Cystic Fibrosis - Wiki

8/3/2019 Cystic Fibrosis - Wiki

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http://en.wikipedia.org/wiki/Cystic_fibrosis

Cystic fibrosisFrom Wikipedia, the free encyclopedia

Cystic fibrosisClassification and external resources

A breathing treatment for cystic fibrosis, using a masknebuliser and a ThAIRapy Vest

ICD-10 E84

ICD-9 277.0

OMIM 219700

DiseasesDB 3347

MedlinePlus 000107

eMedicine ped /535

MeSH D003550

Cystic fibrosis (also known as CF ormucoviscidosis) is arecessivegenetic disease affectingmost critically the lungs, and also thepancreas, liver, and intestine. It is characterized byabnormal transport ofchlorideand sodium across epithelium, leading to thick, viscous secretions.[1]

The name cystic fibrosis refers to the characteristic scarring (fibrosis) and cyst formation withinthepancreas, first recognized in the1930s.[2]Difficulty breathing is the most serious symptomand results from frequent lung infections that are treated with, though not cured by,antibioticsand other medications. Othersymptoms, including sinus infections,poor growth, diarrhea, andinfertility affect other parts of the body.

CF is caused by a mutationin the gene for theproteincystic fibrosis transmembrane conductanceregulator(CFTR). This gene is required to regulate the components of sweat, digestive juices,andmucus. Although most people without CF have two working copies of the CFTR gene, onlyone is needed to prevent cystic fibrosis. CF develops when neither gene works normally andtherefore has autosomalrecessive inheritance.

CF is most common among Caucasians; one in 25 people of European descentcarries one allelefor CF.[3][4]
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Ireland has both the highest incidence of CF in the world; 2.98 per 10,000 - and the highestcarrier rate in the world with 1 in 19 individuals classed as carriers. Cystic fibrosis is Ireland'smost common life-threatening inherited disease. Ireland also has the largest proportion offamilies with more than one child suffering from CF.[5][6][7]

Individuals with cystic fibrosis can be diagnosed before birth by genetic testing, or by a sweat

test in early childhood. Ultimately, lung transplantation is often necessary as CF worsens.

Contents[hide]

1 Signs and symptoms

1.1 Lung and sinus

1.2 Gastrointestinal

1.3 Endocrine

1.4 Infertility

2 Cause

3 Pathophysiology

3.1 Chronic infections

4 Diagnosis and monitoring

4.1 Prenatal

5 Management

5.1 Antibiotics

5.2 Other treatments for lung disease

5.3 Transplantation

5.4 Treatment of other aspects

6 Quality of life

7 Prognosis

8 Epidemiology

8.1 Theories about prevalence

9 History

10 Research

10.1 Gene therapy 10.2 Small molecules

11 See also

12 References

13 Further reading

14 External links
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[edit] Signs and symptoms

A diagram showing clinical manifestations of cystic fibrosis[8]

The hallmark symptoms of cystic fibrosis are salty tasting skin,[9] poor growth and poor weightgain despite a normal food intake,[10] accumulation of thick, sticky mucus,[11] frequent chestinfections and coughing or shortness of breath.[12] Males can be infertile due tocongenitalabsence of the vas deferens.[13] Symptoms often appear in infancy and childhood, such asbowelobstruction due to meconium ileus in newborn babies.[14] As the child grows, they must exerciseto release mucus in the alveoli.[15]Ciliatedepithelial cells in the patient have a mutated proteinthat leads to abnormally viscous mucus production.[11] The poor growth in children typicallypresents as an inability to gain weight or height at the same rate as their peers and is occasionallynot diagnosed until investigation is initiated for poor growth. The causes of growth failure aremulti-factorial and include chronic lung infection, poor absorption of nutrients through thegastrointestinal tract, and increased metabolic demand due to chronic illness. [10]

In rare cases, cystic fibrosis can manifest itself as a coagulation disorder. A double recessiveallele is needed for cystic fibrosis to be apparent. Young children are especially sensitive tovitamin Kmalabsorptive disorders because only a very small amount of vitamin K crosses theplacenta, leaving the child with very low reserves. Because factors II, VII, IX, and X (clottingfactors) are vitamin Kdependent, low levels of vitamin K can result in coagulation problems.
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Consequently, when a child presents with unexplained bruising, a coagulation evaluation may bewarranted to determine whether there is an underlying disease.[16]

[edit] Lung and sinus

Respiratory infections in CF varies according to age.

Green =Pseudomonas aeruginosaBrown =Staphylococcus aureusBlue = Haemophilus influenzaeRed = Burkholderia cepaciacomplex

Lung disease results from clogging of the airways due to mucus build-up, decreased mucociliaryclearanceand resultinginflammation.[17][18] Inflammation and infection cause injury andstructural changes to the lungs, leading to a variety of symptoms. In the early stages, incessantcoughing, copiousphlegm production, and decreased ability to exercise are common. Many of

these symptoms occur whenbacteria that normally inhabit the thick mucus grow out of controland cause pneumonia. In later stages, changes in the architecture of the lung such as pathology inthe major airways (bronchiectasis) further exacerbate difficulties in breathing. Other symptomsinclude coughing up blood (hemoptysis), highblood pressure in the lung (pulmonaryhypertension), heart failure, difficulties getting enough oxygento the body (hypoxia), andrespiratory failure requiring support with breathing masks such asbilevel positive airwaypressure machines orventilators.[19]Staphylococcus aureus, Haemophilus influenzae, andPseudomonas aeruginosa are the three most common organisms causing lung infections in CFpatients.[18] In addition to typical bacterial infections, people with CF more commonly developother types of lung disease. Among these isallergic bronchopulmonary aspergillosis, in whichthe body's response to the commonfungusAspergillusfumigatus causes worsening of breathingproblems. Another is infection with Mycobacterium avium complex (MAC), a group of bacteria

related to tuberculosis, which can cause a lot of lung damage and does not respond to commonantibiotics.[20]

Mucus in the paranasal sinusesis equally thick and may also cause blockage of the sinuspassages, 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 toinflammation from chronic sinus infections.[21] Recurrent sinonasal polyps can occur in as manyas 10% to 25% of CF patients.[18] These polyps can block the nasal passages and increasebreathing difficulties.[22][23]
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Cardiorespiratory complications are the most common cause of death (~80%) in patientsfollowed by most CF centers in the United States.[18]

[edit] Gastrointestinal

Prior to prenatal and newborn screening, cystic fibrosis was often diagnosed when a newborninfant failed to pass faeces (meconium). Meconium may completely block the intestines andcause serious illness. This condition, calledmeconium ileus, occurs in 510%[18][24] of newbornswith CF. In addition, protrusion of internal rectal membranes (rectal prolapse) is more common,occurring in as many as 10% of children with CF,[18] and it is caused by increased fecal volume,malnutrition, and increased intraabdominal pressure due to coughing.[25]

The thick mucus seen in the lungs has a counterpart in thickened secretions from thepancreas, anorgan responsible for providing digestive juices that help break down food. These secretionsblock the exocrine movement of the digestive enzymes into theduodenumand result inirreversible damage to the pancreas, often with painful inflammation (pancreatitis).[26] Thepancreatic ducts are totally plugged in more advanced cases, usually seen in older children oradolescents.[18] This causes atrophy of the exocrine glands and progressive fibrosis.[18]

The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequentexcretion in the feces, a disorder known asmalabsorption. Malabsorption leads to malnutritionand poor growth and development because of calorie loss. Resultant hypoproteinemia may besevere enough to cause generalized edema.[18]Individuals with CF also have difficultiesabsorbing 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.[27] Older individuals with CF maydevelop distal intestinal obstruction syndromewhen thickened feces cause intestinal blockage.[28]

Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF.[18] Itis mainly associated with "severe" CFTR mutations, where both alleles are completelynonfunctional (e.g. F508/F508).[18] 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.[18] In these milder cases, there is still sufficient pancreatic exocrinefunction so that enzyme supplementation is not required.[18]There are usually no other GIcomplications in pancreas-sufficient phenotypes, and in general, such individuals usually haveexcellent growth and development.[18]Despite this, idiopathic chronic pancreatitis can occur in asubset of pancreas-sufficient individuals with CF, and is associated with recurrent abdominalpain and life-threatening complications.[18]

Thickened secretions also may cause liver problems in patients with CF.Bile secreted by theliver to aid in digestion may block thebile ducts, leading to liver damage. Over time, this canlead to scarring and nodularity (cirrhosis). The liver fails to rid the blood of toxins and does notmake importantproteinssuch as those responsible forblood clotting.[29][30] Liver disease is the

third most common cause of death associated with CF.[18]

[edit] Endocrine
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Clubbing in the fingers of a person with cystic fibrosis

Thepancreas contains the islets of Langerhans, which are responsible for making insulin, ahormone that helps regulate blood glucose. Damage of the pancreas can lead to loss of the isletcells, leading to a type of diabetes that is unique to those with the disease. [31] This cystic fibrosisrelated 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.[32]

Vitamin D is involved incalcium andphosphate regulation. Poor uptake of vitamin D from the diet because ofmalabsorption can lead to the bone disease osteoporosisin which weakened bones are moresusceptible to fractures.[33]In addition, people with CF often develop clubbingof their fingersand toes due to the effects of chronic illness and low oxygenin their tissues.[34][35]

[edit] Infertility

Infertility affects both men and women. At least 97% of men with cystic fibrosis are infertile, butnot sterile and can have children with assisted reproductive techniques.[36] These men makenormal sperm but are missing the tube (vas deferens), which connects thetestesto theejaculatory ducts of thepenis.[37]Many men found to have congenital absence of the vas deferensduring evaluation for infertility have a mild, previously undiagnosed form of CF.[38] Some

women have fertility difficulties due to thickened cervical mucus or malnutrition. In severecases, malnutrition disrupts ovulation and causes amenorrhea.[39]

[edit] Cause
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Cystic fibrosis has an autosomal recessive pattern of inheritance

CF is caused by a mutationin the genecystic fibrosis transmembrane conductance regulator(CFTR). The most common mutation, F508, is a deletion () of three nucleotides[40] that resultsin a loss of the amino acidphenylalanine(F) at the 508th position on the protein. This mutation

accounts for two-thirds (66-70%[18]) of CF cases worldwide and 90% of cases in the UnitedStates; however, there are over 1500 other mutations that can produce CF.[41] Although mostpeople have two working copies (alleles) of the CFTR gene, only one is needed to prevent cysticfibrosis. CF develops when neither allele can produce a functional CFTR protein. Thus, CF isconsidered an autosomal recessive disease.

The CFTR gene, found at the q31.2locus ofchromosome 7, is 230,000base pairs long, andcreates a protein that is 1,480amino acidslong. Structurally, CFTR is a type of gene known asanABC gene.[19]The product of this gene (the CFTR) is a chloride ion channel important increating sweat, digestivejuices andmucus. This protein possesses two ATP-hydrolyzingdomains, which allows the protein to use energy in the form ofATP. It also contains twodomains comprising 6 alpha helices apiece, which allow the protein to cross the cell membrane.

A regulatorybinding site on the protein allows activation byphosphorylation, mainly by cAMP -dependent protein kinase.[19] The carboxyl terminal of the protein is anchored to the cytoskeletonby aPDZ domain interaction.[42]

In addition, there is increasing evidence that genetic modifiers besides CFTR modulate thefrequency and severity of the disease. One example is mannan -binding lectin, which is involvedin innate immunity by facilitatingphagocytosis of microorganisms. Polymorphisms in one orboth mannan-binding lectin alleles that result in lower circulating levels of the protein areassociated with a threefold higher risk of end-stage lung disease, as well as an increased burdenof chronic bacterial infections.[18]

[edit] Pathophysiology

Molecular structure of the CFTR protein

There are several mutations in the CFTR gene, and different mutations cause different defects inthe CFTR protein, sometimes causing a milder or more severe disease. These protein defects are
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also targets for drugs which can sometimes restore their function. F508-CFTR, which occurs in>90% of patients in the U.S., creates a protein that does not fold normally and is degraded by thecell. Other mutations result in proteins that are too short (truncated) becauseproductionis endedprematurely. Other mutations produce proteins that do not use energy normally, do not allowchloride,iodideand thiocyanate to cross the membrane appropriately,[43] or are degraded at afaster rate than normal. Mutations may also lead to fewer copies of the CFTR protein beingproduced.[19]

The protein created by this gene is anchored to the outer membrane ofcells in thesweat glands,lungs, pancreas, and other affectedorgans. The protein spans this membrane and acts as achannelconnecting the inner part of the cell (cytoplasm) to the surrounding fluid. This channel isprimarily responsible for controlling the movement of halogens from inside to outside of the cell;however, in the sweat ducts it facilitates the movement of chloride from the sweat into thecytoplasm. When the CFTR protein does not work, chloride and thiocyanate[44]are trapped insidethe cells in the airway and outside in the skin. Then hypothiocyanite, OSCN, cannot be producedby immune defense system.[45][46] Because chloride is negatively charged, this creates a differencein the electrical potential inside and outside the cell causing cationsto cross into the cell. Sodiumis the most common cation in the extracellular space and the combination of sodium and chloridecreates the salt, which is lost in high amounts in the sweat of individuals with CF. This lost saltforms the basis for the sweat test.[19]

Most of the damage in CF is due to blockage of the narrow passages of affected organs withthickened secretions. These blockages lead to remodeling and infection in the lung, damage byaccumulated digestive enzymes in the pancreas, blockage of the intestines by thick faeces, etc.There are several theories on how the defects in the protein and cellular function cause theclinical effects. One theory is that the lack of halogen and pseudohalogen (mainly, chloride,iodide and thiocyanate) exiting through the CFTR protein leads to the accumulation of moreviscous, nutrient-rich mucus in the lungs that allows bacteria to hide from the body'simmunesystem. Another theory is that the CFTR protein failure leads to a paradoxical increase in sodiumand chloride uptake, which, by leading to increased water reabsorption, creates dehydrated and

thick mucus. Yet another theory is that abnormal chloride movement outof the cell leads todehydration of mucus, pancreatic secretions, biliary secretions, etc.[19]

[edit] Chronic infections

The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an earlyage. 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 bacterialmicroenvironments known as biofilms that are difficult for immune cells and antibiotics topenetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lung bygradually remodeling the airways, which makes infection even more difficult to eradicate. [47]

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 andHemophilusinfluenzaecolonize and infect the lungs.[18] Eventually,Pseudomonas aeruginosa (andsometimes Burkholderia cepacia) dominates. By 18 years of age, 80% of patients with classicCF harborP. aeruginosa, and 3.5% harborB. cepacia.[18]Once within the lungs, these bacteriaadapt to the environment and develop resistanceto commonly used antibiotics.Pseudomonascan 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.[47]
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One way infection spreads is by passing between different individuals with CF.[48] In the past,people with CF often participated in summer "CF Camps" and other recreational gatherings. [49][50]

Hospitals grouped patients with CF into common areas and routine equipment (such asnebulizers)[51] was not sterilized between individual patients.[52] This led to transmission of moredangerous strains of bacteria among groups of patients. As a result, individuals with CF areroutinely isolated from one another in the healthcare setting and healthcare providers areencouraged to wear gowns and gloves when examining patients with CF to limit the spread ofvirulent bacterial strains.[53]

CF patients may also have their airways chronically colonized by filamentous fungi (such asAspergillus fumigatus, Scedosporium apiospermum,Aspergillus terreus) and/or yeasts (such asCandida albicans); other filamentous fungi less commonly isolated includeAspergillus flavusandAspergillus nidulans (occur transiently in CF respiratory secretions), andExophialadermatitidis and Scedosporium prolificans (chronic airway-colonizers); some filamentous fungilikePenicillium emersonii andAcrophialophora fusispora are encountered in patients almostexclusively in the context of CF.[54]Defective mucociliary clearance characterizing CF isassociated with local immunological disorders. In addition, the prolonged therapy withantibiotics and the use of corticosteroid treatments may also facilitate fungal growth. Althoughthe clinical relevance of the fungal airway colonization is still a matter of debate, filamentousfungi may contribute to the local inflammatory response, and therefore to the progressivedeterioration of the lung function, as often happens with allergic broncho-pulmonaryaspergillosis (ABPA) - the most common fungal disease in the context of CF, involving a Th2-driven immune response to Aspergillus.[54][55]

[edit] Diagnosis and monitoring
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The location of the CFTR gene on chromosome 7

Cystic fibrosis may be diagnosed by many different methods including newborn screening,sweattesting, andgenetic testing. As of 2006 in the United States, 10 percent of cases are diagnosedshortly after birth as part of newborn screening programs. The newborn screen initially measuresfor raised blood concentration ofimmunoreactive trypsinogen.[56] Infants with an abnormalnewborn screen need a sweat test to confirm the CF diagnosis. In many cases, a parent makes thediagnosis because the infant tastes salty.[18]Trypsinogen levels can be increased in individualswho have a single mutated copy of the CFTR gene (carriers) or, in rare instances, in individualswith two normal copies of the CFTR gene. Due to these false positives, CF screening in

newborns can be controversial.

[57][58]

Most states and countries do not screen for CF routinely atbirth. Therefore, most individuals are diagnosed after symptoms (e.g. sinopulmonary disease andGI manifestations[18]) prompt an evaluation for cystic fibrosis. The most commonly used form oftesting is the sweat test. Sweat-testing involves application of a medication that stimulatessweating (pilocarpine). 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 aseparate electrode on the skin. The resultant sweat is then collected on filter paper or in acapillary tube and analyzed for abnormal amounts ofsodium and chloride. People with CF haveincreased amounts of sodium and chloride in their sweat. In opposite, people with CF have less
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thiocyanate and hypothiocyanite in their saliva (Minarowski[59] et al.) and mucus (Banfi et al.).CF can also be diagnosed by identification of mutations in the CFTR gene .[60]

People with CF may be listed in a disease registry that allows researchers and doctors to trackhealth results and identify candidates forclinical trials.[61]

[edit] Prenatal

Couples who are pregnant or planning a pregnancy can have themselves tested for the CFTRgene mutations to determine the risk that their child will be born with cystic fibrosis. Testing istypically performed first on one or both parents and, if the risk of CF is high, testing on thefetusis performed. The American College of Obstetricians and Gynecologists (ACOG) recommendstesting for couples who have a personal or close family history of CF, and they recommend thatcarrier testing be offered to all Caucasian couples and be made available to couples of otherethnic backgrounds.[62]

Because development of CF in the fetus requires each parent to pass on a mutated copy of theCFTR gene and because CF testing is expensive, testing is often performed initially on oneparent. If testing shows that parent is a CFTR gene mutation carrier, the other parent is tested to

calculate the risk that their children will have CF. CF can result from more than a thousanddifferent mutations, and as of 2006 it is not possible to test for each one. Testing analyzes theblood for the most common mutations such as F508most commercially available tests lookfor 32 or fewer different mutations. If a family has a known uncommon mutation, specificscreening for that mutation can be performed. Because not all known mutations are found oncurrent tests, a negative screen does not guarantee that a child will not have CF.[63]

During pregnancy, testing can be performed on theplacenta (chorionic villus sampling) or thefluid around the fetus (amniocentesis). However, chorionic villus sampling has a risk of fetaldeath of 1 in 100 and amniocentesis of 1 in 200;[64] a recent study has indicated this may be muchlower, approximately 1 in 1,600.[65]

Economically, for carrier couples of cystic fibrosis, when comparing preimplantation genetic

diagnosis (PGD) with natural conception (NC) followed by prenatal testing and abortion ofaffected pregnancies, PGD provides net economic benefits up to a maternal age of approximately40 years, after which NC, prenatal testing and abortion has higher economic benefit.[66]

[edit] ManagementWhile there are no cures for cystic fibrosis there are several treatment methods. The managementof cystic fibrosis has improved significantly over the past 70 years. While infants born withcystic fibrosis 70 years ago would have been unlikely to live beyond their first year, infantstoday are likely to live well into adulthood. Recent advances in the treatment of cystic fibrosishave meant that an individual with cystic fibrosis can live a fuller life less encumbered by theircondition. The cornerstones of management are proactive treatment ofairway infection, and

encouragement of good nutrition and an active lifestyle. Management of cystic fibrosis continuesthroughout a patient's life, and is aimed at maximizing organ function, and therefore quality oflife. At best, current treatments delay the decline in organ function. Because of the wide variationin disease symptoms treatment typically occurs at specialist multidisciplinary centers, and istailored to the individual. Targets for therapy are thelungs,gastrointestinal tract(includingpancreatic enzyme supplements), the reproductive organs (including assisted reproductivetechnology(ART)) and psychological support.[56]
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The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung damagecaused 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 devicesand 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 importantbattles that CF patients face is finding the time to comply with prescribed treatments whilebalancing a normal life.

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

[edit] Antibiotics

Many CF patients are on one or moreantibiotics at all times, even when healthy, to

prophylactically suppress infection. Antibiotics are absolutely necessary whenever pneumonia issuspected or there has been a noticeable decline in lung function, and are usually chosen basedon the results of a sputum analysis and the patient's past response. This prolonged therapy oftennecessitates hospitalization and insertion of a more permanent IV such as aperipherally insertedcentral catheter(PICC line) orPort-a-Cath. Inhaled therapy with antibiotics such as tobramycin,colistin, and aztreonam is often given for months at a time to improve lung function by impedingthe growth of colonized bacteria.[67][68][69] Oral antibiotics such as ciprofloxacin orazithromycinare given to help prevent infection or to control ongoing infection. [70] Theaminoglycosideantibiotics (e.g. tobramycin) used can cause hearing loss, damage to thebalance system in theinner earorkidney problems with long-term use.[71] To prevent these side-effects, the amount ofantibiotics in the blood are routinely measured and adjusted accordingly.

[edit] Other treatments for lung disease

Several mechanical techniques are used to dislodge sputum and encourage its expectoration. Inthe hospital setting, chest physiotherapy (CPT) is utilized; a respiratory therapist percusses anindividual's chest with his or her hands several times a day, to loosen up secretions. Devices thatrecreate this percussive therapy include the ThAIRapy Vest and the intrapulmonary percussiveventilator(IPV). Newer methods such as Biphasic Cuirass Ventilation, and associated clearancemode available in such devices, integrate a cough assistance phase, as well as a vibration phasefor dislodging secretions. These are portable and adapted for home use.[72]

Aerosolized medications that help loosen secretions include dornase alfa and hypertonicsaline.[73] Dornase is a recombinant humandeoxyribonuclease, which breaks down DNA in the sputum,thus decreasing its viscosity.[74]Denufosol is an investigational drug that opens an alternativechloride channel, helping to liquefy mucus.[75]

As lung disease worsens, mechanical breathing support may become necessary. Individuals withCF may need to wear special masks at night that help push air into their lungs. These machines,known asbilevel positive airway pressure (BiPAP) ventilators, help prevent low blood oxygenlevels during sleep. BiPAP may also be used during physical therapy to improve sputumclearance.[76] During severe illness, atubemay be placed in the throat (a procedure known as atracheostomy) to enable breathing supported by a ventilator.
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For children living with CF, preliminary studies show pediatric massage therapy may improvepatients and their families quality of life, though more rigorous studies must be done.[77]

[edit] Transplantation

Lung transplantation often becomes necessary for individuals with cystic fibrosis as lungfunction and exercise tolerance declines. Although single lung transplantation is possible in otherdiseases, individuals with CF must have both lungs replaced because the remaining lung mightcontain bacteria that could infect the transplanted lung. A pancreatic or liver transplant may beperformed at the same time in order to alleviate liver disease and/or diabetes.[78] Lungtransplantation is considered when lung function declines to the point where assistance frommechanical devices is required or patient survival is threatened. [79]

[edit] Treatment of other aspects

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

Newborns with CF typically require surgery, whereas adults withdistal intestinal obstructionsyndrome typically do not. Treatment of pancreatic insufficiency by replacement of missingdigestive enzymes allows the duodenum to properly absorb nutrients and vitamins that would

otherwise be lost in the feces.So far, no large-scale research involving the incidence ofatherosclerosisand coronary heart disease in adults with cystic fibrosis has been conducted. Thisis likely due to the fact that the vast majority of people with cystic fibrosis do not live longenough to develop clinically significant atherosclerosis or coronary heart disease.

Diabetes is the most common non-pulmonary complication of CF. It mixes features oftype 1 andtype 2 diabetes, and is recognized as a distinct entity, cystic fibrosis-related diabetes (CFRD).[80][81] While oralanti-diabetic drugsare sometimes used, the only recommended treatment is the useofinsulin injections or an insulin pump,[82]and, unlike in type 1 and 2 diabetes, dietaryrestrictions are not recommended.[80]

Development ofosteoporosis can be prevented by increased intake of vitamin D and calcium,and can be treated bybisphosphonates, although adverse effects can be an issue.[83] Poor growth

may be avoided by insertion of a feeding tube for increasing calories through supplemental feedsor by administration of injected growth hormone.[84]

Sinus infections are treated by prolonged courses of antibiotics. The development of nasal polypsor 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 nasalobstruction and to limit further infections. Nasal steroids such as fluticasone are used to decreasenasal inflammation.[85] Female infertility may be overcome by assisted reproduction technology,particularly embryo transfertechniques. Male infertility caused by absence of the vas deferens
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may be overcome with testicular sperm extraction (TEST), collecting sperm cells directly fromthe testicles. If the collected sample contains too few sperm cells to likely have a spontaneousfertilization, intracytoplasmic sperm injection can be performed.[86]Third party reproduction isalso a possibility for women with CF.

[edit] Quality of lifeChronic illnesses are very difficult to manage. Cystic fibrosis (CF) is a chronic illness that affectsthe digestive and respiratory tracts resulting in generalized malnutrition and chronic respiratoryinfections.[87]The thick secretions clog the airways in the lungs, which often cause inflammationand severe lung infections.[88]Therefore, mucus makes it challenging to breathe. If it iscompromised, it affects the quality of life of someone with CF, and their ability to complete suchtasks as everyday chores. It is important for CF patients to understand the detrimentalrelationship that chronic illnesses place on the quality of life. According to Schmitz andGoldbeck (2006), the fact that Cystic Fibrosis significantly increases emotional stress on both theindividual and the family, and the necessary time-consuming daily treatment routine may havefurther negative effects on quality of life (QOL).[89]However, Havermans and colleagues (2006)have shown that young outpatients with CF that have participated in the CFQ-R (Cystic Fibrosis

Questionnaire-Revised) rated some QOL domains higher than did their parents.[90]

Consequently, outpatients with CF have a more positive outlook for themselves. Furthermore,there are many ways to improve the QOL in CF patients. Exercise is promoted to increase lungfunction. The fact of integrating an exercise regime into the CF patients daily routine cansignificantly improve the quality of life.[91] There is no definitive cure for Cystic Fibrosis.However, there are diverse medications used such as, mucolytics, bronchodilators, steroids andantibiotics that have the purpose of loosening mucus, expanding airways, decreasinginflammation and fighting lung infections.[92]

[edit] PrognosisThe prognosis for cystic fibrosis in the U.S. has improved due to earlier diagnosis through

screening, better treatment and access to health care. Patient compliance is major factorpatients that are more aggressive in following treatment recommendations live longer.

In 1959, the median age of survival of children with cystic fibrosis in the U.S. was six months.Now, it is 37.4 years.[93] In Canada, median survival increased from 24 years in 1982 to 47.7 in2007.[94]

The U.S. Cystic Fibrosis Foundation reported that in 2008, 92% had graduated from high schooland 66% had at least some college education. 15% of adults were disabled and 7% wereunemployed. 54.8% of adults were single and 40.1% were married or living with a partner. In2008, 240 American women with CF were pregnant.[95]

[edit] Epidemiology

MutationFrequency

worldwide[96]

F508 66%-70%[18]

G542X 2.4%

G551D 1.6%

N1303K 1.3%

W1282X 1.2%
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All others 27.5%

Cystic fibrosis is the most common life-limiting autosomal recessive disease among people ofEuropean heritage.[97]In the United States, approximately 30,000 individuals have CF; most arediagnosed 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,[98] 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 abnormalCFTR gene.[99][100]

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. Anexception is Finland, where only one in 80 people carry a CF mutation.[101] In the United States, 1in 4,000 children are born with CF.[102] In 1997, about 1 in 3,300 caucasian children in the UnitedStates was born with cystic fibrosis. In contrast, only 1 in 15,000 African American childrensuffered from cystic fibrosis, and in Asian Americans the rate was even lower at 1 in 32,000.[103]

Cystic fibrosis is diagnosed in males and females equally. For reasons that remain unclear, datahas shown that males tend to have a longerlife expectancy than females,[104][105] however recent

studies suggest this gender gap may no longer exist perhaps due to improvements in health carefacilities,[106][107] while a recent study from Ireland identified a link between the female hormoneoestrogen and worse outcomes in CF.[108]

The distribution of CF alleles varies among populations. The frequency of F508 carriers hasbeen estimated at 1:200 in northern Sweden, 1:143 in Lithuanians, and 1:38 in Denmark. NoF508 carriers were found among 171Finns and 151Saami people.[109] F508 does occur inFinland, but it is a minority allele there. Cystic fibrosis is known to occur in only 20 families(pedigrees) in Finland.[110]

[edit] Theories about prevalence

The F508 mutation is estimated to be up to 52,000 years old.[111] Numerous hypotheses have

been advanced as to why such a lethal mutation has persisted and spread in the humanpopulation. Other common autosomal recessive diseases such as sickle-cell anemia have beenfound to protect carriers from other diseases, a concept known as heterozygote advantage.Resistance to the following have all been proposed as possible sources of heterozygoteadvantage:

Cholera: With the discovery thatcholeratoxin requires normal host CFTR proteins tofunction properly, it was hypothesized that carriers of mutant CFTR genes benefited fromresistance to cholera and other causes of diarrhea.[112] Further studies have not confirmedthis hypothesis.[113][114]

Typhoid: Normal CFTR proteins are also essential for the entry ofSalmonella typhi intocells,[115] 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 cysticfibrosis outside of Europe, in places where both cholera and typhoid fever are endemic, isnot immediately explicable.

Diarrhea: It has also been hypothesized that the prevalence of CF in Europe might beconnected with the development of cattle domestication. In this hypothesis, carriers of asingle mutant CFTR chromosome had some protection from diarrhea caused bylactoseintolerance, prior to the appearance of the mutations that created lactose tolerance.[116]
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Tuberculosis: Another possible explanation is that carriers of the gene could have someresistance to TB.[117][118]

[edit] History

National Library of Medicine photo ofDorothy Hansine Andersen. Andersen first describedcystic fibrosis in 1938.

It is supposed that CF appeared about 3,000 BC as a cause of migration of peoples, genemutations, and new conditions in nourishment.[119] Although the entire clinical spectrum of CFwas not recognized until the 1930s, certain aspects of CF were identified much earlier. Indeed,literature[specify] from Germany and Switzerland in the 18th century warned Wehe dem Kind, das

beim Ku auf die Stirn salzig schmekt, er ist verhext und muss bald sterbe or "Woe is the childwho tastes salty from a kiss on the brow, for he is cursed, and soon must die," recognizing theassociation between the salt loss in CF and illness.[119]

In the 19th century, Carl von Rokitansky described a case of fetal death with meconiumperitonitis, a complication of meconium ileus associated with cystic fibrosis. Meconium ileuswas first described in 1905 by Karl Landsteiner.[119]In 1936, Guido Fanconipublished a paperdescribing a connection between celiac disease, cystic fibrosis of the pancreas, andbronchiectasis.[120]

In 1938 Dorothy Hansine Andersenpublished an article, "Cystic Fibrosis of the Pancreas and ItsRelation to Celiac Disease: a Clinical and Pathological Study," in theAmerican Journal ofDiseases 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.[2]

She also firsthypothesized that CF was a recessive disease and first used pancreatic enzyme replacement totreat affected children. In 1952 Paul di Sant' Agnese discovered abnormalities in sweatelectrolytes; a sweat test was developed and improved over the next decade.[121]

In 1988 the first mutation for CF, F508 was discovered byFrancis Collins,Lap- Chee Tsui andJohn R. Riordan on the seventh chromosome. Subsequent research has found over 1,000different mutations that cause CF.
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Because mutations in the CFTR gene are typically small,classical genetics techniques had beenunable to accurately pinpoint the mutated gene.[122] Using protein markers, gene-linkage studieswere able to map the mutation to chromosome 7. Chromosome-walkingand-jumping techniqueswere then used to identify and sequence the gene.[123]In 1989 Lap-Chee Tsui led a team ofresearchers at the Hospital for Sick Childrenin Torontothat discovered the gene responsible forCF. Cystic fibrosis represents the first genetic disorder elucidated strictly by the process ofreverse genetics.

[edit] Research

[edit] Gene therapy

Gene therapyhas been explored as a potential cure for cystic fibrosis. Ideally, gene therapyattempts to place a normal copy of theCFTR geneinto affected cells. Transferring the normalCFTR gene into the affected epithelium cells would result in the production of functional CFTRin all target cells, without adverse reactions or an inflammation response. Studies have shownthat to prevent the lung manifestations of cystic fibrosis, only 510% the normal amount ofCFTRgene expression is needed.[124] Multiple approaches have been tested for gene transfer,

such as liposomes and viral vectors in animal models and clinical trials. However, both methodswere found relatively inefficient treatment options.[125] The main reason is that very few cells takeup the vector and express the gene, so the treatment has little effect. Additionally, problems havebeen noted in cDNA recombination, such that the gene introduced by the treatment is renderedunusable.[126] Gene therapy has made massive advances in the way that cystic fibrosis has beentreated throughout the world[citation needed]. With the help of the Cystic Fibrosis Trust, which has aleague of highly professional gene therapists, both somatic and Adeno-associated viral vectorhave made advances. The Adenoviridae, or more commonly known as the cold virus, isgenetically altered, allowing the CFTR gene to enter lung cells. They are currently stage 3clinical trial, and following the success of these trials, the treatment can become readily availableand valid in the eyes of the medical world[citation needed].

[edit] Small moleculesA number ofsmall molecules that aim at compensating various mutations of the CFTR gene areunder development. One approach is to develop drugs that get the ribosome to overcome thestopcodon and synthesize a full-length CFTR protein. About 10% of CF result from a premature stopcodon in the DNA, leading to early termination of protein synthesis and truncated proteins.These drugs target nonsense mutations such as G542X, which consists of the amino acid glycinin position 542 being replaced by a stop codon. Aminoglycoside antibiotics interfere with DNAsynthesis and error-correction. In some cases, they can cause the cell to overcome the stopcodon, insert a random amino acid, and express a full-length protein.[127]The aminoglycosidegentamicinhas been used to treat lung cells from CF patients in the laboratory to induce the cellsto grow full-length proteins.[128] Another drug targeting nonsense mutations is ataluren, which is

undergoing Phase III clinical trials as of October 2011.

[129]

Ivacaftor, also in Phase III trials, targets the mutation G551D (glycin in position 551 issubstituted withaspartic acid). VX-809 aims at F508del (phenylalanin in position 508 ismissing).[130]
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