Jeremiah Alt, MD, PhD
Bradford A. Woodworth, M.D.
Cystic fibrosis (pronounced "sis-tick fy-broh-sus" and abbreviated CF) is a disease that affects multiple systems in the body including the lungs, the digestive tract, and the sinuses. CF is inherited in an autosomal recessive fashion and is the most common lethal inherited disease in the Caucasian population, with an incidence of 1 in 20 newborns. Chromosomes (how genes or traits are carried from parent to child) come in sets of two. If a trait is “recessive”, then the expected or “healthy” trait will be expressed if there is a normal chromosome associated with it. If the individual receives two recessive genes, one from each parent, then the result is that the disease trait will be expressed. Thus, two parents who are “carriers” of the recessive trait, despite NOT expressing the diseased trait themselves, can have a child who has CF (Figure 1).
Secretory glands are found in many organs of the body and produce mucus to keep the lining of the organs moist and function as an immunological barrier, as seen in the sinuses and lungs. The basic underlying deficit in CF is the lack of a crucial protein (the Cystic Fibrosis Transmembrane Conductance Regulator or CFTR) that allows the transport of ions, specifically chloride and bicarbonate, between the cells lining the surface of the respiratory system and the liquid that coats the cells (Figure 2). Under normal conditions, the balance of transport of these ions maintains the hydration (wetness) of the liquid. One of the components of this liquid is mucus. In people who have CF, chloride ions are not well transported across the cell membranes so the mucus becomes extremely dehydrated and sticky.
Inside the respiratory system, there are small fingerlike protein projections called cilia (like tiny hairs) that transport mucus through the nose (see nasal physiology) or up and out of the lungs to be swallowed. Pushing very thin and watery mucus is much easier than pushing very thick mucus. Due to plugging or obstruction of the airway from the thick mucus, patients develop pulmonary disease. The loss of bicarbonate secretion also acidifies the airways and causes diminished function of innate immunity proteins. The abnormally thick mucus obstructs the smaller airways resulting in bronchiolitis and mucopurulent (pus) plugging of the airways. This causes permanent scarring in the lungs. Death usually results from respiratory failure.
Additionally, nearly all patients with this disease will have swelling of the mucosa and thickened, non-moving mucus that leads to sinus blockage. Subsequent infections then develop inside of the sinuses. When swelling becomes severe, large bags of watery inflamed skin may form called polyps (see chronic sinusitis with nasal polyps). This creates further mechanical obstruction in addition to the thick mucus. People with CF may develop significant sinus pain and infections. Also, the bacteria that grow inside of their sinuses can infect their lungs and worsen the lung disease that is already present.
In summary, the key fundamental steps in the disease process include:
1. A reduction of water in mucus secretions.
2. A failure to clear thick sticky mucus secretions.
3. Decreased innate immunity (self-protection) of the airway.
4. Chronic infections that are particularly localized to the sinuses and lungs.
This is quite varied amongst individuals with CF. The earliest sign of CF is meconium ileus and is seen at birth in approximately 20% of infants with CF. Meconium (first stool) becomes thickened and sticky and forms a mechanical obstruction of the intestine (ileum). This results in abdominal distention and vomiting that needs to be treated urgently. Pancreatic insufficiency is also very common and causes blunted growth and development. The most common presenting symptom is respiratory manifestations including a chronic cough, wheezing, and recurrent upper or lower airway infections. Patients with upper respiratory manifestations commonly have severe nasal polyposis and thick tenacious mucus. Undiagnosed children may have nasal polyposis as their presenting finding. Other symptoms of sinus disease include post nasal drip, headaches, constant need to clear one’s throat, nasal obstruction, loss of taste or smell, and severe bad breath.
Chest computed tomography (CT) or x-ray finding can be very helpful in diagnosing CF. Pulmonary function tests can further evaluate the extent of the pulmonary disease. This test shows low oxygen levels and reduced ability to exhale with increased residual volume in the lungs. The sweat test evaluates for elevated salt (sodium chloride) in the sweat secreted from the skin. Genetic testing is routinely utilized for diagnosis as well as to determine suitability for certain drugs, such as the CFTR protein modulator, ivacaftor (see below). Genetic testing should be considered for at-risk family members, but parents often do not know that they are carriers until they have a child with CF.
Currently there is no cure for CF. Patients benefit from a CF team consisting of multiple medical specialists, including pulmonologists and otolaryngologists. Medical therapies like hypertonic saline, intravenous and topical/nebulized antibiotics, and pancreatic enzymes have somewhat alleviated the symptoms of this disease and have helped extend expected life spans of CF patients. Nasal irrigations are particularly helpful in the sinuses to help clear thick sticky mucus. Medical treatment of the sinuses, although individually assigned to each patient, commonly consists of saline irrigations, oral or topical antibiotics, and nasal steroids. Another promising therapy is intranasal nebulized Dornase alfa (Pulmozyme), which has shown benefit in several randomized, controlled clinical trials. Surgical treatment of sinus disease could be considered for frequent recurring pulmonary exacerbations, pre or post lung transplant, and/or persistent symptoms such as headaches or nasal obstruction. Endoscopic sinus surgery removes the obstructing nasal polyps and opens the sinuses, which facilitates mucus clearance and allows access for mechanical irrigations. Sinus surgery should be accompanied by postoperative aggressive medical management.
Research efforts dedicated to improving the quality of life and life expectancy of individuals with this debilitating disease are ongoing. The recent approval of Ivacaftor by the Food and Drug Administration in January, 2012 has led to significant improvement in pulmonary and sinus disease for individuals carrying at least one copy of the G551D mutation. Other exciting drugs that affect processing and function of the CFTR protein are currently being evaluated in clinical trials.
Figure 1 – Autosomal Recessive Inheritance. If one parent is a carrier, then two out of four children will be carriers (note half blue/half black illustration). If BOTH parents are carriers, then one child will be affected, two will be carriers, and one will not have carrier status or the disease.