Abnormal Liver Function Tests

LuisLuis S.S. Marsano,Marsano, M.D.M.D. ProfessorProfessor ofof MedicineMedicine DirectorDirector ofof HepatologyHepatology DivisionDivision ofof Gastroenterology/HepatologyGastroenterology/Hepatology Interpretation of Abnormal Liver Enzymes

„ BiochemicalBiochemical TestsTests „ ViralViral SerologiesSerologies „ AutoAuto--antibodiesantibodies „ HistoryHistory andand PhysicalPhysical ExamExam FindingsFindings Bilirubin

„ 7070--80%80% fromfrom destroyeddestroyed RBCRBC „ TotalTotal bilirubinbilirubin isis << 11 mg/dlmg/dl inin 99%;99%; directdirect ≤≤0.30.3 mg/dlmg/dl (Van(Van denden Bergh)Bergh) oror ≤≤ 0.10.1 mg/dlmg/dl (Ektachem)(Ektachem) „ FreeFree directdirect bilirubinbilirubin (half(half lifelife == 44 h)h) „ DeltaDelta conjugatedconjugated bilirubinbilirubin (T1/2(T1/2 == 1212--1414 d)d) „ HemolysisHemolysis givesgives T.T. bilirubinbilirubin ≤≤ 55 mg/dl,mg/dl, mostlymostly indirectindirect (no(no bilirubinbilirubin inin urine)urine) Bilirubin

„ BilirubinBilirubin ≥≥ 1010 mg/dl,mg/dl, absenceabsence ofof biliarybiliary treetree dilatationdilatation supportssupports nonnon--obstructiveobstructive jaundicejaundice „ DegreeDegree ofof bilirubinbilirubin elevationelevation dodo notnot correlatecorrelate wellwell withwith severityseverity ofof acuteacute diseasedisease „ InIn ESLD,ESLD, aa compositecomposite scorescore ofof Bilirubin,Bilirubin, CreatinineCreatinine && INR,INR, predictspredicts survival.survival. (MELD)(MELD) „ BilirubinBilirubin inin urineurine usuallyusually indicatesindicates hepatobiliaryhepatobiliary diseasedisease (direct(direct bilirubin)bilirubin) „ UrobilinogenUrobilinogen (in(in urine)urine) isis decreaseddecreased inin biliarybiliary obstructionobstruction (but(but alsoalso withwith antibiotics)antibiotics) Isolated Bilirubin Elevation Case # 1

„ 2323 y.oy.o.. caucasiancaucasian,, female,female, nursenurse--student,student, inin usualusual statestate ofof goodgood healthhealth foundfound toto havehave mildmild conjunctivalconjunctival icterusicterus whilewhile practicingpracticing physicalphysical examexam skills.skills. OnlyOnly symptomsymptom isis anorexiaanorexia andand nausea,nausea, thatthat sheshe usuallyusually getsgets duringduring herher menstruation.menstruation. „ DeniesDenies darkdark urine,urine, alcoholalcohol abuse,abuse, drugdrug abuse,abuse, previousprevious hepatitis.hepatitis. NotNot takingtaking medicationsmedications otherother thanthan naproxennaproxen forfor herher menstrualmenstrual cramps.cramps. Case # 1 Labs.

„ T.T. bili=bili= 3.23.2 mg/dlmg/dl ((nlnl:: 0.10.1--1);1); D.D. bili=bili= 0.10.1 „ ALT,ALT, AST,AST, Alk.Alk. PhosphPhosph.,., T.T. protein,protein, albumin,albumin, LDHLDH werewere allall normalnormal „ CBCCBC waswas normal;normal; ReticRetic count=count= NlNl „ IntravenousIntravenous NicotinicNicotinic acidacid (50(50 mg)mg) causedcaused 22--3X3X increaseincrease ofof IndirectIndirect Bilirubin.Bilirubin. Case # 1

„„DIAGNOSISDIAGNOSIS:: GilbertGilbert’’ss SyndromeSyndrome (decreased(decreased activityactivity ofof UridineUridine--DiphosphateDiphosphate GlucoronosyltransferaseGlucoronosyltransferase)) Causes of Hyperbilirubinemia

IndirectIndirect (Isolated)(Isolated) „ GilbertGilbert’’ss SyndromeSyndrome (<(< 66 mg/dl)mg/dl) „ CriglerCrigler--NajjarNajjar II (25(25--4848 mg/dl)mg/dl) „ CriglerCrigler--NajjarNajjar IIII (6(6--2525 mg/dl)mg/dl) „ HemolysisHemolysis (<(< 55 mg/dl)mg/dl) „ IneffectiveIneffective erythropoiesiserythropoiesis „ NeonatalNeonatal jaundicejaundice „ SepsisSepsis Causes of Isolated Hyperbilirubinemia

IndirectIndirect (Isolated)(Isolated) ,, continuedcontinued „ CongestiveCongestive heartheart failurefailure „ PortocavalPortocaval shuntshunt „ DrugsDrugs ‹ PregnanediolPregnanediol ‹ ChloramphenicolChloramphenicol ‹ NovobiocinNovobiocin ‹ Rifampin/rifamycinRifampin/rifamycin ‹ ProbenecidProbenecid Causes of Isolated Hyperbilirubinemia

DirectDirect (60%)(60%) ++ IndirectIndirect (Isolated)(Isolated) „ DubinDubin--JohnsonJohnson SS (2(2--2525 mg/dl)mg/dl) „ RotorRotor SS (<(< 1010 mg/dl)mg/dl) „ HepaticHepatic StorageStorage DiseaseDisease Causes of Hyperbilirubinemia

HyperbilirubinemiaHyperbilirubinemia ++ ElevationElevation ofof LiverLiver EnzymesEnzymes

„ HepatocellularHepatocellular diseasedisease „ IntrahepaticIntrahepatic cholestasischolestasis „ ExtraExtra hepatichepatic cholestasischolestasis „ Mixed.Mixed. Markers of Hepatocellular Necrosis

ALTALT (SGPT)(SGPT) oror AlanineAlanine AminotransferaseAminotransferase „ Almost all from liver cytosol; lesser amounts in muscle; injury causes rise „ True normal range is lower than that accepted by most labs „ Alcohol injury: usually < 200 IU/L + AST/ALT ≥ 2 „ Hepatocellular injury: usually > >300 IU/L (peak 350- 10000) „ Obstruction: usually < 400 IU/L „ Acute bile duct obstruction or liver ischemia: > 300 IU/L x < 48-72 h Markers of Hepatocellular Necrosis

ALTALT (SGPT)(SGPT) oror AlanineAlanine AminotransferaseAminotransferase „ HalfHalf--lifelife ofof ALTALT >>>> ASTAST „ InIn acuteacute muscularmuscular injury,injury, peakpeak AST/ALTAST/ALT >> oror == 3;3; afterafter 33--44 daysdays levelslevels areare similar;similar; (peak(peak ASTAST 400400-- 10000)10000) „ InIn chronicchronic musclemuscle injuryinjury (polymyositis)(polymyositis) ASTAST andand ALTALT levelslevels areare similarsimilar (50(50--1000).1000). (Hepatology.(Hepatology. 20052005 Feb;41(2):380Feb;41(2):380--2)2) Markers of Hepatocellular Necrosis

ASTAST (SGOT)(SGOT) oror AspartateAspartate AminotransferaseAminotransferase „ HigherHigher in:in: liver,liver, heart,heart, skeletalskeletal muscle,muscle, kidney,kidney, brain,brain, pancreas,pancreas, lungs,lungs, WBCWBC andand RBC;RBC; injuryinjury causescauses riserise „ InIn liver:liver: 80%80% mitochondrial/20%mitochondrial/20% cytosolcytosol „ InIn serum:serum: mostlymostly fromfrom cytosolcytosol „ AlcoholAlcohol injuryinjury:: usuallyusually << 300300 IU/LIU/L andand AST/ALTAST/ALT ≥≥ 22 „ HepatocellularHepatocellular injuryinjury:: usuallyusually >>>> 300300 IU/LIU/L „ ObstructionObstruction:: usuallyusually << 400400 IU/LIU/L AST/ALT ratio in different disorders

100 90 80 70 60 50 AST/ALT>1 40 AST/ALT>2 30 20 10 0 Alcoholic Cirrhosis Chronic Obstructive Viral Liver Dz Hepatitis Jaundice Hepatitis Markers of Hepatocellular Necrosis

ClassicClassic PatternsPatterns ofof ElevationElevation „ RapidRapid andand highhigh (>>(>> 300300 IU/L)IU/L) upup andand down:down: acuteacute biliarybiliary obstructionobstruction oror liverliver ischemiaischemia „ SustainedSustained andand highhigh (>>(>> 300300 IU/LIU/L xx >>>> 11 week):week): viralviral oror toxictoxic hepatitishepatitis „ ProlongedProlonged (months)(months) withwith peakspeaks andand troughstroughs:: chronicchronic HCVHCV „ ProlongedProlonged (months)(months) mild/moderatemild/moderate elevationelevation:: chronicchronic viralviral hepatitis,hepatitis, metabolic,metabolic, immuneimmune oror toxictoxic liverliver diseasedisease Case # 2

„ 55 y/o female with 3 months history of fatigue and progressive weakness and muscular achines. Over the last month has difficulty climbing the stairs to her third floor apartment. Has mild dysphonia and dysphagia. Denies jaundice. Does not take medications, OTC drugs, nor “natural therapies”. Denies alcohol abuse, or other drug abuse. „ LABS: -CBC=nl; -U/A= nl; -TSH= nl; -CMP: electrolytes, glucose, creat, protein, albumin, alk. phosphatase & bilirubin are nl. ALT= 320 U/L (nl: 10-40), AST= 350 U/L (nl: 10-40) Case # 2 Additional studies

„ LABS:LABS:

‹ CreatineCreatine kinasekinase (CK)=(CK)= 520520 U/LU/L (normal:(normal: 2626-- 140140 U/L)U/L)

‹ Aldolase=Aldolase= 3030 U/LU/L (normal:1(normal:1--88 U/L)U/L) „ ElectromyogramElectromyogram andand musclemuscle Bx:Bx: consistentconsistent withwith polymyositis.polymyositis. „ WorkWork upup forfor occultoccult malignancymalignancy waswas negative.negative. „ DIAGNOSISDIAGNOSIS:: PRIMARYPRIMARY POLYMYOSITISPOLYMYOSITIS Markers of Cholestasis

AlkalineAlkaline PhosphatasePhosphatase „ Liver,Liver, bone,bone, intestineintestine (a(allll heatheat labile)labile) andand placentaplacenta (heat(heat stable)stable) „ ConcomitantConcomitant elevationelevation ofof GGTGGT inin personperson olderolder thanthan 44 yearsyears oldold excludesexcludes bonebone originorigin „ ConcomitantConcomitant elevationelevation ofof ALTALT oror DirectDirect BilirubinBilirubin supportssupports liverliver originorigin „ NormalNormal GGTGGT makesmakes liverliver originorigin veryvery unlikelyunlikely Markers of Cholestasis

AlkalineAlkaline PhosphatasePhosphatase,, continuedcontinued „ ElevationElevation ≥≥ 44--foldfold suggestssuggests intraintra--hepatichepatic oror extraextra--hepatichepatic cholestasischolestasis „ ElevationElevation << 33--foldfold isis lessless specificspecific „ ““IsolatedIsolated”” elevationelevation :: partialpartial bilebile ductduct obstruction,obstruction, infiltrationinfiltration (eg:(eg: granulomas,granulomas, PrimaryPrimary BiliaryBiliary Cirrhosis),Cirrhosis), oror focalfocal liverliver massmass (eg:(eg: metastasis).metastasis). „ ElevatedElevated ““liverliver typetype”” alkalinealkaline phosphatasephosphatase withoutwithout liverliver involvementinvolvement:: HodgkinHodgkin’’ss disease,disease, myeloidmyeloid metaplasia,metaplasia, congestivecongestive heartheart failure,failure, renalrenal cellcell carcinoma,carcinoma, intraintra--abdominalabdominal infectionsinfections Markers of Cholestasis

GGTGGT ((ϒϒ--GlutamylGlutamyl Transpeptidase)Transpeptidase) „ NotNot inin bonebone „ NormalNormal rangerange reachedreached inin childrenchildren >> 44 y.o.y.o. andand persistspersists duringduring pregnancy.pregnancy. „ Elevation:Elevation: alcohol,alcohol, Dilantin,Dilantin, COPD,COPD, diabetes,diabetes, renalrenal failurefailure „ ElevatedElevated alkalinealkaline phosphatasephosphatase with:with:

‹ ElevatedElevated GGTGGT suggestsuggest liverliver originorigin

‹ NormalNormal GGT,GGT, unlikelyunlikely liverliver originorigin Markers of Cholestasis

55'' NucleotidaseNucleotidase

„ InIn elevatedelevated alkalinealkaline phosphatase:phosphatase:

‹ ElevatedElevated 5'5' nucleotidasenucleotidase inin absenceabsence ofof pregnancypregnancy indicatesindicates liverliver originorigin

‹ NormalNormal 5'5' nucleotidasenucleotidase doesdoes notnot excludeexclude liverliver originorigin (less(less sensitivesensitive thanthan GGT)GGT) Case # 3

„ 4545 y.oy.o.. femalefemale withwith 11 yearyear hx.hx. itching.itching. InvestigationInvestigation byby herher dermatologistdermatologist showsshows abnormalabnormal liverliver enzymes.enzymes. „ PastPast hx.:hx.: Hypothyroidism,Hypothyroidism, controlledcontrolled onon thyroidthyroid replacement,replacement, andand ofof breastbreast CaCa treatedtreated byby lumpectomylumpectomy && radiationradiation 22 yearsyears ago.ago. LastLast oncologyoncology checkcheck 33 monthsmonths agoago waswas ““freefree ofof diseasedisease””.. „ HasHas somesome fatiguefatigue andand persistentpersistent itching.itching. Case # 3 Labs

„ CBCCBC == normal,normal, PT=PT= normalnormal „ AST,AST, ALT,ALT, T.T. Bilirubin,Bilirubin, T.T. Protein,Protein, AlbuminAlbumin == NormalNormal „ AlkalineAlkaline PhosphatasePhosphatase == 580580 ((nlnl << 98),98), GGTPGGTP== 10801080 ((nlnl << 50)50) „ AMAAMA == 1/640;1/640; TSHTSH && T4T4 == nlnl „ CTCT scanscan ofof abdomenabdomen == normal;normal; nono metastasis/focalmetastasis/focal lesionslesions Case # 3

„ LiverLiver Bx:Bx: PrimaryPrimary BiliaryBiliary Cirrhosis,Cirrhosis, stagestage 2;2; nono evidenceevidence ofof tumortumor metastasis.metastasis.

„ DIAGNOSIS:DIAGNOSIS: PrimaryPrimary BiliaryBiliary CirrhosisCirrhosis --NoNo evidenceevidence ofof cirrhosiscirrhosis (Stage(Stage 2)2) Markers of Synthetic Function

ProthrombinProthrombin TimeTime „ ActivityActivity ofof FactorsFactors VIIVII (shortest(shortest halfhalf life),life), V,V, XX andand IIII „ ProlongedProlonged whenwhen FactorFactor VIIVII << 40%40% „ PTPT longerlonger thanthan 44 secondsseconds overover control,control, notnot correctedcorrected byby parenteralparenteral VitaminVitamin K,K, indicatesindicates severesevere hepatocellularhepatocellular diseasedisease „ InIn jaundice,jaundice, normalizationnormalization ofof PTPT withwith parenteralparenteral VitaminVitamin KK indicatesindicates cholestasischolestasis oror warfarinwarfarin use.use. Markers of Altered Immunoregulation: Gammaglobulins ƒƒ SuggestSuggest reticuloendothelialreticuloendothelial cellcell dysfunctiondysfunction oror portocavalportocaval shunting.shunting. GIGI tracttract antigensantigens notnot clearedcleared byby thethe liverliver causecause systemicsystemic inflammatoryinflammatory responseresponse ƒƒ SevereSevere hypergammaglobulinemiahypergammaglobulinemia (>(> 33 gm)gm) seenseen inin autoimmuneautoimmune hepatitis;hepatitis; mostlymostly polyclonalpolyclonal IgGIgG .. ƒƒ ModerateModerate hypergammaglobulinemiahypergammaglobulinemia inin cirrhosiscirrhosis andand chronicchronic hepatitishepatitis ƒƒ VeryVery highhigh polyclonalpolyclonal IgMIgM inin primaryprimary biliarybiliary cirrhosiscirrhosis ƒƒ VeryVery highhigh IgAIgA oftenoften inin alcoholicalcoholic liverliver diseasedisease Serologic Markers of Viral Hepatitis A, B, and C Markers of Viral Hepatitis A: Anti-HAV

„ TotalTotal antibodyantibody (IgA(IgA ++ IgGIgG ++ IgM)IgM) „ RemainsRemains (+)(+) forfor decadesdecades „ IndicatesIndicates immunityimmunity Markers of Viral Hepatitis A: Anti-HAV IgM

„ (+)(+) atat onsetonset ofof symptomssymptoms ofof HepatitisHepatitis AA „ RemainsRemains (+)(+) upup toto 77 monthsmonths „ BestBest testtest toto diagnosediagnose acuteacute hepatitishepatitis AA Hepatitis A Markers of Viral Hepatitis B: HBsAg

„ VeryVery sensitive;sensitive; nono falsefalse ((--)) „ FalseFalse (+)(+) 1/10,0001/10,000 toto 1/1,0001/1,000 „ TurnsTurns (+)(+) duringduring incubationincubation andand declines;declines; 10%10% ((--)) atat onsetonset ofof symptomssymptoms „„ AlwaysAlways (+)(+) inin chronicchronic hepatitishepatitis BB (best(best marker)marker) Markers of Viral Hepatitis B: Anti-HBs

„ TiterTiter ≥≥ 11 IU/LIU/L isis (+);(+); TiterTiter ≥≥ 1010 IU/LIU/L isis protectiveprotective „ FalseFalse (+)(+) inin 1%1% „ PostPost--acuteacute HBV:HBV: 20%20% nevernever havehave antianti--HBsHBs andand 20%20% loselose antianti--HBsHBs inin aa fewfew yearsyears „ TiterTiter ≥≥ 1010 IU/LIU/L indicatesindicates responseresponse toto vaccinevaccine Markers of Viral Hepatitis B: Anti-HBc

„ FalseFalse (+)(+) inin 3%3% „ NoNo falsefalse ((--)) „ NotNot presentpresent postpost--vaccinationvaccination „„ BestBest && mostmost lastinglasting markermarker ofof previousprevious (or(or current)current) HBVHBV infectioninfection Markers of Viral Hepatitis B: Anti-HBc IgM

„ StronglyStrongly (+)(+) beforebefore symptomssymptoms ofof acuteacute HBVHBV „ RemainsRemains (+)(+) forfor monthsmonths „ MayMay bebe weaklyweakly (+)(+) inin chronicchronic HBVHBV „„ BestBest DiagnosticDiagnostic testtest forfor acuteacute HBVHBV Markers of Viral Hepatitis B: HBeAg

„ ActiveActive viralviral replicationreplication „ 90%90% havehave HBVHBV--DNADNA >> 10105 g.e./mlg.e./ml (10(105 g.e.g.e. == 0.350.35 pg)pg) „ NegativeNegative inin prepre--corecore mutantmutant virusvirus infection,infection, eveneven whenwhen replicatingreplicating rapidly.rapidly. Markers of Viral Hepatitis B: HBV-DNA by Hybridization or PCR

„ Hybridization detects > 105 g.e./ml (20000 IU/mL) (1 pg = 2.86 x 105 g.e./ml ) „ PCR detects > 100 g.e./ml (20-40 IU/mL) „ HBV-DNA < 200 pg/ml (6 x 107 g.e./ml) respond better to interferon „ With “wild” HBe(+) infection: elevated ALT plus values of 105 g.e./ml (20000 IU/mL) indicate active chronic hepatitis. „ With “pre-core” or “core-promoter” HBe(-) mutant virus: elevated ALT plus values > 104 g.e./ml (2000 IU/mL) indicate chronic active disease. Acute HBV Infection Chronic HBV Infection Case # 4

„ 2323 y/oy/o female,female, whowho diddid notnot havehave prepre--natalnatal care,care, comescomes inin laborlabor andand givesgives birthbirth toto aa ““healthyhealthy boyboy””.. HerHer admissionadmission labslabs showsshows sheshe isis HBsAg(+),HBsAg(+), hashas mildmild microcyticmicrocytic anemia,anemia, U/AU/A waswas normal,normal, andand hashas ALT=ALT= 9595 U/LU/L ((nlnl:: 1010--40),40), AST=AST= 8080 U/LU/L ((nlnl:: 1010-- 40),40), alk.alk. PhosphPhosph.. == 210210 U/LU/L ((nlnl:: 4040--100);100); bilirubin,bilirubin, protein,protein, andand albuminalbumin werewere normal.normal. „ DeniesDenies alcoholalcohol oror otherother drugdrug abuse.abuse. NoNo sexualsexual promiscuity.promiscuity. HerHer parentsparents camecame fromfrom ItalyItaly 33 yearsyears beforebefore herher birth.birth. Case # 4

„ NewbornNewborn receivedreceived immediatelyimmediately ““HepatitisHepatitis BB immuneimmune globulinglobulin”” andand HBVHBV vaccination.vaccination. „ MotherMother labs:labs: antianti--HBcIgMHBcIgM((--),), HBeAg(HBeAg(--),), antianti--HBe(HBe(--),), HBVHBV--DNADNA == 60,00060,000 gege/mL/mL (12000(12000 IU/mL)IU/mL) „ LiverLiver Bx:Bx: PortalPortal activity:activity: 3,3, Lobular:Lobular: 2,2, StageStage 33 fibrosis.fibrosis. „ Plan:Plan: treattreat patientpatient (likely(likely prepre--corecore mutant).mutant). Markers of Viral Hepatitis C: Anti-HCV

„ UsuallyUsually ELISAELISA--33 „ FalseFalse (+)(+) inin lowlow prevalenceprevalence populationpopulation withoutwithout riskrisk factorsfactors (40%)(40%) andand hypergammaglobulinemiahypergammaglobulinemia „ RareRare falsefalse ((--)) „ AcuteAcute HCVHCV turnsturns (+)(+) atat weekweek 44 inin 74%;74%; 98%98% areare (+)(+) byby weekweek 2020 Markers of Viral Hepatitis C: Anti-HCV, continued

„ NotNot aa protectiveprotective antibodyantibody „ MayMay remainremain (+)(+) upup toto 1010 yearsyears postpost--acuteacute infectioninfection „ AlmostAlmost allall patientspatients withwith chronicchronic HCVHCV areare antianti--HCVHCV (+)(+) „„ IndicatesIndicates pastpast oror currentcurrent infectioninfection Markers of Viral Hepatitis C: HCV-RNA (Target Amplification Quantitation)

„ DetectsDetects moremore thanthan 600600 IU/mLIU/mL (more(more thanthan 1010 IU/mLIU/mL withwith ““RealReal TimeTime”” techniques)techniques) „ LowLow viralviral loadload ((≤≤ 400,000400,000 IU/mL)IU/mL) respondrespond betterbetter toto therapytherapy „ InfrequentlyInfrequently falsefalse (+)(+) oror falsefalse ((--)) Prediction of SVR (Naïve) PEG-Interferons + Ribavirin HCVHCV--RNARNA %% NonNon-- %% SVRSVR StatusStatus @@ 1212 wkwk RespondersResponders HCVHCV--RNARNA ((--)) (less than 50 IU/ml) 2020 8080 HCVHCV--RNARNA (+)(+) 6060 && dropdrop >> 22 loglog 4040 HCVHCV--RNARNA (+)(+) 1.61.6 && dropdrop << 22 loglog 98.498.4 Acute Hepatitis C Virus Chronic Hepatitis C Virus Case # 5

„ 5252 y.oy.o.. warwar veteranveteran withwith intermittentlyintermittently elevatedelevated ALTALT && ASTAST overover 22 years.years. Hx.Hx. EtOHEtOH abuseabuse xx 1515 y;y; quitquit 33 yy ago.ago. HxHx tattoos,tattoos, IVIV drugsdrugs andand sexualsexual promiscuitypromiscuity fromfrom ageage 1818 toto 25.25. NoNo medicationsmedications nornor ““naturalnatural therapiestherapies””.. FamFam HxHx ((--).). HasHas somesome fatigue.fatigue. „ Examination:Examination: Small,Small, hardhard liver.liver. Splenomegaly.Splenomegaly. SpiderSpider angiomas.angiomas. Case # 5 Labs

„ CBCCBC normalnormal exceptexcept forfor plat=85Kplat=85K;; PT=PT= normalnormal „ ALT:ALT: 4545--88;88; AST:AST: 3434--74;74; AlkAlk Phos,Phos, T.T. bilibili && T.T. proteinprotein == nlnl.. Alb=Alb= 3.13.1 „ antianti--HAHA IgM(IgM(--),), antianti--HA(+)HA(+) == pastpast HAVHAV „ HBsAg(HBsAg(--),), antianti--HBcHBc (+),(+), antianti--HBcIgMHBcIgM((--),), antianti--HBs(+)HBs(+) == pastpast HBVHBV „ antianti--HCV(+)HCV(+) == pastpast oror currentcurrent HCVHCV Case # 5

„ HCVHCV--RNARNA == 650,000650,000 IU/mlIU/ml

„ LiverLiver Bx:Bx: ChronicChronic hepatitishepatitis withwith cirrhosis.cirrhosis. Case # 5

„„ DIAGNOSIS:DIAGNOSIS: ChronicChronic hepatitishepatitis CC withwith cirrhosiscirrhosis Markers of Autoimmune Liver disease ANA (anti-nuclear antibody)

„ GranulocyteGranulocyte specificspecific (anti(anti--centromere,centromere, -- ribonucleoprotein,ribonucleoprotein, or,or, --ribonucleoproteinribonucleoprotein complex)complex) „ Pattern:Pattern: homogeneoushomogeneous oror speckledspeckled „ TiterTiter ≥≥ 1:401:40 inin adults,adults, ≥≥ 1:201:20 inin childrenchildren „ ANAANA (+)(+) inin 67%67% ofof AIHAIH--11 andand 24%24% ofof PBCPBC „ AutoAuto--ImmuneImmune HepatitisHepatitis typetype 11 (AIH(AIH--1)1) defineddefined byby ANAANA (+)(+) and/orand/or ASMAASMA (+)(+) ASMA (anti-smooth muscle antibody)

„ CanCan be:be: antianti--actin,actin, --tubulin,tubulin, --vimentin,vimentin, --desmin,desmin, oror --skeletinskeletin „ SometimesSometimes (+)(+) inin hepatitishepatitis CC „ TiterTiter ≥≥ 1:401:40 inin adults,adults, ≥≥ 1:201:20 inin childrenchildren „ ASMAASMA (+)(+) foundfound inin 87%87% ofof AIH;AIH; 54%54% ANA(+)ANA(+) && ASMAASMA (+)(+) Anti LKM-1 (anti-liver/kidney microsomal)

„ AntiAnti--cytochromecytochrome P450P450 2D62D6 „ DefinesDefines TypeType 22 AIHAIH (4%(4% ofof adultadult AIHAIH inin USA)USA) „ TiterTiter ≥≥ 1:401:40 inin adults,adults, ≥≥ 1:201:20 inin childrenchildren „ 22--10%10% ofof HepatitisHepatitis CC AMA (anti-mitochondrial antibody)

„ AntiAnti--pyruvatepyruvate dehydrogenasedehydrogenase –– EE2/anti/anti--MM2 AMAAMA „ 95%95% ofof PBCPBC areare AMAAMA (+)(+) „ TiterTiter ≥≥ 1:1601:160 Evaluation of a Patient With Jaundice

Patient With Jaundice: History

„ FamilyFamily HistoryHistory „ TravelTravel HistoryHistory

‹ WilsonWilson’’ss (Cu)(Cu) ‹ HAVHAV

‹ HemochromatosisHemochromatosis ‹ HydatidHydatid cystcyst

‹ AA1 AntitrypsinAntitrypsin ‹ HEVHEV DeficiencyDeficiency ‹ AmoebicAmoebic liverliver ‹ BenignBenign recurrentrecurrent abscessabscess intrahepaticintrahepatic cholestasischolestasis Patient With Jaundice: History

„ SexualSexual PromiscuityPromiscuity && „ IVIV DrugsDrugs

MaleMale HomosexualityHomosexuality ‹ HBV

‹ HBV ‹ HDV

‹ Amoeba ‹ HCV

‹ HDV ‹ HIV + mycobacteria or

‹ HCV fungus

‹ Syphilis

‹ HIV + mycobacteria or fungus Patient With Jaundice: History

„ SkinSkin RashRash „ WorkWork ‹ Health Care: viral ‹ HBVHBV hepatitis ‹ DrugsDrugs ‹ Plastics: Vinyl Chloride - angiosarcoma ‹ Insecticides: Arsenic – angiosarcoma, hepatoma ‹ Ceramics: Beryllium - granulomas Patient With Jaundice: History

„ BloodBlood ProductsProducts „ PainPain inin RUQRUQ

‹ HBVHBV ‹ GallstonesGallstones

‹ HDVHDV ‹ LiverLiver AbscessAbscess ‹ HCV (before 1986) HCV (before 1986) ‹ HepatitisHepatitis ‹ HIVHIV ++ otherother pathogenspathogens Patient With Jaundice: History „ Pruritus:Pruritus: ‹ ChronicChronic extrahepaticextrahepatic obstructionobstruction ‹ PrimaryPrimary BiliaryBiliary CirrhosisCirrhosis (PBC)(PBC) „ HighHigh Fever:Fever: ‹ CholangitisCholangitis ‹ LiverLiver abscessabscess ‹ AlcoholicAlcoholic hepatitishepatitis „ SymptomsSymptoms ofof CHFCHF oror HxHx ofof Hypotension:Hypotension: ‹ IschemicIschemic hepatitishepatitis Patient With Jaundice: Physical Exam - General

„ ParotidParotid enlargement:enlargement: AlcoholAlcohol „ Clubbing:Clubbing: CirrhosisCirrhosis „ DupuytrenDupuytren’’ss contracture:contracture: AlcoholAlcohol „ Gynecomastia:Gynecomastia: Alcohol,Alcohol, cirrhosis;cirrhosis; AldactoneAldactone „ TesticularTesticular atrophy:atrophy: AlcoholicAlcoholic cirrhosiscirrhosis

Patient With Jaundice: Physical Exam - Skin

„ SpiderSpider Angiomata:Angiomata: CirrhosisCirrhosis „ PalmarPalmar erythema:erythema: CirrhosisCirrhosis „ Xanthelasma:Xanthelasma: PBC,PBC, chronicchronic biliarybiliary obstructionobstruction „ BronzeBronze color:color: HemochromatosisHemochromatosis „ Excoriations:Excoriations: CholestasisCholestasis (itching),(itching), PBCPBC „ PhotosensitivityPhotosensitivity blisters:blisters: PorphyriaPorphyria „ AzureAzure nailnail beds:beds: WilsonWilson’’ss „ Urticaria:Urticaria: HBVHBV

Patient With Jaundice: Physical Exam - Eye

„ KayserKayser--FleischerFleischer ring:ring: WilsonWilson’’s,s, PBCPBC

„ Lacrimegaly:Lacrimegaly: AlcoholAlcohol Patient With Jaundice: Physical Exam - Abdomen

„ Splenomegaly:Splenomegaly: PortalPortal hypertensionhypertension „ Ascites:Ascites: PortalPortal hypertension;hypertension; ⇓⇓ albuminalbumin „ CollateralCollateral circulation:circulation: PortalPortal hypertensionhypertension „ HepaticHepatic rub:rub: TumorTumor

Patient with Jaundice: Physical Exam

„ GIGI Tract:Tract: „ NeurologicNeurologic

‹ Inflammatory Bowel ‹ Asterixis:Asterixis: Disease: Primary EncephalopathyEncephalopathy sclerosing cholangitis (PSC) ‹ Hyperreflexia:Hyperreflexia:

‹ Esophageal or rectal EncephalopathyEncephalopathy varices: Portal hypertension

‹ Colitis: PSC, amoebic abscess Questions ? Acute Hepatocellular Disease

„ AcuteAcute HAVHAV:: antianti--HAVHAV IgMIgM (+)(+) „ AcuteAcute HBVHBV:: antianti--HBcHBc IgMIgM (+)(+) highhigh titertiter „ AcuteAcute HBV/HDVHBV/HDV coinfectioncoinfection:: antianti--HBcHBc IgMIgM (+),(+), andand antianti--HDHD IgMIgM (+),(+), oror HDAgHDAg(+)(+) „ AcuteAcute HDVHDV onon chronicchronic HBVHBV:: HBsAg(+)HBsAg(+) ++ HBcHBc IgM(IgM(--)) plusplus antianti--HDHD IgMIgM oror HDAgHDAg(+)(+) „ AcuteAcute HCVHCV:: HCVHCV--RNA(+),RNA(+), andand serosero--conversionconversion toto antianti--HCV.HCV. Acute Hepatocellular Disease

„ AcuteAcute HEVHEV:: antianti--HEVHEV IgM(+)IgM(+) „ AcuteAcute CMVCMV:: antianti--CMVCMV IgM(+),IgM(+), CMVCMV (+)(+) byby cultureculture oror PCRPCR inin bloodblood oror tissuetissue „ AcuteAcute EBVEBV:: acuteacute EBVEBV serologyserology patternpattern „ AcuteAcute HSVHSV:: antianti--HSVHSV I/III/II IgM(+),IgM(+), HSV(+)HSV(+) byby cultureculture oror PCRPCR inin bloodblood oror tissue.tissue. „ DrugDrug oror ToxinToxin inducedinduced:: historyhistory andand improvementimprovement withwith removalremoval ofof drug/toxin.drug/toxin. Acute Hepatocellular Disease

„ Ischemic hepatitis: history of hypotension, or passive hepatic congestion/heart failure „ “Acute” Alcoholic Hepatitis: alcohol abuse > 20 gm/d in females or > 40 gm/d in males, for > 5 years, with AST > ALT, AST & ALT < 300 IU/L, or Liver Bx. „ “Acute” Auto-immune Hepatitis: ANA, ASMA, AMA, QIG’s, anti-LKM1, anti-SLA, anti- LP, ANCA, and Liver Biopsy „ “Acute” Wilson : ceruloplasmin, free serum Cu, 24 hour urine Cu, eye exam for K-F rings, low uric acid, evidence of hemolysis, Liver Bx with quantitative Cu. Chronic Hepatocellular Disease

„ Chronic HBV: HBsAg(+) > 6 months, HBcIgM(-) , HBV-DNA quantitation, HBeAg, anti-HBe; Liver Bx „ Chronic HBV/HDV: HBsAg(+), anti-HBc IgM(-) , anti- HD IgG(+) high titer; Liver Bx „ Chronic HCV: HCV-RNA quantitation; Liver Bx „ Hemochromatosis: high fasting transferrin saturation & ferritin, HFE analysis, Liver Bx with Hepatic Iron Index > 1.9; quantitative therapeutic phlebotomy. „ Non-Alcoholic Steato-Hepatitis: (overweight, hyperglycemia, hypertrigliceridemia, hypertension); Liver Bx Chronic Hepatocellular Disease

„ Alpha1 anti-trypsin: alpha1 anti-trypsin phenotype and quantitation; Liver Bx „ Wilson Disease: ceruloplasmin, free serum Cu, 24 h urine Cu, eye exam for K-F rings, low uric acid, Liver Bx for Cu quantitation. „ Auto-Immune Hepatitis: ANA, ASMA, AMA, anti- LKM1, anti-SLA, anti-LP, ANCA, serum QIG’s, Liver Bx. „ Primary Sclerosing Cholangitis: MRCP. ERCP. „ Drug or Toxin Induced: history and improvement with removal of drug/toxin; may need Liver Bx. Isolated Alkaline Phosphatase

„ Extrahepatic vs. Hepatic: GGTP, alkaline phosphatase isoenzymes, triple-phase spiral or multi-detector CT scan of abdomen & pelvis (liver, biliary tree, pancreas, kidneys, spleen, lymph nodes). „ Hepatic without focal lesion: AMA, serum QIG’s, MRCP, Liver Bx with culture (AFB, fungus, virus). „ Hepatic with solid focal lesion: AFP, guided Bx, complementary imaging techniques. „ Hepatic with cystic focal lesion: CT scan for lesions in other organs, serologies (ameba, echinococcus, cysticercus) Extrahepatic Cholestasis

„ PancreasPancreas:: TripleTriple--phasephase spiralspiral oror multidetectormultidetector CTCT scan,scan, EUSEUS withwith Bx.;Bx.; maymay needneed therapeutictherapeutic ERCP.ERCP. „ BiliaryBiliary stonestone:: TherapeuticTherapeutic ERCPERCP „ BiliaryBiliary ductduct lesionlesion:: MRCPMRCP ++ MRI,MRI, CA19CA19--9,9, CEA,CEA, ?? PETPET scan;scan; maymay needneed ERCPERCP ++ Cytology/BxCytology/Bx ++ stentstent Intrahepatic Cholestasis

„ PBCPBC:: AMA,AMA, serumserum QIGQIG’’ss,, LiverLiver Bx.Bx. „ PSCPSC:: MRCPMRCP oror ERCP;ERCP; ANCAANCA „ WithoutWithout focalfocal lesionlesion (granulomas,(granulomas, infiltration):infiltration): LiverLiver BxBx withwith cultureculture (AFB,(AFB, fungus,fungus, virus)virus) „ WithWith focalfocal lesionlesion:: guidedguided BxBx „ AscendingAscending cholangitischolangitis:: therapeutictherapeutic ERCPERCP „ AlcoholicAlcoholic hepatitishepatitis:: historyhistory && enzymeenzyme pattern;pattern; LiverLiver BxBx Intrahepatic Cholestasis

„ CholestaticCholestatic HAVHAV:: antianti--HAVHAV IgM(+)IgM(+) „ GraftGraft vs.vs. hosthost diseasedisease:: historyhistory && LiverLiver BxBx „ SepsisSepsis:: historyhistory „ DrugDrug inducedinduced:: historyhistory && improvementimprovement afterafter discontinuation;discontinuation; maymay needneed liverliver Bx.Bx. „ TPNTPN inducedinduced:: historyhistory && improvementimprovement withwith enteralenteral nutrition;nutrition; maymay needneed liverliver Bx.Bx. „ BenignBenign RecurrentRecurrent IntrahepaticIntrahepatic CholestasisCholestasis ofof PregnancyPregnancy:: PregnancyPregnancy ++ familyfamily history.history. Questions ? Causes of Intrahepatic Cholestasis 1.1. DrugsDrugs (phenothiazines,(phenothiazines, erythromycin,erythromycin, sulphonylureas,sulphonylureas, estrogens,estrogens, etc.)etc.) 2.2. PrimaryPrimary biliarybiliary cirrhosiscirrhosis 3.3. SclerosingSclerosing cholangitischolangitis 4.4. InfiltrativeInfiltrative diseasesdiseases (granulomas,(granulomas, tumors,tumors, etc.)etc.) 5.5. AscendingAscending cholangitischolangitis 6.6. SepticemiaSepticemia Causes of Intrahepatic Cholestasis

7.7. AlcoholicAlcoholic hepatitishepatitis 8.8. CholestaticCholestatic HAVHAV 9.9. GraftGraft vs.vs. hosthost diseasedisease 10.10. TotalTotal parenteralparenteral nutritionnutrition 11.11. IntrahepaticIntrahepatic cholestasischolestasis ofof pregnancypregnancy 12.12. BenignBenign recurrentrecurrent intrahepaticintrahepatic cholestasischolestasis 13.13. DubinDubin JohnsonJohnson Causes of Extrahepatic Cholestasis

1.1. CholedocholithiasisCholedocholithiasis (CBD(CBD stone)stone) 2.2. BiliaryBiliary stricturesstrictures (benign,(benign, malignant,malignant, intrinsicintrinsic oror extrinsic)extrinsic) 3.3. PancreaticPancreatic carcinomacarcinoma 4.4. PancreatitisPancreatitis Causes of Extrahepatic Cholestasis 5.5. PeriampullaryPeriampullary carcinomacarcinoma 6.6. CholangiocarcinomaCholangiocarcinoma 7.7. CholedocalCholedocal cystcyst 8.8. MiscellaneousMiscellaneous (blood,(blood, worms,worms, PSC,PSC, etc.)etc.) Anti-SLA (anti-soluble liver antigen)

„ AntiAnti--cytokeratincytokeratin 88 and/orand/or 1818 „ DefinesDefines AIHAIH--33 (100%)(100%) Markers of Viral Hepatitis B: Anti-HBe

„ AntiAnti--HBeHBe withwith lossloss ofof HBeAgHBeAg indicatesindicates lowerlower oror nono replicationreplication „ 70%70% ofof AntiAnti--HBeHBe havehave HBVHBV--DNADNA ≤≤ 10105g.e./mlg.e./ml Markers of Viral Hepatitis B: HBV-DNA by RT-PCR

„ HBVHBV--DNADNA ≥≥ 100100 g.e./mlg.e./ml „ TooToo sensitivesensitive „ UsefulUseful toto decidedecide ifif virusvirus waswas trulytruly eliminatedeliminated Markers of Viral Hepatitis D: HD Ag

„ TransitorilyTransitorily (+)(+) inin acuteacute HDVHDV „ PersistentlyPersistently (+)(+) inin chronicchronic HDVHDV „ PositivePositive inin liverliver tissuetissue inin chronicchronic infections;infections; bestbest testtest Markers of Viral Hepatitis D: Anti-HDV

„ AcuteAcute coinfection:coinfection: ((--)) oror weakweak (+)(+) [1:10[1:10 toto 1:100]1:100] „ Superinfection:Superinfection: strongstrong (+)(+) ≥≥ 1:1,0001:1,000 „ ChronicChronic HDV:HDV: strongstrong andand persistentpersistent (+)(+) Markers of Viral Hepatitis D: Anti-HDV IgM

„ IndicatesIndicates activeactive infectioninfection „ AcuteAcute coinfectioncoinfection oror superinfectionsuperinfection == transitorilytransitorily (+)(+) „ ChronicChronic infection:infection: PersistentlyPersistently atat highhigh titertiter HDV Coinfection with HBV Chronic Hepatitis D Markers of Viral Hepatitis C: HCV-RNA by RT-PCR

„ DetectsDetects ≥≥ 100100 IU/mLIU/mL „ BestBest testtest toto assessassess truetrue responseresponse toto therapytherapy „ MoreMore falsefalse (+)(+) andand falsefalse ((--)) thanthan thethe qualitativequalitative testtest Markers of Viral Hepatitis E: Anti-HEV

„ 11--88 weeksweeks fromfrom onsetonset ofof clinicalclinical illnessillness „ PersistsPersists forfor aa fewfew yearsyears Markers of Viral Hepatitis E: Anti-HEV IgM

„ 11 weekweek earlierearlier thanthan IgGIgG antibodyantibody „ PersistsPersists 44--55 monthsmonths „ BestBest testtest forfor acuteacute infectioninfection HEV Infection