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CysticFibrosis
Author:GirishDSharma,MD,FCCP,FAAPChiefEditor:MichaelRBye,MDmore...
Updated:Mar19,2015

PracticeEssentials
Cysticfibrosis(CF)isadiseaseofexocrineglandfunctionthatinvolvesmultipleorgansystemsbutchieflyresults
inchronicrespiratoryinfections,pancreaticenzymeinsufficiency,andassociatedcomplicationsinuntreated
patients.Pulmonaryinvolvement(seetheimagebelow)occursin90%ofpatientssurvivingtheneonatalperiod.
Endstagelungdiseaseistheprincipalcauseofdeath.

Chestradiographofapatientw ithadvancedcysticfibrosis.Notemarkedhyperinflation,peribronchialthickening,andbilateralinfiltrates
w ithevidenceofbronchiectasisespeciallyoftheupperlobes.

Essentialupdate:FDAapprovesbroaderuseofivacaftorincysticfibrosis
TheFDAhasapprovedanexpandedindicationforivacaftor(Kalydeco)inpatientsaged2yearsorolderwithCF
causedbyanyof10mutationsintheCFtransmembraneconductanceregulator(CFTR)gene.Thedrugwas
originallyapprovedforpatientswithatleast1copyoftheG551DmutationintheCTFRgene,andisnowalso
approvedforuseinpatientswiththefollowingCFTRgenemutations: [1]
G551D
G1244E
G1349D
G178R
G551S
R117H
S1251N
S1255P
S549N
S549R
ACFTRpotentiator,ivacaftorfacilitatesincreasedchloridetransportacrossCFTRchannelsbypotentiatingopen
channelprobability.Approvalforexpandeduseofivacaftorwasbasedonarandomizedcontrolledtrialin39CF
patientsinwhichivacaftorsignificantlyimprovedlungfunctioninpatientswiththesemutations. [1]

Signsandsymptoms
Medianageatdiagnosisis68monthshowever,ageatdiagnosisvarieswidely.Clinicalmanifestationsvarywith
thepatientsageatpresentation.
Gastrointestinal(GI)symptomsmayincludethefollowing:
Meconiumileus
Abdominaldistention
Intestinalobstruction
Increasedfrequencyofstools
Failuretothrive(despiteadequateappetite)
Flatulenceorfoulsmellingflatus,steatorrhea
Recurrentabdominalpain
Jaundice
GIbleeding
Respiratorysymptomsmayincludethefollowing:
Cough
Recurrentwheezing
Recurrentpneumonia
Atypicalasthma
Dyspneaonexertion
Chestpain

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Genitourinarysymptomsmayincludethefollowing:
Undescendedtesticlesorhydrocele
Delayedsecondarysexualdevelopment
Amenorrhea
Physicalsignsdependonthedegreeofinvolvementofvariousorgansandtheprogressionofdisease,asfollows:
NoseRhinitis,nasalpolyps
PulmonarysystemTachypnea,respiratorydistresswithretractions,wheezeorcrackles,cough(dryor
productiveofmucoidorpurulentsputum),increasedanteroposteriorchestdiameter,clubbing,cyanosis,
hyperresonantchestonpercussion
GItractAbdominaldistention,hepatosplenomegaly,rectalprolapse,dryskin,cheilosis
SeeClinicalPresentationformoredetail.

Diagnosis
RequirementsforaCFdiagnosisincludeeitherpositivegenetictestingorpositivesweatchloridetestfindingsand
1ofthefollowing:
Typicalchronicobstructivepulmonarydisease(COPD)
Documentedexocrinepancreaticinsufficiency
Positivefamilyhistory(usuallyanaffectedsibling)
Parametersforthesweatchloridetestareasfollows:
Thereferencevalueislessthan40mmol/L
Avaluehigherthan60mmol/LofchlorideisconsistentwithCF
Avalueof4060mmol/Lisconsideredborderline,andthetestmustberepeated
Inbabiesaged3monthsoryounger,avalueof3060mEq/Lisconsideredborderlineandrequiresretesting
[2]

Imagingstudiesthatmaybehelpfulincludethefollowing:
Radiography(chest,sinus,abdomen)
CTofthechest(notyetadvisedasaroutinemodalityinCF)
Ultrasonography
Contrastbariumenema
Additionalteststhatmaybewarrantedareasfollows:
Genotyping
Nasalpotentialdifferencemeasurement
Pulmonaryfunctiontesting
Bronchoalveolarlavage
Sputummicrobiology
Immunoreactivetrypsinogen
SeeWorkupformoredetail.

Management
TheprimarygoalsofCFtreatmentincludethefollowing:
Maintaininglungfunctionasneartonormalaspossiblebycontrollingrespiratoryinfectionandclearing
airwaysofmucus
Administeringnutritionaltherapy(ie,enzymesupplements,multivitaminandmineralsupplements)to
maintainadequategrowth
Managingcomplications
MildacutepulmonaryexacerbationsofCFcanbetreatedsuccessfullyathomewiththefollowingmeasures:
Increasingthefrequencyofairwayclearance
Inhaledbronchodilatortreatment
Chestphysicaltherapyandposturaldrainage
Increasingthedoseofthemucolyticagentdornasealfa
Useoforalantibiotics(eg,fluoroquinolones)
MedicationsusedtotreatCFmayincludethefollowing:
Pancreaticenzymesupplements
Multivitamins(includingfatsolublevitamins)
Mucolytics
Nebulized,inhaled,oral,orintravenousantibiotics
Bronchodilators
Antiinflammatoryagents
Agentstotreatassociatedconditionsorcomplications(eg,insulin,bisphosphonates)
Agentsdevisedtoreverseabnormalitiesinchloridetransport(eg,ivacaftor [3])
Inhaledhypertonicsaline
Surgicaltherapymayberequiredforthetreatmentofthefollowingrespiratorycomplications:
RespiratoryPneumothorax,massiverecurrentorpersistenthemoptysis,nasalpolyps,persistentand

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chronicsinusitis
GIMeconiumileus,intussusception,gastrostomytubeplacementforsupplementalfeeding,rectal
prolapse
Lungtransplantationisindicatedforthetreatmentofendstagelungdisease. [4]
SeeTreatmentandMedicationformoredetail.

Background
Cysticfibrosis(CF)isthemostcommonlethalinheriteddiseaseinwhitepersons. [5]Cysticfibrosisisan
autosomalrecessivedisorder,andmostcarriersofthegeneareasymptomatic.
Cysticfibrosisisadiseaseofexocrineglandfunctionthatinvolvesmultipleorgansystemsbutchieflyresultsin
chronicrespiratoryinfections,pancreaticenzymeinsufficiency,andassociatedcomplicationsinuntreated
patients(seeClinical).Pulmonaryinvolvementoccursin90%ofpatientssurvivingtheneonatalperiod.Endstage
lungdiseaseistheprincipalcauseofdeath.
Thediagnosisofcysticfibrosisisbasedontypicalpulmonarymanifestations,GItractmanifestations,afamily
history,andpositivesweatchloridetestresults(seeWorkup).Newbornscreeningforcysticfibrosisisuniversally
offeredintheUnitedStates.Asaresultofthecomplexandmultisystemicinvolvementofcysticfibrosisandthe
needforcarebyspecialists,treatmentandfollowupcareatspecialtycenterswithmultidisciplinarycareteams
(ie,cysticfibrosiscenters)isrecommended(seeTreatment).

Pathophysiology
Cysticfibrosisiscausedbydefectsinthecysticfibrosisgene,whichcodesforaproteintransmembrane
conductanceregulator(CFTR)thatfunctionsasachloridechannelandisregulatedbycyclicadenosine
monophosphate(cAMP).MutationsintheCFTRgeneresultinabnormalitiesofcAMPregulatedchloridetransport
acrossepithelialcellsonmucosalsurfaces.
SixclassesofdefectsresultingfromCFTRmutationshavebeendescribedandareasfollows [6]:
CompleteabsenceofCFTRproteinsynthesis
Defectiveproteinmaturationandearlydegradation(causedbythemostcommonmutation,F508)
Disorderedregulation(diminishedATPbindingandhydrolysis)
Defectivechlorideconductanceorchannelgating
Diminishedtranscriptionduetopromoterorsplicingabnormality
Acceleratedchannelturnoverfromthecellsurface
CFTRmutationshavepoorpenetrance.Thismeansthatthegenotypedoesnotpredictthepatternorseverityof
disease.
DefectiveCFTRresultsindecreasedsecretionofchlorideandincreasedreabsorptionofsodiumandwateracross
epithelialcells.Theresultantreducedheightofepithelialliningfluidanddecreasedhydrationofmucusresultsin
mucusthatisstickiertobacteria,whichpromotesinfectionandinflammation.Secretionsintherespiratorytract,
pancreas,GItract,sweatglands,andotherexocrinetissueshaveincreasedviscosity,whichmakesthemdifficult
toclear.
Mostpatientswithcysticfibrosishaveseverechroniclungdiseaseandexocrinepancreaticinsufficiency.
Additionalmanifestationsincludethefollowing:
Nasalpolyposis
Pansinusitis
Rectalprolapse
Chronicdiarrhea
Pancreatitis
Cholelithiasis
Cirrhosisorotherformsofhepaticdysfunction

Sinusdisease
TheexactmechanismbywhichmalfunctioningCFTRcausessinusdiseaseisnotcompletelyunderstood.
Chlorideionscannotbeexcreted,sodiumisexcessivelyabsorbed,andwaterpassivelyfollows.Thisdesiccates
themucosalsurfaceandalterstheviscosityofthenormalmucusblanket,whichalonecanleadtoobstructionof
sinusostia. [7]
Additionalabnormalitiesexistinthesepatients,includingciliarydysfunction,increasedinflammatorymediators,
andincreasedcolonizationwithPseudomonasaeruginosa,allofwhichfurtherimpairnormalsinusclearanceand
aeration. [8]Chronicsinusinfectionandinflammationarethenetresult.

Lungdisease
Mostdeathsassociatedwithcysticfibrosisresultfromprogressiveandendstagelungdisease.Inindividualswith
cysticfibrosis,thelungsarenormalinutero,atbirth,andafterbirth,beforetheonsetofinfectionandinflammation
(exceptpossiblyforthepresenceofdilatedsubmucosalglandductsintheairways).Shortlyafterbirth,many
personswithcysticfibrosisacquirealunginfection,whichincitesaninflammatoryresponse.Infectionbecomes
establishedwithadistinctivebacterialflora.Arepeatingcycleofinfectionandneutrophilicinflammationdevelops.
CleavageofcomplementreceptorsCR1andC3biandimmunoglobulinG(IgG)byneutrophilelastase(NE)results
infailureofopsonophagocytosis,leadingtobacterialpersistence.NEalsocausesproductionoftheneutrophil
chemoattractantinterleukin(IL)8fromepithelialcellsandelastindegradationandactsassecretogogue,thereby

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contributingtopersistenceofinflammationandinfection,structuraldamage,impairedgasexchange,and,
ultimately,endstagelungdiseaseandearlydeath.
Onestudyreportedthatexposuretosecondhandsmokeadverselyaffectsbothcrosssectionalandlongitudinal
measuresoflungfunctioninindividualswithcysticfibrosis. [9]VariationsinCFTRandacysticfibrosismodifier
gene(TGF1)amplifythenegativeeffectsofsecondhandsmokeexposure.

Intestinaldisease
DefectsinCFTRleadtoreducedchloridesecretionwithwaterfollowingintothegut.Thismayresultinmeconium
ileusatbirthandindistalintestinalobstructionsyndrome(DIOS)laterinlife.
Inaddition,otherpathologicdisorderscomplicatethesimplerelationshipbetweentheapicalchlorideandwater
secretionandthedisease.Thepancreaticinsufficiencydecreasestheabsorptionofintestinalcontents.
Mechanicalproblemsassociatedwithinflammation,scarring,andstricturesmaypredisposethepatientto
sludgingofintestinalcontents,leadingtointestinalobstructionbyfecalimpactionortointussusception.
Adhesionsmayform,leadingtocompleteobstruction.Acompleteobstructionmayrequireresection,leadingto
lossofabsorptiveepitheliumofthedistalileum.
Meconiumileus
Themeconiumoffetuseswithcysticfibrosisandmeconiumileushasincreasedviscosityanddecreasedwater
contentcomparedwiththoseofhealthycontrols.Thedevelopmentalsequenceofmucinsecretioninthefetal
intestineisnotfullyunderstood,althoughtheCFTRionchanneldefectpossiblyleadstodehydrationof
intraluminalcontents.
Meconiuminpatientswithmeconiumileusalsohashigherproteinandlowercarbohydrateconcentrationthanthat
incontrolpopulations.Albuministhemajorproteininthemeconiumofinfantswithmeconiumileus,andis
presentinconcentrations510timeshigherthannormal. [10]Inaddition,thereisasignificantincreaseintheliver's
productionofintraluminalglutamyltranspeptidase(GGTP)and5'nucleotidase,whichentersthemeconiumand
promotesmeconiumileus.
Theadditionofalbumintonormalmeconiummakesitviscidtheadditionofpancreaticproteaseliquefiesthe
viscidmass.Thisledtothebeliefthatpancreaticinsufficiencyplayedacentralroleinthepathogenesisof
meconiumileus,althoughpancreaticinsufficiencyisnotthesolecauseofabnormalmeconiuminmeconiumileus.
In1988,however,Landsetalreported2infantswithcysticfibrosisandmeconiumileus,aged9and11months,
whodisplayednoclinicalevidenceofpancreaticinsufficiency. [11]
Inthemurinemodelofcysticfibrosis,developedin1992,newbornmicehadsevereintestinalobstructionatbirth
withminimalpulmonaryorpancreaticinvolvement.Theseanimalstudiessupporttheconceptthatmeconiumileus
mayoccurinpatientswithsufficientpancreaticactivity.Thelackofconcordancebetweenmeconiumileusand
severityofpancreaticdiseasesuggeststhatintraluminalintestinalfactorscontributetomeconiumileus
development.
Abnormalintestinalmotilitymayalsocontributetomeconiumileusdevelopment.Somepatientswithcystic
fibrosishaveprolongedsmallintestinaltransittimes.Diseasesotherthancysticfibrosisinwhichthereis
abnormalgutmotility(eg,Hirschsprungdisease,chronicintestinalpseudoobstruction)havebeenassociatedwith
meconiumileuslikedisease,suggestingthatdecreasedperistalsismayallowincreasedresorptionofwater,thus
favoringmeconiumileusdevelopment.

Pancreaticdisease
Asapartofnormaldigestion,stomachacidisneutralizedbypancreaticbicarbonate,leadingtotheoptimalpHfor
pancreaticenzymeaction.Reducedbicarbonatesecretioninresponsetosecretinstimulationhasbeen
demonstratedinpatientswithcysticfibrosiswithbothpancreaticinsufficiencyandsufficiency.Reduced
bicarbonatesecretionaffectsthedigestionsothatneitherendogenousnorexogenouspancreaticenzymescan
workattheiroptimalpH.
Otherfactors,suchasreducedwatercontentofsecretions,precipitationofproteins,andpluggingofductulesand
acini,preventthepancreaticenzymesfromreachingthegut.Autodigestionofthepancreasoccasionallyleadsto
pancreatitis.
Mostpatientswithcysticfibrosis(9095%)havepancreaticenzymeinsufficiencyandpresentwithdigestive
symptomsand/orfailuretothriveearlyinlife.Onsetofpancreaticinsufficiencyvaries,however,andmayoccurin
patientsolderthan6months.Somepatientsneverdeveloppancreaticinsufficiency.
Patientswithpancreaticinsufficiencytypicallypresentwithpoorweightgaininassociationwithfrequentstools
thataremalodorous,greasy,andassociatedwithflatulenceandcolickypainafterfeeding.Thecombinationof
increasedenergyintakedemandatbaseline,theaddedenergyintakedemandofchronicdisease,difficulty
sustainingenergyuptakebecauseofmalabsorption,andanorexiaassociatedwithongoinglunginflammation
leadstopoorweightgain.
PancreaticinsufficiencypredisposespatientstopoorabsorptionoffatsolublevitaminsA,D,E,andK.
Symptomaticdeficiencyofanyofthesevitaminscanoccurbeforediagnosisorasalatercomplicationofthe
disease.

Liverdisease
AbsenceoffunctionalCFTRinepithelialcellsliningthebiliaryductulesleadstoreducedsecretionofchlorideand
reductioninpassivetransportofwaterandchloride,resultinginincreasedviscosityofbile.Thebiliaryductules
maybepluggedwithsecretions.Ifthisprocessisextensive,obstructivecirrhosiscomplicatedbyesophageal
varices,splenomegaly,andhypersplenismmayoccur.

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Secondaryinvolvementofthelivermayalsooccurbecauseofinvolvementofotherorgans.Forexample,
malnutritionmaybeassociatedwithhepaticsteatosis,andrightheartfailurecausedbychronichypoxiamay
resultinpassivecongestionoftheliver.
Gallstonesaremoreprevalentinpatientswithcysticfibrosisthaninagematchedcontrolsubjects.Asmanyas
15%ofyoungadultswithcysticfibrosishavegallstones,irrespectiveofthestatusoftheirpancreaticfunction.
AbnormalmucininthegallbladderandmalabsorptionofbileacidsinapatientwithPIresultinahigherfrequency
ofgallstones.

Urogenitaldisease
Congenitalabsenceofvasdeferensmayresultinmaleinfertility.Undescendedtesticlesorhydrocelesmaybe
presentinboys.Fertilityispossiblydecreasedinfemales.Amenorrheamayoccurinfemaleswithsevere
nutritionalorpulmonaryinvolvement.

Etiology
CysticfibrosisisanautosomalrecessivediseasecausedbydefectsintheCFTRgene,whichencodesfora
proteinthatfunctionsasachloridechannel,andalsoregulatestheflowofotherionsacrosstheapicalsurfaceof
epithelialcells.In1989,theCFlocuswaslocalizedthroughlinkageanalysistothelongarmofhuman
chromosome7,bandq31. [12]
Thusfar,1893CFTRmutationshavebeenidentified. [13]HalfofaffectedindividualsofnorthernEuropeandescent
arehomozygousfortheF508mutation,whichisthedeletionofasinglephenylalanineresidueataminoacid508
oftheCFTRgene(aclassIIdefect).Another25%30%haveonecopyofF508plusanothermutation. [14]
Certainallelesclusterwithincreasedfrequencyinspecificpopulations.Forexample,W1282Xiscommonin
AshkenaziJews,andA455EiscommonbothinDutchpeopleandinindividualsfromnorthernQuebec.1152His
thethirdmostprevalentalleleinAshkenaziandotherethnicJewishgroups.Theprevalenceof1152mutationin
Jewishpopulationscomprises5.2%ofallCFTRmutations.
CFTRmutationsresultinabnormalitiesofcAMPregulatedchloridetransportacrossepithelialcellsonmucosal
surfaces.Thefailureofchlorideconductancebyepithelialcellsandassociatedwatertransportabnormalitiesresult
inviscidsecretionsintherespiratorytract,pancreas,GItract,sweatglands,andotherexocrinetissues.
Increasedviscosityofthesesecretionsmakesthemdifficulttoclear.
GenotypephenotypecorrelationdemonstratesthatF508homozygositynearlyalwaysconfersapancreatic
exocrineinsufficiency.Individualswith1or2copiesofmissensemutations(eg,R117H)tendtobepancreatic
sufficientandhavemilderdisease.
TheincidenceofmeconiumileusishigherinpatientswhoarehomozygousforF508orwhohaveF508plus
G542X.Conversely,notallpatientswiththesegenotypeshavemeconiumileus,soothernonCFTRfactorsmust
beinvolvedinmeconiumileuspathogenesis.
Theincompletecorrelationofgenotypewithphenotypesuggestseitheranenvironmentalcomponentoforgan
dysfunctionormodifyinggenesthatareonlyrecentlybeingcharacterized. [15]Theroleofmodifiergenesis
supportedbythefactthatneonateswithcysticfibrosiswhohaveintestinalobstructionmostcommonlyhave
abnormalitiesin2ormoreCFTRmodifiergenes.Incontrast,olderchildrendevelopobstructionmostlyasaresult
ofenvironmentalfactors,suchasintroductionofpancreaticenzymescausingastricture. [16,17]
StudiesinmurineCFmodelshaveshownanincreaseinmastcellsandneutrophilsaspartoftheimmune
response.Forexample,theKITLgeneplaysavitalroleinthedifferentiationofmastcells,asdemonstratedbya
decreasedexpressionofMCPT2.Anotherfocusincludestheproteinsselectinandintercellularadhesion
molecule1(ICAM1),whichfacilitateneutrophilextravasation.Neutrophilsandmastcellsreleaseproteases,
prostaglandins,andhistamine,influencingmucusproduction.
AresearchmodelfoundinCFTRknockoutgenemicehighlightedtheimportanceofMCLCA3expressioningoblet
cells.Thisgeneinfluencesmucusproduction,amongotheractivities,anditsexpressionwasnotedtobe
diminishedinthesemice.Correctionofthisdeficiencyincreasedsurvivalanddecreasedintestinaldisease.In
humans,thisfindingmaytranslatetoapplicationssuchascorrectingmodifiergenes(eg,HCLCA1)inorderto
improveoutcomesinpatientswithCF. [18]
Additionalgeneticmodifiersincludea129/Svalleliccontributioninmicethatyieldsamilderinflammatory
responseinCFandispotentiallylinkedtochromosomes1,9,and10.Theregulationofthesegenesand
processeshelpsexplaintherangeofphenotypicvariabilityinsimilargeneticmutations.

Epidemiology
Cysticfibrosisisanautosomalrecessivedisease.Itsestimatedheterozygotefrequencyinwhitepeopleisupto1
in20.Eachoffspringof2heterozygoteparentshasa25%chanceofdevelopingcysticfibrosis.
Cysticfibrosisisthemostcommonlethalhereditarydiseaseinthewhitepopulation.IntheUnitedStates,the
prevalenceisasfollows:
WhitesofnorthernEuropeanorigin1caseper3,2003,500population
Hispanics1caseper9,2009,500population
AfricanAmericans1caseper15,00017,000population
AsianAmericans1caseper31,000population
Theworldwideincidencevariesfrom1per377livebirthsinpartsofEnglandto1per90,000Asianlivebirthsin
Hawaii.ThehigherfrequencyinAsianAmericanorAfricanAmericanpopulationscomparedwithnativeAsiansor
Africansreflectswhiteadmixture. [19]

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Racedemographics
ThedistributionofCFTRmutationsvariesaccordingtothebackgroundofpatientsforexample,F508isthemost
commonmutationfoundinthewhitepopulationofnorthernEuropeanorigin.Variabilityinclinicalfeaturesbetween
peopleofdifferentraceswithsamegenotypehasnotbeenreported.
Clinicalmanifestationsaresimilarinblackandwhitepopulations,exceptthatapoorernutritionalstatusis
observedinblackpatients.Blackpatientswithcysticfibrosisareyoungeratdiagnosisandhavepoorernutritional
statusandpulmonaryfunctionthanwhitepatientswithcysticfibrosis.Whetherthisisgeneticordueto
socioeconomicfactorsisunclearlowsocioeconomicstatusisassociatedwithsignificantlyworsepulmonary
outcomesinpatientswithcysticfibrosis.

Sexdemographics
Comparedwithmales,femaleswithcysticfibrosishavegreaterdeteriorationofpulmonaryfunctionwithincreasing
ageandyoungermeanageatdeath. [20]Althoughithasbeensuggestedthattheincreaseinhormonesecretion
withpubertyinfemalesmayinterferewiththedefensemechanismsoftheimmunesystem,therebypromoting
progressivepulmonaryinvolvement,theimmunesysteminpatientswithcysticfibrosisisfundamentallyintact.

Prognosis
Worldwide,themediansurvivalageinpatientswithcysticfibrosisvariesfromcountrytocountryitishighestin
theUnitedStates. [21]Mediansurvivalageis36.9years,butprogressinmedicalandsurgicaltreatmentoptions
haveimprovedtheprognosisoverthelastfewdecades.AnindividualwithcysticfibrosisbornintheUnitedStates
todayisexpectedtosurvivelongerthan40years. [22]Themediansurvivalageishigherinmalesthaninfemales.
Withcurrenttreatmentstrategies,80%ofpatientsshouldreachadulthood.Nevertheless,cysticfibrosisremainsa
lifelimitingdisease,andacureforthediseaseremainselusive.
Theclinicalpresentation,ageatdiagnosis,severityofsymptoms,andrateofdiseaseprogressionintheorgans
involvedwidelyvary.Sweatabnormalitiesmayresultinheatstrokeandsaltdepletion,especiallyininfants.
Mucoceleandmucopyoceleassociatedwithchronicsinusitisandnasalpolypscancauseerosionofthesinus
wall,resultinginCNScomplicationsfromthespaceoccupyingeffectofmucopyoceleorfromassociated
complications. [23]
GItractcomplicationsincludepancreaticinvolvement.Pancreatictissuedamageleadstodiabetesmellitusin8
12%ofpatientsolderthan25years.Excessiveadministrationofexogenouspancreaticenzymescanresultin
fibrosingcolonopathy.Intestinalcomplicationsrangefrommeconiumileuswithassociatedcomplicationsduring
theneonatalperiod(12%ofneonateswithcysticfibrosis)todistalintestinalobstructionsyndrome,rectal
prolapse,pepticulcer,andgastroesophagealreflux.
Liverinvolvementmayresultinafattyliver(3060%ofpatients),focalbiliarycirrhosis,multinodularbiliarycirrhosis,
andassociatedportalhypertension.Portalhypertensionoccasionallycausesdeaththroughesophagealvarices.
Theprevalenceofcholecystitisandgallstonesishigherinpatientswithcysticfibrosisthaninotherindividuals.
Delayedpubertyandreducedfertilityareothercomplicationsmostmalesareazoospermicbecauseofagenesis
ofthevasdeferens.Femalefertilityisprobablyonlymildlyimpaired,andmanysuccessfulpregnancieshavebeen
reportedinwomenwithcysticfibrosis.
Severityofpulmonarydiseasedeterminesprognosisandultimateoutcome.Pulmonaryinvolvementisprogressive:
beginningasbronchitis,bronchiolitis,andthenbronchiectasis,pulmonaryinvolvementleadstocorpulmonaleand
endstagelungdisease.Causeofdeathisgenerallyrespiratoryfailureandcorpulmonale.
Areviewof6750deathsduetocysticfibrosisinEnglandandWalesfrom19592008reportedthatfemalesexand
lowsocioeconomicstatusareassociatedwithpooreroutcomesthanmalesexandhighsocioeconomicstatus. [24]
Astudyof1517patientswithcysticfibrosiswhowereregisteredwiththeUKCysticFibrosisRegistryshowedthat
lowermusclemass,shorterstature,andalowbodymassindexareassociatedwithincreasedmortality. [25]
Inaprospectiveobservationalstudyof3142patientsfromtheCysticFibrosisFoundationRegistry,weightforage
percentileat4yearsofagewasassociatedwithimprovedclinicaloutcomesincludinglungfunction,fewer
complicationsofcysticfibrosisandbettersurvivalthroughtheageof18. [26]

PatientEducation
Providecounselingatthetimeofinitialdiagnosis,includinginformationregardinginheritanceandriskfor
recurrenceinsubsequentpregnancies,andinstructpatientsandparentsregardingappropriateairwayclearance
techniqueandtheneedforchestphysicaltherapy.Also,instructpatientsandparentsregardingtheuseofvarious
drugdeliverydevices,suchasvalvedholdingchambers,andnebulizers,andthemethodsformodifyingthe
pancreaticenzymedosage.
Discusswhentocontactcysticfibrosiscenterpersonnel(eg,foracutepulmonaryexacerbationorcomplications)
withpatientsandparents,andbepreparedtocounselfamiliesregardingtheimpactofthediagnosisonthe
emotionallifeofparents,siblings,andmembersoftheextendedfamily.

ContributorInformationandDisclosures
Author
GirishDSharma,MD,FCCP,FAAPProfessorofPediatrics,Director,SectionofPediatricPulmonologyand
RushCysticFibrosisCenter,RushMedicalCollegeSeniorAttending,DepartmentofPediatrics,Rush
UniversityMedicalCenter

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GirishDSharma,MD,FCCP,FAAPisamemberofthefollowingmedicalsocieties:AmericanAcademyof
Pediatrics,AmericanCollegeofChestPhysicians,AmericanThoracicSociety,andRoyalCollegeof
PhysiciansofIreland
Disclosure:Nothingtodisclose.
SpecialtyEditorBoard
SusannaAMcColley,MDProfessorofPediatrics,NorthwesternUniversity,TheFeinbergSchoolofMedicine
DirectorofCysticFibrosisCenter,Head,DivisionofPulmonaryMedicine,Children'sMemorialMedicalCenterof
Chicago
SusannaAMcColley,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,
AmericanCollegeofChestPhysicians,AmericanSleepDisordersAssociation,andAmericanThoracicSociety
Disclosure:GenentechHonorariaSpeakingandteachingGenentechHonorariaConsultingBostonScientific
ConsultingfeeConsultingGileadHonorariaSpeakingandteachingCaremarkConsultingfeeConsulting
VertexPharmaceuticalsHonorariaSpeakingandteaching
MaryLWindle,PharmDAdjunctAssociateProfessor,UniversityofNebraskaMedicalCenterCollegeof
PharmacyEditorinChief,MedscapeDrugReference
Disclosure:Nothingtodisclose.
CharlesCallahan,DOProfessor,DeputyChiefofClinicalServices,WalterReedArmyMedicalCenter
CharlesCallahan,DOisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,
AmericanCollegeofChestPhysicians,AmericanCollegeofOsteopathicPediatricians,AmericanThoracic
Society,AssociationofMilitarySurgeonsoftheUS,andChristianMedical&DentalSociety
Disclosure:Nothingtodisclose.
MaryECataletto,MDProfessorofClinicalPediatrics,StateUniversityofNewYorkatStonyBrook
MaryECataletto,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatricsand
AmericanCollegeofChestPhysicians
Disclosure:Nothingtodisclose.
ChiefEditor
MichaelRBye,MDProfessorofClinicalPediatrics,StateUniversityofNewYorkatBuffaloSchoolof
MedicineAttendingPhysician,PediatricPulmonaryDivision,Women'sandChildren'sHospitalofBuffalo
MichaelRBye,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,American
CollegeofChestPhysicians,andAmericanThoracicSociety
Disclosure:Nothingtodisclose.

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