interactive case presentation #2: autoimmune liver and ......autoimmune liver and biliary diseases...
TRANSCRIPT
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• Tooknitrofurantoinx12weeksforrecurrentUTIs 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?
DifferentialDiagnosis•NAFLD
+Metabolicsyndromefeatures: overweight, centraladiposity,prediabetes,hyperlipidemia,HTN- Liverenzymes tooelevated forNAFLD
• HepatitisC+TailendofBabyBoomer generation,greatest riskofhavingHCV,tattoo- Noother riskfactors
• AutoimmuneHepatitis(AIH)+Personalhx hypothyroidism,familyhx autoimmunedisease, tookmedsbelieved tobepossible triggers forAIH,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-CTexasLiver Institute
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).PathPediawebsite.
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
%ofPatientsAffectedComplications ofchroniccholestasis1
Osteoporosis 20%-44%Hyperlipidemia 75%-95%Vitamindeficiency 8%-33%
Complications relatedtocirrhosis
Varices associatedwithportalhypertension
6%(withearly-stagedisease)1
~31%(withlate-stagedisease)2
Hepatocellular carcinoma 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
Excludeothercauses ofliverdisease includingalcoholanddrugs
Crosssectional imagingoflivertoexcludebiliaryobstruction
AMA(antimitochondrial antibody),ANA(antinuclear antibody),ASMA(anti-smoothmuscleantibody)
Consider liverbiopsy,especially ifAST>5xULNorAMAnegative
Additional UsefulTests• 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:endoscopic retrogradecholangio-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
• Rangesfromasymptomatic topruritus,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• HCCmeeting transplantcriteria
– Patientswithintractablepruritus,recurrentbacterialcholangitis,orcholangiocarcinoma
• EventuallymostpatientswillrequireLTasthereisnoeffectivetreatment
PSCSummary
• Chronicprogressiveinflammatorydiseaseaffectextra- and/orintrahepaticbileducts
• Noestablishedtherapy,howeverursodiol canbeused
• Riskofbiliarycancersandcoloncancer
• Livertransplantationisoftentheonlytreatmentoption
SimilaritiesandDifferencesPrimaryBiliary Cholangitis PrimarySclerosing Cholangitis
EtiologyUnclear EtiologyUnclear
EffectsIntrahepaticbileducts Caneffectextra-intrahepatic bileducts
Vanishing bileducts
Presencelymphocytes, plasma cells,macrophages, andPMNsonbiopsy
Stricturing ofbileducts
Absencesofinflammatory cellsonbiopsy
AssociatedwithSICCAorCRESTsyndrome AssociatedwithUC
UDCAhelpsinmajority ofpatients;OCA recentlyapproved
Newdrug therapiesareinclinicaldevelopment; ingeneralPSCleads
tolivertransplantation
BacktoRebekah
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
RebekahasksChristytopresentonAIH
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
BacktoRebekah
PatientT.H.:TreatmentPlan
• PBC–Ursodiol–Obeticholic acidifnoresponse
• AIH–Treatwithazathioprineandprednisone,weaningthelatteroffinfewmonths
Roundtable/Q&A