LiverDiseaseThatPresentswithJaundice(PBC,AlcoholandDrugs):DiagnosisandPatientManagement

EmmaPham,PA-C

Case:JL(jaundicedlady)• A72yearoldwomanpresentstoherprimarycareproviderwithcomplaintsoffatigueandgeneralizedpruritus.• Shewastreatedforaurinarytractinfectionwithanantibioticshecannotrecall6weeksprior•Medications:none• PMH/PSH:noknownmedicalproblems,cholecystectomyatage50

Case:JL(jaundicedlady)• SocialHx:drinks1-2glassesofwine4-5daysperweek;notravel,noexposures• Examshowsthinfemale,jaundiced,normalmusculature,noencephalopathy,noorganomegaly,ascitesoredema• Ultrasoundofabdomenshowsnoabnormalities• Labs:CBCnormal,Tbilirubin12(direct10),AST314,ALT428,AP158,GGT210• INR1.2,creatinine0.9

IssuestoConsiderforthisJaundicedLady

•Alcohol•Medication• IntrinsicLiverDisease

• DisproportionatelyaffectslowSES/marginalizedpopulations• Upto48%ofcirrhosis-relateddeathsinUS

AlcoholisaGlobalProblem

Rehm Lancet 2009.

AlcoholisaMajorBurden• 3.8%ofALL deathsworldwidein2004• 6.3%formenvs.1.1%forwomen• 9.5per10,000menvs2.1per10,000womeninAfrica

Rehm Lancet 2009.

Only15-20%ofchronicalcoholicsdevelopchronicliverdisease.Geneticsclearlyimportantbutpoorlyunderstood.

HowManyofTheseGuysWillDevelopCirrhosis?

ClinicalFeaturesAcuteAlcoholicHepatitis

Acutealcoholichepatitisvsdecompensatedalcoholiccirrhosis?Noreliableindicatorasidefromrecentalcoholintake.

• History• Alcoholintake– usuallybinge,usuallyhonest(notalways)• Fever• Weightloss– malnutrition

• Exam• Toxiclooking,fever,tachycardia• Tenderhepatomegaly+/- bruit• Signsofchronicliverdisease&malnutrition– oftensevere

LabFeatures• LiverTests• AST:ALT>2:1

• Rarelyabove300(neverabove500IU/L)• ASTincreasedduetomitochondrialdamage

• GGT+/- ALPelevation– mayappearverycholestatic• Bilirubin&INRincreased,albumindepressed

• CBC• WBCelevationwithPMNs→butmaybeinfection• Lowplatelets→directbonemarrowsuppressionvsportalhypertension• Lowhemoglobin→nutritionaldeficiency,bleeding

• Creatinine• Predictorofoutcome– veryimportant

DiscriminantFunction

mDF ≥32Withencephalopathy45%mortality

Withoutencephalopathy35%mortality

Morerecentdataà upto100%survival

Treatment

• Sickpatients!• Addressotherissues:• Ascitesà taptor/oSBP• Infectionà lowthresholdforantibiotics• Renalfunctionàmakesurefluidreplete,noNSAIDs,carefulwithdiureticsandcontrastdye,albumin• Encephalopathyà lactulose• Alcoholwithdrawalà benzodiazepines• Nutritioniscriticallyimportant• VitaminsBcomplex(Wernicke’s)• Protein

Resuscitation

•Pentoxyfilline ofnobenefit

•PrednisonelikelyhasamodestEARLYbenefitbutnolong-termbenefit

•ABSTINENCEiskey(andtheonlythingthatmatters)

EffectiveTherapies?

ImportanceofDrug-InducedLiverInjury(DILI)

• Theliverisamajortargetorganforseriousadverseeffectsofdrugs•Majorcauseoffulminanthepaticfailure•Drugsareafrequentcauseofundiagnosedliverdisease•DILIismostcommonreasonforpostmarketingwithdrawalofmedications

ClassificationofDILI

•Direct(intrinsic)hepatotoxicity• Usuallydose-related• Shortintervalbetweeningestionandevidenceoftoxicity• Reproducibleinanimalmodels

• Idiosyncratichepatotoxicity• Notalwaysdose-related• Usuallynotreproducibleinanimalmodels• Hostfactorsplayimportantroleinrisk

DirectHepatotoxicity:AcuteNecrosis• ElevationinALTandAST,evenupto1000s• ElevatedbilirubinandINRindicateseverity• Examples• Acetaminophen• Cocaine• Niacin• Ecstasy• Somechemotherapeuticagents• IVamiodarone

IdiosyncraticDrugReactions

•Metabolicidiosyncrasy•Unusualmetabolismofadrugleadstoinjury

• Immunologicidiosyncrasy• Thehostimmuneresponse“sees” thedrugasaforeignantigenandthisleadstoreaction

ClinicalSpectrumofIdiosyncraticDILI•Hepatocellularinjury•ALTandASTareprimarilyelevated

• Intrahepaticcholestasis•Alk phos isprimarilyelevated

•Mixedcholestatic/hepatocellularinjury•ALT/AST&Alk phos arebothelevated

Top10CausesofIdiosyncraticDILI1. Amoxicillin-clavulanate2. Isoniazid*3. Nitrofurantoin*4. TMP-SMX5. Minocycline

6.Cefazolin7.Azithromycin*8.Ciprofloxacin*9.Diclofenac*10.Levofloxacin*

• *Ifjaundiced,fatalityrate>10%• Allareolderdrugsapprovedbefore2000

NewerDrugsinTop50DILICases• Duloxetine• Rosuvastatin• Telithromycin• Imatinib• Atomoxetine• Oxaliplatin• Flavocoxid

HerbalandDietarySupplements

•16%ofallcasesofhepatotoxicityareOTC•Anabolicsteroids—blandcholestasis•Manycauseacutenecrosis/inflammation•Herbalife,Hydroxycut

PrimaryBiliaryCholangitis(PBC)

PBCischaracterizedbydestructionoftheinterlobularandseptalbileductsthatmayleadtocirrhosis

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.

PBCisaChronic,ProgressiveAutoimmuneDisease• Factorspossiblyassociatedwithonsetandperpetuationofbile-ductinjuryinPBC

• Usually>45yearsAge

• Female>Male(9:1)Gender

• AMAin~95%;disease-specificANAin~30%–50%;ASMAmaybepresentSerology

• IgMtypicallyelevatedImmunoglobulin

• NormalMRCP

• Lymphocyticinfiltrate;inflammatoryductlesion;granulomamaybepresentLiver Histology

• NottypicalCoexistingIBD

PBCPhenotype

Abbreviations:AMA,antimitochondrial antibody;ANA,antinuclearantibody;ASMA,anti-smooth-muscleantibody;IBD,inflammatoryboweldisease;MRCP,magneticresonancecholangiography;PBC,primarybiliarycirrhosis.TrivediPJ,etal.AlimentPharmacol Ther.2012;36:517-533.

Frequency(%)Sjögren’ssyndrome 7-34Raynaud’ssyndrome 9-13Hashimoto’sthyroiditis 11-13Rheumatoidarthritis 3-8Psoriasis 6SclerodermaorCREST* 1-2Inflammatoryboweldisease 1Anyautoimmunedisease 33-55

*CREST(calcinosis,Raynaud’sphenomenon,esophagealdysfunction,sclerodactyly,andtelangiectasia)

ConcomitantAutoimmuneDiseaseinWomenwithPBC

CareyEJ,AliAH,Lindor KD.PrimaryBiliaryCirrhosis.TheLancet.2015Oct.;386(10003):1565-1575.

DiagnosisofPBC:IsBiopsyNeeded?

• If:• IncreasedAMA• ALP>1.5xULN• AST98%• Sensitivity80%,specificity92%

Zein CO,AnguloP,Lindor K.Whenisliverbiopsyneededinthediagnosisofprimarybiliarycirrhosis?;Clin GastroandHepatol2003;1(2):89-95.

PruritusIsCommonAmongPBCPatients

• Prevalencereportedashighas69%1

• Unknownetiology1,2• Bilesalts,endogenousopioids,histamine,serotonin,progesterone/estrogen,andautotaxin/lysophosphatidicacidaresuspectedpruritogens2

• Diurnalvariation– mostintenseitchinthelateevening2

• Localizationreportedatlimbs– solesandpalmss2

• Exacerbatedbypregnancyorcontactwithwool/heat3

1.ImamMH,etal.JGastroenterolHepatol.2012;27(7):1150-1158;2.Beuers U,etal.Hepatology.2014;60(1):399-407;3.LindorKD,etal.Hepatology.2009;50(1):291-308.

FirstLine:Ursodeoxycholic Acid(UDCA)

•Orallyadministered,naturallyoccurring,hydrophilicsecondarybileacid•Dose:13-15mg/kg/day• Improvementinlivertestsmaybeseenwithinafewweeksand90%oftheimprovementusuallyoccurswithin6-9months

Kuiper,etal.Gastroenterology 2009;136(4):1281-7.

SecondLine:Obeticholic Acid(OCA)

• Approvedin2016forpatientswithaninadequateresponsetoUDCAorcannottolerateit• Farnesoid Xreceptor(FXR)agonist• OralmedicationtakenincombinationwithUDCAorbyitselfinpatientswhocannottolerateUDCA• ApprovedbasedonastudyshowingareductioninALP• Nodataavailableshowingimprovementinsymptomsorreductionoflong-termmorbidityandmortality

Event Placebo(N=73)OCA

5-10 mg(N=70)

OCA10mg(N=73)

OpenLabel(N=193)

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)

SAE 3(4) 11(16) 8(11) 27(14)

OCAAdverseEventsinClinicalTrials

ModifiedfromNevensF,etal.NEnglJMed.2016;375:631-643.

• AMAnegative• Viralserologies negative

• Liverbiopsyisperformedandconsistentwithcholestasis,moderateportalinflammation

• CalltopharmacyrevealsshehadtakennitrofurantoinforUTI

BacktoOurCase:JL(jaundicedlady)

•Resolvedslowlyover2months•Avoidedalcoholandothermedsduringthattime•Noteddrugallergyinherrecords

OutcomeofJL(jaundicedlady)

•Manyconditionspresentwithjaundice• Alcoholandmedications/drugsaretwoofthemorecommonreasons• Primaryautoimmuneconditionsareontherise

• Athoroughhistory,imagingandlaboratorytestingareessentialtomakingthediagnosis

Summary

RoundtableDiscussion/Q&ADr.Alkhouri andEmmaPham

Lunch/Non-AccreditedSymposium

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