CYSTIC FIBROSIS OF THE PANCREAS Cystic Fibrosis .5/01/2011 1 Cystic Fibrosis 1938 CYSTIC FIBROSIS

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Text of CYSTIC FIBROSIS OF THE PANCREAS Cystic Fibrosis .5/01/2011 1 Cystic Fibrosis 1938 CYSTIC FIBROSIS

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    Cystic Fibrosis

    1938CYSTIC FIBROSIS OF THE PANCREAS

    AND ITS RELATION TO CELIAC DISEASE.

    D ANDERSEN.American Journal Diseases Children.

    Cystic Fibrosis : The beginningCystic Fibrosis : The beginning

    20

    25

    May 1938: 49 cases

    0

    5

    10

    15Nos of cases

    0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

    Age at death

    Cystic Fibrosis

    Commonest lethal inherited condition in WWCommonest lethal inherited condition in WWLife limiting and incurable.Life limiting and incurable.

    600 ti t i Vi t i ith CF600 ti t i Vi t i ith CF600 patients in Victoria with CF.600 patients in Victoria with CF.One in every 2,500 live birthsOne in every 2,500 live births

    About 15About 15--25 new born pts per year25 new born pts per year

    Cystic Fibrosis

    Median age survival late 30s Median age survival late 30s 95% survive till 20 years 95% survive till 20 years

    80% till 30 years80% till 30 years80% till 30 years80% till 30 years

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    Cystic Fibrosis

    New Born screening: HitsNew Born screening: HitsAll states of AustraliaDay 3Day 32 part test: IRT and CF genePositive results by 4-6 weeks

    Cystic Fibrosis

    New Born screeningNew Born screening2 part test: IRT top 1%

    CF genotypeCF genotype

    Cystic Fibrosis

    CF gene:CF gene:Over 1500 different mutations508 commonest present in 90% pts in Australia508 commonest - present in 90% pts in AustraliaCurrent Vic program screens for 13 commonestMutations screened for differ between states

    CYSTIC FIBROSISCYSTIC FIBROSIS

    GENOTYPES 5 ClassesClass 1: Premature termination of mRNA translation

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    CYSTIC FIBROSISCYSTIC FIBROSIS

    GENOTYPES Class 1: Premature termination of mRNA translation

    due to base substitution causing stop codonsdue to base substitution causing stop codons

    CYSTIC FIBROSISCYSTIC FIBROSIS

    GENOTYPES Class 1: Premature termination of mRNA translation

    due to base substitution causing stop codonsdue to base substitution causing stop codonsor mutations that shift the reading frame Producing defective proteins

    CYSTIC FIBROSISCYSTIC FIBROSIS

    GENOTYPES Class 1: Premature termination of mRNA translation

    due to base substitution causing stop codonsdue to base substitution causing stop codonsor mutations that shift the reading frame Producing defective proteins

    G542X and W1282X

    CYSTIC FIBROSISCYSTIC FIBROSIS

    GENOTYPES Class 2: Defects in protein processing

    CFTR is degraded in ER and does not reachCFTR is degraded in ER and does not reach apical membrane

    508 and N1303K

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    CYSTIC FIBROSISCYSTIC FIBROSIS

    GENOTYPES Class 3: Regulatory mutations

    CFTR reaches apical membrane but failsCFTR reaches apical membrane but failsrespond to activation signals

    G551D

    CYSTIC FIBROSISCYSTIC FIBROSIS

    GENOTYPES Class 4: Defective protein conduction

    Reaches apical membrane but has alteredReaches apical membrane but has altered channel properties

    R117H and R347P

    CYSTIC FIBROSISCYSTIC FIBROSIS

    GENOTYPES Class 5: Reduced levels of RNA for CFTR

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    Cystic Fibrosis

    New Born screening: MissesNew Born screening: MissesChronic Cough

    Cystic Fibrosis

    New Born screening: MissesNew Born screening: MissesChronic CoughFailure to thriveFailure to thrive

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    Cystic Fibrosis

    New Born screening: MissesNew Born screening: MissesChronic CoughFailure to thriveFailure to thriveChronic Diarrhoea

    Underlying defect in CFUnderlying defect in CF

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    Mechanisms of lung damage in CF

    Viscous secretions

    Viscous secretions

    CFTR dysfunction

    CFTR dysfunction

    InfectionInfection InflammationInflammation

    Lung damage

    Abnormal lung function

    Lung damage

    Abnormal lung function

    DeathDeath

    secretionssecretions

    CF update: Early lung disease

    Aim to minimise/ delay onset disease thru new born screening

    Early intervention in CF patientsprevents severe malnutrition

    Wisconsin CF Neonatal Screening Study

    Randomised controlled trial with 650,000 newborns. Split into two groups:Split into two groups: an early-diagnosis screened cohort a standard diagnosis control group

    Newborns screened for CF by immunoreactive trypsinogen (IRT) test (1985-91) IRT test + DNA-based detection of F508 (1991-94)

    Effect of screening on weight

    -0.6-0.4-0.2

    00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

    t SD

    S

    -1.8-1.6-1.4-1.2

    -1-0.8

    ScreenedUnscreened

    Wei

    ght

    p

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    CF update: Early lung disease

    Regular assessments: BAL30% infants will have Pseudomonas by age 3 despite aggressive cross infection policiesgg p

    CF update: Early lung disease

    Regular assessments: BAL30% infants will have Pseudomonas by age 3 despite aggressive cross infection policiesgg pAggressive eradication programs 85% successful

    CF update

    Reculture:Sputum or BAL

    +ve sample culture for

    P. aeruginosa

    Nebulised tobramycinNebulised tobramycin

    Cipro Cipro

    3 months? IVs

    POSITIVE NEGATIVE

    2 weeks of IV anti-pseudomonal

    antibiotics and then repeat

    No further treatment or back to prophylactic

    antibiotics

    If following second attempt of eradication sputum or BAL is still positive is likely chronic Pa infection

    CF update: Early lung disease

    Regular assessments: BAL30% infants will have Pseudomonas by age 3 despite aggressive cross infection policiesgg pAggressive eradication programs 85% successfulPseudomonas EVER is a bad prognostic factor

    CF update: Early lung disease

    Regular assessments: CT scans90% infants will show signs of bronchiectasis

    on CT at age 5 yearson CT at age 5 years

    Wainwright C

    CF update: Early lung disease

    Regular assessments: PFTsChanges occur very early and are progressive

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    Linnane B

    CF update: Early lung disease

    Future management? Trials anti inflammatory Medication

    CF update: Early lung disease

    Future management? Trials anti inflammatory Medication -

    AZTAZT

    CF update Antibiotic therapy in CF

    TargetedNon Pseudomonal: Staph/ H Inf

    Incidence airway pathogens by age

    60

    80

    100S. aureusH. influenzae

    ture

    s (%

    )

    0

    20

    40

    0-1 2-5 6-10 11-15 16-20 21-25 26-30 31-35 >35

    Age group (years)

    Tota

    l cul

    t

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    CYSTIC FIBROSISCYSTIC FIBROSIS

    B. CEPACIAGenomovars (1-9)Aggressive lung disease (cenocepacia type 3)Aggressive lung disease (cenocepacia type 3)Non 3 mild diseaseBactrimSome clearance

    CYSTIC FIBROSISCYSTIC FIBROSIS

    ASPERGILLUSABPAAirway colonisationAirway colonisationAspergillomaInfection in pre existing cyst

    Incidence airway pathogens by age

    60

    80

    100 P. aeruginosaS. aureusH. influenzae

    ture

    s (%

    )

    0

    20

    40

    0-1 2-5 6-10 11-15 16-20 21-25 26-30 31-35 >35

    Age group (years)

    Tota

    l cul

    t