CommonCommon CausesCauses AcuteAcute andand ChronicChronic HepatitisHepatitis

Luis S. Marsano, MD Professor of Medicine Division of Gastroenterology, Hepatology and Nutrition Nov 2011 AcuteAcute HepatitisHepatitis HepatitisHepatitis AA n HepatovirusHepatovirus fromfrom PicornavirusPicornavirus family.family. n 2727--3232 nm,nm, linear,linear, (+)(+) sense,sense, simplesimple strandedstranded RNA.RNA. n ReservoirReservoir:: humanhuman onlyonly n AcquisitionAcquisition:: fecalfecal--oral;oral; concentratedconcentrated inin oysters.oysters. ContaminatedContaminated waterwater oror food,food, menmen havinghaving sexsex withwith men,men, bloodblood duringduring shortshort viremicviremic phase.phase. n NonNon--cytopatic;cytopatic; immuneimmune mediatedmediated injuryinjury byby lymphocyteslymphocytes HepatitisHepatitis AA SeroSero--PrevalencePrevalence

nnPoorPoor sanitationsanitation countriescountries:: –– nearnear 100100 %% byby ageage 5.5. nnGoodGood sanitationsanitation countriescountries (USA)(USA) :: –– 1010 %% byby ageage 14;14; –– 3737 %% inin adults.adults. AcuteAcute HepatitisHepatitis AA ClinicalClinical FeaturesFeatures n IncubationIncubation:: 22--44 (up(up toto 6)6) weeksweeks n ClinicalClinical Presentation:Presentation: – Children < 2 year: 80% anicteric & asymptomatic – Children > 2 y and adults: 80% icteric & symptomatic n SymptomsSymptoms:: – Fatigue (90%), - anorexia (85%), – jaundice (80%), - nausea (75%), – low fever (65%), - headache, – abdominal pain and - myalgias. n DurationDuration:: usuallyusually << 88 weeksweeks AcuteAcute HepatitisHepatitis AA AtypicalAtypical ManifestationsManifestations n Relapsing hepatitis: less than 10%; 2 or more bouts of elevated enzymes. n Cholestatic hepatitis: Severe and prolonged jaundice > 10 weeks. Is rare. n Fulminant Hepatitis: very rare but lethal in 50%. n Extrahepatic Disease: – renal failure, - red cell aplasia, – hemolysis, - pancreatitis, – neurologic disease. n Mortality: Not increased by pregnancy. – a) younger than 49 = 0.3%; – b) older than 49 = 1.8%. AcuteAcute HepatitisHepatitis AA HepatitisHepatitis AA VaccinationVaccination RecommendationRecommendation

n Children in areas with rate >20/100000 n High risk: – traveler to endemic area, – men having sex with men, – illegal drug users, – person with clotting factor disorder, – researcher working with HAV. n Chronic disease: HBV, HCV n During community outbreaks. n Immunogenicity: – > 70% within 2-4 weeks after 1st dose, and – 94-99% after second dose. HepatitisHepatitis AA PostPost--ExposureExposure ManagementManagement

n Post-exposure prophylaxis can be done: – with Intramuscular “Immune Serum Globulin” (ISG) within 14 days from exposure at 0.06 mL/kg (69-89% effective and lasting 12-20 weeks) or – with Inactivated Vaccine given also within 14 days post-exposure. – Response to vaccine is less robust and ISG is preferred: » before age 1 (due to circulating maternal antibodies), and » after age 40. n Inactivated Vaccine is the preferred approach from age 1 to 40. n Immune serum globulin is contraindicated in IgA deficiency or hypersensitivity to ISG. n Active immunization with Hepatitis A vaccine can be given at the same time of ISG. HepatitisHepatitis EE

n 27-30 nm non-enveloped, single-stranded, positive-sense RNA Hepevirus. n There are 4 (maybe 6) genotypes. – 1: India, China, Pakistan; – 2: Mexico; – 3: USA, France, Japan. – 4: China, Japan – There is an avian and a rat HEV variant. n Acquisition: – Waterborne, fecal-oral, by organ meat ingestion, or by contact with animals. In USA swine is a common source. – Rare person-person (1.5% intra-familial). – Increased risk in homosexual men. HepatitisHepatitis EE

n Types: – Sporadic: traveler to endemic areas, pet owners, organ meat eaters, male homosexuals, military service (Midwest USA). – Epidemic: after heavy rain and flooding in areas with poor sanitation (India, China, Latin America, Africa) – Endemic: In areas were asymptomatic infection occurs at early age, like in Egypt – Chronic hepatitis: in immunosuppressed patients, with progressive liver damage and cirrhosis (worse with Tacrolimus than with CSA). n Reservoir: human, pig, sheep, cattle, rat,… n Prevention: there is an experimental recombinant vaccine. HepatitisHepatitis EE n Incubation: 2-10 weeks. n Prodrome: 2 weeks of malaise, mild chills & fever, transitory macular rash. n Symptoms & Signs: jaundice, nausea, vomiting, anorexia, aversion to food & smoking, abdominal pain, clay-color stool. Hepatomegaly in 65-80%; symptoms usually for 4 weeks. n Mortality: – 0.1-0.6%; 15-25% during pregnancy in the epidemic form in India. – Mortality in pregnancy is low in Egypt and other endemic areas. n Diagnosis: – Anti HEV-IgM last only 3 months, and is not always present in acute infection; – Anti-HEV IgG lasts for years; – HEV can be found by PCR in stool, serum, and bile. n Treatment: – Support. – Peg-IFN and Ribavirin have effect in chronic HEV. AcuteAcute HepatitisHepatitis EE HepatitisHepatitis BB n 4242 nm,nm, partiallypartially doubledouble--strandedstranded circularcircular DNADNA virus.virus. n 350350 millionmillion carrierscarriers worldworld--wide;wide; causescauses 250000250000 deathsdeaths aa year.year. n 1.251.25 millionmillion carrierscarriers inin USA.(0.5USA.(0.5 %);%); >> 8%8% inin AlaskanAlaskan Eskimos.Eskimos. n NewNew infections:infections: 260K/y260K/y inin 19801980’’s;s; nownow 73,000/y73,000/y n TransmissionTransmission:: InIn mostmost ofof USAUSA predominantlypredominantly sexualsexual andand percutaneouspercutaneous duringduring adultadult age.age. InIn AlaskaAlaska predominantlypredominantly perinatal.perinatal. HepatitisHepatitis BB TransmissionTransmission n SexualSexual:: heterosexualheterosexual inin 41%41% ofof acuteacute cases.cases. MenMen havinghaving sexsex withwith menmen havehave 10%10% risk.risk. n PercutaneousPercutaneous (mostly(mostly illicitillicit drugdrug use):15%use):15% ofof acuteacute HBVHBV casescases n PerinatalPerinatal:: 10%10% ofof acuteacute casescases (mother(mother--child)child) n TransfusionTransfusion:: 1/630001/63000 transfusions.transfusions. n OtherOther:: organorgan transplant,transplant, tattoo,tattoo, piercing,piercing, acupuncture,acupuncture, …… HepatitisHepatitis BB HighHigh--RiskRisk GroupsGroups n Born in high prevalence n Intravenous drug abuser area n Person requiring frequent n Active homosexual men transfusions n Promiscuous n Inmate in long-term heterosexuals correctional facility n Healthcare & Public n Hemodialysis patient Safety workers n Traveler > 6 months to n Attendant/family of endemic area institutionalized mentally n Sexual partner of handicapped HBsAg(+) person HepatitisHepatitis BB VaccinationVaccination nAllAll childrenchildren andand adolescentsadolescents nIfIf notnot previouslypreviously vaccinated:vaccinated: AllAll highhigh--riskrisk groupsgroups nPostPost--VaccinationVaccination testing:testing: –– HealthcareHealthcare && PublicPublic--SafetySafety workersworkers –– InfantsInfants fromfrom HBsAg(+)HBsAg(+) mothermother –– HemodialysisHemodialysis patientspatients –– SexualSexual partnerpartner ofof HBsAg(+)HBsAg(+) personspersons AcuteAcute HepatitisHepatitis BB n IncubationIncubation:: 11--44 monthsmonths n ProdromeProdrome:: arthralgia,arthralgia, arthritis,arthritis, skinskin rashrash n SymptomsSymptoms && SignsSigns:: – malaise, anorexia, jaundice, nausea, fatigue, low-grade fever, myalgia, change in taste and smell. – tender hepatomegaly in most patients; splenomegaly in 5-15%. n Infrequently:Infrequently: confusion,confusion, edema,edema, coagulopathy,coagulopathy, comacoma (Fulminant(Fulminant FailureFailure inin 0.5%)0.5%) AcuteAcute HepatitisHepatitis BB

n Diagnosis: anti-HBc IgM antibody; frequently HBsAg(+) in early phase and anti-HBs(+) in late phase. n Evolution to Chronicity: – a) Infants: 90%, – b) Children 1-5: 25-50%, – c) Adults & older children: 5% n Treatment: Supportive; Anti-virals in “protracted hepatitis”, or failure to regenerate/sub-massive necrosis. AcuteAcute HepatitisHepatitis BB nPostPost--ExposureExposure ProphylaxisProphylaxis:: HyperimmuneHyperimmune globulinglobulin HBHB ++ ImmediateImmediate vaccination.vaccination. nNeonateNeonate fromfrom HBsAg(+)HBsAg(+) mothermother:: HyperimmuneHyperimmune globulinglobulin HBHB 0.50.5 mlml IMIM withinwithin 1212 hh fromfrom birthbirth ++ ImmediateImmediate vaccinationvaccination @@ 0,0, 1,1, 2,2, && 1212 monthsmonths AcuteAcute HepatitisHepatitis BB AcuteAcute HepatitisHepatitis DD n DefectiveDefective RNARNA virusvirus -- n Parenteral,Parenteral, sexual,sexual, needsneeds HBVHBV perinatalperinatal n CoinfectionCoinfection withwith n Diagnosis:Diagnosis: TransitoryTransitory HBV:HBV: severesevere hepatitishepatitis HDAgHDAg(+)(+) oror IgMIgM antianti-- n SuperinfectionSuperinfection ofof HD(+);HD(+); strongstrong antianti--HDHD HBV:HBV: frequentfrequent inin superinfectionsuperinfection fulminantfulminant oror chronicchronic n HBVHBV vaccinevaccine isis HDVHDV protectiveprotective HepatitisHepatitis CC n 5050 nmnm enveloped,enveloped, positivepositive--sense,sense, singlesingle--strandedstranded RNARNA hepacivirushepacivirus.. SixSix genotypesgenotypes andand >> 100100 subtypes.subtypes. n 170170 millionmillion infectedinfected worldwide;worldwide; 44--77 millionmillion inin USAUSA (1.8%);(1.8%); 38,00038,000 newnew infections/year.infections/year. n RiskRisk ofof Transmission:Transmission: – a) Needle stick: 1.8% – b) Sexual intercourse: 1/95 patient-year (2.2%), – c) Perinatal: » HIV(-) mother: 5%; » HIV(+): 14% PrevalencePrevalence ofof HCVHCV nGROUPGROUP %% nGROUPGROUP %% n HemophiliaHemophilia <<’’8787 8282 n Infant of RNA(+) mother 55 n IVDAIVDA 8080 n HomosexualHomosexual menmen 44 n HemodialysisHemodialysis 1010 n Monogamous partner 22 n TransfusionTransfusion << ’’9090 77 n GeneralGeneral populationpopulation 1.81.8 n PersonPerson ww STDSTD 66 n Volunteer blood donor .16.16 RiskRisk ofof HCVHCV inin IVDUIVDU (%(% infected)infected)

100 94 90 83 80 78 70 60 50 % HCV infected 40 30 20 10 0 year 1 year 5 year 10 HCVHCV PrevalencePrevalence HemodialysisHemodialysis PatientsPatients n EgyptEgypt general=general= 18.1%18.1% HD=HD= 80%80% n MoldaviaMoldavia 4.9%4.9% 75%75% n BulgariaBulgaria 1.1%1.1% 66%66% n SaudiSaudi ArabiaArabia 1.8%1.8% 57%57% n TurkeyTurkey 1.5%1.5% 31%31% n ItalyItaly 0.5%0.5% 22%22% n FranceFrance 1.1%1.1% 16%16% n BelgiumBelgium 0.9%0.9% 9%9% n USAUSA 1.8%1.8% 9%9% n NetherlandsNetherlands 0.1%0.1% 3%3% AcuteAcute HCVHCV n Incubation: 2-26 weeks (usually 7-8) n Symptoms: – occur in < 30%, usually mild & lasts < 1 month. – anorexia, arthralgia, myalgia, fatigue; – rarely jaundice, fever or skin rash. – very rare FHF. n DX: – HCV-RNA (+) days to weeks after acquisition ; – anti-HCV (+) in 6 weeks. n Spontaneous HCV clearance: – Children < 2 y.o. & young women = 45%; – Others = 23% AcuteAcute HCVHCV AcuteAcute HCVHCV TreatmentTreatment n IfIf HCVHCV--RNA(+)RNA(+) 33 monthsmonths afterafter inoculation,inoculation, spontaneousspontaneous clearanceclearance isis rare.rare. n BestBest regimenregimen isis unknown:unknown: startingstarting 33 monthsmonths afterafter inoculation,inoculation, – IFN 5 MU QD x 4 wks + 3 MU TIW x 20 wks gave 98% clearance; the mildest & shortest effective therapy is unknown. – Pegasys 180 mcg/week +/- RBV x 12 weeks n PatientsPatients shouldshould bebe abstinentabstinent fromfrom alcoholalcohol andand drugsdrugs (anti(anti--HCVHCV isis notnot protective).protective). TreatmentTreatment ofof AcuteAcute HCVHCV @@ 8,12,8,12, && 2020 wks,wks, PegasysPegasys vsvs RebetronRebetron xx 1212 wkswks Kamal et al Abst # 37 AASLD, 2004 n6868 ptspts withwith AcuteAcute hepatitishepatitis C;C; 77 hadhad spontaneousspontaneous clearance.clearance. nTreatmentTreatment startedstarted at:at: –– A)A) WkWk 88 (21),(21), –– B)B) WkWk 1212 (20),(20), –– C)C) WkWk 2020 (20)(20) nRebetronRebetron vsvs PegasysPegasys xx 1212 wks;wks; ifif HCVHCV--RNARNA (+)(+) atat wkwk 12,12, treatedtreated 1212 moremore wks.wks. RESULTSRESULTS Abstr # 37

100 100 100100 90 90 90 90 90 80 80 80 70 60 50 Start Wk 8 PEG Start Wk 12 PEG 40 Start Wk 20 PEG 30 20 10 0 Rpx12 Wks Rpx24 Wks SVR RESULTSRESULTS Abstr # 37

nStartingStarting therapytherapy atat weekweek 1212 gavegave bestbest results.results. nPegasysPegasys monotherapymonotherapy xx 1212 weeks,weeks, waswas superiorsuperior toto RebetronRebetron treatmenttreatment xx 1212 weeks,weeks, inin allall groups.groups. PracticalPractical ApproachApproach toto TreatTreat AcuteAcute HCVHCV n WaitWait forfor 1212 weeksweeks fromfrom timetime ofof acquisitionacquisition toto seesee ifif spontaneousspontaneous clearanceclearance occurs.occurs. n SpontaneousSpontaneous clearanceclearance isis moremore likelylikely ifif patientpatient is:is: – IL28B (rs12979860) CC regardless of symptoms or jaundice, or – IL28B CT and jaundiced. n InIn absenceabsence ofof spontaneousspontaneous clearance,clearance, treattreat withwith PegPeg--IFNIFN ++ RBVRBV (may(may improveimprove outcome)outcome) for:for: – 3 months if HCV-RNA (-) at 4 weeks; – otherwise treat longer. AutoAuto--ImmuneImmune HepatitisHepatitis -- AcuteAcute PresentationPresentation n 30%30% presentpresent acutely,acutely, likelike viralviral hepatitishepatitis n ExtrahepaticExtrahepatic manifestationsmanifestations areare common:common: –– arthralgiaarthralgia -- skinskin rashrash -- chronicchronic diarrheadiarrhea –– pleuropleuro--pericarditispericarditis -- thyroiditisthyroiditis –– ulcerativeulcerative colitiscolitis -- glomerulonephritisglomerulonephritis –– vitiligovitiligo -- neuropathyneuropathy n DxDx::

– 1) Autoantibodies (+): ANA, ASMA, Anti-LKM1, anti-SLA, anti-LP, ANCA, increased gammaglobulins (IgG), AND – 2) Compatible Liver Biopsy; frequently has centrilobular zone 3 necrosis with plasmacytic infiltrate and bile duct injury. AutoAuto--ImmuneImmune HepatitisHepatitis -- AcuteAcute PresentationPresentation n TreatmentTreatment:: PrednisonePrednisone ++ AzathioprineAzathioprine n Prognosis:Prognosis: failurefailure toto improveimprove bilirrubinbilirrubin,, oror markermarker ofof inflammationinflammation withinwithin 22 weeksweeks stronglystrongly suggestssuggests thatthat liverliver transplantationtransplantation maymay bebe needed.needed. n PatientsPatients whowho presentpresent withwith MELDMELD >/=>/= 1212 areare likelylikely toto failfail corticosteroidcorticosteroid therapytherapy (Sens(Sens == 97%,97%, SpecifSpecif == 68%)68%) ChronicChronic HepatitisHepatitis ChronicChronic HepatitisHepatitis nDx:Dx: PersistentPersistent oror IntermittentIntermittent elevationelevation ofof liverliver enzymesenzymes forfor >> 66 months*months* PLUSPLUS consistentconsistent liverliver biopsybiopsy

*Some*Some disordersdisorders areare alwaysalways chronicchronic andand dodo notnot needneed toto bebe documenteddocumented forfor 66 month:month: AIH,AIH, WilsonWilson’’s,s, Hemochromatosis,Hemochromatosis,

αα1--antitrypsin,antitrypsin, overlapoverlap syndromesyndrome ChronicChronic HCVHCV n Most common chronic viral hepatitis in USA. n Most are asymptomatic; 6% symptomatic before diagnosis. n Symptoms: fatigue, RUQ discomfort, anorexia, nausea, itching, arthralgia, myalgia. n Extrahepatic: – mixed cryoglobulinemia, - purpura, – mononeuritis multiplex, - PCT, – xerostomy, - low-grade B-cell lymphoma, – corneal ulcers, - idiopathic pulmonary fibrosis, – lichen planus, – membrano-proliferative glomerulonephritis, ChronicChronic HCVHCV n Diagnosis: – Persistent HCV-RNA (+); – Most patients are anti-HCV(+). – Liver Bx useful to asses severity of disease. n False (-) anti-HCV: 0.45% in HIV & hemodyalisis. n False (+) are common & antibody remains (+) many years after clearance of infection. n “Cut-off” for “high” vs. “low” viral load: 400,000 IU/mL PatternPattern ofof ALTALT ElevationElevation inin ChronicChronic HCVHCV

Pattern of ALT Elevation

12 31 15 Normal ALT ALT < 2X-ULN ALT 2-3X-ULN ALT > 3X-ULN

42 DegreeDegree ofof FibrosisFibrosis inin ChronicChronic HCVHCV

Degree of Fibrosis

22 19 None Stage 1 Stage 2 Bridging 19 16 Cirrhosis 24 ChronicChronic HCVHCV GenotypeGenotype andand ViralViral LoadLoad inin USUS PatientsPatients

Genotype 4,5,6 Genotype 4,5,6 Low 2.7% High Viral Load 1.3% Viral Load

Genotype 2,3 Low 7.3% Viral Load

14.7% Genotype 2,3 HVL Genotype 1 49.5% HVL Genotype 1 LVL

24.5%

Alter et al. N Engl J Med. 1999;341;556-562. Blatt et al. J Viral Hepatitis. 2000;7:196-202. OutcomeOutcome ofof HCVHCV 2525--3030 yearyear FollowFollow--upup

Resolves @ acute hepatitis Chronic / No-cirrhosis Compensated Cirrhosis Decompensated Cirrhosis Death/ Decompensated 60 Death/ HCC 20 80

13 3 3 1

HistologicalHistological ScoringScoring ofof FibrosisFibrosis

Description Modified HAI HAI Batts-Ludwig, METAVIR Scheuer, or (Ishak) (Knodell) IASL None 0000

Mild: Portal fibrosis (some p. areas) 1111

Moderate: Periportal Fibrosis (most p. areas, 2322 or occasional portal-portal septa) Severe:occasional Bridging bridges, fibrosis any portal-central)(few / 3332 Severe: Bridging fibrosis (many portal-central 4333 bridges) Incomplete cirrhosis 5444 Cirrhosis 6444

Treat METAVIR =/> 2, or Ishak/Batts-Ludwig/Scheuer/Knodell =/> 3 TreatmentTreatment ofof ChronicChronic HCVHCV n Genotype 1: Peg-Interferon weekly + Ribavirin 1000- 1200 mg/d + Boceprevir or Telaprevir x 24 to 48 weeks (response guided) – SVR: 66-75% n Genotypes 2 and 3: Peg-Interferon weekly + RBV 800 mg/d x 24 weeks – SVR: 78-80% n Genotypes 4, 5, or 6: Peg-Interferon weekly + Ribavirin 1000-1200 mg/d x 48 weeks – SVR: 55-60% PredictingPredicting SVRSVR byby HCVHCV--RNARNA fallfall PegPeg--IFNIFN alphaalpha 2a2a ++ RBVRBV

91 100 90 80 72 70 60 60 48 50 43 SVR (%) 40 30 20 10 2 0 wk4(-) wk4 >2log/ wk4 <2log/ wk4 >2log/ wk4 <2log/ wk24(+) wk12(-) wk12(-) wk24(-) wk24(-)

Ferenci P, et al. J Hepatol 2005; 43:425-433 PEGASYSPEGASYS ++ RibavirinRibavirin SustainedSustained VirologicVirologic ResponseResponse

100 90 80 78 78 77 73 70 60 24 wk & 800 51 50 24 wk & 1/1200 41 40 40 48 wk & 800 30 29 48 wk & 1/1200 20 10 0 Genotype 1 Genotype 2/3 ChronicChronic HepatitisHepatitis BB n InIn lowlow prevalenceprevalence areasareas (USA)(USA) 3030--50%50% historyhistory ofof acuteacute hepatitishepatitis (rare(rare inin highhigh prevalence)prevalence) n SymptomsSymptoms:: – frequently asymptomatic; – sometimes RUQ or epigastric pain or acute-like hepatitis episodes. n ExtrahepaticExtrahepatic:: – serum-sickness, - polyarteritis nodosa, – mixed cryoglobulinemia, - IgA nephropathy, – membranous- or membranoproliferative- glomerulonephritis, - papular acrodermatitis. ChronicChronic HBVHBV

ChronicChronic HepatitisHepatitis BB

nDiagnosisDiagnosis:: –– HBsAgHBsAg (+)(+) && HBVHBV--DNADNA (+)(+) forfor >> 66 monthsmonths ,, withwith antianti--HBcHBc IgMIgM ((--)) butbut antianti--HBcHBc totaltotal (+)(+) [excludes[excludes incubation]incubation] StatesStates ofof ChronicChronic HepatitisHepatitis BB

InactiveInactive CarrierCarrier ImmunotolerantImmunotolerant ImmunoactiveImmunoactive OccultOccult HBVHBV ChronicChronic HepatitisHepatitis BB statesstates

nnInactiveInactive CarrierCarrier statestate n NormalNormal ALTALT (normal(normal malemale << 3030 U/L,U/L, normalnormal femalefemale << 1919 U/L)U/L) andand – Wild-HBe(+) or Wild-HBe(-): HBV-DNA < 20000 IU/mL, – Mutant-HBe(-): HBV-DNA < 2000 IU/mL,

(in HBe(-): if HBV-DNA > 2000 IU/mL but < 20000 IU/mL, needs testing for PreCore or Core-promoter to classify, but management will not change) ChronicChronic HepatitisHepatitis BB statesstates

nFollowFollow--upup ofof InactiveInactive CarrierCarrier statestate n Repeat ALT every 3 months x 1 year; then every 6-12 months. After age 40, add HBV-DNA every year. n If ALT elevates > ULN and HBV-DNA remains low: investigate cause & consider liver Bx n If ALT elevates > ULN & HBV-DNA increases to > 20000 IU/mL: treat n If ALT remains normal but HBV-DNA elevates > 2000 IU/mL: Liver Bx if older than 40; otherwise observe (immunotolerant state). ChronicChronic HepatitisHepatitis BB statesstates

nImmunotolerantImmunotolerant statestate n Normal ALT (normal male < 30 U/L, normal female < 19 U/L) and – Wild-HBe(+) or Wild-HBe(-): HBV-DNA > 20000 IU/mL, – Mutant-HBe(-): HBV-DNA > 2000 IU/mL

– NOTE: Consider Liver Bx in older than 40 years & HBV- DNA > 2000 IU/mL (104 copies/mL), (May be immunoactive) ChronicChronic HepatitisHepatitis BB statesstates

nFollowFollow--upup ofof ImmunotolerantImmunotolerant statestate n ALT every 3-6 months n If ALT elevates > ULN & HBV-DNA still > 20000 IU/mL: consider liver Bx and/or treat n If person is or reaches age =/> 40: consider liver Bx to decide about treatment ChronicChronic HepatitisHepatitis BB statesstates

nImmunoactiveImmunoactive statestate n Elevated ALT (male > 30 U/L, female > 19 U/L) – Wild-HBe(+) or Wild-HBe(-): HBV-DNA > 20000 IU/mL – Mutant-HBe(-): HBV-DNA > 2000 IU/mL n Treat

ChronicChronic HepatitisHepatitis BB TreatmentTreatment CandidatesCandidates

n HBsAg(+)HBsAg(+) >> 66 months,months, and:and: a)a) HBVHBV--DNADNA >> 20,00020,000 IU/mLIU/mL inin HBe(+),HBe(+), oror b)b) HBVHBV--DNADNA >> 2,000/mL2,000/mL inin mutantmutant HBe(HBe(--)) – with ALT > ULN, or – with moderate or severe activity in liver biopsy c)c) CirrhoticCirrhotic withwith HBVHBV--DNADNA >> 20002000 IU/mLIU/mL (independently(independently ofof ALTALT value)value) ChronicChronic HepatitisHepatitis BB TreatmentTreatment OptionsOptions n Interferon: if non-cirrhotic, and ALT > 2 x ULN, and HBV- DNA < 12 x 106 IU/mL n Peg-IFN: if non-cirrhotic, and HBV-DNA < 3.6 x 109 IU/mL, with any abnormal ALT n Entecavir or Tenofovir : if not candidate for interferon or not interested on interferon, but candidate for treatment. n In Patients with HIV co-infection: Only use Peg-IFN, or Adefovir, unless the anti-HBV drug is being use as part of HAART. n InIn Pregnancy:Pregnancy: inin thethe followingfollowing orderorder – Tenofovir (category B & conditionally safe for lactation depending on dose or patient-group). – Telbivudine (category B & possibly unsafe for lactation). – Lamivudine (category C & unsafe for lactation) ChronicChronic HBVHBV GoalsGoals ofof TherapyTherapy nnIdealIdeal:: –– ClearClear HBsAgHBsAg andand curecure disease;disease; (infrequently(infrequently reached).reached). ChronicChronic HBVHBV GoalsGoals ofof TherapyTherapy n PracticalPractical:: – HBe(+): Convert to “inactive carrier state” with: » HBV-DNA < 20,000 IU/mL and » sero-conversion to HBe(-)/anti-HBe(+); » ideally < 60 IU/mL (complete response) – Mutant-HBe(-): Convert to “inactive carrier state” with: » HBV-DNA < 2,000 IU/mL » ideally < 60 IU/mL (complete response) – Cirrhotic: Convert to: » HBV-DNA < 2,000 IU/mL » ideally < 60 IU/mL (complete response) ChronicChronic HBVHBV TherapyTherapy PointsPoints toto KeepKeep inin MindMind

n SustainedSustained lossloss ofof HBeAgHBeAg requiresrequires toto continuecontinue Adefovir,Adefovir, Entecavir,Entecavir, oror TenofovirTenofovir forfor atat leastleast 66 monthsmonths afterafter lossloss ofof HBeAg.HBeAg. n LongLong therapytherapy withwith oraloral agentsagents increasesincreases frequencyfrequency ofof drugdrug--resistance.resistance. n IfIf patientspatients werewere HBe(HBe(--)) prepre--treatment,treatment, therapytherapy willwill bebe lifelife--long.long. DefinitionsDefinitions && ManagementManagement forfor TreatmentTreatment withwith OralOral AntiviralsAntivirals n PrimaryPrimary nonnon--responseresponse:: dropdrop ofof HBVHBV--DNADNA << 11 loglog afterafter 1212 wkswks ofof therapytherapy – Check for viral resistance (INNO-Lipa HBV DR v2). May be compliance issue, or host pharmacologic effect. – Change or add second drug without cross-resistance. n PartialPartial ResponseResponse:: HBVHBV--DNADNA >> 20002000 IU/mLIU/mL afterafter 2424 weeksweeks ofof therapy.therapy. – Predicts high risk for resistance. (Resistance risk is low if HBV-DNA is < 200 IU/mL). – Change or add second drug without cross-resistance. DefinitionsDefinitions forfor TreatmentTreatment withwith OralOral AntiviralsAntivirals n Breakthrough: a) Increase of HBV-DNA > 1 log from nadir, at any time, b) Reappearance of HBV-DNA(+) after 2 negative HBV- DNA, at least 1 month apart. – Check for viral resistance (INNO-Lipa HBV DR v2). May be compliance problem. – Change or add second drug without cross-resistance. n Complete Response: – HBV-DNA < 60 IU/mL n Commercial Test for Drug Resistance: – Inno-LiPA HBV DR v2 (Lamivudine, Telbuvidine, Emtricitabine and Adefovir) DrugDrug CrossCross--ResistanceResistance ProfileProfile (reverse transcriptase ) Zoulim F et al. J of Hepatology 2008;48: S2-S19

Lamivudine Telbivudine Entecavir Adefovir Tenofovir

Wild SSSSS

M204I RRRS S

L180M + M204V RR I S S

A181T/V ISSRS

N236T SSSRI

I169T + V173L + RRRS S M250V T184G + S202I/G RRRS S

I233V Resistance ?

A194T Resistance ? TreatmentTreatment OptionsOptions forfor AntiviralAntiviral ResistanceResistance

Resistance to Rescue Therapy

Lamivudine or Add: Adefovir, or Tenofovir, or Telbivudine Switch to: Tenofovir + Emtricitabine (Truvada) Adefovir Add: Lamivudine, or Entecavir, or Switch to: Tenofovir + Emtricitabine (Truvada) Entecavir Add: Adefovir, or Tenofovir

Multidrug ? ReactivationReactivation ofof HBVHBV byby ImmunosuppressionImmunosuppression n GroupsGroups atat Risk:Risk: HBsAg(+)HBsAg(+) oror antianti--HBc(+)HBc(+) n CommonCommon Causes:Causes: Rituximab,Rituximab, Alemtuzumab,Alemtuzumab, Infliximab,Infliximab, liverliver transplant,transplant, hematologicalhematological malignancies,malignancies, HIVHIV infection,infection, stemstem cellcell transplantation,transplantation, chemotherapy,chemotherapy, kidneykidney oror heartheart transplantation.transplantation. n Recommendation:Recommendation: TestTest allall patientspatients forfor HBsAgHBsAg && antianti--HBcHBc beforebefore immunosuppression.immunosuppression. PreventionPrevention ofof HBVHBV ReactivationReactivation byby ImmunosuppressionImmunosuppression HepatocellularHepatocellular CarcinomaCarcinoma RecommendedRecommended SurveillanceSurveillance GroupsGroups (Risk(Risk >> 1.5%1.5% // year)year) nHepatitisHepatitis BB nOtherOther CirrhosisCirrhosis n All HBV cirrhotics n Hepatitis C (F3 ?) n Africans > 20 y.o. n Alcoholic n 1st degree w HCC & > 20 n Genetic Hemochromatosis y.o. n Primary Biliary Cirrhosis n Asian males > 40 y.o. n +/- Alpha-1 antitrypsin n Asian females > 50 y.o. n +/- NASH n Caucasians w. high HBV- n +/- Autoimmune hepatitis DNA / activity & > 40 y.o. SurveillanceSurveillance TestTest n SEROLOGYSEROLOGY n ULTRASOUNDULTRASOUND n AFP should be used only n Method of choice. if U/S is not available – Sensitivity: 65-80% n AFP > 20 ng/mL: – Specificity > 90% sens=60%, PPV=41% n False (+) Rate: n AFP > 200 ng/mL: – U/S=2.9%; sens=22%, PPV=60% – AFP=5%; – AFP+U/S=7.5% n Des-gamma-carboxy n Classic is hypoechoic; can prothrombin (PIVKA II), be isoechoic w halo, AFP L3 fraction, Alpha hyperechoic, or mixed. fucosidase, Glypican 3 n Interval: 6-12 months n Positive Result: nodule > 1 cm ChronicChronic HepatitisHepatitis B+DB+D nUncommonUncommon inin USAUSA n[HBsAg(+)[HBsAg(+) && increasedincreased liverliver enzymesenzymes >> 66 months]months] ++ [anti[anti--HDV(+)HDV(+) highhigh titerstiters oror HDAg(+)HDAg(+) inin liverliver biopsy]biopsy] nMoreMore aggressiveaggressive thanthan chronicchronic HBVHBV nINFINFαα 33--1818 MUMU qdqd xx 11 yearyear (poor(poor success)success) nHepatocellularHepatocellular CaCa isis uncommonuncommon (early(early death)death) AlcoholicAlcoholic HepatitisHepatitis n AlcoholAlcohol forfor >> 55 yearsyears – > 40-60 g/d in men, – > 20-40 g/d in women n (12(12 ozoz beerbeer == 1.51.5 ozoz liquorliquor == 55 ozoz winewine == 13.3g)13.3g) n SuspectSuspect inin AST/ALTAST/ALT >1>1 andand ASTAST <280<280 n PrognosisPrognosis byby DiscriminantDiscriminant FunctionFunction == 4.6(PT4.6(PT sec)sec) ++ T.T. BiliBili mg/dLmg/dL – Mortality at 3 months: » DF <55 = 4%, » DF 55-89 = 20%, » DF >90 = 66% GlasgowGlasgow AlcoholicAlcoholic HepatitisHepatitis ScoreScore GUT 2005;54:1174-1179

POINTSPOINTS 11 22 33 AgeAge << 5050 >> 5050 WBCWBC countcount << 1515 >> 1515 BUNBUN << 1414 >> 1414 INRINR << 1.51.5 1.51.5 -- 22 >> 22 T.T. BiliBili << 7.357.35 7.357.35 –– 14.714.7 >> 14.714.7

Minimum = 5; Maximum = 12 points SurvivalSurvival byby GAHSGAHS

100 100

90 90

80 80

70 70

60 60

50 W-4 durvival 50 W-4 s urvival W-12 survival W-12 survival 40 40

30 30

20 20

10 10

0 0 56789101112 56789101112

Day 1 score Day 7 score Prediction of 90-day mortality in patients with AH based on MELD. The curve demonstrates probability of 90-day mortality in AH for given MELD (black line) with confidence intervals (gray shading).

HEPATOLOGY 2005;41:353-358

http://www.mayoclinic.org/meld/mayomodel7.html

MELD was calculated using the following formula: MELD9.57loge (Cr mg/dL)3.78loge (bili mg/dL)11.20loge (INR)6.43.16 AlcoholicAlcoholic HepatitisHepatitis n Diagnosis:Diagnosis: ClinicalClinical picturepicture && history,history, oror LiverLiver Bx.Bx. – Acetaminophen therapeutic misadventure - Hepatic necrosis with regular doses (2-4 gm/d) n Treatment:Treatment: – 1) Abstinence, – 2) Aggressive nutrition (35-40 kcal/kg and 1.2 to 1.5 g/kg of protein (>2100 k-cal/d) po, or tube feed) – 3) Pentoxyphilline 400 mg TID (decreases HRS) – 4) For DF > 90 + encephalopathy: Prednisolone x 30 d (without infection nor GI bleed) +/- NAC, or Pentoxyphilline. NonNon--AlcoholicAlcoholic SteatoSteato--HepatitisHepatitis n PrevalencePrevalence:: 2.12.1--3%3% n DemographicsDemographics:: - mean age 50-55, - female/male:2/1, - diabetes 66%, - obesity 66%, - hyperlipidemia 55% - BMI: USA (F:25, M:30); Asia (F:23, M:25) - Waist Circumference (cm):USA (F:88, M:102); Asia (F:80, M:90) n PredictorsPredictors ofof progressionprogression (2(2 oror moremore ofof ):): – Obesity, – Type II DM, – Age > 45, – Elevated ALT, with AST > ALT NonNon--AlcoholicAlcoholic SteatoSteato--HepatitisHepatitis n Symptoms: – usually asymptomatic; – may have RUQ discomfort, fatigue, hepatomegaly, elevated ALT > AST. n Diagnosis: – Bx with [steatosis + ballooning], or [steatosis + fibrosis] or [Mallory bodies] n Mortality: – 11% at 10 years. – Elevated risk of HCC. n Treatment: – weight control, and “tight control” of DM and hyperlipidemia. – Vitamin E 800 IU/d – Pentoxyphilline 400 mg po TID AutoAuto--ImmuneImmune HepatitisHepatitis n Diagnosis: – Compatible liver biopsy +

– autoantibody (ANA, ASMA, anti-LKM1, LC1, pANCA (pANNA), anti- SLA, anti-ASGPR, anti-LKM3, anti-LKM2, anti-LM) positive or hypergammaglobulinemia (IgG dominant) + – No other cause n More common in women (3.6/1); incidence 1-2/100,000; point prevalence 11-17/100,000 n Frequent auto-immune disorders n Type I: ANA/ASMA(+). Most common (80%). – Females 10-20 or 45-70 yo. – Acute onset in 40%. Cirrhosis in 25% at Dx. – Common assoc: UC, autoimmune thyroiditis, synovitis, & RA. – Very steroid responsive AutoAuto--ImmuneImmune HepatitisHepatitis (contd.)(contd.)

n Type II: anti-LKM1(+) or anti-LC1(+); 4% of AIH; Girls 2-14 yo; – Common associations: IDDM, thyroid disease, vitiligo, APECED » Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy : is anti-LM(+) with mutation in chrom 21q22.3 – Steroid responsive +/- n Prognostic Ab & HLA: – a) Relapse: anti-SLA, anti-chromatin.

– b) Severity: anti-actin, anti-LC1, HLA-DR3 n Concurrent PSC: should be investigated by MRCP in: – Adults with no-response or poor response to therapy. – All adults with AIH + IBD – All children with AIH RevisedRevised AIHAIH ScoreScore (1(1 ofof 2)2)

Gender Female +3

Alk Ph/AST ratio >3 -2 < 1.5 +2 IgG or gamma-glob above Normal > 2 +3 1.5-2 +3 1-1.5 +1 ANA, ASMA, or anti-LKM1 titer > 1:80 +3 1:80 +2 1:40 +1 < 1:40 0 AMA Positive -4

Viral markers Positive -3 Negative +3 Drugs Yes -4 No +1 Alcohol < 25 g/day +2 > 60 g/day -2 RevisedRevised AIHAIH ScoreScore (2(2 ofof 2)2)

HLA DR3 or DR4 +1

Immune disease Thyroiditis, colitis, other +2

Other auto-Ab Anti-SLA, anti-actin, anti-LC1, pANCA +2

Histology Interface hepatitis +3 Plasmacytic infiltrate +1 Rosettes +1 None of above -5 Biliary changes -3 Other feature -3 Treatment response Complete +2 Relapse +3 Pre-Treatment Aggregate Score > 15 Definite Diagnosis 10-15 Probable Diagnosis Post-Treatment Aggregate Score > 17 Definite Diagnosis 12-17 Probable diagnosis AutoAuto--ImmuneImmune HepatitisHepatitis SimplifiedSimplified ScoringScoring

Variable Result Points ANA or ASMA >/= 1:40 +1* >/= 1:80 +2* Anti-LKM1 >/= 1:40 +2* Anti-SLA + +2* Immunoglobulins level > ULN +1 > 1.1 ULN +2 Histology Compatible +1 Typical +2 Viral hepatitis markers Absent +2 DEFINITIVE AIH >/= 7 PROBABLE AIH 6 * Maximal 2 Points Total from auto-antibodies AutoAuto--ImmuneImmune HepatitisHepatitis (contd.)(contd.) n Treatment: Prednisone + Azathioprine, or Budosenide + Azathioprine for years or life Prolongs survival. With “excellent control”, fibrosis may decrease over time. n Drug Schedule: – Vaccinate against Hep A&B; check TPMT activity – Wk 1: Pred 60, or Imuran 50 (1-2/kg) + Pred 30 – Wk 2: Pred 40, or Imuran 50 (1-5/kg) + Pred 20 – Wk 3: Pred 30, or Imuran 50 (1-2/kg) + Pred 15 – Wk 4: Pred 30, or Imuran 50 (1-2/kg) + Pred 15 – Maintenance: Pred

– 13% of AIH in Caucasians lack ANA, ASMA, and anti-LKM1 – Some have anti-SLA, anti-pANCA (atypical). – AMA(+) in 8-35% but without bile duct injury (no overlap) – They behave and respond to therapy as classic AIH AutoAuto--ImmuneImmune HepatitisHepatitis SpecialSpecial GroupsGroups n AIHAIH withwith cholangiographiccholangiographic changeschanges – MRCP resembling PSC in 8% of adults; true PSC in only 2%. – Those with PSC like changes without IBD behave like classic AIH. – Those with IBD may have true PSC and are frequently steroid refractory. n AIHAIH inin malesmales – Have less concurrent immune diseases. – Have better survival. – Management is the same. AutoAuto--ImmuneImmune HepatitisHepatitis SpecialSpecial GroupsGroups n AIHAIH inin nonnon--CaucasiansCaucasians – Blacks have more cirrhosis at Dx (85% vs 38%) – South Americans are younger, with severe hepatitis. – Japanese have milder disease with late onset. – Alaskans have more acute icteric disease and severe fibrosis. – Native Americans have more cholestasis, advanced fibrosis, and autoimmune disorders. – Africans, Asians and Arabs have more bile damage in liver biopsy. – Management is the same. HemochromatosisHemochromatosis n Autosomic recessive. n High intestinal Fe absorption. n Fasting morning transf sat >45% & high n Metocarpophalangeal arthritis, male impotence, DM, cardiomyopathy/ arrhythmia, bronze skin n Diagnosis: – 1) Hepatic Index (µmol/g ÷ age) > 1.9 – 2) Phlebotomy 1 unit q 1 week for > 20 g Fe after age 40, or > 10 gm for age 20-40, before Fe deficiency (250 mg Fe / phlebotomy unit) – 3) HFE C282Y homozygote; C282Y/H63D + (1) or (2) HemochromatosisHemochromatosis nLiverLiver BxBx needed:needed: –– a)a) AgeAge >> 39,39, –– b)b) FerritinFerritin >> 10001000 ng/mL,ng/mL, –– c)c) ElevatedElevated ALTALT oror ASTAST nTreatment:Treatment: phlebotomyphlebotomy 11 unitunit qq 11 weekweek untiluntil FeFe deficientdeficient (ferritin(ferritin << 50);50); avoidavoid vitvit CC NonNon--HFEHFE HemochromatosisHemochromatosis && OtherOther PrimaryPrimary FeFe--OverloadOverload n NonNon--HFEHFE HEMOCHROMATOSISHEMOCHROMATOSIS – RECEPTOR-2 Mutation (TfR2) » Autosomal recessive. » TfR2 is regulator of Hepcidin. Low hepcidin causes increased Fe influx. » High Transferrin sat in 2nd-3rd decade. » Onset 1-2 decade before HHC (2nd to 4th). » Mild to severe Liver Fe overload (periportal hepatocytes). Hypochromic anemia. » May cause cirrhosis. NonNon--HFEHFE HemochromatosisHemochromatosis && OtherOther PrimaryPrimary FeFe--OverloadOverload n Non-HFE HEMOCHROMATOSIS – HEPCIDIN ANTIMICROBIAL PEPTIDE (HAMP/19q13.1) Mutation & HEMOJUVELIN (HJV) Mutation » Autosomal recessive. » HJV is regulator of Hepcidin. Very low hepcidin causes massive Fe influx. » High Ferritin & Transferrin sat in 1st decade. » Hypogonadism before end of 2nd decade, cardiac disease & abdominal pain. » Cirrhosis is later occurrence (massive hepatocyte Fe). » Death on 3rd decade from heart failure. NonNon--HFEHFE HemochromatosisHemochromatosis && OtherOther PrimaryPrimary FeFe--OverloadOverload n FERROPORTINFERROPORTIN DISEASEDISEASE – Autosomal dominant. Worldwide distribution. – Decreased Fe efflux. – High Ferritin in 1st decade. – Fe deposit in RES with very high Ferritin but low or normal transferrin saturation; high saturation late in life. – Mild hypochromic anemia. – Mild liver injury with sinusoidal fibrosis. – Treatment: Phlebotomy q 2-3 weeks (not weekly) NonNon--HFEHFE HemochromatosisHemochromatosis && OtherOther PrimaryPrimary FeFe--OverloadOverload n – Autosomal recessive. – Decreased Fe efflux. – Lack of ceruloplasmin, who has ferroxidase activity needed to release Fe from cells, causes deposit in: » basal ganglia& dentate nucleus giving ataxia and dementia; in » pancreas, causing diabetes, and in » RES giving hypochromic microcytic anemia. – Liver disease is mild. – Treatment: Chelation, Exjade® (deferasirox) & desferoxamine NonNon--HFEHFE HemochromatosisHemochromatosis && OtherOther PrimaryPrimary FeFe--OverloadOverload n /ATRANSFERRINEMIA/ HYPOTRANSFERRINEMIAHYPOTRANSFERRINEMIA – Autosomal recessive. – Increased Fe influx. – Severe anemia – Onset in 1st & 2nd decade n HH--FERRITINFERRITIN ASSOCIATEDASSOCIATED HEREDITARYHEREDITARY FeFe--OverloadOverload – Autosomal dominant. – Increased Fe influx. – Liver Fe overload in 4th-5th decade αα11--antitrypsinantitrypsin StorageStorage DiseaseDisease n PhenotypePhenotype PiPi ZZZZ (Mmalton,(Mmalton, Mduarte,Mduarte, MZ,MZ, SZ,SZ, andand MSMS maymay worsenworsen otherother typestypes ofof liverliver disease).disease). n LowLow serumserum αα1 antitrypsinantitrypsin (low(low normalnormal inin acuteacute illness)illness) n HxHx:: neonatalneonatal oror childhoodchildhood hepatitis/jaundicehepatitis/jaundice n FamilyFamily hxhx emphysemaemphysema atat << 4040 yearsyears inin smokers,smokers, andand atat ageage << 6060 withoutwithout tobacco.tobacco. n TreatmentTreatment:: – liver transplant for end stage liver disease – Carbamazepine ? (increases autophagy) WilsonWilson’’ss DiseaseDisease n AutosomalAutosomal recesive.recesive. n MutationMutation inin ATP7BATP7B (chr(chr 13)13) oror WNDWND genegene – encodes metal-transporting P-type ATPase in hepatocytes, causing decreased hepatocyte excretion of Cu in bile, causing systemic Cu accumulation. n Prevalence:Prevalence: 3030 perper million.million. n Presentations:Presentations: – Neuro-psychiatric disorder + increased liver enzymes (any age) – Increased liver enzymes in < 55 years of age, or – Coombs(-) hemolysis in < 55 years of age WilsonWilson’’ss DiseaseDisease n Liver (42%): Hepatomegaly, Splenomegaly, elevated ALT or AST, fatty liver, acute hepatitis, AI-like hepatitis, cirrhosis, FHF n Neuro (34%): movement disorder, dysarthria, dystonia, pseudobulbar palsy, seizures, migraine, drooling, dysautonomia, insomnia n Psych (10%): depression, neuroses, personality change, psychosis. n Other (14%): Fanconi S., kidney stones, hemolysis, osteoporosis, cardiomyopathy, dysrhythmia, pancreatitis, hypoparathyroidism, menstrual irregularity, miscarriages, infertility, lunulae ceruleae. WilsonWilson’’ss DiseaseDisease n Most have low or low-normal ceruloplasmin and increased 24 h urine ; low alkaline phosphatase & uric acid. – Low ceruloplasmin due to failure to incorporate Cu into ceruloplasmin, forming apoceruloplasmin which has a reduced half-life. n Ceruloplasmin is elevated by acute inflammation and estrogens. Normal ceruloplasmin do not exclude WD. n Ceruloplasmin < 5 mg/dL strongly suggest WD. n Tests: ceruloplasmin, MRI of brain (basal ganglia hyperintensity in T2), slit-lamp exam for K-F rings, 24 h urine for copper; Liver Bx with Cu quant. WilsonWilson’’ss DiseaseDisease

n Diagnosis:Diagnosis: considerconsider diagnosisdiagnosis inin agesages 33 toto 55.55. – 1) Low ceruloplasmin + K-F Rings; – 2) Hepatic copper > 250 µg/g dry weight (1-2 cm core) in absence of chronic cholestasis + consistent histology – 3) 24 hour urine Cu > 40 mcg/day – 4) Direct mutation analysis (whole- sequencing), or studies based in “proband” mutant, for ATP7B mutation. AlgorithmAlgorithm forfor DiagnosisDiagnosis ofof WilsonWilson disease:disease: UnexplainedUnexplained LiverLiver DiseaseDisease

Hepatology Volume 47, Issue 6, pages 2089-2111, 4 FEB 2008 DOI: 10.1002/hep.22261 http://onlinelibrary.wiley.com/doi/10.1002/hep.22261/full#fig1 AlgorithmAlgorithm forfor DiagnosisDiagnosis ofof WilsonWilson disease:disease: NeuropsychiatricNeuropsychiatric DisorderDisorder +/+/-- LiverLiver DiseaseDisease

Hepatology Volume 47, Issue 6, pages 2089-2111, 4 FEB 2008 DOI: 10.1002/hep.22261 http://onlinelibrary.wiley.com/doi/10.1002/hep.22261/full#fig2 WilsonWilson’’ss DiseaseDisease n Treatment: – penicillamine 250 mg/ x 4d, then BID x 4 d, then 500 mg BID 1 hour before meals + Pyridoxine 50 mg /d or – Trientine 500 mg BID 1 hour before meals; – Zn (elemental) 50 mg TID (5 h away from chelators: 6am: Zn, 7am: BF, 11 am: chelator, noon: lunch, 5 pm: Zn, 6pm: dinner, 9 pm chelator)); – Tetrathiomolibdate. n In pregnancy, decrease chelator by 50% in 3rd trimester. No breastfeed if on penicillamine.. n Follow 24 h urine Cu (should be 200-500 mcg/d) and “free serum Cu” (> 15 mcg/dL = poor compliace; < 5 mcg/dL = overtreatment). In Zn therapy, 24h urine Cu < 75 mcg/d. n “Fulminant Hemolytic Wilson’s” needs urgent liver transplant DrugDrug--InducedInduced HepatitisHepatitis n DefinitiveDefinitive:: alphaalpha--methyldopa,methyldopa, nitrofurantoin,nitrofurantoin, DantroleneDantrolene sodium,sodium, oxyphenisatinoxyphenisatin n ProbableProbable:: IsoniazidIsoniazid n RareRare:: Clometacine,Clometacine, Acetaminophen,Acetaminophen, Halothane,Halothane, aspirin,aspirin, propylthiouracil,propylthiouracil, solfonamides,solfonamides, etretinate,etretinate, benzarone,benzarone, papaverine;papaverine; (almost(almost anyany drug)drug) n TreatmentTreatment:: discontinuediscontinue drug.drug. SometimesSometimes needneed steroidssteroids QuestionsQuestions ?? OverlapOverlap SyndromeSyndrome nAIH/PBC,AIH/PBC, AIH/PSCAIH/PSC nA)A) BxBx ofof chronicchronic hepatitishepatitis ANA/ASMA(ANA/ASMA(--)) && AMA(+);AMA(+); B)B) BxBx ofof PBCPBC AMA(AMA(--)) withwith ANAANA oror ASMA(+);ASMA(+); C)C) AIHAIH withwith PSCPSC onon cholangiogramcholangiogram n LookLook for:for: antianti--piruvatepiruvate dehydrogenasedehydrogenase--EE2,, dominantdominant immunoglobulinimmunoglobulin (IgG(IgG vsvs IgM),IgM), responseresponse toto corticosteroidscorticosteroids withwith repeatrepeat liverliver bxbx atat 33--66 monthsmonths AscitesAscites n PhysicalPhysical examexam unreliableunreliable -- U/SU/S n EdemaEdema andand hydrothoraxhydrothorax areare commoncommon n SerumSerum--ascitesascites albuminalbumin gradientgradient (SAAG)(SAAG) n SAAG>1.1SAAG>1.1 g/dlg/dl -- portalportal hypertensionhypertension n SAAG<1.1SAAG<1.1 g/dlg/dl -- peritonealperitoneal diseasedisease (TB,(TB, Ca,Ca, pancreatitis,pancreatitis, etc.)etc.) n DXDX paracentesis:paracentesis: newnew onset,onset, everyevery admission,admission, postpost-- GIGI bleed,bleed, changechange inin conditioncondition (pain,(pain, fever,fever, encephalopathy,encephalopathy, etc.)etc.) AscitesAscites (contd.)(contd.) n NeededNeeded tests:tests: cellcell countcount ++ diff,diff, T.T. protein,protein, albumin,albumin, LDH,LDH, glucose,glucose, cultureculture inin ““bloodblood cultureculture”” bottlebottle n OptionalOptional tests:tests: T.T. bili,bili, amylase,amylase, triglycerides,triglycerides, cytology,cytology, AFB/fungusAFB/fungus stainstain andand cultureculture n Treatment:Treatment: – Na restriction + diuretics (monitor spot urine Na/K pre-diuretic) – Single large volume paracentesis (LVP) – Serial LVP + albumin – Total paracentesis + albumin – TIPSS or portocaval shunt SpontaneousSpontaneous BacterialBacterial PeritonitisPeritonitis n PMNPMN >>250/mm250/mm3 inin lowlow proteinprotein fluidfluid (<1.5(<1.5 g)g) n FrequentlyFrequently asymptomatic.asymptomatic. SometimesSometimes pain,pain, fever,fever, encephalopathyencephalopathy n UsuallyUsually enterobacteria:enterobacteria: E.coli,E.coli, KlebsiellaKlebsiella n HighHigh mortalitymortality andand frequentfrequent recurrencerecurrence n HighHigh LDH,LDH, highhigh protein,protein, lowlow glucoseglucose oror multiplemultiple micromicro--organismsorganisms suggestsuggest secondarysecondary peritonitisperitonitis n Treatment:Treatment: CefotaximeCefotaxime 22 gg IVIV q8hq8h xx 55 daysdays ++ albuminalbumin IVIV @@ DxDx && 72h72h later;later; repeatrepeat paracentesisparacentesis 4848 hh afterafter initiationinitiation ofof therapytherapy (>50%(>50% decreasedecrease inin PMN)PMN) SBPSBP && HRSHRS (Sort et al NEJM 1999;341:403-409) n POORPOOR PROGNOSISPROGNOSIS n ALBUMINALBUMIN inin SBPSBP n CreatinineCreatinine > 2.1 mg/dl n Prosp.& Random n HRSHRS n SBP: >250 PMN/mm3 n Albumin < 2.5 mg/dl n Creatinine < 3 mg/dl n Bilirubin > 8 mg/dl n 63 Pts.: Cefotaxime n PSE n 63 Pts.: Cefotaxime + Albumin 1.5gm/kg & 1 n UGI bleed Albumin 1.5gm/kg & 1 gm/kg 3 days later SBPSBP && HRSHRS (Sort et al. NEJM 1999;341:404-409) n RenalRenal impairment:impairment: a)a) >50%>50% incr.incr. BUNBUN oror 35 CrCr ifif basebase CrCr >1.5>1.5 30 25 b)b) >50%>50% incr.incr. toto 20 Albumin % Cr>1.5Cr>1.5 oror BUN>30BUN>30 ifif 15 No- basebase CrCr <1.5<1.5 10 Albumin 5 0 Renal Mortality Imp VaricealVariceal BleedingBleeding nFirstFirst bleedingbleeding decreaseddecreased byby ββ blockers.blockers. NoNo mortalitymortality changechange nAcuteAcute bleedingbleeding controlledcontrolled withwith banding.banding. AdjuvantAdjuvant OctreotideOctreotide ++ QuinoloneQuinolone xx 77 days.days. nRebleedingRebleeding decreaseddecreased byby ββ blockersblockers oror chronicchronic sclerotherapy/banding.sclerotherapy/banding. NoNo changechange inin mortalitymortality nLiverLiver TransplantTransplant RiskRisk FactorsFactors FailureFailure toto ControlControl AcuteAcute HemorrhageHemorrhage

70 n SpurtingSpurting varixvarix 60 n ChildChild--PughPugh CC 50 40 n HVPG PortalPortal veinvein thrombosisthrombosis <20 30 n InfectionInfection HVPG 20 >20 n HVPGHVPG >> 2020 mmmm HgHg 10

0 Continued Early Mortality Bleed Rebleed

Gastrenterology 1999;117(3):626-31 RiskRisk FactorsFactors RebleedingRebleeding inin << 66 weeksweeks nAgeAge >> 6060 nAscitesAscites nActiveActive bleedingbleeding atat EndoscopyEndoscopy nRedRed--colorcolor signssigns nPlateletPlatelet plugplug onon varixvarix nRenalRenal FailureFailure nSevereSevere InitialInitial BleedBleed (Hb(Hb << 88 g/dL)g/dL) nHVPGHVPG >> 2020 mmmm HgHg RiskRisk FactorsFactors RebleedingRebleeding inin >> 66 weeksweeks nSeveritySeverity ofof LiverLiver FailureFailure nAscitesAscites nHepatomaHepatoma nRedRed--colorcolor signssigns nActiveActive AlcoholAlcohol abuseabuse EffectEffect ofof AntibioticAntibiotic ProphylaxisProphylaxis onon RebleedingRebleeding raterate afterafter EndoscopicEndoscopic treatmenttreatment ofof VaricealVariceal bleedbleed (283)(283) n Prospective,Prospective, randomized.randomized. n 9191 cirrhoticcirrhotic patientspatients withwith varicealvariceal bleedbleed receivingreceiving endoscopicendoscopic treatmenttreatment n Outcome:Outcome: raterate ofof rebleedingrebleeding andand infectioninfection n Intervention:Intervention: OfloxacinOfloxacin 200mg200mg BIDxBIDx 7d7d vsvs antibioticantibiotic forfor infectioninfection (46(46 vsvs 45)45) n NoNo differencedifference on:on: age,age, sex,sex, etiology,etiology, endoscopicendoscopic finding,finding, timetime toto EGD,EGD, hepatoma,hepatoma, severityseverity ofof bleed.bleed. ResultsResults (%)(%)

50 n CONCLUSIONCONCLUSION 45 40 35 n ProphylacticProphylactic 30 Ofloxacin 25 antibioticsantibiotics inin varicealvariceal 20 On bleedbleed decreasedecrease demand 15 rebleedingrebleeding raterate andand 10 transfusiontransfusion needsneeds (0.7(0.7 5 0 vsvs 2.72.7 Units)Units) Infection Rebleed RiskRisk ofof InfectionInfection CirrhoticCirrhotic withwith GastrointestinalGastrointestinal HemorrhageHemorrhage n RiskRisk ofof Infection:Infection: 60%60% n AcquisitionAcquisition timetime:: –– A)A) 20%20% beforebefore oror atat timetime ofof admission,admission, –– B)B) 40%40% afterafter hospitalhospital admission.admission. n TypesTypes ofof InfectionInfection:: –– UTIUTI (20(20--25%),25%), -- SBPSBP (15(15--20%),20%), –– RespiratoryRespiratory (8%),(8%), -- BacteremiaBacteremia (8%).(8%). RiskRisk ofof InfectionInfection CirrhoticCirrhotic withwith GastrointestinalGastrointestinal HemorrhageHemorrhage n ProphylacticProphylactic antibioticsantibiotics:: –– DecreasesDecreases mortalitymortality byby 25%25% (RR 0.75) ,, –– ReducesReduces infectioninfection riskrisk byby 60%60% (RR 0.4) –– DecreaseDecrease rebleedingrebleeding raterate byby 56%56% (RR 0.44) –– DecreasesDecreases TransfusionTransfusion needsneeds (2.7 vs 0.7 units) n RegimensRegimens:: 77 toto 1010 daysdays ofof –– A)A) OfloxacinOfloxacin 200200 mgmg BID,BID, –– B)B) NorfloxacinNorfloxacin 400400 mgmg BID,BID, –– C)C) CiprofloxacinCiprofloxacin 500500 mgmg BIDBID –– D)D) CeftriaxoneCeftriaxone 11 g/dg/d