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Cystic fibrosis
SpecialtyMedical genetics, pediatrics, pulmonology Edit this on Wikidata

Cystic Fibrosis (also known as CF) is a common hereditary disease which affects the entire body, causing progressive disability and often early death. The name cystic fibrosis refers to the characteristic scarring (fibrosis) and cyst formation within the pancreas, first recognized in the 1930s.[1] Difficulty breathing is the most serious symptom and results from frequent lung infections that are treated, though not cured, by antibiotics and other medications. A multitude of other symptoms, including sinus infections, poor growth, diarrhea, and infertility result from the effects of CF on other parts of the body.[citation needed]

CF is caused by a mutation in the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR). This gene is required to regulate the components of sweat, digestive juices, and mucus. Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither gene works normally. Therefore, CF is considered an autosomal recessive disease.[citation needed]

CF is most common among Caucasians and Ashkenazi Jews; one in 25 people of European descent carry one gene for CF. [citation needed] Approximately 30,000 Americans have CF, making it one of the most common life-shortening inherited diseases. Individuals with cystic fibrosis can be diagnosed before birth by genetic testing, or by a sweat test in early childhood. There is no cure, and most individuals with cystic fibrosis die at a young age — many in their 20s and 30s from lung failure. Ultimately, lung transplantation is often necessary as CF worsens. [citation needed]

Signs and symptoms

A diagram showing clinical manifestations of cystic fibrosis[2]
Clubbing of the fingers in a person with cystic fibrosis

The hallmark symptoms of cystic fibrosis are salty tasting skin,[3] poor growth and poor weight gain despite a normal food intake,[4] accumulation of thick, sticky mucus,[5] frequent chest infections and coughing or shortness of breath.[6] Males can be infertile due to congenital absence of the vas deferens.[7] Symptoms often appear in infancy and childhood, such as bowel obstruction due to meconium ileus in newborn babies.[8] As the child grows, he or she will need to exercise to release mucus in the alveoli.[9] Ciliated epithelial cells in the patient have a mutated protein that leads to abnormally viscous mucus production.[5] The poor growth in children typically presents as an inability to gain weight or height at the same rate as their peers and is occasionally 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.[4]

Lung and sinus

Lung disease results from clogging of the airways due to mucus build-up, decreased mucociliary clearance and resulting inflammation.[10][11] Inflammation and infection will cause injury and structural changes to the lungs, leading 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, changes in the architecture of the lung such as pathology in the major airways (bronchiectasis) further exacerbate difficulties in breathing. Other symptoms include coughing up blood (hemoptysis), high blood pressure in the lung (pulmonary hypertension), heart failure, difficulties getting enough oxygen to the body (hypoxia), and respiratory failure requiring support with breathing masks such as bilevel positive airway pressure machines or ventilators.[12] Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa are the three most common organisms causing lung infections in CF patients.[11] In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease. Among these is allergic bronchopulmonary aspergillosis, in which the body's response to the common fungus Aspergillus fumigatus causes worsening of breathing problems. Another is infection with Mycobacterium avium complex (MAC), a group of bacteria related to tuberculosis, which can cause further lung damage and does not respond to common antibiotics.[13]

Mucus in the paranasal sinuses is equally thick and may also cause blockage of the sinus passages, leading to infection. This may cause facial pain, fever, nasal drainage, and headaches. Individuals with CF may develop overgrowth of the nasal tissue (nasal polyps) due to inflammation from chronic sinus infections.[14] Recurrent sinonasal polyps can occur in as many as 10% to 25% of CF patients.[11] These polyps can block the nasal passages and increase breathing difficulties.[15][16]

Cardiorespiratory complications is the most common cause of death (~80%) in patients followed by most CF centers in the United States.[11]

Gastrointestinal

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 5[11] – 10%[11][17] of newborns with CF. In addition, protrusion of internal rectal membranes (rectal prolapse) is more common, occurring in as many as 10% of children with CF,[11] and it is caused by increased fecal volume, malnutrition, and increased intra–abdominal pressure due to coughing.[18]

The thick mucus seen in the lungs has a counterpart in thickened secretions from the pancreas, an organ responsible for providing digestive juices which help break down food. These secretions block the exocrine movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis).[19] The pancreatic ducts are totally plugged in more advanced cases, usually seen in older children or adolescents.[11] This causes atrophy of the exocrine glands and progressive fibrosis.[11] The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the feces, a disorder known as malabsorption. Malabsorption leads to malnutrition and poor growth and development because of calorie loss. Resultant hypoproteinemia may be severe enough to cause generalized edema.[11] 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.[20] Older individuals with CF may develop distal intestinal obstruction syndrome when thickened feces cause intestinal blockage.[21] Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF.[11] It is mainly associated with "severe" CFTR mutations, where both alleles are completely nonfunctional (e.g. ΔF508/ΔF508).[11] It occurs in 10% to 15% of patients with one "severe" and one "mild" CFTR mutation where there still is a little CFTR activity, or where there are two "mild" CFTR mutations.[11] In these milder cases, there is still sufficient pancreatic exocrine function so that enzyme supplementation is not required.[11] There are usually no other GI complications in pancreas-sufficient phenotypes, and in general, such individuals usually have excellent growth and development.[11] Despite this, idiopathic chronic pancreatitis can occur in in a subset of pancreas-sufficient individuals with CF, and is associated with recurrent abdominal pain and life-threatening complications.[11]

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 scarring and nodularity (cirrhosis). The liver fails to rid the blood of toxins and does not make important proteins such as those responsible for blood clotting.[22][23] Liver disease is the third most common cause of death associated with CF.[11]

Endocrine

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 a type of diabetes that is unique to those with the disease.[24] This cystic fibrosis related diabetes (CFRD) shares characteristics that can be found in Type 1 and Type 2 diabetics, and is one of the principal non-pulmonary complications of CF.[25] Vitamin D is involved in calcium and phosphate regulation. Poor uptake of vitamin D from the diet because of malabsorption can lead to the bone disease osteoporosis in which weakened bones are more susceptible to fractures.[26] 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.[27][28]

Infertility

Infertility affects both men and women. At least 97% of men with cystic fibrosis are infertile, but not sterile and can have children with assisted reproductive techniques.[29] These men make normal sperm but are missing the tube (vas deferens), which connects the testes to the ejaculatory ducts of the penis.[30] Many men found to have congenital absence of the vas deferens during evaluation for infertility have a mild, previously undiagnosed form of CF.[31] Some women have fertility difficulties due to thickened cervical mucus or malnutrition. In severe cases, malnutrition disrupts ovulation and causes amenorrhea.[32]

Cause

Cystic fibrosis has an autosomal recessive pattern of inheritance

CF is caused by a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR). 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 (66-70%[11]) 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.[33] Although most people 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. Thus, CF is considered an autosomal recessive disease.

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. Structurally, CFTR is a type of gene known as an ABC gene.[12] The product of this gene (the CFTR) is a halide anion channel important in creating sweat, digestive juices and mucus. This 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.[12] The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ domain interaction.[34]

In addition, there is increasing evidence that genetic modifiers besides CFTR modulate the frequency and severity of the disease. One example is mannan-binding lectin, which is involved in innate immunity by facilitating phagocytosis of microorganisms. Polymorphisms in one or both mannan-binding lectin alleles that result in lower circulating levels of the protein are associated with a threefold higher risk of end-stage lung disease, as well as an increased burden of chronic bacterial infections.[11]

Pathophysiology

Molecular structure of the CFTR protein

There are several mechanisms by which 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 that 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, iodide and thiocyanate to cross the membrane appropriately,[35] or are degraded at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.[12]

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. This channel is primarily responsible for controlling the movement of halogen 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 and thiocyanate[36] are trapped inside the cells in the airway and outside in the skin. Then hypothiocyanite, OSCN, cannot be produced by immune defense system.[37][38] Because chloride is negatively charged, positively charged cations 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.[12]

How this malfunction of cells in cystic fibrosis causes the clinical manifestations is not well understood. One theory suggests that the lack of halogen and pseudohalogen (mainly, chloride, iodide and thiocyanate) 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.[12]

Chronic infections

The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread among individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus leads to the formation of bacterial microenvironments known as biofilms that are difficult for immune cells and antibiotics to penetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways which makes infection even more difficult to eradicate.[39]

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.[11] Eventually, Pseudomonas aeruginosa (and sometimes Burkholderia cepacia) dominates. By 18 years of age, 80% of patients with classic CF harbor P. aeruginosa, and 3.5% harbor B. cepacia.[11] 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, which are rarely seen in people that do not have CF.[39]

One way in which infection has spread is by passage between different individuals with CF.[40] In the past, people with CF often participated in summer "CF Camps" and other recreational gatherings.[41][42] Hospitals grouped patients with CF into common areas and routine equipment (such as nebulizers)[43] was not sterilized between individual patients.[44] 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 to limit the spread of virulent bacterial strains.[45]

CF patients may also have their airways chronically colonized by filamentous fungi (such as Aspergillus fumigatus, Scedosporium apiospermum, Aspergillus terreus) and/or yeasts (such as Candida albicans); other filamentous fungi less commonly isolated include Aspergillus flavus and Aspergillus nidulans (occur transiently in CF respiratory secretions), and Exophiala dermatitidis and Scedosporium prolificans (chronic airway-colonizers); some filamentous fungi like Penicillium emersonii and Acrophialophora fusispora are encountered in patients almost exclusively in the context of CF.[46] Defective mucociliary clearance characterizing CF is associated with local immunological disorders. In addition, the prolonged therapy with antibiotics and the use of corticosteroid treatments may also facilitate fungal growth. Although the clinical relevance of the fungal airway colonization is still a matter of debate, filamentous fungi may contribute to the local inflammatory response, and therefore to the progressive deterioration of the lung function, as often happens with allergic broncho-pulmonary aspergillosis (ABPA) - the most common fungal disease in the context of CF, involving a Th2-driven immune response to Aspergillus.[46][47]

Diagnosis and monitoring

The location of the CFTR gene on chromosome 7

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.[48] Infants with an abnormal newborn screen need a sweat test in order to confirm the CF diagnosis. In many cases, a parent makes the diagnosis because the infant tastes salty.[11] Trypsinogen levels can be increased in individuals who have a single mutated copy of the CFTR gene (carriers) or, in rare instances, in individuals with two normal copies of the CFTR gene. Due to these false positives, CF screening in newborns can be controversial.[49][50] Most states and countries do not screen for CF routinely at birth. Therefore, most individuals are diagnosed after symptoms (e.g. sinopulmonary disease and GI manifestations[11]) 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). In order to deliver the medication through the skin, iontophoresis is used to, whereby one electrode is placed onto the applied medication and an electric current is passed to a separate electrode on the skin. The resultant 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. In opposite, people with CF have less thiocyanate and hypothiocyanite in their saliva (Minarowski[51] et al.) and mucus (Banfi et al.). CF can also be diagnosed by identification of mutations in the CFTR gene.[52]

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. The examination of the sputum is required to isolate organisms which may be causing an infection or colonising the lower respiratory tract so that effective antimicrobial therapy can be provided. Culture for organisms such as Burkholderia (previously Pseudomonas) cepacia is required for candidates of Lung transplantation as persistent bacterial colonisation reduces the chances of survival.[citation needed]

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 abnormalities, vitamin deficiencies, and the onset of diabetes. DXA scans can screen for osteoporosis and testing for fecal elastase can help diagnose insufficient digestive enzymes.[citation needed]

In individuals with a mild mutation in the CFTR gene the sweat test may be near normal (i.e. a chloride concentration of less than 60mM/L). As an adjunct to diagnosis, the nasal transepithelial potential difference (TEPD) may be used. Due to abnormalities in the CFTR gene in exocrine glands, chloride secretion is reduced and sodium and water reabsorption is increased. The net effect of the preceding is a more negative baseline resulting in a higher than normal TEPD that can be used as an ancillary or necessary form of diagnosis for mild mutations.[citation needed]

People with CF may be listed in a disease registry that allows researchers and doctors to track health results and identify candidates for clinical trials.[53]

Prenatal

Couples who are pregnant or who are planning a pregnancy can themselves be tested for CFTR gene mutations to determine the degree of risk 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. The American College of Obstetricians and Gynecologists (ACOG) recommends testing for couples who have a personal or close family history of CF, and they recommend that carrier testing be offered to all Caucasian couples and be made available to couples of other ethnic backgrounds.[54]

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 initially on one parent. 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.[55] 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.[citation needed]

Couples 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 three 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.[citation needed]

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;[56] a recent study has indicated this may be much lower, approximately 1 in 1,600.[57] In any case, 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.[citation needed]

Economically, for carrier couples of cystic fibrosis, when comparing preimplantation genetic diagnosis (PGD) with natural conception (NC) followed by prenatal testing and abortion of affected pregnancies, PGD provides net economic benefits up to a maternal age of approximately 40 years, after which NC, prenatal testing and abortion has higher economic benefit.[58]

Management

The cornerstones of management are proactive treatment of airway infection, and encouragement of good nutrition and an active lifestyle. Management of 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. Because of the wide variation in disease symptoms treatment typically occurs at specialist multidisciplinary centers, and is tailored to the individual. Targets for therapy are the lungs, gastrointestinal tract (including pancreatic enzyme supplements), the reproductive organs (including assisted reproductive technology (ART)) and psychological support.[48]

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 for the patient. One of the most important battles that CF patients face is finding the time to comply with prescribed treatments while balancing a normal life.

In addition, therapies such as transplantation and gene therapy aim to cure some of the effects of cystic fibrosis. Gene therapy aims to introduce normal CFTR to airway. Theoretically this process should be simple as the airway is easily accessible and there is only a single gene defect to correct. There are two CFTR gene introduction mechanisms involved, the first use of a viral vector (adenovirus, adeno-associated virus or retro virus) and secondly the use of liposome. However there are some problems associated with these methods involving efficiency (liposomes insufficient protein) and delivery (virus provokes an immune response).

Antibiotics

Many CF patients are on one or more antibiotic at all times, even when they are considered healthy, in order to prophylactically suppress infection. Antibiotics are absolutely necessary whenever pneumonia is suspected or there has been a noticeable decline in lung function, and are usually chosen based on the results of a sputum analysis and the patient's 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.[citation needed] This prolonged therapy often necessitates hospitalization and insertion of a more permanent IV such as a peripherally inserted central catheter (PICC line) or Port-a-Cath. Inhaled therapy with antibiotics such as tobramycin, colistin, and cayston is often given for months at a time in order to improve lung function by impeding the growth of colonized bacteria.[59][60][61] Oral antibiotics such as ciprofloxacin or azithromycin are given to help prevent infection or to control ongoing infection.[62] The aminoglycoside antibiotics (e.g. tobramycin) used can cause hearing loss, damage to the balance system in the inner ear or kidney problems with long-term use.[63] In order to prevent these side-effects, the amount of antibiotics in the blood are routinely measured and adjusted accordingly.

Other treatments for lung disease

Several mechanical techniques are used to dislodge sputum and encourage its expectoration. In the hospital setting, chest physiotherapy (CPT) is utilized; a respiratory therapist percusses an individual's chest with his or her hands several times a day, to loosen up secretions. 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, integrate a cough assistance phase, as well as a vibration phase for dislodging secretions. These are portable and adapted for home use.[64] Physiotherapy is essential to help manage an individual’s chest on a long term basis, and can also teach techniques for the older child and teenager to manage themselves at home. 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.[citation needed]

Aerosolized medications that help loosen secretions include dornase alfa and hypertonic saline.[65] Dornase is a recombinant human deoxyribonuclease, which breaks down DNA in the sputum, thus decreasing its viscosity.[66] N-Acetylcysteine may also decrease sputum viscosity, but research and experience have shown its benefits to be minimal.[citation needed] Albuterol and ipratropium bromide are inhaled to increase the size of the small airways by relaxing the surrounding muscles.[citation needed]

As lung disease worsens, mechanical breathing support may become necessary. Individuals with CF may need to wear special masks at night that help push air into their lungs. These machines, known as bilevel positive airway pressure (BiPAP) ventilators, help prevent low blood oxygen levels during sleep. BiPAP may also be used during physical therapy to improve sputum clearance.[67] During severe illness, a tube may be placed in the throat (a procedure known as a tracheostomy) to enable breathing supported by a ventilator.

Transplantation

Lung transplantation often becomes necessary for individuals with cystic fibrosis as lung function and exercise tolerance declines. Although single lung transplantation is possible in other diseases, individuals with CF must have both lungs replaced because the remaining lung might contain bacteria that could infect the transplanted lung. A pancreatic or liver transplant may be performed at the same time in order to alleviate liver disease and/or diabetes.[68] Lung transplantation is considered when lung function declines to the point where assistance from mechanical devices is required or patient survival is threatened.[69] This point typically occurs when lung function declines to approximately 20 to 30 percent,[citation needed] however there is a small time frame when transplantation is feasible as the patient must be healthy enough to endure the procedure.

Treatment of other aspects

Intracytoplasmic sperm injection can be used to provide fertility for men with cystic fibrosis

Newborns with meconium ileus (bowel obstruction) 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 feces. Even so, most individuals with CF are advised take additional amounts of vitamins A, D, E, and K and eat high-calorie meals. [citation needed] 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.

Diabetes is the most common non-pulmonary complication of CF. It mixes features of type 1 and type 2 diabetes, and is recognized as a distinct entity, cystic fibrosis-related diabetes (CFRD).[70][71] While oral anti-diabetic drugs are sometimes used, the only recommended treatment is the use of insulin injections or an insulin pump,[72] and, unlike in type 1 and 2 diabetes, dietary restrictions are not recommended.[70]

Development of osteoporosis can be prevented by increased intake of vitamin D and calcium, and can be treated by bisphosphonates, although adverse effects can be an issue.[73] Poor growth may be avoided by insertion of a feeding tube for increasing calories through supplemental feeds or by administration of injected growth hormone.[74]

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, and over time reduce the patient's sense of smell. 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.[75] Female infertility may be overcome by assisted reproduction technology, particularly embryo transfer techniques. Male infertility caused by absence of the vas deferens may be overcome with testicular sperm extraction (TEST), collecting sperm cells directly from the testicles. If the collected sample contains too few sperm cells to likely have a spontaneous fertilization, intracytoplasmic sperm injection can be performed.[76] Third party reproduction is also a possibility for women with CF.

Prognosis

Life expectancy for people with CF depends largely upon access to health care. In 1959, the median age of survival of children with cystic fibrosis was six months. In the United States, the life expectancy for infants born in 2008 with CF is 37.4 years, based upon data compiled by the Cystic Fibrosis Foundation.[77] The median survival age in Canada has increased from 24 in 1982 to 47.7 in 2007, based on data compiled by the Canadian Cystic Fibrosis Foundation.[78]

The U.S. Cystic Fibrosis Foundation 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.[citation needed]

Epidemiology

Mutation Frequency
worldwide[79]
ΔF508 66%-70%[11]
G542X 2.4%
G551D 1.6%
N1303K 1.3%
W1282X 1.2%
All others 27.5%

Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of European heritage.[80] 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 one in 30 of Caucasian Americans,[81] 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.[82][83]

Although technically a rare disease, cystic fibrosis is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world. An exception is Finland, where only one in 80 people carry a CF mutation.[84] In the United States, 1 in 4,000 children are born with CF.[85] In 1997, about 1 in 3,300 caucasian children in the United States was born with cystic fibrosis. In contrast, only 1 in 15,000 African American children suffered from cystic fibrosis, and in Asian Americans the rate was even lower at 1 in 32,000.[86]

Cystic fibrosis is diagnosed in males and females equally. For unclear reasons, males tend to have a longer life expectancy than females[87][88] although recent studies suggest this gender gap may no longer exist in younger patients with access to excellent health care facilities.[89][90]

The distribution of CF alleles varies among populations. The frequency of ΔF508 carriers has been estimated to be 1:200 in northern Sweden, 1:143 in Lithuanians, and 1:38 in Denmark. No ΔF508 carriers were found among 171 Finns and 151 Saami people.[91] ΔF508 does occur in Finland, but it is a minority allele there. Cystic fibrosis is known to occur in only 20 families (pedigrees) in Finland.[92]

Theories about prevalence

The ΔF508 mutation is estimated to be up to 52,000 years old.[93] Numerous hypotheses have been advanced as to why such a lethal mutation has persisted and spread in the human population. Other common autosomal recessive diseases such as sickle-cell anemia have been found to protect carriers from other diseases, a concept known as heterozygote advantage. Resistance to the following have all been proposed as possible sources of heterozygote advantage:

  • Cholera: With the discovery that cholera toxin requires normal host CFTR proteins to function properly, it was hypothesized that carriers of mutant CFTR genes benefited from resistance to cholera and other causes of diarrhea.[94] Further studies have not confirmed this hypothesis.[95][96]
  • Typhoid: Normal CFTR proteins are also essential for the entry of Salmonella typhi into cells,[97] suggesting that carriers of mutant CFTR genes might be resistant to typhoid fever. No in vivo study has yet confirmed this. In both cases, the low level of cystic fibrosis outside of Europe, in places where both cholera and typhoid fever are endemic, is not immediately explicable.
  • Diarrhea: 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.[98]
  • Tuberculosis: Another possible explanation is that carriers of the gene could have some resistance to TB.[99][100]

History

National Library of Medicine photo of Dorothy Hansine Andersen. Andersen first described cystic fibrosis in 1938.

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, er ist verhext und muss bald sterbe or "Woe is the child who tastes salty from a kiss on the brow, for he is cursed, and soon must die," recognizing the association between the salt loss in CF and illness.[101]

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.[101] In 1936, Guido Fanconi published a paper describing a connection between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis.[102]

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 was the first to describe the characteristic cystic fibrosis of the pancreas and to correlate it with the lung and intestinal disease prominent in CF.[1] She also first hypothesized that CF was 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.[103]

In 1988 the first mutation for CF, ΔF508 was discovered by Francis Collins, Lap-Chee Tsui and John R. Riordan on the seventh chromosome. Subsequent research has found over 1,000 different mutations that cause CF.

Because mutations in the CFTR gene are typically small, classical genetics techniques had been unable to accurately pinpoint the mutated gene.[104] 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.[105] In 1989 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.

Research

Gene therapy has been explored as a potential cure for cystic fibrosis. Ideally, gene therapy attempts to place a normal copy of the CFTR gene into affected cells. Transferring 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. Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 5–10% the normal amount of CFTR gene expression is needed.[106] Multiple approaches have been tested for gene transfer, such as liposomes and viral vectors in animal models and clinical trials. However, both methods were found to be relatively inefficient treatment options.[107] The main reason is that very 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.[108]

See also

References

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Further reading

  • Fungal etiology in CF-associated infections reviewed extensively by Pihet et al.: Pihet M, Carrere J, Cimon B, Chabasse D, Delhaes L, Symoens F, Bouchara JP (2009). "Occurrence and relevance of filamentous fungi in respiratory secretions of patients with cystic fibrosis--a review". Med Mycol. 47 (4): 387–97. doi:10.1080/13693780802609604. PMID 19107638. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  • Mowska, Patryk, Daniel Lorentzen, Katherine Excoffon, Joseph Zabner, Paul B. McCray, William M. Nauseef, Corinne Dupuy, and Botond Bánfi. A novel host defense system of airways is defective in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine, 1 Nov. 2006. Web. 26 Nov. 2009
  • Childers M, Eckel G, Himmel A, Caldwell J. A new model of cystic fibrosis pathology: lack of transport of glutathion and its thiocyanate conjugates. Med Hypotheses. 2007;68(1):101-12.
  • Conner GE, Salathe M, Forteza R Lactoperoxidase and hydrogen peroxide metabolism in the airway, AmJ Respir Crit Care Med 2002 Dec 15;166 (12 Pt2):S57-1 Review
  • Conner GE, Wijkstrom-Frei C, Randell SH, Fernandez VE, Salathe M. The lactoperoxidase system links anion transport to host defense in cystic fibrosis. FEBS Lett. 2007;581(2):271-8.
  • Minarowski Ł, Sands D, Minarowska A, Karwowska A, Sulewska A, Gacko M, Chyczewska E. Thiocyanate concentration in saliva of cystic fibrosis patients. Folia Histochem Cytobiol. 2008;46(2):245-6.
  • Rada B, Leto TL. Redox warfare between airway epithelial cells and Pseudomonas : dual oxidase versus pyocyanin. Immunol. Res. 2008
  • Fischer H. Mechanism and function of DUOX in epithelia of the lung. Antioxid Redox Signal. 2009;11(10):1-13.
  • Pedemonte N, Caci E, Sondo E, Caputo A, et al. Thiocyanate transport in resting & IL-4-stimulated human bronchial epithelial cells: role of pendrin and anion channels. J Immunol. 2007;178(8):5144-53.
  • Wijkstrom-Frei C, El-Chemaly S, Ali-Rachedi R, Gerson C, Cobas MA, Forteza R, Salathe M, Conner GE. Lactoperoxidase and human airway host defense. Am J Respir Cell Mol Biol 2003;29(2):206-12.
  • Xu Y, Szep S, Lu Z. The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation related diseases, PNAS. 2009; Early edition, November 16
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