SUMMARY
1. Cystic Fibrosis is one of the most common (1 in 3000) autosomal recessive disease among Caucasians. Patients classically develop persistent sinus and lung infections, pancreatic insufficiency, and elevated sweat chloride levels. The clinical features of recurrent sinopulmonary infections can mimic the phenotype of antibody deficiency syndromes.
2. This disease is caused by mutations in the CFTR protein which leads to aberrant chloride transport and generation of viscous mucous secretions in the lung, pancreas, liver, intestine, and reproductive tract.
3. Accumulation of thick mucous in the lungs leads to colonization with bacteria including Pseudomonas aeruginosa and Burkholderia cepacia. Neutrophils recruited to the lungs release proteases that lead to tissue destruction and progressive respiratory failure.
4. Meconium ileus, rectal prolapse, steatorrhea, nasal polyps, and digital clubbing are clinical clues that warrant investigation for CF.
5. The primary test for diagnosing CF is the sweat chloride test. This should be performed for patients with suggestive clinical history, patients with a family history of CF, or patients with positive CF newborn screen results.
6. Confirmatory DNA testing can be performed on patients with intermediate or positive sweat chloride test results.
OVERVIEW
Cystic Fibrosis (CF) is an autosomal recessive disease which occurs with high frequency (1 in 3000 live births) among Caucasians. However, the frequency in Hispanics (1 in 9000) and African Americans (1 in 15000) is not insignificant. This disease is characterized by progressive lung disease which eventually leads to respiratory failure. Patients suffer from chronic sinopulmonary infections similar to patients with antibody deficiency syndromes. Given the high frequency of CF, it is critical to keep this diagnosis in mind when evaluating patients for suspected immune deficiency.
Non-infectious complications include pancreatic insufficiency and fat malabsorption leading to growth failure. Liver cirrhosis and male infertility are other findings.
PATHOGENESIS
CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). To date, more than 1300 mutations have been described. Aberrant chloride transport across this channel leads to viscous secretions in the respiratory tract, pancreas, liver, intestine, and the reproductive tract. Thick mucous accumulation in the lungs leads to bacterial colonization with organisms such as Staphylococcus aureus and Pseudomonas aeruginosa. Infections with Burkholderia cepacia can be a poor prognostic sign. Neutrophils are recruited to the site of bacterial colonization and release elastase which can lead to lung tissue destruction and development of bronchiectasis. Chronic sinus infections are common in patients and can lead to the development of nasal polyps in childhood (a finding usually only seen in adults). Inability to secrete thick pancreatic secretions leads to pancreatic autodigestion and progressive damage. Impaired secretion of pancreatic lipase leads to fat malabsorption, foul smelling oily stool (steatorrhea), and failure to thrive. Meconium ileus is the presenting problem in 20% of newborns with CF. Rectal prolapse is another clinical finding which should raise suspicion for CF. Most men with CF are infertile due to aberrant development of the vas deferens.
EVALUATION
An evaluation of CF is indicated when there are suspicious clinical findings, there is a family history of CF, or a positive CF newborn screen.
Step 1: Sweat Chloride Test
This remains the best initial test to perform to diagnose CF. This test involves collection of sweat with pilocarpine iontophoresis and determination of chloride concentration. The following are the guidelines for sweat test interpretation in persons aged 6 months old and above:
- 39 mmol/L = normal
- 40 to 59 mmol/L = intermediate
- 60 mmol/L = abnormal
-Sweat testing should be repeated in patients with intermediate testing results. Genetic testing can be performed for patients with continued equivocal results. Sweat chloride testing should only be performed at an accredited CF center: www.cff.org/aboutCFFoundation/Locations/FindACareCenter/
Step 2: Mutation Analysis
DNA testing for CFTR mutations can be helpful in patients with intermediate sweat chloride test results.
MANAGEMENT
For confirmed cystic fibrosis, a multidisciplinary team approach is necessary to treat issues including pulmonary infections, impaired nutrition, diabetes, and psychosocial needs. The best care for CF patients is provided at specialized CF centers. Treatment of patients at these specialized centers is associated with better patient outcomes.
RESOURCES
Diagnostic Resources
1. Genzyme Genetic Testing
Literature Resources
1. Rowe 2005
Cystic fibrosis review
Update on cystic fibrosis