Cystic Fibrosis

Disease Overview

Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by changes (variants) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that affect the regulation of water and salt flow into and out of cells.¹ CF affects the exocrine glands, leading to the production of abnormally thick mucus. This mucus clogs essential organs such as the lungs, pancreas and intestines, causing inflammation, obstruction and frequent infections.² CF affects multiple organ systems, with common symptoms including the following:

• chronic cough
• shortness of breath
• persistent lung infections
• malnutrition and poor growth
• difficulty with bowel movements
• Salty tasting skin

Historically, lung (pulmonary) disease has been the major cause of health problems and death related to CF. Over time, CF causes progressive lung damage, leading to scarring of the airways, loss of lung function and eventual respiratory failure.  Research identifying the structure and function of the CFTR gene has helped develop drugs that treat the basic defect, modulating CFTR to increase the quantity of the protein produced by the gene and how well it functions. These drugs work for only specific CFTR gene variants but could improve the health of most people with CF. Nearly 90% of people with CF have a variant that is responsive to these medications, although not all are able to tolerate the treatment.¹

A newborn screening program in the U.S. allows for early diagnosis, which has significantly reduced the number of people identified later in life, however, people still can be diagnosed in adulthood.³ The incidence of CF is estimated to be 1/4,000 births in the United States.⁴

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Synonyms

• CF
• fibrocystic disease of pancreas
• mucoviscidosis
• pancreatic fibrosis

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Signs & Symptoms

Cystic fibrosis (CF) causes mucus in the body to become thicker and stickier than normal, which can block vital passageways and tubes in the body. These blockages primarily affect the lungs and pancreas, but they can also impact on the intestines, liver, sweat glands, and reproductive organs.⁵

The symptoms of CF can vary widely between individuals. Some people may only have mild respiratory issues, while others experience severe complications in multiple organs. Not everyone with CF will have all the symptoms discussed below. ^2,6

Respiratory problems ^7,8,9

Many people with CF experience breathing problems due to mucus blocking their airways. These blockages can lead to more serious lung diseases over time. Possible symptoms and complications include:

• Persistent mucus or phlegm, where thick mucus often gets stuck in the airways, making it hard to breathe
• Wheezing, a whistling sound when breathing due to airway narrowing
• Shortness of breath, difficulty breathing because of mucus clogging the lungs
• Chronic respiratory infections where frequent infections in the lungs and sinuses can cause inflammation and damage
• Difficulty breathing where breathing may feel harder or labored
• Nasal polyps, growths inside the nose caused by chronic inflammation
• Coughing up blood (hemoptysis) which occurs when inflamed lung tissues bleed
• Lung collapse (pneumothorax), a condition where air leaks into the space between the lung and chest wall, causing the lung to collapse
• Abnormally rapid breathing (tachypnea) as the body struggles to get enough oxygen

Pancreatic problems⁷

Most people with CF have pancreatic insufficiency, meaning their pancreas cannot produce enough enzymes to digest food or hormones like insulin to regulate blood sugar

• Mucus blockage as thick mucus can block pancreatic ducts, preventing enzymes from reaching the intestines to help digest and absorb nutrients
• Malabsorption, the inability to properly absorb nutrients leads to deficiencies and can cause:
  • Poor growth and weight gain in children (failure to thrive)
  • Nutritional deficiencies, such as low levels of fat-soluble vitamins (A, D, E, and K)

Gastrointestinal problems^10,11

CF can also affect the digestive system causing:

• Meconium ileus, found in about 10–20% of infants with CF, where the first stool (meconium) is abnormally thick and blocks the intestines at birth
• Constipation and abdominal pain, with many people with CF having trouble passing stools
• Distal intestinal obstruction syndrome (DIOS), a blockage in the small intestine caused by a mix of undigested food, mucus and stool. DIOS can cause:
  • Stomach aches or cramping
  • Nausea, vomiting and loss of appetite
  • Watery, foul-smelling stools

 People with CF may also have a higher risk of:⁷

• Celiac disease, inflammatory bowel disease and gastrointestinal cancers.
• Portal hypertension, high blood pressure in the vein carrying blood from the intestines to the liver
• Bile duct obstruction, the blockage of the tubes carrying bile from the liver

 Additional symptoms include:¹²

• Bloating (abdominal distention)
• Gastroesophageal reflux where stomach contents flow back into the esophagus, causing heartburn
• Rectal prolapse where part of the rectum protrudes through the anus due to chronic straining or coughing
• Gallbladder issues where thick mucus in the gallbladder can lead to gallstones.
• Hormonal problems that can include:
  • Cystic fibrosis-related diabetes (CFRD) due to damage to the pancreas, resulting in the pancreas producing less insulin and the body’s cells become resistant to insulin. This leads to difficulty controlling blood sugar levels, gut abnormalities and altered intestinal movements and an increased risk of liver disease.
  • Osteopenia, lower-than-normal bone density
  • Osteoporosis, the severe loss of bone density, increasing the risk of fractures
• Exocrine system issues because CF causes the sweat glands to lose excessive salt because the CFTR protein cannot reabsorb it. This leads to:⁵
  • High salt levels in sweat (testing the salt content of sweat is a key diagnostic method for CF)
  • Salt loss syndrome due to excessive salt loss can upset the body’s balance of minerals causing:
    • Dehydration
    • Abnormal heart rhythms
    • Overheating during physical activity
• Musculoskeletal problems because CF can affect the bones, joints and posture causing:^7,14
  • Clubbing, the rounded or flattened tips of fingers or toes due to low oxygen levels
  • Arthritis, joint inflammation
  • Postural defects, such as thoracic kyphosis (hunchback) or scoliosis (curved spine)
  • Osteopenia and osteoporosis, weak or brittle bones that are more prone to fractures
  • Genital and urinary problems because CF can affect fertility differently in males and females:
  • Congenital bilateral absence of the vas deferens (CBAVD): This means that the small tubes that carry sperm from the testes are missing or blocked
  • Men with CF produce sperm but often have low sperm counts or poor sperm motility, making them infertile but not sterile.
  • Women with CF are usually fertile, but thick cervical mucus can block sperm from reaching the egg and irregular ovulation may occur in women with severe disease or malnutrition (note that the CFTR modulators medications can improve cervical mucus and increase pregnancy rates).

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Causes

Cystic fibrosis is caused by changes (variants) of the CFTR gene.

The CFTR gene is primarily active (expressed) in cells lining the airways, gastrointestinal tract, pancreas, sweat glands and genitourinary system. The gene controls the production of a protein that regulates the transfer of chloride and sodium across cell membranes. Without chloride, sodium cannot form salt water. In many organs, this leads to abnormally thick secretions (mucus), leading to tissue damage. This thick mucus in the lungs allows bacteria to accumulate, leading to inflammation and pulmonary damage. In the pancreas, thick secretions block the ducts that allow pancreatic enzymes to enter the digestive system, creating pancreatic insufficiency. This blockage of ducts affects the function of many organs (liver disease, infertility/subfertility, bowel obstruction, pansinusitis).⁷

There are over 700 disease-causing CFTR variants identified resulting in a large range of protein dysfunction and variable signs and symptoms of the disease. The most common variants are classified into 6 groups or classes. Classes I, II, and III result in little to no CFTR protein function and are often associated with more severe disease, whereas classes VI, V, and IV result in some CFTR protein function and milder disease.¹

CF is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.⁵

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Affected populations

CF affects at least 100,000 individuals worldwide, with 40,000 individuals in the US.⁷ One thousand new cases are diagnosed each year, with males and females affected in equal numbers. The disorder occurs predominantly among Caucasians but is clearly affecting other races. CF occurs in many different ethnicities and should not be limited to Caucasians in consideration. CF occurs in approximately one of every 3,200 live Caucasian births compared to one in 3,900 live births of all Americans. Although incidences of CF are increased in several populations (ex: Amish, Ashkenazi Jewish, etc.), CF occurs in individuals of all ethnicities. CF affects individuals of all ages; with improved survival associated with treatment now more than 50% of people with CF in the US are adults (i.e. older than age 18 years). In many cases, CF is apparent soon after birth, and most affected individuals are diagnosed by age 3. Most people with CF are now identified at birth through newborn screening, but there are still adults being diagnosed.⁶

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of cystic fibrosis (CF). Comparisons may be useful for a differential diagnosis.

Primary ciliary dyskinesia (PCD) is a rare disorder involving the tiny hair-like structures that cover many cells of the body. Cilia in the respiratory passageways help move mucus out of these passageways. In individuals with PCD, the cilia are defective, allowing mucus to build up in the airways and respiratory passages of the body. Symptoms may include inflammation of the sinuses (sinusitis), repeated respiratory infections and pneumonia, which can cause progressive lung damage.^5,9  PCD can also affect the middle ear and the reproductive organs. PCD is inherited in an autosomal recessive pattern.²

Shwachman syndrome is a rare genetic disorder with multiple and varied symptoms. The disorder is typically characterized by signs of insufficient absorption (malabsorption) of fats and other nutrients due to abnormal development of the pancreas (pancreatic insufficiency) and improper functioning of the bone marrow (bone marrow dysfunction), resulting in low levels of circulating blood cells (hematologic abnormalities).^16,18 Additional characteristic findings may include short stature, abnormal bone development affecting the rib cage and/or bones in the arms and/or legs (metaphyseal dysostosis), and/or liver abnormalities. Shwachman syndrome is thought to follow autosomal recessive inheritance.⁶

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Diagnosis

A diagnosis of cystic fibrosis may be suspected based on newborn screening, identification of characteristic symptoms (e.g., pulmonary disease, pancreatic insufficiency) or a positive family history. ^3,11 All 50 states have newborn screening for CF. In most states, immunoreactive trypsinogen (IRT) assays are performed on dried blood spots from newborns. The IRT assays measure the amount of trypsinogen in a person’s blood. IRT assays are used as a screening test for cystic fibrosis (CF) in newborns and to diagnose pancreatic problems in children and adults. Trypsinogen is synthesized in the pancreas and high IRT levels are typically seen in CF. People who have abnormal IRT results must be followed up with sweat testing and/or molecular genetic (DNA-based) testing.^16,3

Sweat testing is a painless and simple procedure that measures the amount of salt in the sweat.³ Elevated chloride level results (≥60 mEq/L) establish a diagnosis of CF. Intermediate chloride level results (30-59 mEq/L) require nasal potential difference (NPD) testing¹. The NPD test measures how well the cells in the nasal passage are moving ions (charged particles), which can be used to diagnose CF as people with CF often have an abnormal test due to a faulty protein that regulates ion movement.

After diagnosis, the parents of the affected person should receive molecular genetic testing to confirm that both parents are carriers of a CFTR variant.

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Standard Therapies

Cystic fibrosis (CF) is a complex condition that requires individualized and tailored treatments to address its impact on different parts of the body. While there is no cure, the treatment focuses on reducing thick mucus in the lungs, preventing infections, managing digestive issues and supporting overall health.⁵ Treatment may include:

• Pulmonary (lung) therapies for long-term care
  • Airway clearance techniques which are methods that help loosen and clear mucus from the lungs¹⁰
  • Chest physiotherapy: Applying cupped hands to the chest or back to dislodge thick mucus
  • Mechanical oscillating devices: Special vests or devices vibrate the chest to loosen mucus
• Mucolytics (mucus thinners)^1,16
  • Dornase alfa: This is an aerosolized medication that is inhaled using a nebulizer. It thins mucus, making it easier to clear from the airways.
  • Hypertonic saline or mannitol: These aerosolized medications hydrate the airways and help clear mucus more effectively.
• Antibiotics to treat or prevent lung infections which are common in CF ^1,17
  • Inhaled antibiotics like TOBI (tobramycin) and Cayston (aztreonam) used chronically to suppress bronchopulmonary infections caused by Pseudomonas aeruginosa
  • Oral or intravenous antibiotics for severe infections
  • Pulmonary exacerbations (acute worsening of respiratory symptoms) can be managed with 10–14-day courses of antibiotics to decrease bacteria in the lungs and improve lung function.¹
• Bronchodilators: These medications, like albuterol, help open airways, making it easier to breathe and clear mucus.¹
• Anti-inflammatory agents that reduce swelling in the lungs and improve breathing over time
• Breathing support for severe lung disease such as oxygen therapy, pulmonary rehabilitation, ventilators and extracorporeal membrane oxygenation (ECMO) for advanced cases.²¹
• CFTR Modulators: CFTR modulators are medicines designed to fix the underlying protein problem caused by CF. These treatments work only for people with specific CF gene variants. The following are the FDA-approved modulators:
  • Ivacaftor (Kalydeco) is a CFTR potentiator that opens the protein channel to allow chloride and bicarbonate to flow through the cell membrane.
  • Ivacaftor/lumacaftor (Orkambi) combines the corrector lumacaftor with the potentiator ivacaftor. This pairing helps CFTR protein reach the cell surface and increases the amount of available CFTR protein. As of 2022, it is approved for people with CF aged 1 and older who have two F508del gene variants.
  • Tezacaftor/ivacaftor (Symdeko) combines the corrector tezacaftor with the potentiator ivacaftor to improve CFTR protein function and keep it working longer. It has fewer side effects (like chest tightness) and drug interactions compared to Orkambi. As of 2019, it is approved for people with CF aged 6 and older who either have two F508del gene variants or have one of 154 specific variants.
  • Elexacaftor/ivacaftor/tezacaftor (Trikafta) combines two correctors (elexacaftor and tezacaftor) with the potentiator ivacaftor. This combination helps the CFTR protein work better than treatments with fewer drugs. It improves lung function and helps more people with CF than earlier treatments. It is approved for people with CF aged 2 and older who have at least one F508del variant or one of 271 other variants.
  • Vanzacaftor/tezacaftor/deutivacaftor (Alyftrek) combines two correctors (vanzacaftor and tezacaftor) to help the CFTR protein reach the cell surface and form the right shape, plus deutivacaftor, a modified potentiator, to open the protein’s chloride channel. It improves lung function and lowers sweat chloride levels better than Trikafta. As of January 2025, it is approved for people with CF aged 6 and older who are eligible for Trikafta or have one of 31 rare variants.
• Managing digestive problems in CF ^2,11,12
  • Nutritional support: A high-calorie diet and supplements of fat-soluble vitamins (A, D, E, and K) are essential to meet the body’s needs.
  • Pancreatic enzyme replacement therapy: Supplements help the body digest food and absorb nutrients when the pancreas isn’t working properly.
  • Preventing malnutrition: Early neonatal screening and intervention can prevent growth delays in infants diagnosed with CF.

In severe cases, lung transplantation may be an option for people with advanced-stage lung disease. This option requires careful consideration of risks and benefits and long-term commitment to anti-rejection medications. ^{3, 20}

Because CF affects many systems, patients are cared for by a team of specialists, including pulmonologists, gastroenterologists, nutritionists, physical therapists and genetic counselors as well as mental health and fertility specialists, as needed. ²¹ Working with a CF care team can help affected people manage their symptoms, prevent complications and have healthier lives.

Patients and families should consult genetic counselors to help them understand CF inheritance and assess risks for future children.⁶

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

1. Ong T, Ramsey BW. Cystic fibrosis: A review. JAMA. 2023;329(21):1859-1859. doi:https://doi.org/10.1001/jama.2023.8120
2. Kasper, DL, Fauci AS, Longo DL, et al. Eds. Harrison’s Principles of Internal Medicine.16th ed. McGraw-Hill Companies. New York, NY; 2005:419-420.
3. Farrell PM, Rosenstein BJ, White TB, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr 2008;153:S4-S14.
4. Scotet V, Gutierrez H, Farrell PM. Newborn Screening for CF across the Globe—Where Is It Worthwhile? International Journal of Neonatal Screening. 2020; 6(1):18. https://doi.org/10.3390/ijns6010018
5. Behrman RE, Kliegman RM, Jenson HB. Eds. Nelson Textbook of Pediatrics. 17th ed. Elsevier Saunders. Philadelphia, PA; 2005:1437-1449.
6. Welsh MJ, Ramsey BW, Accurso F, Cutting GR. Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Metabolic & molecular bases of inherited disease. 8th ed. Vol. 3. New York: McGraw-Hill, 2001:5121-5188.
7. Savant A, Lyman B, Bojanowski C, Jariya Upadia. Cystic Fibrosis. Nih.gov. Published August 8, 2024. https://www.ncbi.nlm.nih.gov/books/NBK1250/#cf.Nasal_Transmembrane_Epithelial_Potent
8. Moskowitz SM, Gibson RL, Effmann EL. Cystic fibrosis lung disease: genetic influences, microbial interactions, and radiological assessment. Pediatr Radiol. 2005;35:739-757.
9. Flume PA, Mogayzel PJ Jr, Robinson KA, Rosenblatt RL, Quittell L, Marshall BC; Clinical Practice Guidelines for Pulmonary Therapies Committee; Cystic Fibrosis Foundation Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax. Am J Respir Crit Care Med. 2010;182:298-306.
10. Flume PA, Robinson KA, O’Sullivan BP, Finder JD, Vender RL, Willey-Courand DB, White TB, Marshall BC; Clinical Practice Guidelines for Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respir Care. 2009;54:522-537.
11. Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, Spear SL, Michel SH, Parad RB, White TB, Farrell PM, Marshall BC, Accurso FJ. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009 Dec;155(6 Suppl):S73-93.
12. Robertson MB, Choe KA, Joseph PM. Review of the abdominal manifestations of cystic fibrosis in the adult patient. Radiographics. 2006;26:679-690.
13. Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B; CFRD Guidelines Committee. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33:2697-2708.
14. Ong T, Ramsey BW. Modifying disease in cystic fibrosis: current and future therapies on the horizon. Curr Opin Pulm Med. 2013;19:645-651.
15. Nick JA and Rodman DM. Manifestations of cystic fibrosis diagnosed in adulthood. Curr Opin Pulm Med. 2005;11:513-518.
16. Flume PA, O’Sullivan BP, Robinson KA, Goss CH, Mogayzel Jr PJ, Willey-Courand DB, Bujan J, Finder J, Lester M, Quittell L, Rosenblatt R, Vender RL, Hazle L, Sabadosa K, Marshall B; Cystic Fibrosis Foundation, Pulmonary Therapies Committee Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007;176:957-69.
17. Sharma GD. Cystic Fibrosis. Medscape. Last Update Oct 03, 2024. Available at: https://emedicine.medscape.com/article/1001602-overview Accessed Jan 15, 2025.
18. Yamada T, Alpers DH, Kaplowitz N, Laine L, et al. Eds. Textbook for Gastroenterology. 4th ed. Lippincott Williams & Wilkins. Philadelphia, PA; 2003:2153-2159, 2636-2637.
19. Konstan MW, Wagener JS, Pasta DJ, et al. Clinical use of dornase alpha is associated with a slower rate of FEV1 decline in cystic fibrosis. Pediatr Pulmonol 2011; 46:545–553.
20. Brigman C, Feranchak A. Liver involvement in cystic fibrosis. Curr Treat Options Gastroenterol. 2006;9:484-496.
21. National Heart, Lung, and Blood Institute. Cystic fibrosis – treatment. www.nhlbi.nih.gov. Last updated on November 15, 2024. https://www.nhlbi.nih.gov/health/cystic-fibrosis/treatment Accessed Jan 15, 2025.

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