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