Cystic fibrosis (CF) is a chronic, inherited disease affecting the body’s exocrine glands, which produce sweat, mucus, and digestive fluids. This progressive condition is characterized by the production of thick, sticky secretions that clog ducts, passageways, and organs. This abnormal fluid buildup leads to blockages, damage, and inflammation throughout the body. While often associated with the respiratory tract, CF is a multi-system disorder impacting nearly every major organ. Advancements in management now allow many individuals with CF to live well into adulthood.
Genetic Basis of Cystic Fibrosis
The cause of cystic fibrosis lies in mutations within the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. This gene provides instructions for the CFTR protein, which acts as an ion channel on the surface of cells in organs like the lungs and pancreas. The protein regulates the movement of chloride ions and water across the cell membrane. A functioning CFTR protein allows chloride to move out of the cell, drawing water to the surface to thin mucus and other secretions.
When the CFTR gene is mutated, the resulting protein is faulty or insufficient. This malfunction prevents chloride from moving out of the cells, trapping salt and water inside. This causes the body’s mucus and fluids to become abnormally thick and sticky. The most common mutation, Delta F508, accounts for approximately 70% of all CF cases and results in a misfolded protein that is degraded before reaching the cell surface.
CF is inherited in an autosomal recessive pattern, meaning a person must inherit two copies of the mutated CFTR gene, one from each parent, to have the disease. Individuals inheriting only one copy are carriers and generally do not exhibit symptoms. When two carriers have a child, there is a 25% chance the child will develop cystic fibrosis.
Systemic Effects on the Body
The thick, sticky secretions impact numerous organ systems. The most significant complications occur in the respiratory system, where abnormal mucus clogs the small airways. This mucus traps bacteria and pathogens, causing chronic infections, inflammation, and lung damage.
Repeated infections often lead to bronchiectasis, where the airways become widened and scarred, causing a gradual loss of lung function. This deterioration can lead to respiratory failure, the most common cause of death for people with CF. Patients often experience a persistent cough, wheezing, shortness of breath, chronic sinus infections, and nasal polyps.
In the digestive system, thick secretions block the pancreatic ducts, preventing digestive enzymes from reaching the small intestine. Since these enzymes are necessary to break down fats, proteins, and fat-soluble vitamins (A, D, E, and K), this blockage leads to malabsorption and malnutrition. This pancreatic insufficiency causes poor growth in children and difficulty maintaining weight in adults, often resulting in greasy stools. Pancreatic duct blockage can also damage the pancreas, leading to CF-related diabetes.
The malfunctioning CFTR protein also affects the reproductive system and sweat glands. Most males with CF are infertile due to the congenital bilateral absence of the vas deferens, where sperm ducts fail to develop properly because of the thick secretions. A characteristic of CF is the high salt content in sweat, which occurs because the faulty CFTR protein cannot reabsorb chloride from the sweat duct back into the body.
Diagnosis and Screening Methods
Early diagnosis of cystic fibrosis is important because timely intervention improves outcomes and life expectancy. In the United States, all newborns are screened for CF shortly after birth using Newborn Screening (NBS). This involves a heel prick to collect blood, which is tested for elevated levels of immunoreactive trypsinogen (IRT). High IRT levels suggest a blockage in the pancreatic ducts caused by CF.
A positive NBS result requires further, definitive testing. The standard method for confirming CF is the sweat chloride test, which measures the amount of salt in a person’s sweat. The test stimulates a small area of skin to produce sweat, which is then collected and analyzed.
A sweat chloride concentration of 60 millimoles per liter (mmol/L) or greater indicates cystic fibrosis. Genetic testing is also used to confirm a diagnosis, especially when sweat test results are unclear or to identify specific mutations. This testing analyzes DNA from a blood or cheek swab sample to pinpoint the two specific CFTR mutations inherited.
Modern Treatment and Management
Management of cystic fibrosis focuses on controlling symptoms and addressing the underlying protein defect. Symptomatic management involves a daily regimen of therapies designed to manage thick mucus and prevent infection.
Symptomatic Care
Airway clearance techniques, such as chest percussion and specialized devices, are used regularly to clear mucus from the lungs. Medications include inhaled antibiotics to combat chronic bacterial infections that damage the lungs. Nutritional support is also important, requiring pancreatic enzyme supplements taken with every meal and snack. These enzymes aid in the digestion and absorption of fats and nutrients, replacing those blocked from reaching the intestine.
CFTR Modulators
The most significant advancement in CF treatment is the development of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, which target the malfunctioning protein itself. These drugs are classified into different types based on their action. Potentiators help open the chloride channel on the cell surface, and correctors help the misfolded protein achieve the correct shape and move to the cell surface. The first effective modulator, ivacaftor, was approved in 2012 for a small percentage of patients with specific mutations.
A major breakthrough came with the approval of triple-combination therapies, such as elexacaftor/tezacaftor/ivacaftor, which address the most common F508del mutation. These modulators have been transformative, significantly improving lung function, reducing pulmonary exacerbations, and enhancing nutritional status. By correcting the fundamental defect, these targeted therapies have changed the trajectory of the disease for eligible patients.