Autoimmune Autoimmune HepatitisHepatitis

Case PresentationCase Presentation

► 54 yo woman with abnormal liver function 54 yo woman with abnormal liver function testtest 9 years ago patient with ele lfts9 years ago patient with ele lfts No complaintsNo complaints PMH: migraine headaches, arthritis, bilateral tubal PMH: migraine headaches, arthritis, bilateral tubal

ligation, repair of ganglion cystligation, repair of ganglion cyst Meds: Prempro, ImitrexMeds: Prempro, Imitrex SH: rare alcohol, no tobaccoSH: rare alcohol, no tobacco FH: no history of liver diseaseFH: no history of liver disease PE: weight 104 lbs, no stigmata of Chronic liver PE: weight 104 lbs, no stigmata of Chronic liver

diseasedisease

Laboratory DataLaboratory Data

ASTAST 214214

ALTALT 272272

Alk PhosAlk Phos 7474

Total BiliTotal Bili 0.60.6

Total ProteinTotal Protein 8.08.0

AlbAlb 3.03.0

ANAANA 1:12801:1280

ASMAASMA 1:801:80

AMAAMA --

Viral SerologiesViral Serologies --

FerritinFerritin 7575

Other DataOther Data

►Sono: 3 mm CBD, normal gallbladder, Sono: 3 mm CBD, normal gallbladder, increase echogeneity c/w fatty liverincrease echogeneity c/w fatty liver

►Liver Biopsy: moderate piecemeal Liver Biopsy: moderate piecemeal necrosis with early fibrosis, expanded necrosis with early fibrosis, expanded portal tracts with plasma cellsportal tracts with plasma cells

►DX: Autoimmune HepatitisDX: Autoimmune Hepatitis►RX: Steroids and ImuranRX: Steroids and Imuran

DefinitionDefinition

►Self perpetuating hepatocellular Self perpetuating hepatocellular inflammation of unknown causeinflammation of unknown cause

►Characterized by the presence of:Characterized by the presence of: periportal hepatitisperiportal hepatitis HypergammaglobulinemiaHypergammaglobulinemia Serum liver-associated autoantibodiesSerum liver-associated autoantibodies

►Exclusion of other chronic liver Exclusion of other chronic liver diseasesdiseases

EpidemiologyEpidemiology

►1.9 cases per 100,000 incidence of 1.9 cases per 100,000 incidence of Autoimmune Hepatitis in western EuropeAutoimmune Hepatitis in western Europe

►Frequency of AIH among patients with Frequency of AIH among patients with chronic liver disease is 11%chronic liver disease is 11%

►Accounts for 5.9% of transplantations in Accounts for 5.9% of transplantations in the USthe US

Boberg K. 1998: Scad J Gastro;33:99-103

BackgroundBackground

►40% of patients with untreated severe 40% of patients with untreated severe disease die within 6 mos of dxdisease die within 6 mos of dx

►40% develop cirrhosis40% develop cirrhosis 54% develop esophageal varices54% develop esophageal varices

►20% die of hemorrhage20% die of hemorrhage

►An acute onset of illness is seen in An acute onset of illness is seen in 40% patients40% patients

►Prednisone and azathioprine are Prednisone and azathioprine are mainstay of treatmentmainstay of treatment

Clinical ManifestationsClinical Manifestations

►SymptomsSymptoms Fatigue 85%Fatigue 85% Jaundice 77%Jaundice 77% Abdominal pain 48%Abdominal pain 48% Pruritus 36%Pruritus 36% Anorexia 30%Anorexia 30% Polymyalgias 30%Polymyalgias 30% Diarrhea 28%Diarrhea 28% Fevers 18%Fevers 18%

Clinical ManifestationsClinical Manifestations

►Physical FindingsPhysical Findings Hepatomegaly 78%Hepatomegaly 78% Jaundice 69%Jaundice 69% Splenomegaly 32%Splenomegaly 32% Spider nevi 58%Spider nevi 58% Ascites 20%Ascites 20% Encephalopathy 14%Encephalopathy 14% Concurrent immune disease 48%Concurrent immune disease 48%

Clinical ManifestationsClinical Manifestations

►Laboratory featuresLaboratory features Elevated AST 100%Elevated AST 100% Hypergammaglobulinemia 92%Hypergammaglobulinemia 92% Inc immunoglobulin G level 91%Inc immunoglobulin G level 91% Hyperbilirubinemia 83%Hyperbilirubinemia 83% Alk Phos >2x 33%Alk Phos >2x 33%

Differential DiagnosisDifferential Diagnosis

►Wilson’s diseaseWilson’s disease►A1AT deficiencyA1AT deficiency►HemochromatosisHemochromatosis►Viral hepatitisViral hepatitis►Drug induced hepatitisDrug induced hepatitis

Liver HistologyLiver Histology

Autoimmune HistologyAutoimmune Histology

DiagnosisDiagnosis

Diagnostic CriteriaDiagnostic Criteria

►Clinical criteriaClinical criteria Presence of characteristic clinical featuresPresence of characteristic clinical features Liver histologyLiver histology Exclusion of other diseasesExclusion of other diseases

►Scoring criteriaScoring criteria Assess the strength of the diagnosisAssess the strength of the diagnosis Pretreatment and post-treatmentPretreatment and post-treatment Helpful with variant or atypical forms of AIHHelpful with variant or atypical forms of AIH

Diagnostic Scoring System for Diagnostic Scoring System for Atypical Autoimmune HepatitisAtypical Autoimmune HepatitisCategoryCategory FactorFactor ScoreScore CategoryCategory FactorFactor ScoreScore

GenderGender femalefemale +2+2 Other immune Other immune Non-hepatic of Non-hepatic of immune natureimmune nature

+2+2

AP:ASTAP:AST >3>3

<1.5<1.5-2-2

+2+2autoabsautoabs Anti-SLA/Anti-SLA/

LP,actin,LC1LP,actin,LC1+2+2

globglob >2.0>2.0

1.5-2.01.5-2.0

1.0-1.51.0-1.5

<1.0<1.0

+3+3

+2+2

+1+1

00

histologyhistology Interface hepatitisInterface hepatitis

Plasma cellsPlasma cells

RosettesRosettes

None of aboveNone of above

+3+3

+1+1

+1+1

-5-5

ANA,SMA, LKM1ANA,SMA, LKM1 >1:80>1:80

1:801:80

1:401:40

<1:40<1:40

+3+3

+2+2

+1+1

00

HLAHLA DR3 or DR4DR3 or DR4 +1+1

AMAAMA positivepositive -4-4 Rx responseRx response Remission aloneRemission alone

Remission Remission w/relapsew/relapse

+2+2

+3+3

Viral markersViral markers PositivePositive

negativenegative-3-3

+3+3PretreatmentPretreatment

definite dxdefinite dx

probable dxprobable dx>15>15

10-1510-15

drugsdrugs YesYes

nono-4-4

+1+1Post-treatmentPost-treatment

definite dxdefinite dx

probable dxprobable dx>17>17

12-1712-17

alcoholalcohol <25 gm/d<25 gm/d

>60 gm/s>60 gm/s+2+2

-2-2

Subclassification of AIHSubclassification of AIH

►Type IType I

►Type IIType II

►Type IIIType III

Type 1 AIHType 1 AIH

►Diagnostic autoantibodies: ANA, ASMADiagnostic autoantibodies: ANA, ASMA►Age: Bidmodal (10-20 and 45-70)Age: Bidmodal (10-20 and 45-70)►% Women: 78% Women: 78►% Concurrent immune diseases: 41% Concurrent immune diseases: 41►Elevated gamma globulin: +++Elevated gamma globulin: +++►Steroid responsiveness: +++Steroid responsiveness: +++►Progression to cirrhosis (%): 45Progression to cirrhosis (%): 45

Type II AIHType II AIH

►Diagnostic autoantibodies: LKM1Diagnostic autoantibodies: LKM1►Age: Pediatric (2-14), rare adults (4%)Age: Pediatric (2-14), rare adults (4%)►% Women: 89% Women: 89►% Concurrent autoimmune disease: 34% Concurrent autoimmune disease: 34►Elevated gamma-globulins: +Elevated gamma-globulins: +►Steroids responsive: ++Steroids responsive: ++►% progression to cirrhosis: 82% progression to cirrhosis: 82

Type III AIHType III AIH

►Diagnostic autoantibodies: SLA and LPDiagnostic autoantibodies: SLA and LP►Age: adults (30-50)Age: adults (30-50)►% Women: 90% Women: 90►% Concurrent autoimmune disease: % Concurrent autoimmune disease:

5858►Elevated gamma-globulin: ++Elevated gamma-globulin: ++►Steroid responsive: +++Steroid responsive: +++►% progression to cirrhosis: 75% progression to cirrhosis: 75

Prognostic IndicesPrognostic Indices

► Laboratory findings at presentationLaboratory findings at presentation AST>10x nl: 50%, 3-year mortalityAST>10x nl: 50%, 3-year mortality AST>5x nl + GGT>2x; 90%, 10-yr mortalityAST>5x nl + GGT>2x; 90%, 10-yr mortality AST<10x nl + GGT<2x; 49%, cirrhosis at 15 yr; AST<10x nl + GGT<2x; 49%, cirrhosis at 15 yr;

10% 10-yr mortality10% 10-yr mortality► Histologic findings at presentationHistologic findings at presentation

Periportal hepatitis: 17%,cirrhosis at 5 yr; Nl 5 yr Periportal hepatitis: 17%,cirrhosis at 5 yr; Nl 5 yr survival survival

Bridging necrosis: 82%, cirrhosis of 5 yr; 45%, 5-Bridging necrosis: 82%, cirrhosis of 5 yr; 45%, 5-yr mortalityyr mortality

Cirrhosis: 58%, 5 yr-mortalityCirrhosis: 58%, 5 yr-mortality

RecommendationsRecommendations

►Diagnosis of AIH requires Diagnosis of AIH requires aminotransferase and globulin levels; aminotransferase and globulin levels; detection of ANA +/or SMA, anti-LKM1; detection of ANA +/or SMA, anti-LKM1; and histologyand histology

►Diagnostic criteria for AIH should be Diagnostic criteria for AIH should be applied to all patientsapplied to all patients

► If the diagnosis is not clear, a scoring If the diagnosis is not clear, a scoring method should be usedmethod should be used

TreatmentTreatment

Indications for TreatmentIndications for Treatment

AbsoluteAbsolute RelativeRelative

Serum AST>10x ulnSerum AST>10x uln Symptoms (fatigue, Symptoms (fatigue, arthralgia, jaundice)arthralgia, jaundice)

Serum AST>5x uln Serum AST>5x uln and globulin >2x nland globulin >2x nl

Serum AST and Serum AST and globulin less than globulin less than absolute criteriaabsolute criteria

Bridging necrosis or Bridging necrosis or multiacinar necrosismultiacinar necrosis

Interface hepatitisInterface hepatitis

Treatment RegimensTreatment Regimens

Prednisone Prednisone onlyonly

Combination Combination (Pred + AZA)(Pred + AZA)

Week 1Week 1 60 mg60 mg 30 mg+50 30 mg+50 mgmg

Week 2Week 2 40 mg40 mg 20 mg+50 20 mg+50 mgmg

Week 3Week 3 30 mg30 mg 15 mg+50 15 mg+50 mgmg

Week 4Week 4 30 mg30 mg 15 mg+50 15 mg+50 mgmg

Maintenance Maintenance until endpointuntil endpoint

20 mg20 mg 10mg+50 mg10mg+50 mg

Reasons for PreferenceReasons for Preference

► PrednisonePrednisone CytopeniaCytopenia TPMT deficiencyTPMT deficiency PregnancyPregnancy MalignancyMalignancy Short course <6 mosShort course <6 mos

► CombinationCombination Postmenopausal Postmenopausal

statestate OsteoporosisOsteoporosis Brittle diabetesBrittle diabetes ObesityObesity AcneAcne Emotional LabilityEmotional Lability HypertensionHypertension

Treatment EndpointsTreatment Endpoints

►RemissionRemission 10-40% of patients10-40% of patients

►Treatment FailureTreatment Failure► Incomplete ResponseIncomplete Response►Drug ToxicityDrug Toxicity

RemissionRemission

► CriteriaCriteria Disappearance of Disappearance of

symptomssymptoms Normal bilirubin + Normal bilirubin +

globulin levelsglobulin levels Transaminases Transaminases

normal or less than normal or less than 2x2x

Normal histology or Normal histology or minimal minimal inflammationinflammation

► ActionAction Gradual withdrawal Gradual withdrawal

of prednisone of prednisone Discontinuation of Discontinuation of

azathioprineazathioprine Regular monitoring Regular monitoring

for relapsefor relapse

Treatment FailureTreatment Failure

► CriteriaCriteria Worsening clinical, Worsening clinical,

labs and histology labs and histology despite compliancedespite compliance

Inc transaminasis by Inc transaminasis by 67%67%

Development of Development of jaundice, ascites or jaundice, ascites or hepatic hepatic encephalopathyencephalopathy

► ActionAction Pred 60 mg/d or pred Pred 60 mg/d or pred

30 mg/d with aza 30 mg/d with aza 150 mg/d x 1 mo150 mg/d x 1 mo

Reduction of the Reduction of the dose each month of dose each month of improvement until improvement until maintenance levelsmaintenance levels

Incomplete ResponseIncomplete Response

► CriteriaCriteria Some or no Some or no

improvement in improvement in clinical,labs and clinical,labs and histology during histology during therapytherapy

Failure to achieve Failure to achieve remission after 3 remission after 3 yearsyears

No worsening of No worsening of conditioncondition

► ActionAction Reduction of dose to Reduction of dose to

lowest levels lowest levels possible to prevent possible to prevent worseningworsening

Indefinite treatmentIndefinite treatment

Management of Relapse after Management of Relapse after Drug WithdrawalDrug Withdrawal

►Relapse at least twiceRelapse at least twice

Indefinite low dose prednisoneIndefinite low dose prednisone

Indefinite low dose azathioprineIndefinite low dose azathioprine

Management of Suboptimal Management of Suboptimal Response to Initial TherapyResponse to Initial Therapy

►Alternative medicationsAlternative medications Cyclosporine, 6MP, ursodeoxycholic acid, Cyclosporine, 6MP, ursodeoxycholic acid,

budesonide, methotrexate, budesonide, methotrexate, cyclophosphamide and mycophenolate cyclophosphamide and mycophenolate mofetilmofetil

►Liver TransplantationLiver Transplantation 5 year graft survival 83-92%5 year graft survival 83-92% Disease recurrence is mild and easily Disease recurrence is mild and easily

managedmanaged

Hepatocellular CarcinomaHepatocellular Carcinoma

►Uncommon in the absence of cirrhosis Uncommon in the absence of cirrhosis or coexisting hepatitis B or Cor coexisting hepatitis B or C

► If cirrhosisIf cirrhosis RUQ ultrasoundRUQ ultrasound Alfa fetoprotein every 6-12 monthsAlfa fetoprotein every 6-12 months

RecommendationsRecommendations

►High dose prednisone alone or High dose prednisone alone or prednisone and aza should be used in prednisone and aza should be used in treatment failurestreatment failures

►Corticosteroid therapy should be Corticosteroid therapy should be considered in the decompensated patientconsidered in the decompensated patient

►Liver transplantation should be Liver transplantation should be considered in the decompensated patient considered in the decompensated patient unable to undergo salvage therapyunable to undergo salvage therapy

Case PresentationCase Presentation

ASTAST 1919

ALTALT 1212

APAP 5454

Total protein/albuminTotal protein/albumin 7.3/4.67.3/4.6

Total bilirubinTotal bilirubin 0.60.6

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