Cystic fibrosis

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Cystic fibrosis
Lung: Gross; Cystic fibrosis Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
ICD-10	E84
ICD-9	277
OMIM	219700
DiseasesDB	3347
MedlinePlus	000107
MeSH	D003550

Cystic fibrosis Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Diagnosis

History and Symptoms | Physical Examination | Staging | Laboratory tests | Electrocardiogram | X Rays | CT | MRI Echocardiography or Ultrasound | Other images | Alternative diagnostics

Treatment

Medical therapy | Surgical options | Primary prevention | Secondary prevention | Financial costs | Future therapies

Diagnosis and monitoring

Cystic fibrosis may be diagnosed by many different categories of testing including those such as, newborn screening, sweat testing, or genetic testing. As of 2006 in the United States, 10 percent of cases are diagnosed shortly after birth as part of newborn screening programs. The newborn screen initially measures for raised blood concentration of immunoreactive trypsinogen. However, most states and countries do not screen for CF routinely at birth. Therefore, most individuals are diagnosed after symptoms prompt an evaluation for cystic fibrosis. The most commonly-used form of testing is the sweat test. Sweat-testing involves application of a medication that stimulates sweating (pilocarpine) to one electrode of an apparatus and running electric current to a separate electrode on the skin. This process, called iontophoresis, causes sweating; the sweat is then collected on filter paper or in a capillary tube and analyzed for abnormal amounts of sodium and chloride. People with CF have increased amounts of sodium and chloride in their sweat. CF can also be diagnosed by identification of mutations in the CFTR gene.

Prenatal diagnosis

Couples who are pregnant or who are planning a pregnancy can themselves be tested for CFTR gene mutations to determine the likelihood that their child will be born with cystic fibrosis. Testing is typically performed first on one or both parents and, if the risk of CF is found to be high, testing on the fetus can then be performed. Cystic fibrosis testing is offered to many couples in the US. The American College of Obstetricians and Gynecologists (ACOG) recommends testing for couples who have a personal or close family history. Additionally, ACOG recommends that carrier testing be offered to all Caucasian couples and be made available to couples of other ethnic backgrounds.

Because development of CF in the fetus requires each parent to pass on a mutated copy of the CFTR gene and because CF testing is expensive, testing is often performed on just one parent initially. If that parent is found to be a carrier of a CFTR gene mutation, the other parent is then tested to calculate the risk that their children will have CF. CF can result from more than a thousand different mutations and, as of 2006, it is not possible to test for each one. Testing analyzes the blood for the most common mutations such as ΔF508 — most commercially available tests look for 32 or fewer different mutations. If a family has a known uncommon mutation, specific screening for that mutation can be performed. Because not all known mutations are found on current tests, a negative screen does not guarantee that a child will not have CF. In addition, because the mutations tested are necessarily those most common in the highest risk groups, testing in lower risk ethnicities is less successful because the mutations commonly seen in these groups are less common in the general population. These couples may therefore consider testing through labs that offer CF screens with a high number of mutations tested.

Couples who are at high risk for having a child with CF will often opt to perform further testing before or during pregnancy. In vitro fertilization with preimplantation genetic diagnosis offers the possibility to examine the embryo prior to its placement into the uterus. The test, performed 3 days after fertilization, looks for the presence of abnormal CF genes. If two mutated CFTR genes are identified, the embryo is not used for embryo transfer and an embryo with at least one normal gene is implanted.

During pregnancy, testing can be performed on the placenta (chorionic villus sampling) or the fluid around the fetus (amniocentesis). However, chorionic villus sampling has a risk of fetal death of 1 in 100 and amniocentesis of 1 in 200, so the benefits must be determined to outweigh these risks prior to going forward with testing. Alternatively, some couples choose to undergo third party reproduction with egg or sperm donors.

The role of chronic infection in lung disease

The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread amongst individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus encourages the development of bacterial microenvironments (biofilms) that are difficult for immune cells (and antibiotics) to penetrate. The lungs respond to repeated damage by thick secretions and chronic infections by gradually remodeling the lower airways (bronchiectasis), making infection even more difficult to eradicate.

Over time, both the types of bacteria and their individual characteristics change in individuals with CF. In the initial stage, common bacteria such as Staphylococcus aureus and Hemophilus influenzae colonize and infect the lungs. Eventually, however, Pseudomonas aeruginosa (and sometimes Burkholderia cepacia) dominates. Once within the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics. Pseudomonas can develop special characteristics that allow the formation of large colonies, known as "mucoid" Pseudomonas and rarely seen in people that do not have CF.

One way in which infection has spread is by passage between different individuals with CF. In the past, people with CF often participated in summer "CF Camps" and other recreational gatherings. Hospitals grouped patients with CF into common areas and routine equipment (such as nebulizers) was not sterilized between individual patients. This led to transmission of more dangerous strains of bacteria among groups of patients. As a result, individuals with CF are routinely isolated from one another in the healthcare setting and healthcare providers are encouraged to wear gowns and gloves when examining patients with CF in order to limit the spread of virulent bacterial strains. Often, patients with particularly damaging bacteria will attend clinics on different days and in different buildings than those without these infections.

History

National Library of Medicine picture of Dorothy Hansine Andersen. Andersen first described cystic fibrosis of the pancreas.

The name cystic fibrosis refers to the characteristic 'fibrosis' (tissue scarring) of the biliary tract ("cystic" being a generic term for all that is related to the biliary vesicle and/or the bladder), first recognized in the 1930s. Formerly known as cystic fibrosis of the pancreas, this entity has increasingly been labeled simply cystic fibrosis. Although the entire clinical spectrum of CF was not recognized until the 1930s, certain aspects of CF were identified much earlier. Indeed, literature from Germany and Switzerland in the 1700s warned "Wehe dem Kind, das beim Kuß auf die Stirn salzig schmekt, es ist verhext und muss bald sterben," which translates to "Woe is the child kissed on the brow who tastes salty, for he is cursed and soon must die," recognizing the association between the salt loss in CF and illness. Carl von Rokitansky described a case of fetal death with meconium peritonitis, complication of meconium ileus associated with cystic fibrosis. Meconium ileus was first described in 1905 by Karl Landsteiner. In 1936, Guido Fanconi published a paper describing a connection between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis.

In 1938, Dorothy Hansine Andersen published an article titled "Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathological study" in the American Journal of Diseases of Children. In her paper, she described the characteristic cystic fibrosis of the pancreas correlated it with the lung and intestinal disease prominent in CF. She also first hypothesized that CF is a recessive disease and first used pancreatic enzyme replacement to treat affected children. In 1952, Paul di Sant' Agnese discovered abnormalities in sweat electrolytes; the sweat test was developed and improved over the next decade.

In 1988, the first mutation for CF, ΔF508, was discovered by Francis Collins, Lap-Chee Tsui and John R. Riordan on the seventh chromosome. Research has subsequently found over 1000 different mutations that cause CF. Lap-Chee Tsui led a team of researchers at the Hospital for Sick Children in Toronto that discovered the gene responsible for CF in 1989. Cystic fibrosis represents the first genetic disorder elucidated strictly by the process of reverse genetics. Because mutations in the CFTR gene are typically small, classical genetics techniques were not able to accurately pinpoint the mutated gene. Using protein markers, gene linkage studies were able to map the mutation to chromosome 7. Chromosome walking and jumping techniques were then used to identify and sequence the gene.

Public Awareness

Some children with cystic fibrosis in the United States call their disease 65 Roses because the words are easier to pronounce. This trademarked phrase has been popularized by the Cystic Fibrosis Foundation. The phrase came into being when it was used by a young boy who had overheard his mother, a volunteer for the Foundation, speaking of his illness. He later informed her that he knew she was working to help with "sixty-five roses" The term has since been used as a symbol by organizations and families of cystic fibrosis victims.

See also

• List of cystic fibrosis organizations
• Dor Yeshorim

External links

• Template:Dmoz
• Cystic Fibrosis Worldwide
• Cystic Fibrosis Foundation
• Cystic fibrosis pictures (Univ Geneva, Switzerland)
• cf at NIH/UW GeneTests
• Rare Diseases Clinical Research Network
• Search GeneCards for genes envolved in Cystic Fibrosis

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