InteractiveCasePresentation#2:AutoimmuneLiverandBiliary

Diseases

Moderator:RebekahHamner,MSN,RN,AGCNS-BC

TexasLiverInstituteAustin,Texas

ThePatient:T.H.(June10,2016)

HPI:52yo Caucasianfemalew/historyofelevatedliverenzymes,firstnotedApril2016.• 5/12/16:AST/ALT100s-200s,ALP180,Tbili 0.9,Albumin4.4,

Plts 280• 6/4/16:AST/ALTinthe1000s,ALP380,Tbili 1.1,Albumin3.4,

Plts 299• VS:145/92,75,16,97.6,Weight:154,BMI28

Meds:• ASA81mg,Multivit,Lipitor20mg,levothyroxine100mcg• Tooknitrofurantoin x12weeksforrecurrentUTIs lastfall

ThePatient:T.H.PMH/PSH:• Hyperlipidemia• UTIs• Anxiety• HTN• Hypothyroidism• PrediabetesFMH:• M-hypothyroidism,Sjogren

syndrome• D-Alzheimer’s,HTN• Deniesfamilyhistoryofliver

disease

Social:• Married• Nonsmoker• ETOH:2-4perweekwithdinner• IllicitDrugs:Denies• Bloodtransfusionbefore1992:Denies

• Tattoos:1fromtattooparlor10yearsago

ThePatient:T.H.ROS: PE:• +anxiety• +vagueRUQdiscomfort• +fatigue• +mildpruritus• +arthralgia

• +centraladiposity,otherwiseunremarkable

• Unabletoelicitabdtenderness

• Nohepatosplenomegaly• Nosignsofdecompensatedliverdisease

DifferentialDiagnosis• NAFLD

+Metabolicsyndromefeatures:overweight,centraladiposity,prediabetes,hyperlipidemia,HTN- LiverenzymestooelevatedforNAFLD

• HepatitisC+TailendofBabyBoomergeneration,greatestriskofhavingHCV,tattoo- Nootherriskfactors

• AutoimmuneHepatitis(AIH)+Personalhx hypothyroidism,familyhx autoimmunedisease,tookmedsbelievedtobepossibletriggersforAIH,oftenseeveryhighAST/ALT- UsuallyALPisnotelevated

• PrimaryBiliaryCholangitis(PBC)orPrimarySclerosingCholangitis(PSC)

+Middleagedfemale,fatigue,ALPiselevated,pruritus• DrugInducedLiverInjury(DILI)

+NitrofurantoinknowntocauseDILI

WorkupRecommendationLabs

• CBC,CMP,pt/INR,GGT• ImmunoglobulinsA,G,M• Viralserologies,acuteandchronic:Hep CAb,Hep BandHep A,EBV,HSV

• Geneticliverdiseases:ceruloplasmin,iron%,alpha1antitrypsin

• Autoimmune:AMAM2,ASMA,ANA

ImagingandStagingLiverDisease

• AbdominalUS• Elastography orFibroscan

Holdoffonliverbiopsyatthistimeuntillabresultsarein.

AnOverviewofPrimaryBiliaryCholangitis&PrimarySclerosing Cholangitis

EmmaPham,MPAS,PA-CTexasLiverInstitute

TransplantHepatologyUniversityofTexasHealthScienceCenter

SanAntonio,Texas

NormalHepatobiliary Anatomy

http://hb.surgery.ucsf.edu/media/2907208/UCSF045_ExtrahepaticBileDuctAnatomy

PrimaryBiliaryCholangitis(PBC)• Formerly Primary Biliary

Cirrhosis • Autoimmune progressive,

cholestatic disease which may extend over many decades

• Combination of genetic predisposition and environmental triggers

• Destruction of intrahepatic bile ducts

1. CareyEJ,etal.Lancet. 2015;386(10003):1565-1575.2. Primarybiliarycirrhosis(PBC).PathPedia website.

http://www.pathpedia.com/education/eatlas/histopathology/liver_and_bile_ducts/primary_biliary_cirrhosis_(pbc).aspx.AccessedFebruary17,2016.

3. 1. Kumagi T, Heathcote EJ. Orphanet J Rare Dis. 2008;3:1.

Presenceoflymphocytes,plasmacells,macrophages,polymorphonuclear cells

ImportantTidbitstoRemember

• 95% affected are women• After HCV, second most common reason

for transplant in women• Elevated alkaline phosphatase is main lab

feature• Symptoms may be absent early in disease• Untreated, most will progress to advanced

disease over 15 years

ClinicalPresentation

• Most common symptoms– Fatigue– Pruritus

• SICCA syndrome (dry eyes and/or dry mouth)

• CREST syndrome

Symptomshavenocorrelationwiththe

naturalhistoryofdisease

PinheiroNC,etal. BMJCaseRep. 2013.https://thebileflow.wordpress.com/2011/10/19/pathology-pruritus/.

Calcinosis Raynaud’s

Sclerodactyly Telangiectasias

CREST

Esophagealdysmotility

ManyPatientswithPBCAlsoSufferfromCholestasisand/orCirrhosis

%ofPatientsAffectedComplicationsofchroniccholestasis1

Osteoporosis 20%-44%Hyperlipidemia 75%-95%Vitamindeficiency 8%-33%

Complicationsrelatedtocirrhosis

Varices associatedwithportalhypertension

6%(withearly-stagedisease)1

~31%(withlate-stagedisease)2

Hepatocellularcarcinoma 1%-6%ofpatientsperyear1

1. Carey EJ, et al. Lancet. 2015;386(10003):1565-1575; 2. Lindor KD, et al. Hepatology. 2009;50(1):291-308.

FormsofPBC1

• Upto30%mayhaveasevere,progressiveformofPBCresultinginearlydevelopmentofliverfibrosisandliverfailure1

• Somepatientsprogressthroughhistologicalstagesinlessthanadecade2

PBC With AIH Features

0 5 10 15Years

Preductopenic Variant

0 5 10 15Years

Typical PBC

Fibrosis

Interlobularbile ducts

0 5 10Years

15

1. Poupon R. J Hepatol. 2010;52(5):745-758; 2. Al-Harthy N, Kumagi T. Hepat Med. 2012;4:61-71.

AASLD Suggested Diagnostic Algorithm for Patients With Suspected PBC

Elevatedserumalkalinephosphatase(ALP)activity

Excludeothercausesofliverdiseaseincludingalcoholanddrugs

Crosssectionalimagingoflivertoexcludebiliaryobstruction

AMA(antimitochondrial antibody),ANA(antinuclearantibody),ASMA(anti-smoothmuscleantibody)

Considerliverbiopsy,especiallyifAST>5xULNorAMAnegative

AdditionalUsefulTests• IgM elevation• M2 antibody

Ursodeoxycholic Acid (UDCA)• Orally administered nontoxic

bile acid • Balances the bile acid ratio

normally produced by the liver, some of which are more toxic to the liver

• UDCA in a dose of 13-15 mg/kg/day

• UDCA is initiated gradually and given BID

AASLD Guidance Document

Ursodeoxycholic Acid (UDCA)

• Improvement in liver tests will be seen within a few weeks and 90% of the improvement usually occurs within 6-9 months

• Safe, may improve clinical symptoms, delay progression of disease and survival, and improve QOL

• However, up to 40% of PBC patients treated with UDCA have a suboptimal response

Pares A, Gastroenterology, 2006; Marschall HU, Gastroenterology, 2005.

ALP <1.67 x ULN and Normal Bilirubin after 1 Year of UDCA is Highly Predictive of Outcome

Global PBC Study Group (N=4845)

Lammers, EASL, AASLD. 2013.

Obeticholic Acid (OCA)

• A modified bile acid and FXR agonist

• OCA given to individuals with PBC with an inadequate response to or unable to tolerate UDCA

• Produced a significant clinically meaningful improvement in liver biochemistry

• Approved by FDA on May 27, 2016 (Ocaliva)

Long-term Management of Patients with PBC (AASLD Guidance)

• Liver tests every 3-6 months• Thyroid status (TSH) annually• Bone mineral densitometry every 2-4 years• Vitamins A, D, K annually if bilirubin >2.0• Upper endoscopy every 1-3 years if cirrhotic

or Mayo risk score >4.1• Ultrasound ± AFP every 6 months in patients

with known or suspected cirrhosis

PBCPrognosisUsingMayoRiskScore

PBCPrognosisUsingMayoRiskScore

Livertransplantation(LT)• Indicatedfor

– Patientsprogressingtodecompensatedcirrhosis

• Patientswithlatediagnosis• NoresponsetoUDCA(30-40%)

• MELD> 15• HCCmeetingtransplantcriteria

– Patientswithintractablepruritus

PBCSummary• PBCischroniccholestaticdiseaseresultingindestructionofintrahepaticbileducts

• MostcommonsymptomsofPBCisfatigueandprofoundpruritus

• ElevatedALPwithpositiveAMAishighlydisease-specific

• MajorityofpatientsrespondtoUDCA• OCAcanbeusedasadjuncttherapyforpatientsthatarenon-responderorpartialresponderstoUDCA

• Livertransplantationisanoptionforpatientswhoaredecompensatedorhaverefractorypruritus

WhatisPSC?:PrimarySclerosingCholangitis

• Chronicprogressiveinflammatorydiseasethanaffectsextraand/orintrahepaticbileducts–biliarystricturing andfibrosis

– “chainoflakes”oncholangiogram

Bileductstricturing=“chainoflakes”

ERCP:endoscopicretrogradecholangio-pancreatography

Epidemiology,NaturalHistory&Prognosis

• Prevalence6-8/100,000• Usuallydiagnosedin20sand30s• Malepredominance~3:1• 80%haveIBD- usuallyulcerativecolitis(UC)90%

– 4%withUCgetPSC• ~44%asymptomaticatdiagnosis• Mediansurvival~12years• 4th leadingdiagnosisleadingtoLTinNorthAmerica• Associatedwithcancer

– Cholangiocarcinoma– HCC(withcirrhosis)– ColonCancer(ifIBDpresent)

ClinicalPresentation

• Rangesfromasymptomatictopruritus,fatigueorevenjaundice

• Mayhaverecurrentboutsofcholangitiswithfevers/chillsandbacteremia

9%

31%

50%

2% 5%

10%

10Years 20Years 25Years

Ris

k %

PSC/CUC CUC

Broome U, Lofberg R, Veress B, et al. Primary sclerosing cholangitis and ulcerative colitis: Evidence for increased neoplastic potential. Hepatology. 1995;22(5):1404-8

ColonCancerRiskwithIBD/PSC

DiagnosisofPSC• CholestaticLiverTests(elevatedALPandGGT)

• Cholangiography(MRCPorERCP)

• Exclusionofsecondarysclerosing cholangitis

• 95%atleastoneautoantibody– 85%+ pANCA– 50%+ ANA– 25%+ SMA

HistologicFeaturesofPSC

Eaton JE, Talwalkar JA, Lazaridis KN, et al. Pathogenesis of Primary Sclerosing Cholangitis and Advances in Diagnosis and Management. Gastroenterology. 2013;145:521-536.

pANCA isperinuclear antineutrophil cytoplasmicantibody

Treatment

• Medical management– Ursodeoxycholic acid (20-25 mg/kg)

• Uncertain benefit but should not use high dose– Pruritus: cholestyramine, rifampicin, opioid antagonist

• Endoscopic therapy– Balloon dilation and stenting

• Dilation recommended due to decreased risk of infection

• Follow bili and alk phos for treatment improvement• Cholangiocarcinoma (CCA) and HCC

surveillance

LiverTransplantation

• Indicatedfor– Patientsprogressingtodecompensatedcirrhosis

• MELD> 15• HCCmeetingtransplantcriteria

– Patientswithintractablepruritus,recurrentbacterialcholangitis,orcholangiocarcinoma

• EventuallymostpatientswillrequireLTasthereisnoeffectivetreatment

PSCSummary

• Chronicprogressiveinflammatorydiseaseaffectextra- and/orintrahepaticbileducts

• Noestablishedtherapy,howeverursodiol canbeused

• Riskofbiliarycancersandcoloncancer

• Livertransplantationisoftentheonlytreatmentoption

SimilaritiesandDifferencesPrimaryBiliary Cholangitis PrimarySclerosing Cholangitis

EtiologyUnclear EtiologyUnclear

EffectsIntrahepaticbileducts Caneffectextra-intrahepaticbileducts

Vanishingbileducts

Presencelymphocytes,plasmacells,macrophages,andPMNsonbiopsy

Stricturing ofbileducts

Absencesofinflammatorycellsonbiopsy

AssociatedwithSICCAorCRESTsyndrome AssociatedwithUC

UDCAhelpsinmajorityofpatients;OCA recentlyapproved

Newdrugtherapiesareinclinicaldevelopment;ingeneralPSCleads

tolivertransplantation

Lab/ImagingResults(June10,2016)• Labs:

–Alb4.4,Tbili 0.5,Alk Phos 200,AST91,ALT110,IgMandIgGelevated,ferritin444,GGT72,WBC5.9,Hgb 13.1,HCT40.7,Plt 280

–EBVPCRneg,HSVPCRneg,HAVIgMneg,HBVsurfaceAGneg,HBVcoreIgMABneg,HCVABneg

–ANA1:160(pos),AMAM2+,SMA+•AbdominalUS

• Liver:mildfattyliverwithnofocallesions,spleen:normal•Elastography

• 8.2kPa• Moderate fibrosis?

•BiopsyperformedandconfirmedPBCandAIH

AutoimmuneHepatitis(AIH)

ChristyRosas,MPAS,PA-CTexasLiverInstituteSanAntonio,Texas

AIH:ClinicalPresentation

• 30%presentwithcirrhosis

• Upto50%maypresentwithjaundice

• Asymptomatic(35-45%)withabnormalenzymes– Oftendiscoveredduringevaluationforotherautoimmuneconditions

AIH: DemographicsandEpidemiology

• Afflicts~200,000inU.S.A.• Incidence1.9per105peryear

• Prevalence16.9per105

• Afflictsbothchildrenandadults• Femaletomaleratio=4:1

• Bimodalagedistribution:10-20vs.45-75yrs• 6%livertransplantsinUS

AIHPathogenesis

• Geneticfactors– Antigenpresentation/immunocyte activation– DRB1encodesforMHCIIantigenbindinggrooves(antigenpresentationtoTcells)

• Triggeringfactors– Infections(HCV,HDV)– Medications

-Minocycline,Nitrofurantoin,Methyldopa,Atorvastatin,Diclofenac,Augmentin,Isoniazid,Infliximab

Czaja etal.Hepatology 2002;36:479Krawitt. N Engl J Med 2006;354:54

Manns et al. Hepatology 2006;14:S132

Diagnosis

• Serology– PositiveANA,SMAorLKM

– ElevatedserumIgG totwicenormallevels

– 5%haveseronegativedisease

• Histology– BiopsyrequiredfordiagnosisALWAYS

– Sometimesatypicalfeatures

– Overlapsyndromes(PBC/PSC)

GoalsfortreatmentofAIH

• NormalizationofALTandIgG

• Normalizationofhistology

• Regressionoffibrosis

• Preventionofcirrhosis

• Minimizationofsideeffects

AIH: CriteriaforTreatment

• Symptomaticdiseaseandeither–AST>10-foldnormal

–AST5-10foldnormaland>2-foldelevationofIgG

• Presenceoffibrosis

Acute presentation and severe histological activity

Asymptomatic AIH and mild-moderate histological activity

Corticosteroids 30-60 mg/day for 1-2 weeks + AZA 50-100 mg/day

Corticosteroids 20 mg/day for1-2 weeks + AZA 50 mg/day

Adjust the AZA dose depending on the biochemical response and tolerance

Prednisone 10 mg/day +AZA 50-100 mg/d

Prednisone 5-10 mg/day +AZA 50 mg/day

Gradual taper offprednisone

Gradual reduction2.5 mg/week+same AZA dose

Gradual taper offprednisone

ModifiedfromMedina,etal.AlimentPharmacolTher.2003.

Combination Therapy

AIHTreatmentSideEffects

• Longtermprednisone– Osteoporosisandfractures– Diabetes– Obesity– CVdisease

• Cytopenias• AZA-inducedpancreatitis• Longtermlymphomaandskincancerrisks

AIH: TakeHomePoints

• Chronichepatocellulardiseaseingeneticallypredisposedpatientsofuncleartrigger

• Diagnosisbaseduponliverenzymes,serology,gammaglobulins,andhistology

• Immunosuppressivetherapyisthemainstayoftreatmentandislongtermfornearlyallpatients

• Tailortherapybasedupontreatmentendpoints

PatientT.H.:TreatmentPlan

• PBC–Ursodiol–Obeticholic acidifnoresponse

• AIH–Treatwithazathioprineandprednisone,weaningthelatteroffinfewmonths