Cystic Fibrosis

Cystic Fibrosis

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Cystic Fibrosis is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

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

Disorder Subdivisions

  • None

General Discussion

Cystic fibrosis is a genetic disorder that often affects multiple organ systems of the body. Cystic fibrosis is characterized by abnormalities affecting certain glands (exocrine) of the body especially those that produce mucus. Saliva and sweat glands may also be affected. Exocrine glands secrete substances through ducts, either internally (e.g., glands in the lungs) or externally (e.g., sweat glands). In cystic fibrosis, these secretions become abnormally thick and can clog up vital areas of the body causing inflammation, obstruction and infection. The symptoms of cystic fibrosis can vary greatly in number and severity from one individual to another. Common symptoms include breathing (respiratory) abnormalities including a persistent cough, shortness of breath and lung infections; obstruction of the pancreas, which prevents digestive enzymes from reaching the intestines to help break down food and may result in poor growth and poor nutrition; and obstruction of the intestines. Cystic fibrosis is slowly progressive and often causes chronic lung damage, which eventually results in life-threatening complications. Because of improved treatments and new treatment options, the outlook and overall quality of life of individuals with cystic fibrosis has improved and more than 40 percent of individuals with the disorder are adults. Cystic fibrosis is caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is inherited as an autosomal recessive trait.

Symptoms

The symptoms of cystic fibrosis result because mucus secretions, which are normally thin and slippery and serve as a protective lubricant, are abnormally thick and sticky. Other secreted material such as saliva, sweat and digestive juices may also be affected. These abnormal secretions can clog up vital tubes, ducts and passageways throughout the body.



Multiple organ systems may be affected by cystic fibrosis, especially the lungs and pancreas. The intestines, liver, sweat glands and reproductive organs also are frequently affected. The symptoms of cystic fibrosis can vary greatly from one individual to another. Some individuals may only have respiratory problems without other complications. Some individuals may only have a few mild symptoms; others may have serious complications. The severity of specific symptoms also varies. In early life, many individuals may have mild respiratory complications, while others may have serious, life-threatening respiratory complications. Affected individuals will not have all the symptoms discussed below.



Cystic fibrosis is often apparent shortly after birth, but before newborn screening, when symptoms were not severe, CF may not have been detected until years later and, in rare cases, even as late as during adulthood. Most cases diagnosed in adulthood have no associated symptoms (asymptomatic) or only very mild symptoms. At this time, newborn screening for CF is provided throughout the United States, and thus it has become much rarer for CF to be newly diagnosed later in life.



Affected individuals develop a variety of breathing (respiratory) complications due to the production of thick, sticky mucus that clogs various air passages in the body. Associated symptoms include a persistent cough that often produces mucus or phlegm (productive cough), wheezing, and shortness of breath. Because mucus clogs the airways, bacteria become trapped and accumulate within the lungs and air passages making individuals particularly prone to developing repeated (chronic) respiratory infections that lead to inflammation of the main air passages of the lungs (bronchitis), inflammation of the sinuses (sinusitis) and inflammation of the lungs. Clogging of the airways with mucus may also make it difficult to breath.



The immune system of individuals with cystic fibrosis responds to an infection by sending white blood cells to attack the infection. After attacking the infection, white blood cells breakdown and further clog the airways. Debris from the white blood cells can be very destructive to lung tissue, and is thought to be a major contributor to the lung damage that occurs in cystic fibrosis. The repeated cycle of infection and immune system response progressively damages the lungs. Chronic mucus blockage and infection of the respiratory passageways may cause them to become abnormally widened (bronchiestasis), which permits more mucus to build up and further increase the risk of infection. Eventually, continued damage to the lungs can cause life-threatening respiratory failure or enlargement and improper function of the lower right chamber (ventricle) of the heart (cor pulmonale). Enlargement of the ventricle occurs because the heart must work harder to try and pump blood through the damaged lungs.



In many cases, cystic fibrosis causes pancreatic insufficiency. The pancreas is a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other hormones such as insulin, which helps break down sugar. When mucous builds up in the pancreatic ducts, it may block the enzymes from reaching the intestines and helping the breakdown and absorption of food and nutrients. Failure of the body to breakdown and absorb nutrients is called malabsorption and can result in a variety of nutritional deficiencies in affected individuals. In childhood, it may result in failure of an affected child to grow and gain weight at the expected rate for age and sex (failure to thrive). Affected individuals may also have large, loose, foul-smelling stools that contain and excess of fat (steatorrhea) and other nutrients due to malabsorption.



The first symptom in 10-20% of cases diagnosed during infancy is meconium ileus -obstruction of the intestines at birth with a thick, tarry substance called meconium. Meconium is the medical term for an infant's first stool, which is passed shortly after birth.



CF causes an abnormality that prevents the absorption of salt from sweat, which results in higher than normal levels of salt in the sweat. Salt depletion may upset the balance of minerals in the body, causing abnormal heart rhythms or the body to overheat.



Mucus can also accumulated within the small tubes that carry bile from the liver to the intestines (bile ducts) causing obstruction and inflammation. In some cases, high blood pressure of the major vein that carries blood to the liver from the digestive organs may occur (portal hypertension). Obstruction of the bile ducts can damage the liver, eventually leading to scarring of the liver (cirrhosis). Damage to the liver can potentially become life-threatening.



Most boys with cystic fibrosis are born without the small tubes that carry sperm out from the testes (congenital absence of the vas deferens) resulting in infertility. In other cases, male infertility may be caused by underdevelopment (atrophy) or damage (fibrosis) of the vas deferens. In some girls, fertility may be reduced due to the accumulation of abnormal mucus in the cervix and irregular menstrual periods.



Additional respiratory symptoms may be associated with cystic fibrosis including the development of small growths in the nose (nasal polyps), rounding or flattening (clubbing) of the tips of the fingers or toes, coughing up of blood (hemoptysis), recurrent episodes of lung collapse (pneumothorax), and abnormally fast breathing (tachypnea).



Additional gastrointestinal symptoms associated with cystic fibrosis may occur including recurrent abdominal pain, bloating (distention) of the abdomen, backflow of the contents of the stomach into the tube (esophagus) that connects the back of the mouth to the stomach (gastroesophageal reflux) and protrusion of part of the rectum through the anus (rectal prolapse). In some cases, the gall bladder may be filled with thick, sticky mucus and fail to function properly. The gall bladder is a small, pear-shaped organ located under the liver that stores bile. Some individuals may develop gall stones.



Individuals with cystic fibrosis may be at risk for developing cystic fibrosis-related diabetes mellitus (CFRD). CFRD may occur in some adolescents with cystic fibrosis, although the prevalence increases during adulthood. The onset of CFRD is slow and individuals may not have symptoms (asymptomatic). CFRD develops due to damage to the pancreas (which limits insulin production) and increased resistance to insulin. CFRD can also worsen lung function in affected individuals.



Another specific condition that may develop in individuals with cystic fibrosis is known as distal intestinal obstruction syndrome (DIOS), in which food, mucus and stool clog the intestines. This condition can cause stomach aches, bloating, cramping, nausea and loss of appetite. In severe cases, it may cause pain, vomiting and watery stools. The incidence of DIOS appears to increase with age; most cases tend to occur in adolescents and adults.

Causes

Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This defective gene is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.



Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, 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 defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.



Investigators have determined that the CFTR gene is located on the long arm (q) of chromosome 7 (7q31.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 7q31.2" refers to band 31.2 on the long arm of chromosome 7. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



The CFTR gene primarily is 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. Accordingly, investigators speculate that inheritance of the defective CFTR gene results in disruption of chloride and sodium transfer, ultimately leading to low levels of certain bodily fluids (dehydration), abnormally thick mucus and other glandular secretions, salt loss, and impaired glandular functioning.

Affected Populations

Cystic fibrosis is the most common, life-limiting recessive genetic disorder in Caucasians.

Approximately 30,000 people have cystic fibrosis in the United States. One thousand new cases are diagnosed each year, with males and females affected in equal numbers. The disorder occurs predominately among Caucasians, occurring in approximately one of every 3,200 live Caucasian births compared to one in 3,900 live births of all Americans. Among African Americans, CF is manifest in about one in 15-17,000 live births. There is also a small but significant number of Americans of Asian descent who are affected by the disorder. Most individuals are diagnosed by age three.



In many cases, CF is apparent soon after birth and most affected individuals are diagnosed by age 3. Approximately 10% of those affected were diagnosed after 18 years of age, but this figure is falling because of the institution of newborn screening.

Standard Therapies

Diagnosis

A diagnosis of cystic fibrosis may be suspected based upon identification of characteristic symptoms (e.g., pulmonary disease, pancreatic insufficiency) or a positive family history. The standard diagnostic test for cystic fibrosis is the sweat test, a painless and simple procedure that measures the amount of salt in the sweat. Genetic testing can identify carriers of the defective gene. In May 2005, the U.S. Food and Drug Administration (FDA) approved the first DNA-based blood test to help detect cystic fibrosis. The Tag-It Cystic Fibrosis Kit directly analyzes human DNA to find genetic variations indicative of the disease. At present, all 50 States have newborn screening for CF. Immunoreactive trypsinogen (IRT) assays are performed on dried blood spots from newborns. Trypsinogen is synthesized in the pancreas and IRT levels are elevated in CF. Abnormal IRT results are followed up with sweat testing and/or molecular genetic (DNA-based) testing to confirm the diagnosis.



Treatment

There is at present no cure for cystic fibrosis. Treatment depends upon the stage of the disease and the specific organs that are involved. Treatment is geared toward reducing the thickness and amount of mucus in the airways, preventing infections, preventing blockage of the intestines and ensuring the proper intake of vitamins and nutrients.



Various forms of chest physical therapy, such as applying cupped hands vigorously to the back and chest, may help to dislodge thick mucus from the lungs and maintain clear airways. Some physical therapy techniques require assistance from family members or friends; others can be performed by adults with cystic fibrosis without aid. In some cases, devices such as a mechanical vest may be used to help clear airways. This inflatable vest creates vibrations (high-frequency air waves) that loosen mucus in the chest. Other devices require affected individuals to blow into a tube, which helps loosen and dislodge mucus.



Antibiotics may be used to treat lung infections. In addition, inhaling particular medications via nebulizers may help to wet and thin the mucus secretions. The antibiotic drugs tobramycin solution for inhalation (TOBI®, manufactured by Novartis) and aztreonam for inhalation (Cayston®, manufactured by Gilead) have been approved by the FDA for the treatment of bronchopulmonary infections of Pseudomonas aeruginosa (the most common source of chronic lung infection) in individuals with cystic fibrosis.



When the gastrointestinal system is involved, affected individuals may need to eat an enriched diet and/or take replacement vitamins, especially vitamins A, D, E and K. Also, studies have shown that neonatal screening may provide an opportunity to prevent malnutrition in infants with cystic fibrosis. Pancreatic insufficiency may be treated by enzyme replacement therapy and diet.



The drug dornase alfa (Pulmozyme®) inhalation solution was approved by the FDA for the treatment of CF in 1993. It was the first new drug therapy to be developed exclusively for CF in 30 years. In clinical trials, this mucus-thinning drug reduced the rate of respiratory infection and improved pulmonary function. FDA approval is limited to those over the age of five years. Pulmozyme is a mucolytic, a drug designed to help thin, loosen and clear mucus, and is manufactured by Genentech, Inc.



Ivacaftor (Kalydeco), formerly known as VX-770, by Vertex Pharmaceuticals was approved by the FDA in 2012 as a treatment for cystic fibrosis arising from the G551D-CFTR mutation, as it is proven to be effective only in patients with this mutation. The drug targets abnormal chloride trafficking in cystic fibrosis, which is the condition's underlying cause. It works by increasing the time that activated CFTR channels at the cell surface remain open, allowing for more normal chloride flux in lung tissue.



Medications that widen the bronchial tubes and aid in the clearing of mucus (bronchodilators) may be used in some cases. Albuterol is an example of a bronchodilator. Ibuprofen in high doses has been show to slow the rate of lung function decline in individuals with cystic fibrosis. Treatment of individuals with cystic fibrosis with hypertonic saline (sterilized, extra-salty water) has shown better mucus clearance and improved lung function.



In severe cases of cystic fibrosis, a lung transplant may be necessary. A decision concerning lung transplant is made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.



Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

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 web site.



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: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

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.



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.



Behrman RE, Kliegman RM, Jenson HB. Eds. Nelson Textbook of Pediatrics. 17th ed. Elsevier Saunders. Philadelphia, PA; 2005:1437-1449.



JOURNAL ARTICLES

Robertson MB, Choe KA, Joseph PM. Review of the abdominal manifestations of cystic fibrosis in the adult patient. Radiographics. 2006;26:679-690.



Brigman C, Feranchak A. Liver involvement in cystic fibrosis. Curr Treat Options Gastroenterol. 2006;9:484-496.



Nick JA and Rodman DM. Manifestations of cystic fibrosis diagnosed in adulthood. Curr Opin Pulm Med. 2005;11:513-518



Moskowitz SM, Gibson RL, Effmann EL. Cystic fibrosis lung disease: genetic influences, microbial interactions, and radiological assessment. Pediatr Radiol. 2005;35:739-757.



Cohn JA, Mitchell RM, Jowell PS. The role of cystic fibrosis gene mutations in determining susceptibility to chronic pancreatitis. Gastroenterol Clin North Am. 2004;33:817-837.



Koletzko S, Reinhardt D. Nutritional challenges of infants with cystic fibrosis. Early Hum Dev. 2001;65 Suppl:S53-61.



Smyth A, Walters S. Prophylactic antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2001;(3):CD001912.



Jaffe A, Bush A. Cystic fibrosis: review of the decade. Monaldi Arch Chest Dis. 2001;56:240-47.



Moran A, Hardin D, Rodman D, et al. Diagnosis, screening and management of cystic fibrosis related diabetes mellitus: a consensus conference report. Diabetes Res Clin Pract. 1999;45:61-73



INTERNET

Sharma GD. Cystic Fibrosis. Emedicine Journal, December 1, 2011. Available at: http://www.emedicine.com/PED/topic535.htm Accessed on: December 27, 2011.



Moskowitz SM, Chmiel JF, Sternen JF, Cheng E, Cutting GR. Updated: 02/19/2008. CFTR-Related Disorders. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org



Mayo Clinic for Medical Education and Research. Cystic Fibrosis. March 2, 2010. Available at: http://www.mayoclinic.com/health/cystic-fibrosis/DS00287 Accessed On: December 27, 2011.



McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 219700; Last Update: 9/8/11. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=219700

Resources

Cystic Fibrosis Foundation

6931 Arlington Rd.

Bethesda, MD 20814

Tel: (301)951-4422

Fax: (301)951-6378

Tel: (800)344-4823

Email: info@cff.org

Internet: http://www.cff.org



American Lung Association

1301 Pennsylvania Ave NW

Suite 800

Washington, DC 20004

USA

Tel: (202)785-3355

Fax: (202)452-1805

Tel: (800)586-4872

Email: info@lungusa.org

Internet: http://www.lungusa.org



Canadian Cystic Fibrosis Foundation

2221 Yonge Street

Suite 601

Toronto

Ontario, M1B 4G8

Canada

Tel: 4164859149

Fax: 4164850960

Tel: 8003782233

Email: info@cysticfibrosis.ca

Internet: http://www.cysticfibrosis.ca



Cystic Fibrosis Trust

11 London Rd

Bromley

Kent, BR1 1BY

United Kingdom

Tel: 02084647211

Fax: 02083130472

Tel: 03003731000

Email: enquiries@cftrust.org.uk

Internet: http://www.cftrust.org.uk



NIH/National Institute of Diabetes, Digestive & Kidney Diseases

Office of Communications & Public Liaison

Bldg 31, Rm 9A06

31 Center Drive, MSC 2560

Bethesda, MD 20892-2560

Tel: (301)496-3583

Email: NDDIC@info.niddk.nih.gov

Internet: http://www2.niddk.nih.gov/



Cystic Fibrosis Research, Inc.

Bayside Business Plaza

2670 Bayshore Parkway

Suite 520

Mountain View, CA 94043

USA

Tel: (650)404-9975

Fax: (650)404-9981

Email: cfri@cfri.org

Internet: http://www.cfri.org



Cochrane Cystic Fibrosis and Genetic Disorders Group

Institute of Child Health, University of Liverpool

Alder Hey Children's NHS Foundation Trust

Liverpool, L12 2 AP

United Kingdom

Tel: 441512525696

Email: nikkij@liverpool.ac.uk

Internet: http://cfgd.cochrane.org



Cystic Fibrosis Worldwide

Evka 3 Mahallesi

127/19 SOKAK NO/25

Dubleks

Bornova, Izmir,

Turkey

Tel: 902323756856

Fax: 902323756856

Email: information@cfww.org

Internet: http://www.cfww.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Global Fibrosis Foundation

5036 Dr. Phillips Boulevard

Suite 244

Orlando, FL 32819

Tel: (407)909-0753

Fax: (407)909-0153

Tel: (800)872-6874

Email: globalfibrosis@gmail.com

Internet: http://www.globalfibrosis.com



Childhood Liver Disease Research and Education Network

c/o Joan M. Hines, Research Administrator

Children's Hospital Colorado

13123 E 16th Ave. B290

Aurora, CO 80045

Tel: (720)777-2598

Fax: (720)777-7351

Email: joan.hines@childrenscolorado.org

Internet: http://www.childrennetwork.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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