11.14: Cystic Fibrosis

Cystic fibrosis is an inherited disorder that causes abnormally thick mucus to build up in the airways and other organs, leading to chronic lung infections and long-term breathing difficulties.

Master this section and you'll be able to:

• Describe the cause of cystic fibrosis.
• Explain the consequences of the CFTR mutations.
• Summarize major treatments for cystic fibrosis.

Cystic fibrosis (CF) is an inherited disorder that affects epithelial cells of the exocrine glands of not only the lungs, but also the pancreas, intestines, and bile ducts. We will focus only on the pulmonary aspects here and see how CF produces an obstructive lung disease.

*Cystic fibrosis (CF) is an autosomal recessive genetic disorder. An autosomal recessive disorder appears only when a person inherits two nonworking copies of a gene, one from each parent. “Autosomal” means the gene is located on one of the numbered chromosomes that both males and females share, so the condition affects all sexes equally. “Recessive” means that one working copy of the gene is enough to prevent the disease, so individuals with only one mutated copy are healthy carriers and do not show symptoms.

CF is caused by mutations in the CFTR gene, which provides instructions for making a protein that helps chloride and sodium ions move across epithelial cell membranes. When the CFTR protein does not work properly, glands that normally make thin, watery fluids instead produce very thick, sticky mucus. This mucus buildup interferes with normal function in many organ systems, especially the lungs and digestive tract.

In summary:
A person develops CF only when they inherit two mutated CFTR alleles, one from each parent. Individuals with one normal and one mutated allele are carriers and remain symptom-free. 

Inside the Biology of Cystic Fibrosis

Control of the airway fluid relies on the action of ion channels in the apical membranes of epithelial cells, and there are two channels to focus on: CFTR and ENaC. The CFTR channels let chloride out of the cell, while the ENaC lets sodium in (top panel, figure 1.19).

This exchange helps maintain a healthy fluid layer in the airway, but fails in CF because of a nonfunctioning CFTR channel (right panel on the figure below).

Figure \(\PageIndex{1}\): Ion Transport Differences in Normal vs. Cystic Fibrosis Airway Cells. In a healthy airway cell (left), a working CFTR channel allows chloride to exit the cell and helps keep sodium and water movement balanced, resulting in thin, well-hydrated mucus. In cystic fibrosis (right), the CFTR channel is defective, chloride cannot move out, and excess sodium is drawn into the cell, pulling water with it. The airway surface becomes dehydrated, leading to the buildup of thick, sticky mucus.

There are numerous mutations that are known to produce a dysfunctional CFTR channel. So what are the consequences of CFTR dysfunction?

Chloride ends up being trapped inside the cell and this leads to a greater influx of sodium through the ENaC down its electrochemical gradient, leaving a higher concentration of salt inside the cells that pulls water in from the airway lumen. The low fluid volume in the airway results in:

• heavy, viscous mucus, and
• collapse of cilia.

The defective CFTR channel causes thick mucus to build up in the airways, which blocks airflow and traps bacteria. This reduces alveolar ventilation and sets the stage for repeated lung infections. In people with cystic fibrosis, the two most common infectious organisms are Staphylococcus aureus and Pseudomonas aeruginosa. Chronic infection and inflammation can lead to several serious complications, including atelectasis (partial or complete collapse of part of a lung), pneumonia, bronchiectasis (permanently widened and damaged bronchi), and other structural airway changes.

Although cystic fibrosis affects many organs such as the pancreas, modern treatments help manage most non-pulmonary problems. Lung disease, however, remains the major cause of illness because pulmonary involvement can begin at any time — from just weeks after birth to later in childhood.

How Cystic Fibrosis Affects the Body

Lungs

• Change in the composition of the fluid lining the airways leads to thick mucus blocking airways and trapping bacteria.
• This leads to chronic cough, frequent  infections (bronchitis and pneumonia) , and progressive breathing problems.

Pancreas

• Mucus blocks digestive enzyme release.
• Causes poor nutrient absorption, slow growth, and vitamin deficiencies.

Other Effects

• Chronic sinus infections.
• Male infertility (due to blocked or absent vas deferens).
• Salty tasting skin due to high salt content in sweat.
• Poor growth, poor weight gain despite a normal food intake.

Lung disease in CF develops because the thick, sticky mucus clogs the airways, reduces normal mucociliary clearance, and triggers chronic inflammation. Over time, inflammation and repeated infections damage lung tissue and change the structure of the airways.

Early symptoms often include persistent coughing, large amounts of phlegm, and reduced exercise tolerance. Many of these problems occur when bacteria trapped in the thick mucus multiply and cause pneumonia.

In later stages, structural changes such as bronchiectasis widen and distort the major airways, making breathing even more difficult. Ultimately, lung transplantation is often necessary as CF worsens.

CF is most common among Caucasians and can be diagnosed before birth by genetic testing, or by a sweat test in early childhood.

Since 2010, essentially all newborn babies in the United States are screened for Cystic fibrosis (CF) shortly after birth.

Treatment of Cystic Fibrosis

Treatment Overview for Cystic Fibrosis

Many individuals with cystic fibrosis take one or more antibiotics regularly to suppress chronic airway infections. When pneumonia is suspected or lung function declines, antibiotics become essential and are chosen based on sputum culture results and how the patient has responded in the past. Staying current with vaccinations for respiratory illnesses is also an important part of preventive care.

Airway clearance therapy is necessary because it helps move the thick airway secretions out of the lungs. Several inhaled medications thin the mucus and improve clearance. Airway clearance may involve manual chest percussion or the use of a high-frequency chest wall oscillation vest. The vest connects to a compressor that rapidly moves air in and out of the vest, creating vibrations and pressure that loosen thick mucus and make it easier to clear.

Figure \(\PageIndex{2}\): High-Frequency Chest Wall Oscillation Vest for Airway Clearance. This vest uses rapid vibrations to loosen and mobilize thick mucus in the airways. The vest connects to a control unit that pumps air in short bursts, helping patients with cystic fibrosis clear their lungs more effectively. (CC BY 4.0; Rice University & OpenStax)
 

As lung disease progresses, some patients may be candidates for a bilateral lung transplant. A successful transplant can extend life by about five years in children and about eight years in adults.

In children under eighteen, high-dose ibuprofen can slow the loss of lung function. During times when symptoms worsen, corticosteroids help reduce inflammation and inhaled bronchodilators help reduce airway narrowing.

Gene therapy is being studied as a possible long-term treatment by delivering a normal copy of the CFTR gene into affected epithelial cells. If these cells could produce even a small amount of functional CFTR, about five to ten percent of normal, many lung symptoms could be prevented.

Because the CFTR mutation affects more than the lungs, additional care is often needed. Many patients experience digestive problems due to pancreatic insufficiency and require pancreatic enzyme supplements. Most male patients lack a vas deferens but still produce sperm, so sperm retrieval and assisted conception are options for those who want to have children.