Primary Biliary Colangitis(PBC): Deciding Which Patients ... · Primary Biliary Colangitis(PBC):...
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PrimaryBiliaryColangitis (PBC):DecidingWhichPatientsareUrsodiol Nonresponders
FredPoordad,MD
CaseStudy
• 57-year-oldwhitefemalepresentstoyouforroutineannualexam• Reportsfatigueandintermittentitching• OnlymedicationisSynthroid;noOTCproducts• BMI=28;nometabolicsyndrome
• ALP300IU/mL,AST60IU/mL,ALT73IU/mL,totalbilirubin0.7mg/dL,hemoglobin12.3mg/dL,platelets185K
• Viralhepatitisserologies negative• Abdominalultrasoundshowsnormalliver/spleenmorphology,nobileduct
dilatationandnormalgallbladder.
Immuneresponse
Bileductdamage
Environment
Genetics
Poupon R.JHepatol.2010;52(5):745-758;Selmi C,etal.Lancet.2011;377(9777):1600-1609;CareyEJ,etal.Lancet.2015;386(10003):1565-1575.
• PBCischaracterizedbydestructionoftheinterlobularandseptalbileductsthatmayleadtocirrhosis
• FactorspossiblyassociatedwithonsetandperpetuationofbileductinjuryinPBC
PBCisaChronic,ProgressiveAutoimmuneDisease
PBCPhenotype
Abbreviations:AMA,antimitochondrial antibody;ANA,antinuclearantibody;ASMA,anti-smooth-muscleantibody;IBD,inflammatoryboweldisease;MRCP,magneticresonancecholangiography;PBC,primarybiliarycirrhosis.Trivedi PJ,etal.AlimentPharmacol Ther.2012;36:517-533.
Age
Gender
Serology
Immunoglobulin
MRCP
LiverHistology
CoexistingIBD
Usually>45years
Female>Male(9:1)
AMAin~95%;disease-specificANAin~30%-50%;ASMAmaybepresent
IgM typicallyelevated
Normal
Lymphocyticinfiltrate;inflammatoryductlesion;granulomamaybepresent
Nottypical
Boonstra K,Kunst A,Stadhouders P,etal.LiverInternational.2014;34:e35.
PBCPrevalence
PBCcanrangefromasymptomaticandslowlyprogressivetosymptomaticandrapidlyevolving.1
• Fatigue1,2
• Pruritus1,2
• Concurrentautoimmunediseases1,2
• Reducedbonedensity1,2
• Hypercholesterolemia1,2
• XanthomaandXanthelasma2,3
ClinicalFeaturesVaryGreatlyBetweenPatients
1.Selmi C,etal.Lancet.2011;377(9777):1600-1609;2.CareyEJ,etal.Lancet.2015;386(10003):1565-1575;3.Lindor KD,etal.Hepatology.2009;50(1):291-308.
SpectrumofAutoimmuneLiverInjuries1
• Autoimmunehepatitis1
• Primarybiliarycholangitis1
• Primarysclerosingcholangitis1
• IgG4-relateddisease2
DifferentialforCholestaticLiverBiochemistry3
• Drug-inducedliverinjury• Inheritedcholestasis• Idiopathicductopenia• Malignantinfiltration• Nonalcoholicfattyliver
disease• Obstructivebiliarylesion• Primarybiliarycholangitis• Primarysclerosingcholangitis• Sarcoidosis
DiagnosticConsiderations
1.Trivedi PJ,etal.AlimentPharmacol Ther.2012;36:517-533;2.JoshiD,etal.AlimentPharmacol Ther.2014;40:1251-1261;3.HirschfieldGM,etal.BestPract ResClin Gastroenterol.2011;25:701-712.
Elevatedserumalkalinephosphatase(ALP)activity
Excludeothercausesofliverdiseaseincludingalcoholanddrugs
Crosssectionalimagingoflivertoexcludebiliaryobstruction
AMA(Antimitochondrial antibody),ANA(antinuclearantibody),ASMA(anti-smoothmuscleantibody)
Considerliverbiopsy,especiallyifAST>5xULNorAMAnegative
AASLDSuggestedDiagnosticAlgorithmforPatientswithSuspectedPBC
Trivedi PJetal.J Hepatol.2014;60(6):1249-58;Corpechot Cetal.Hepatology.2012;56(1):198-208.
HigherAPRIandElastography AssociatedwithPoorSurvival
DiseaseManagement
RuleOut:
Associatedcausesoffatigue(diseaseormedication):•Anemia2
•Depression2
•Sleepdisorder2
•Hypothyroidism1-3
•Medicationsthatcancauseorcontributetofatigue(eg,excessiveantihypertensivemedication)1
ConsiderFatigueManagementStrategies:
Fatiguemaybeimprovedby:•Maintainingregularphysicalactivity4,5
•Modafinil (100-200mg)6,7
•Methotrexateforpatientswithseverefatigue8
1.EuropeanAssociationfortheStudyoftheLiver.JHepatol.2009;51(2):237-267;2.Lindor KD,etal.Hepatology.2009;50(1):291-308;3.Elta GH,etal.DigDisSci.1983;28(11):971-975;4.CookNF,etal.BrJNurs.1997;6(14):811-815;5.Graydon JE,etal.CancerNurs.1995;18(1):23-28;6.JonesDEJ,etal. AlimentPharmacol Ther.2007;25(4):471-476;7.IanGan S,etal.DigDisSci.2009;54(10):2242-2246;8.Babatin MA,etal.AlimentPharmacol Ther.2006;24(5):813-820.
AssessingandManagingFatigue• ThoughfatiguecausedbyPBCmaynotbereversible,associatedcausesoffatigue
shouldbeactivelyexcluded—oridentifiedandmanaged1,2
1.ImamMH,etal.JGastroenterolHepatol.2012;27(7):1150-1158;2.Beuers U,etal.Hepatology.2014;60(1):399-407;3.Lindor KD,etal.Hepatology.2009;50(1):291-308.
• Prevalencereportedashighas69%1
• Unknownetiology1,2• Bilesalts,endogenousopioids,histamine,serotonin,
progesterone/estrogen,andautotaxin/lysophosphatidicacidaresuspectedpruritogens2
• Diurnalvariation– mostintenseitchinthelateevening2
• Localizationreportedatlimbs– solesoffeet,palmsofhands2
• Exacerbatedbycontactwithwool,heat,orpregnancy3
PruritusIsCommonAmongPBCPatients
General Recommendations1
• Skin moisturizer• Wet, cooling, or moist wraps• Topical agents with symptomatic relief (eg, camphor, menthol)• Relaxation techniques• Training to stop the cycle of itch, scratch, itch
First-line2-4Bile acid sequestrants:•Cholestyramine•Colestipol, colesevelam
The following agents may be used for pruritus that is refractory to bile acid sequestrants:Second-line2-4 Rifampicin
Third-line2-4Oral opioid antagonists:•Naltrexone •Nalmefene
Fourth-line2-4 Selective serotonin reuptake inhibitors:•Sertraline
1.Weisshaar E,etal.ActaDerm Venereol.2012;92(5):563-581;2.European Association forthe Study of the Liver.JHepatol.2009;51(2):237-267;3.Lindor KD,etal.Hepatology.2009;50(1):291-308.4.Hohenester S,etal. Semin Immunopathol.2009;31(3):283-307.
NumerousTreatmentOptionsExisttoHelpPatientsManageTheirPruritus
LongTermManagement
• Liverchemistrytestsevery3-6months• Thyroidstatus(TSH)annually• Bonemineraldensitometryevery2-4years• VitaminsA,D,Kannuallyifbilirubin>2.0• Upperendoscopyevery1-3yearsifcirrhoticorMayoriskscore>4.1
• Ultrasound± AFPevery6monthsinpatientswithknownorsuspectedcirrhosis
Ursodeoxycholic Acid(UDCA)andTreatmentResponse
FirstLine:Ursodeoxycholic Acid(UDCA)
• UDCAistheonlyFDA-approvedfirst-linePBCtherapy
• Recommendedadultdosageis13−15mg/kg/day
• Orallyadministered,naturallyoccurring,hydrophilicsecondarybileacid
• Typicallyadministeredin2divideddoses
Abbreviations:FDA,FoodandDrugAdministration;PBC,primarybiliarycirrhosis;UDCA,ursodeoxycholic acid.Lindor KD,etal.Hepatology.2009;50:291-308.
Tran
splant-freesu
rvival(%
)
a21121482887504b681489337228c271193153137d400345302283
NormalbilirubinandALP≤2.0xULN
ba
a-b:P ≤.001c-d:P ≤.001
5 10 15
100
80
60
40
20
00
Time(years)
AbnormalbilirubinandALP≤2.0xULN
c
NormalbilirubinandALP>2.0xULN
AbnormalbilirubinandALP>2.0xULNd
UDCA:BilirubinandAlkalinePhosphataseat1YearFollow-up
Lammers,etal.Gastroenterology.2014;147:1338-1349.
UDCA:OverallSurvival
UDCATreatedvs.Untreated UDCATreatedvs.HealthyControl
Poupon RE,Bonnand AM,ChretienY,etal.Hepatology.1999;29(6):1668-1671
UDCATreatmentFailure:DependsonDefinition
Study TreatmentFailure (%)
Pells etal,20131(UK-PBCgroup)
• 60%ofpatientspresentingatage<40years
• 10%ofpatientspresentingatage>70years
Corpechot etal,20112 • 13%–37%*
Kuiperetal,20093 • 34%–38%*
Corpechotetal,20084 • 35%–39%*
*Dependingoncriteriaused.1.Pells G,etal.JHepatol.2013;59:67-73;2.Corpechot C,etal.JHepatol.2011;55:1361-1367;3.KuiperEM,etal.Gastroenterology.2009;136:1281-1287;4.Corpechot C,etal.Hepatology.2008;48:871-877.
EstablishedResponseCriteriaModels(2006-2010)ALPdecreasedby>40%frombaselineornormalizedafter1yearUDCA
Barcelona1(2006)
All3ofthefollowing:ALP≤3xULN;AST≤2xULN;andbilirubin≤1mg/dL after1yearUDCAParis-I2
(2008)
Albuminandbilirubinnormalizationwhen1orbothwereabnormalatbaseline;albuminORbilirubinnormalizationwhenbothwereabnormalatbaselineafter1yearUDCA
Rotterdam3
(2009)
ALP<1.67xULNafter2yearsUDCAToronto4(2010)
1.ParésA,etal.Gastroenterology.2006;130:715-720;2.CorpechotC,etal.Hepatology.2008;48:871-877;3.KuiperEM,etal.Gastroenterology.2009;136:1281-1287;4.Kumagi T,etal.AmJGastroenterol.2010;105:2186-2194.
ModificationsofBiochemicalResponseCriteriaModels(2011-2013)
Barcelona, Paris-I, or Toronto criteria met at 6 months UDCA
All 3 of the following: ALP ≤1.5 x ULN; AST ≤1.5 x ULN; and bilirubin ≤1 mg/dL after 1 year UDCA Paris-II1
(2011)
Early Biochemical Response2
(2013)
Abbreviations:ALP,alkalinephosphatase;AST,aspartateaminotransferase;UDCA,ursodeoxycholic acid;ULN,upperlimitofnormal.1.Corpechot C.JHepatol.2011;55:1361-1367;2.ZhangLN,etal.Hepatology.2013;58:264-272.
OptimizedResponseCriteriaModels(2014-2015)
Biochemical response (Barcelona, Paris-I/II, or Toronto) and APRI ≤0.54 after 1 year UDCA
Biochemical + APRI1(2014)
Prognosticindexcomprisingbaselinealbuminandplateletcount,plusbilirubin,ALTorAST,andALPafter1yearUDCA
UK-PBC Risk Score2
(2015)
GLOBE Score3
(2015)
Prognosticindexcomprisingbaselineage,andbilirubin,ALP,albumin,andplateletcountafter1yearUDCA
1.Trivedi PJ,etal.JHepatol.2014;60:1249-1258;2.Carbone M,etal.Hepatology.2015Jul29; 3.LammersWJ,etal.Gastroenterology.2015Aug 7.
TreatingThosewithanInadequateResponsetoUDCA
Farnesoid XReceptorSignaling
BileAcids(Primaryligandsfor
FXR)
↓BileAcidSynthesisandUptake
↑GeneExpression
(BSEP,MDR3,MRP2/3/4,OSTα/β)
↓GeneExpression
(CYP7A1,NTCP,OATP)
FXR(Hepatocytes,biliary
epithelium,smallbowelenterocytes,renal
tubularcells,adrenalcells,adipocytes,beta
cells)
BindingDirectEffects
IndirectEffects
↑BileAcidEfflux
Abbreviations:BSEP,bilesaltexportpump;FXR,farnesoid Xreceptor;MRP2/3/4,multidrugresistantprotein2/3/4;NTCP,sodium/taurocholate cotransporting polypeptide;OATP,organicaniontransportingpolypeptide;OSTα/β,organicsolubletransporterα/β.Neuschwander-Tetri BA.Curr Gastroenterol Rep. 2012;14:55-62.
OCAinPatientswithPBC:POISEStudyDesign
Placebo(n=73)
OCA10mg(n=73)
OCA5mg
TitratetoOCA10mg(n=33)
RemainatOCA5mg(n=36)
Screen
ing OCA5-10mgdoseadjustmentoption
Months in Open-Label Phase
0 3 6 9 12 60
OCA5mg
0 W2 M3 M6 M9 M12
ModifiedfromNevens Fetal.NEngl JMed2016;375:631-643.
• IfpatientswereonUDCAatbaseline,theywereallowedtocontinuethroughoutthecourseoftherapy.
Month in Double-Blind Phase
No. of PatientsPlaceboObeticholic acid, 5-10 mgObeticholic acid, 10 mg
0.5
737073
737073
737073
737073
737073
646364
606259
596261
596059
0
20
40
60
80
100
Placebo Obeticholic acid, 5-10 mg Obeticholic acid,10 mg
3 6 9 12
5 mg Dose adjustment
3 6 9 12Pa
tient
s w
ith R
espo
nse
(%)
Month in Open-Label Phase
Open-Label PhaseDouble-Blind Phase
PrimaryEndpoint:POISEStudy
Nevens F,etal.NEngl JMed.2016;375:631-643.
Positiveresponseat12monthsdefinedas:• ALP<1.67xULNand• bilirubinWNLand• ≥15%ALPreduction
BothOCA10mgandOCA5-10mgtitrationarmsignificantlybetterthanplaceboarm(p<0.0001)
EventPlaceboN=73n(%)
OCA5-10 mgN=70
n(%)
OCA10mgN=73n(%)
OpenLabelN=193n(%)
Pruritus 28(38) 39(56) 50(68) 138(72)
Nasopharyngitis 13(18) 17(24) 13(18) 45(23)
Headache 13(18) 12(17) 6(8) 36(19)
Fatigue 10(14) 11(16) 17(23) 50(26)
Nausea 9(12) 4 (6) 8(11) 28(15)
Serious AdverseEvents 3(4) 11(16) 8(11) 27(14)
AdverseEventsinPOISEandOpen-LabelExtension
Modified fromNevens F,etal.NEngl JMed.2016;375:631-643.
Conclusions
• PBCisaslowlyprogressivediseasethatisassociatedwithmorbidityandmortality
• Fatigueandprurituslimithealth-relatedqualityoflife• UDCAhasbeenamainstayoftherapy• DefinitionofUDCAnonresponsestillnotstandardized• OCAgiventothosewithaninadequateresponsetoorunableto
tolerateUDCAproducedasignificantclinicallymeaningfulimprovementinliverbiochemistry,whichhavebeenshowntocorrelatestronglywithclinicalbenefit.