weight loss, fever, and fatigue
  • May lead to a spontaneous pneumothorax
  • May lead to hemoptysis (hemorrhage of pulmonary arteries, with potentially lethal outcome if blood loss > 0.5 L in 24 hours)
Chronic microbial colonization
  • Evidence of 1 pathogenic microorganism in at least 3 sputum cultures over at least 6 months
  • Toddlers:
    • Staphylococcus aureus infection
    • Haemophilus influenzae
  • Children and teenagers:
    • Pseudomonas aeruginosa (biofilm formation)
    • Stenotrophomonas maltophilia
  • Viral infections
Allergic bronchopulmonary aspergillosisAspergillus airway colonization, followed by vigorous IgE- and IgG-mediated immune response, varied presentation which can include worsening fever, malaise, mucous plugging that may not improve with antibiotics
Biliary cirrhosisBile duct obstruction in adults
Endocrine pancreatic insufficiencyDevelopment of diabetes mellitus, including the destruction of the islets of Langerhans in adulthood

Diagnosis

Cystic fibrosis testing algorithm

Testing algorithm for CF as conducted in many countries. IRT: immunoreactive trypsinogen

Image by Lecturio.

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
Newborn screening

Principle and conduction of a sweat chloride test

Image by Lecturio.

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.

Organ systemApproach to therapy
Lung infections, respiratory lung insufficiency
  • Promote lung health: CFTR modulator, endurance sports
  • Enhance airway clearance: inhaled DNase, inhaled hypertonic saline, chest physiotherapy
  • Prevention of infection: all routine childhood vaccines, annual influenza vaccine, high-risk protocol for pneumococcal vaccine, palivizumab to prevent respiratory syncytial virus infection, contact precautions in all healthcare settings
  • Bronchodilators: beta-2 adrenergic agonist before chest physio, inhaled meds or if symptomatic
  • Anti-inflammatory measures: oral azithromycin 3x/week, high-dose ibuprofen if under the age of 18 with good lung function
  • Prevention of acute exacerbations: treatment of chronic P. aeruginosa infection with inhaled tobramycin
  • Treatment of acute exacerbation: systemic antibiotics guided by culture data, intensified airway clearance, steroids only if concurrent asthma is present
  • Referral to transplant center: previously thought of as “last resort” but now recommended earlier in disease course if:
    • Rapid decline in FEV1
    • Hypoxia (paO2 < 88)
    • Hypercarbia (pCO2 > 50 on ABG)
    • Significant pulmonary hypertension OR
    • Exacerbation needing positive pressure ventilation
Hypotonic dehydration/hypochloremic alkalosis
  • Adequate hydration, liberal salt intake at baseline
  • Increase salt intake if patient or environmental factors are expected to encourage fluid loss (e.g., high heat, sweating, vomiting, diarrhea, fever)
Exocrine pancreatic insufficiencyA dose of pancreatic enzymes (defined lipase and protease concentration) with every meal
Failure to thrive
  • High-calorie diet, rich in fats
  • Enteral nutrition via feeding tube
Vitamin and mineral deficitsProphylactic substitution of liposoluble vitamins in supranormal doses, replace minerals and trace elements
CF-related diabetes
  • Different from Type 1 and Type 2 diabetes, different dietary recommendations
  • Treat with insulin

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.

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