What is Cystic Fibrosis?

Cystic Fibrosis (CF) is one of the most common life-threatening inherited diseases, primarily affecting populations of white Caucasian descent, such as those of Europe, North America and Australasia (Table 1). CF affects about 1 in 2,500 newborn babies in the UK where the population of CF patients is in excess of 10,000. CF is an autosomal monogenic recessive disorder for which there is no cure at present.

The mutated gene responsible for this disease was identified in 1989 as the cystic fibrosis transmembrane conductance regulator (CFTR) gene, found on chromosome 7². Over 1000 disease-associated mutations of this 1480 amino acid protein have been described3 (see Table 2 for some common mutations). Some mutations result in severe disease impacting many organ systems, while other mutations produce milder symptoms. The most common CFTR mutation, accounting for approximately 70% of all mutant CFTR alleles, is the delta F508 mutation: a single phenylalanine amino acid deletion at position 508 in the protein³.

The CFTR gene product regulates and facilitates the transport of electrolytes across epithelial cell membranes. CF patients have abnormalities with chloride conductance in and out of cells. The mis-folded CFTR protein is either non-functional at the cell surface, or is retained in the endoplasmic reticulum of the cell and is targeted for degradation¹.

In spite of the fact that over 1000 CF-linked CFTR mutations described, less than 20 mutations occur at a frequency greater 0.1%, and only 5 mutations at a frequency more than 1%¹.

Symptoms

CF is a pleiotropic disease affecting all exocrine epithelia, not just that of the lungs, therefore CF is a complex and demanding disease¹. Most people with CF will suffer from chronic lung infections, gradually declining respiratory function and eventual respiratory failure which is the most common cause of mortality in CF patients.

Early symptoms of CF are; increased susceptibility to lung infections, persistent coughing and increased sputum production. As infecting microbes fail to be cleared, excessive inflammation begins to cause permanent damage to the lung architecture, resulting in bronchiectasis and pulmonary hypertension and hypoxia⁴. Late stages of CF require the use of air masks or ventilators by patients to mechanically assist breathing. CF can also lead to nutrient loss by the progressive scarring of the pancreas, which becomes dehydrated in a fashion similar to that of the lungs⁴.

Physiological aspects

Chloride ion flow through CFTR is required for normal function of epithelia that line airways, the intestinal tract and ducts in the pancreas, testes and sweat glands³. Without anion flow, water movement slows and dehydrated mucus clogs ducts, collecting in the lung where it ultimately leads to propagation of lethal bacterial infections3. In the healthy lung, foreign particles are removed from the airways through the surface liquid layer over the beating cilia5. The depth of the liquid layer is regulated by a balance between the opposing processes of sodium absorption and chloride secretion⁵.

This mechanical clearance of mucus, known as the mucociliary escalator, is considered the primary innate airway defense mechanism4. Additionally normal functioning epithelia have a “chemical shield” with the production of salt-sensitive defensins that are secreted into the airway lumen, and the production of a low-salt (<50 mM NaCl) liquid on airway surfaces that activates the defensins, together protecting the lung against inhaled bacteria5,6. In CF patients, chloride secretion in epithelia is impaired while sodium absorption is increased which causes mucus to accumulate. Respiratory pathogens which are usually removed by mucociliary escalator are no longer cleared as the normally beating cilia are matted in viscous mucus4. Respiratory pathogens are therefore able accumulate to develop polymicrobial biofilm-based infections in the lower airways which causes inflammation of the lungs leading to tissue damage.

For further information about CF, you are referred to the following websites:

http://www.cftr.info
http://en.wikipedia.org/wiki/Cystic_fibrosis
http://www.cysticfibrosis.org.uk
http://www.cff.org