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  • Atypicalcholestasisinpregnancy

    NASOM,MontrealOctober2016

    FlorenceWeber

  • Objectives

    Recognizeatypicalpresentationofpruritusinpregnancy(ICP)

    Recognizediseasesthatmimicintrahepaticcholestasisofpregnancy(ICP)

    Usesecondorthirdlinetreatmentforintractablepruritusinthesepatients

  • atypicalcaseofICP

    32yearoldG1,16thweeksofgestation Pruritussinceweek10 Norash ALT88(N14-40) Totalbileacids(TBA)15(N

  • Whatsnew/Areasuncertainty

    Diagnosticcriteria/

    DefinitionTreatment

    Question1: Whichdiseasesshould

    beexcluded?

    Question2: Whichabnormallabsarenecessaryfordiagnosisof

    ICP?

    Question3: Whatarethetreatmentoptionsforherpruritus?

    Question4: Whatshouldbethetimingofdelivery?

  • Question1: Whichdiseasesshouldbeexcluded?

    UsualdefinitionICP:typical

    Prurituslate2ndor3rdtrimester Norash ElevatedTBAand/ortransaminase Exclusionofotherliverdiseases Postpartumresolution

  • Question1: Whichdiseasesshouldbeexcluded?

    Greatvariabilitybetweenstudies,guidelines,expertopinions.Include: Virus:hepatitisA,B,C,EBV,CMV Hereditary:hemochromatosis,a1antitrypsindeficiency,

    Wilsonsdisease Auto-immune:hepatitis,primarybiliarycirrhosis Fattyliverdisease Extrahepaticbiliaryobstruction Mutationsbilesalttransporters

  • Question2: Whichdiseasesshouldbeexcluded?

    Shouldn'tweusetheconceptof:

    PrimaryversussecondaryICP?

  • Association with genetic bile salts transporter defects

    Michael Trauner, and James L. Boyer Physiol Rev 2003;83:633-671

    2003 by American Physiological Society

    MutationsABCB4gene

    MutationsABCB11gene

    Mutations ATP8B1gene

  • Geneticcause

    Largespectrumofclinicalpresentationofmutationsincluding: ICP BRIC(Benignrecurringintrahepaticcholestasis) Cholesterolgallstones PFIC(Progressivefamilialintrahepaticcholestasis)

    BacqYandal*: Identified4mutationsalmostexclusivelyin16%

    ofCaucasianswithICP*(versuscontrolswithoutICP)

    *BacqY,JMetGenet2009;46:711-715

  • Geneticcause

    BacqYandal.DigestiveandLiverdisease2016(acceptedmanuscript)

    Onsetpruritus TBAconcentration

    TBAconcentration>40umol/L

    ABCB4mutation17/98

    301/7weeks 42,9umol/L 35,3%

    Nomutation81/98

    332/7weeks 24,3umol/L 13,6%

    * Johnson RC and al. Journal of Perinatology 2014; 34: 711-712

  • Question1: Whichdiseasesshouldbeexcluded?

    Greatvariabilitybetweenstudies,guidelines,expertopinions.Include: Virus:hepatitisA,B,C,EBV,CMV Hereditary:hemochromatosis,a1antitrypsindeficiency,

    Wilsonsdisease Auto-immune:hepatitis,primarybiliarycirrhosis Fattyliverdisease Extrahepaticbiliaryobstruction Mutationsofbilesalttransporters

  • Question2: WhichabnormallabsarenecessaryfordiagnosisofICP?

    WhydoALTincreasebeforeGGT.Isntthischolestasis????

    Pruritusnolab

    abnormality:Pruritus

    Gestationis(23%pregnancies)

    TBAelevation(versus

    individualbileacid

    measurement*)DxICP

    Transaminaseelevation(30%)

    Mildalkalinephosphataseelevation

    RareGGTandbilirubinelevation

    Probablesequenceofabnormalities

    *HuandWM.AmJPerinatol2009;26:291

  • Question2: WhichabnormallabsarenecessaryfordiagnosisofICP?

    Whydoguidelines/expertsmentionelevatedTBAand/ortransaminase? ProbablybecauseTBAlevelsnotuniversallyavailable Serumbileacidsareincreasinglyrecognizedasthemostdefinitive

    laboratorytestfordiagnosisofICP*

    CanwediagnoseICPifelevationoftransaminasebutnotTBA?probablynot

    CanwediagnoseICPifelevatedTBAbutasymptomatic?Yes

    *DixonHandWilliamsonC.ThePathophysiologueofintraheptaiccholestasisofpregnancy.ClinicsandresearshinHepatologyandGatroenterology2016;40:141-153

  • Backtoourcase

    TBA:15umol/Latdiagnosis

    TreatedwithUDCA500mg3timesaday

    InitiallybetterwithALTdecreasetonormal

    Deteriorationat26weeks:severepruritus,ALT120,TBA50umol/L

  • Question3: Whatarethetreatmentoptionsforherpruritus?

    Drug Improvedchemistry

    Improvedpruritus Improvedfetaloutcome

    UDCA450-1000mg/day**

    + + +

    SAMe + + -/?

    Activatedcharchoal

    - - -

    Guargum ? + ?

    Cholestyramine +(lessthanUDCA)

    +(lessthanUDCA)

    LessthanUDCA

    Dexamethasone(versusUDCA)

    - - -

    Rifampicin(combinationwith

    UDCA)

    + + ?

    *OvadiaCandal.Clinicsindermatology2016;34:327-334 **KongXandal.Medicine2016;95(40)

  • Question3: Whatarethetreatmentoptionsforherpruritus?

    Othertreatmentoptions: Phenobarbital:noeffet

    PhototherapyUV-B:anecdotal

    Plasmapheresis:casereportswithsuccess

    Sertraline(SSRI):nodatainICP

    Oralnaltrexone(opioidantagonist):nodatainICP

  • Question3: Whatarethetreatmentoptionsforherpruritus?

    Treatmentplanforourpatient:

    UDCA(maximumdose15mg/kg/day) Upto3,5gperdaydescribed*:safe? plusrifampicin(cautionifALTveryhigh).

    Considercholestyramine8g/day(cautionwithtiming)

    Ifveryextremelysevereand

  • Question3: Whatarethetreatmentoptionsforherpruritus?

    Teaser:Useofgrapefruitjuice SeeposterbyDahlKandal.NASOM2016

    4patientswithsecondaryICP

  • Question4: Whatshouldbethetimingofdelivery?

    Roleofgestationalageonfetalprognosis,whatweknow: Seriesof20UIFDs:median38weeks,2/20before37weeks**

    *WilliamsonCandal.BJOC2004;111:676

  • Question4: Whatshouldbethetimingofdelivery?

    2recentpublicationsusingdifferentexperimentalapproachessuggestdelivery36weeks=bestoutcome*,**

    Multiplemethodologicalflaws,donottakeintoaccountTBA,subjectofdebatebetweenexperts.

    *PuljicAandal.AmJObstetGynecol2015;212:667 **LoJOandal.TheJouranelofMaternal-FetalandNeonatalMedicine2015;18(18):2254-2258

  • Question4: Whatshouldbethetimingofdelivery?

    Positionthatseemsmostconsensual:continuedeliveringICPat37weeksunless: PasthistoryofIUFD Intolerablepruritus Otherindicationfordelivery Personalpreference ElevatedTBA

  • RoleofTBAs

    Roleofbileacidsinfetalmorbidityandmortality*

    Inductionofarrhythmia/fetalheartUSabnormalities** Affectplacentalvasculature Couldincreasepretermlabor(viaprostaglandinpathways) Stimulategutmotility:meconium-stainedamnioticfluid Disruptpulmonarysurfactantinneonates Longterm:effectonmetabolichealthofteenagers

    *DixonHandWilliamsonC.ThePathophysiologueofintraheptaiccholestasisofpregnancy.ClinicsandresearshinHepatologyandGatroenterology2016;40:141-153 **Alaalla WM and al. J Mat Fetal Neonat Med 2016; 29((): 1445-1450

  • RoleofTBAs

    GeenesVandal.Hepatology2014;59:1482

    Prospectivecase-control

    669ICPsingletonpregnancieswithTBA>40umol/L Stillbirth1,5%versus0.5%

    10stillbirthsinICPgroup 6/10before37weeks 7/10anotherpregnancycomplication(PE,gestationaldiabetes)

    MedianTBA137umol/L(104-159)versuslivebirths72umo/Ll(52-107)

  • RoleofTBAs

    TBA>100umol/L:10-15%IUFD*,** TowardsanewclassificationofICPdependingonmaxTBA: Mild10-39umol/L Moderate40-99 Severe>100

    IsthefetusprotectedifTBA>100andthendecrease

  • Conclusions

    Mutationsofbilesalttransporterslinkedtoupto15%ofcasesofICP Shouldwetesteverycase?Selectedcases?

    NotionofprimaryversussecondaryICP

    TBAsisthemostacceptedmarkerfordiagnosisofICP TowardanewclassificationofICPbasedonmaximal

    recordedTBA? 10-39umol/L:mild 40-99umol/L:moderate >100umol/L:severe

  • Conclusions

    Treatementoptionsremainlimited

    ShouldalwaysincludeUDCA

    Consider:rifampicin,cholestyramine8g/day,Grapefruitjuice(500-1000ml/day)

    Ifveryextremelysevereand

  • Conclusions

    Theidealtimingofdeliveryisnotyetknown

    Difficultquestionwithmedicallegalimplications,necessityofgroupconsensus

    VariableavailabilityofTBAtesting

    37weeksorearlierif: Pasthistoryofstillbirth Intolerablepruritus Otherindicationfordelivery Personalpreference TBA>40umol/L(especiallyif>100)

  • Newdiagnostictests

    Noveldiagnosticavenues? Measurementofsulfatedprogestinmetabolites* Measurementofautotaxinactivity**

    *Abu-HayyefSA,WilliamsonCandal.Hepatology2016;63(4):1287 **KremerAEandal.JournalofHepatology2015:vol62:897-901

    InductionofAutotaxin

    Bycholestasis

    LPA(inskin)potentiates

    actionpotentialinitchfibers

    Lysophosphatidylcholine

  • Question:Whyher?Riskfactors

    PriorICP(60-70%recurrence)

    LatinAmerican: ICPincidence0,1-15% Geographicvariations

    Winter(seleniumdeficiency?)

    Twinpregnancies

    Exogenousprogesterone

    Geneticpredisposition

  • Exogenousprogesterone

    BacqYandal.Hepatology1997;26:358 50womenwithICP,64%oralnaturalprogesterone

    Abu-HayyefSA,WilliamsonCandal.Hepatology2016;63(4):1287: InICP:Elevatedsulfatedprogesteronemetabolites: Competitivelyinhibitbileaciduptakeandefflux:

    contributetocholestasis

    Participatetopruritus Futurepathwayfortreatmentanddiagnosis?

  • Exogenousprogesterone

    Clinicalsignificance: Someexpertsrecommendavoidingprogesteronesupplementationif: PriorICP CurrentICP

  • Question: Riskforotherpregnancyrelatedproblems?

    MartineauMGandal.DiabetesCare2015;38:243 26ICPversus27normalpregnancies: ICPassociatedwithimpairedglucoseintolerance Dyslipidemia Increasedfetalgrowth

    ICP Controls

    Weeksatdelivery 37,4 40,1

    Birthweight(g) 3,298(69,9centile) 3,381(36,1centile)

  • Question: Riskforotherpregnancyrelatedproblems?

    RazYandal.AmJournalObstetGynecol2015;213:395 SevereICP(TBS>40umol/L): majorriskfactorforPE:

    Singletons:7,4%versus1,5% Twins:33%versus6,2%

    IncreaseinseverePE TBSnormalin33patientswithPEbutnoICP

    Closelyfoll


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