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Cystic fibrosis
ICD-10 E84
ICD-9 277.0
OMIM 219700
DiseasesDB 3347
MedlinePlus 000107
eMedicine ped/535
MeSH {{{MeshNumber}}}

Cystic fibrosis (also known as CF, mucovoidosis, or mucoviscidosis) is a hereditary disease affecting the exocrine (mucus) glands of the lungs, liver, pancreas, and intestines, causing progressive disability due to multisystem failure.

Thick mucus production results in frequent lung infections. Diminished secretion of pancreatic enzymes is the main cause of poor growth, greasy stools, and deficiency in fat-soluble vitamins. Males can be infertile due to the condition congenital bilateral absence of the vas deferens. Often, symptoms of CF appear in infancy and childhood. Meconium ileus is a typical finding in newborn babies with CF.

Individuals with cystic fibrosis can be diagnosed prior to birth by prenatal genetic testing. Newborn screening tests are increasingly common and effective (although false positives may occur, and children need to be brought in for a sweat test to distinguish disease vs carrier status). The diagnosis of CF may be confirmed if high levels of salt are found during a sweat test, although some false positives may occur.


Cystic fibrosis is one of the most common life-shortening, genetic diseases. In the United States, 1 in 4,000 children are born with CF.[1] It is most common among western European populations; one in twenty-two people of Mediterranean descent are carriers of one gene for CF, making it the most common genetic disease in these populations.

CF is caused by a mutation in the gene, cystic fibrosis transmembrane conductance regulator (CFTR). The product of this gene is a chloride ion channel important in creating sweat, digestive juices, and mucus. Although most people without CF have two working copies (alleles) of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither allele can produce a functional CFTR protein. Therefore, CF is considered an autosomal recessive disease.

Symptomatic diseasesEdit

Lung and sinus diseaseEdit

Lung disease results from clogging the airways due to mucosa buildup and resulting inflammation. Inflammation and infection cause injury to the lungs and structural changes that lead to a variety of symptoms. In the early stages, incessant coughing, copious phlegm production, and decreased ability to exercise are common. Many of these symptoms occur when bacteria that normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages of CF, changes in the architecture of the lung further exacerbate chronic difficulties in breathing.
File:Aspergillus fumigatus 01.jpg


Gastrointestinal, liver and pancreatic diseaseEdit

Prior to prenatal and newborn screening, cystic fibrosis was often diagnosed when a newborn infant failed to pass feces (meconium). Meconium may completely block the intestines and cause serious illness. This condition, called meconium ileus, occurs in 10% of newborns with CF.[5] In addition, protrusion of internal rectal membranes (rectal prolapse) is more common in CF because of increased fecal volume, malnutrition, and increased intra–abdominal pressure due to coughing.[6]

The thick mucus seen in the lungs and its counterpart in thickened secretions from the pancreas, an organ responsible for providing digestive juices which help break down food. These secretions block the movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis).[7] The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the faeces, a disorder known as malabsorption. Malabsorption leads to malnutrition and poor growth and development because of calorie loss. Individuals with CF also have difficulties absorbing the fat-soluble vitamins A, D, E, and K. In addition to the pancreas problems, people with cystic fibrosis experience more heartburn, intestinal blockage by intussusception, and constipation.[8] Older individuals with CF may also develop distal intestinal obstruction syndrome when thickened feces cause intestinal blockage.[9]

Thickened secretions also may cause liver problems in patients with CF. Bile secreted by the liver to aid in digestion may block the bile ducts, leading to liver damage. Over time, this can lead to cirrhosis, in which the liver fails to rid the blood of toxins and does not make important proteins such as those responsible for blood clotting.[10][11]

Endocrine disease and growthEdit


Example of clubbing as seen with some CF patients

The pancreas contains the islets of Langerhans, which are responsible for making insulin, a hormone that helps regulate blood glucose. Damage of the pancreas can lead to loss of the islet cells, leading to diabetes that is unique to those with the disease.[12] Cystic Fibrosis Related Diabetes (CFRD), as it is known as, shares characteristics that can be found in Type 1 and Type 2 diabetics and is one of the principal non-pulmonary complications of CF.[13] Vitamin D is involved in calcium and phosphorus regulation. Poor uptake of vitamin D from the diet because of malabsorption leads to the bone disease osteoporosis in which weakened bones are more susceptible to fractures.[14] In addition, people with CF often develop clubbing of their fingers and toes due to the effects of chronic illness and low oxygen in their tissues.

Poor growth is a hallmark of CF. Children with CF typically do not gain weight or height at the same rate as their peers, and occasionally are not diagnosed until investigation is initiated for poor growth. The causes of growth failure are multi–factorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness.


Infertility affects both men and women. At least 97 percent of men with cystic fibrosis are sterile.[15] These men make normal sperm but are missing the tube (vas deferens), which connects the testes to the ejaculatory ducts of the penis.[16] Many men found to have congenital absence of the vas deferens during evaluation for infertility have a mild, previously undiagnosed form of CF.[17] Some women have fertility difficulties due to thickened cervical mucus or malnutrition. In severe cases, malnutrition disrupts ovulation and causes amenorrhea.[18]

Diagnosis and monitoringEdit

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.[19] Infants with an abnormal newborn screen need a sweat test in order to confirm the CF diagnosis. Trypsinogen levels can be increased in individuals who have a single mutated copy of the CFTR gene (carriers) or, in rare instances, even in individuals with two normal copies of the CFTR gene. Due to these false positives, CF screening in newborns is somewhat controversial.[How to reference and link to summary or text] 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.[20]

A multitude of tests are used to identify complications of CF and to monitor disease progression. X-rays and CAT scans are used to examine the lungs for signs of damage or infection. Examination of the sputum under a microscope is used to identify which bacteria are causing infection so that effective antibiotics can be given. Pulmonary function tests measure how well the lungs are functioning, and are used to measure the need for and response to antibiotic therapy. Blood tests can identify liver problems, vitamin deficiencies, and the onset of diabetes. DEXA scans can screen for osteoporosis and testing for fecal elastase can help diagnose insufficient digestive enzymes.

Prenatal diagnosisEdit

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.[21] 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.[22]


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,[24] although a recent study has indicated this may actually be much lower, perhaps 1 in 1,600,[1] 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.


Cystic fibrosis occurs when there is a mutation in the CFTR gene. The protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and other affected organs. The protein spans this membrane and acts as a channel connecting the inner part of the cell (cytoplasm) to the surrounding fluid. In the airway this channel is primarily responsible for controlling the movement of chloride from inside to outside of the cell, however in the sweat ducts it facilitates the movement of chloride from the sweat into the cytoplasm. When the CFTR protein does not work, chloride is trapped inside the cells in the airway and outside in the skin. Because chloride is negatively charged, positively charged ions also cannot cross into the cell because they are affected by the electrical attraction of the chloride ions. Sodium is the most common ion in the extracellular space and the combination of sodium and chloride creates the salt, which is lost in high amounts in the sweat of individuals with CF. This lost salt forms the basis for the sweat test.[2]

How this malfunction of cells in cystic fibrosis causes the clinical manifestations of CF is not well understood. One theory suggests that the lack of chloride exodus through the CFTR protein leads to the accumulation of more viscous, nutrient-rich mucus in the lungs that allows bacteria to hide from the body's immune system. Another theory proposes that the CFTR protein failure leads to a paradoxical increase in sodium and chloride uptake, which, by leading to increased water reabsorption, creates dehydrated and thick mucus. Yet another theory focuses on abnormal chloride movement out of the cell, which also leads to dehydration of mucus, pancreatic secretions, biliary secretions, etc. These theories all support the observation that the majority of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick faeces, etc.[2]

The role of chronic infection in lung diseaseEdit

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.[25]


One way in which infection has spread is by passage between different individuals with CF.[26] In the past, people with CF often participated in summer "CF Camps" and other recreational gatherings.[27][28] Hospitals grouped patients with CF into common areas and routine equipment (such as nebulizers)[29] was not sterilized between individual patients.[30] 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.[31] Often, patients with particularly damaging bacteria will attend clinics on different days and in different buildings than those without these infections.

Molecular biologyEdit


The CFTR gene is found at the q31.2 locus of chromosome 7, is 230,000 base pairs long, and creates a protein that is 1,480 amino acids long. The most common mutation, ΔF508 is a deletion (Δ) of three nucleotides that results in a loss of the amino acid phenylalanine (F) at the 508th (508) position on the protein. This mutation accounts for two-thirds of CF cases worldwide and 90 percent of cases in the United States; however, there are over 1,400 other mutations that can produce CF.[32] In Caucasian populations, the frequency of mutations is as follows:[33]

Mutation Frequency
ΔF508 66.0%
G542X 2.4%
G551D 1.6%
N1303K 1.3%
W1282X 1.2%
All others 27.5%

There are several mechanisms by which these mutations cause problems with the CFTR protein. ΔF508, for instance, creates a protein that does not fold normally and is degraded by the cell. Several mutations, which are common in the Ashkenazi Jewish population, result in proteins that are too short because production is ended prematurely. Less common mutations produce proteins that do not use energy normally, do not allow chloride to cross the membrane appropriately, or are degraded at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.[2]


Structurally, CFTR is a type of gene known as an ABC gene.[2] Its protein possesses two ATP-hydrolyzing domains which allows the protein to use energy in the form of ATP. It also contains two domains comprising 6 alpha helices apiece, which allow the protein to cross the cell membrane. A regulatory binding site on the protein allows activation by phosphorylation, mainly by cAMP-dependent protein kinase.[2] The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ domain interaction.[34]



The cornerstones of management are proactive treatment of airway infection, and encouragement of good nutrition and an active lifestyle. The treatment for cystic fibrosis continues throughout a patient's life, and is aimed at maximizing organ function, and therefore quality of life. At best, current treatments delay the decline in organ function. Treatment typically occurs at specialist multidisciplinary centres, and is tailored to the individual, because of the wide variation in disease symptoms. Targets for therapy are the lungs, gastrointestinal tract (including insulin treatment and pancreatic enzyme supplements), the reproductive organs (including Assisted Reproductive Technology (ART)) and psychological support.[19] In addition, therapies such as transplantation and gene therapy aim to cure some of the effects of cystic fibrosis.

The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung damage caused by thick mucus and infection with the goal of maintaining quality of life. Intravenous, inhaled, and oral antibiotics are used to treat chronic and acute infections. Mechanical devices and inhalation medications are used to alter and clear the thickened mucus. These therapies, while effective, can be extremely time consuming to the patient. One of the most important battles that CF patients face is finding the time to comply with all the prescribed treatments while balancing a normal life.

Antibiotics to treat lung diseaseEdit

Many CF patients are on one or more antibiotics at all times, even when they are considered healthy, to suppress the infection as much as possible. Antibiotics are absolutely necessary whenever pneumonia is suspected or there has been a noticeable decline in lung function. Antibiotics are usually chosen based on the results of a sputum analysis and the patients past response. Many bacteria common in cystic fibrosis are resistant to multiple antibiotics and require weeks of treatment with intravenous antibiotics such as vancomycin, tobramycin, meropenem, ciprofloxacin, and piperacillin. This prolonged therapy often necessitates hospitalization and insertion of a more permanent IV such as a PICC line or Port-a-Cath. Inhaled therapy with antibiotics such as tobramycin and colistin is often given for months at a time in order to improve lung function by impeding the growth of colonized bacteria.[35][36] Inhaled therapy with the antibiotic aztreonam is also being developed and clinical trials have shown great promise.[37] Oral antibiotics such as ciprofloxacin or azithromycin are given to help prevent infection or to control ongoing infection.[38] Some individuals spend years between hospitalizations for antibiotics, whereas others require several antibiotic treatments each year.

Several common antibiotics such as tobramycin and vancomycin can cause hearing loss, damage to the balance system in the inner ear or kidney problems with long-term use. In order to prevent these side-effects, the amount of antibiotics in the blood are routinely measured and adjusted accordingly.

Other methods to treat lung diseaseEdit

Several mechanical techniques are used to dislodge sputum and encourage its expectoration. In the hospital setting, physical therapy is utilized; a therapist pounds an individual's chest with his or her hands several times a day. Devices that recreate this percussive therapy include the ThAIRapy Vest and the intrapulmonary percussive ventilator (IPV). Newer methods such as Biphasic Cuirass Ventilation, and associated clearance mode available in such devices, now integrate a cough assistance phase, as well as a vibration phase for dislodging secretions. Biphasic Cuirass Ventilation is also shown to provide a bridge to transplantation.[How to reference and link to summary or text] These are portable and adapted for home use.[39] Aerobic exercise is of great benefit to people with cystic fibrosis. Not only does exercise increase sputum clearance but it also improves cardiovascular and overall health.

Aerosolized medications that help loosen secretions include dornase alfa and hypertonic saline.[40] Dornase is a recombinant human deoxyribonuclease, which breaks down DNA in the sputum, thus decreasing its viscosity.[41] N-Acetylcysteine may also decrease sputum viscosity, but research and experience have shown its benefits to be minimal. Albuterol and ipratropium bromide are inhaled to increase the size of the small airways by relaxing the surrounding muscles.


Treatment of other aspects of CFEdit


Newborns with meconium ileus typically require surgery, whereas adults with distal intestinal obstruction syndrome typically do not. Treatment of pancreatic insufficiency by replacement of missing digestive enzymes allows the duodenum to properly absorb nutrients and vitamins that would otherwise be lost in the faeces. Even so, most individuals with CF take additional amounts of vitamins A, D, E, and K and eat high-calorie meals. It should be noted, however, that nutritional advice given to patients is, at best, mixed: Often, literature encourages the eating of high-fat foods without differentiating between saturated, unsaturated fat, and trans-fats; this lack of clear information runs counter to health advice given to the general population, and creates the risk of further serious health problems for people with cystic fibrosis as they grow older. So far, no large-scale research involving the incidence of atherosclerosis and coronary heart disease in adults with cystic fibrosis has been conducted. This is likely due to the fact that the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease.

The diabetes common to many CF patients is typically treated with insulin injections or an insulin pump.[43] Development of osteoporosis can be prevented by increased intake of vitamin D and calcium, and can be treated by bisphosphonates.[44] Poor growth may be avoided by insertion of a feeding tube for increasing calories through supplemental feeds or by administration of injected growth hormone.[45]

Sinus infections are treated by prolonged courses of antibiotics. The development of nasal polyps or other chronic changes within the nasal passages may severely limit airflow through the nose. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such as fluticasone are used to decrease nasal inflammation.[46] Female infertility may be overcome by assisted reproduction technology, particularly embryo transfer techniques. Male infertility may be overcome with intracytoplasmic sperm injection.[47] Third party reproduction is also a possibility for women with CF.

Transplantation and gene therapyEdit


Gene therapy holds promise as a potential avenue to cure cystic fibrosis. Gene therapy attempts to place a normal copy of the CFTR gene into affected cells. Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 5–10% the normal amount of CFTR gene expression is needed.[50] Multiple approaches have been tested for gene transfer, such as liposomes and viral vectors in animal models and clinical trials. However, at this time gene therapy is still a relatively inefficient treatment option.[51] Ideally, transfering the normal CFTR gene into the affected epithelium cells would result in the production of functional CFTR in all target cells, without adverse reactions or an inflammation response. But if too few cells take up the vector and express the gene, the treatment has little effect. Additionally, problems have been noted in cDNA recombination, such that the gene introduced by the treatment is rendered unusable. [52]


In most cases, CF causes an early death. Average life expectancy is around 36.8 years according to the Cystic Fibrosis Foundation, although improvements in treatments mean a baby born today could expect to live longer.[53]



Cystic Fibrosis has an autosomal recessive pattern of inheritance.

Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of European heritage.[54] In the United States, approximately 30,000 individuals have CF; most are diagnosed by six months of age. Canada has approximately 3,000 citizens with CF. Approximately 1 in 25 people of European descent and 1 in 22 people of Ashkenazi Jewish descent is a carrier of a cystic fibrosis mutation. Although CF is less common in these groups, approximately 1 in 46 Hispanics, 1 in 65 Africans and 1 in 90 Asians carry at least one abnormal CFTR gene.[55][56][57]


The Cystic Fibrosis Foundation also compiles lifestyle information about American adults with CF. In 2004, the foundation reported that 91% had graduated high school and 54% had at least some college education. Employment data revealed 12.6% of adults were disabled and 9.9% were unemployed. Marital information showed that 59% of adults were single and 36% were married or living with a partner. In 2004, 191 American women with CF were pregnant.

Theories about the prevalence of CFEdit


  • Diarrhoea: It has also been hypothesized that the prevalence of CF in Europe might be connected with the development of cattle domestication. In this hypothesis, carriers of a single mutant CFTR chromosome had some protection from diarrhoea caused by lactose intolerance, prior to the appearance of the mutations that created lactose tolerance.[64]
  • Tuberculosis: Poolman and Galvani from Yale University have added another possible explanation - that carriers of the gene have some resistance to TB.[65][66]


File:Dorothy Hansine Andersen.jpg

The name cystic fibrosis comes from the characteristic histologic (microscopic) appearance of the pancreas in the disease, with cysts (fluid filled cavities) and fibrosis prominently seen.[67] Formerly known as "cystic fibrosis of the pancreas," this entity has increasingly been labeled simply "cystic fibrosis."[68]

Although the entire clinical spectrum of CF was not recognized until the 1930s, certain aspects were identified much earlier. Indeed, literature from Germany and Switzerland in the 18th century warned, "Wehe dem Kind, das beim Kuß auf die Stirn salzig schmekt, es ist verhext und muss bald sterben" — "Woe is the child kissed on the forehead who tastes salty, for it is cursed and soon must die," recognizing the association between the salt loss in CF and illness.

In the 19th century, Carl von Rokitansky described a case of fetal death with meconium peritonitis, a complication of meconium ileus associated with cystic fibrosis. Meconium ileus was first described in 1905 by Karl Landsteiner.[69] In 1936, Guido Fanconi published a paper describing a connection between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis.[70]

In 1938 Dorothy Hansine Andersen published an article, "Cystic Fibrosis of the Pancreas and Its Relation to Celiac Disease: a Clinical and Pathological Study," in the American Journal of Diseases of Children. She described the characteristic cystic fibrosis of the pancreas and correlated it with the lung and intestinal disease prominent in CF.[67] 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; a sweat test was developed and improved over the next decade.[71]

In 1988 the first mutation for CF, ΔF508 on the seventh chromosome, was discovered by Francis Collins, Lap-Chee Tsui and John R. Riordan. Research has subsequently found over 1,000 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 had been unable to accurately pinpoint the mutated gene.[72] 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.[73]

See alsoEdit


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