CHAIRED BY : Dr. Raminderpal Singh Sibia PRESENTED BY : Dr. Rintu Sharma

Immunity

Case scenariosHISTORY AND CLINICAL FINDINGS:

Case 1: A 46-year old female patient presented with a recently occurred icterus of unknown origin as well as dark urine and decolored stool. No diseases were found in the patient's medical history. Clinical examination showed no other findings except from the icterus.

Case 2: A 48-year old female patient was admitted to hospital with epigastric pain and icterus. Similar symptoms reoccurred regularly since several years.

She reported chronic pain in her finger joints and appearance of haematomas without adequate trauma.

CLINICAL INVESTIGATIONS:Case 1: Highly elevated liver enzymes and bilirubin. Ultrasound examination was unremarkable. Negative serology for hepatitis A, B and C Marked immunoglobulin G (IgG) elevation and

hypergammaglobulinaemia. ANA and smooth muscle antibodies (SMA)+++ Case 2: reduced liver function with low albumin and prothrombin time moderate elevation of liver enzymes and a high bilirubin. Ultrasound examination revealed hepatic parenchymal

changes, splenomegaly, and ascites. Oesophagogastroduodenoscopy showed oesophageal varices I°. Serology for hepatitis A, B, and C was negative. a marked IgG elevation and hypergammaglobulinaemia Autoimmune antibodies (ANA and SMA)++

AUTOIMMUNE HEPATITISContinuing/unresolving hepatocellular

inflammation and necrosis of unknown etiology

Can progress to cirrhosisExclusion of other chronic liver diseasesCharacteristics include: presence of autoimmune antibodyevidence of hepatitis (interface being

characteristic)elevation of serum globulins

OTHER NAMESActive chronic hepatitis or chronic active

hepatitisChronic aggressive hepatitisLupoid hepatitisPlasma cell hepatitisAutoimmune chronic active hepatitis

BACKGROUNDFirst described in 1950’sAccounts for 5.6% of liver transplants in the

USAffects women more than men (3.6:1)If untreated approximately 40% die within 6

months40% develop cirrhosis

54% develop esophageal varices20% die of hemorrhage

EPIDEMIOLOGYIncidence: 1.9 cases per 100,000 persons per yrFrequency of AIH among patients with chronic

liver disease in North America is between 11%- 22%

Accounts for 5.6% of liver transplants in the USPrevalence greatest among northern European

white persons Japenese have a lower frequency

Scand J Gastroenterol1998;33:99.

PATHOGENESISUnknown mechanism but several proposed

mechanisms

Genetically predisposed individual with exposure

to an environmental agent triggers the

autoimmune pathogenic process

Genetic predisposing factors:

HLA-DR3: early onset, severe form

HLA-DR4: caucasian, late onset, better response to

steroids, higher incidence of extrahepatic manifestations

Triggering factorsInfections (HAV, HBV, HCV, HSV, EBV,

measles)?Medications (ABX, statins, NSAIDs etc.)?Toxins?Molecular mimicry?Recognition of antigen-MHC II complex by

uncommitted CD4 cells Cytokine release from TH1 and TH2 CD4 cells

IL-12 and IL-2: proliferation of CD8 cellsIL-4 and IL-10: proliferation of B cells

Evidence supporting autoimmune pathogenesis

Histopathological lesions composed of cytotoxic Tcells and plama cells

Circulating autoantibodiesHyperglobulinemiaOther autoimmune disorders: thyroiditis, RA ,

autoimmune hemolytic anemia, ulcerative colitis, membranoproliferative glomerulonephritis, diabetes mellitus, celiac disease, sjogren’s syndrome

Histocompatibility haplotypes assosciationsResponse to steroids and immunosuppression.

CLASSIFICATIONTYPE 1TYPE 2TYPE 3OVERLAP SYNDROMES

TYPE 1Classically in young femalesANA or Anti-Smooth Muscle

antibody positiveTiter usually > 1:10010% will have an antibody to

Soluble Liver antigens (SLA)Other Antibodies: anti-DNA,

pANCA, Anti-mitochondrial, Anti-Actin (AAA), cytoskeletal antibody, nuclear envelope proteins lamin A and C, plasma membrane sulfatides

Anti-actin antibodies have greater specificity

TYPE 1Bimodal Age distribution (ages 10-20 and 45-70)Female:male (3.6:1)HLA DR3 or DR4 assosciationAssociated with extrahepatic manifestations(38%):

Autoimmune thyroiditis, Graves disease, Chronic UCLess commonly with RA, pernicious anemia, systemic

sclerosis, ITP, SLE,coombs positive hemolytic anemia, leucocytoclastic vasculitis, erythema nodosum

40% present with acute onset of symptoms similar to toxic hepatitis or acute viral hepatitis

TYPE 2Seen in children (2-14 years)in

Meditteranean populationHLA DR1 or DQB1

assosciationPresence of anti-Liver/Kidney

Microsome Antibodies (anti- LKM1 )directed against cytochrome p450 2D6 {same as LKM seen in patients with chronic hepatitis C}

Anti-Liver Cytosol antibody (ALC-1)

Acute or fulminant presentation possible

TYPE 3 Antibodies to soluble liver

antigen / liver pancreas antigen

Lack ANA and anti- LKM 1 antibodies

More in women, part of spectrum of type 1 AIH

% Concurrent autoimmune disease: 58

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

75

OVERLAP SYNDROMESPrimary Biliary CirrhosisPrimary Sclerosing Cholangitis

5% of patients with chronic hepatitis C will have an ANA titer of >1:100

A homogeneous pattern of staining is more common in ANA positive autoimmune hepatitis compared to that of ANA positive chronic hepatitis C

Autoimmune hepatitis and Chronic hepatitis C 8% of white North American adults have

Concurrent infection with HCV52% of chronic hepatitis C patients have

autoantibodiesInterferon therapy can enhance immune

manifestations of AIH and concurrent HCV infectionImmunosuppressive treatment can increase serum

viral levels in patients with chr hepatitis CTreatment should be appropriate for predominant

disease , based on nature of concurrent immune disease

Autoimmune hepatitis and Chronic hepatitis C

CLINICAL PRESENTATIONSimilar as chronic hepatitisMay be confused with acute hepatitis Can hav acute severe or fulminant

presntation; history of recurrent boutsAsymptomatic in 34%-45% cases

Symptoms:

Fatigue, Malaise- 86%Jaundice- 77%abdominal pain- 48%Pruritis – 36%Anorexia- 30%AmenorrheaArthralgiasnausea, vomitingmyalgias Fever

Arthritismaculopapular

eruptionserythema nodosum,

colitisanemiaFeatures of

concurrent immune disease

SignsHepatomegaly- 78% Jaundice- 69%Splenomegaly -32%Concurrent immune disease- < 38%Ascites- 20 %Encephalopathy – 14% Stigmata of chronic liver disease

Lab findings Similar to chronic viral hepatitisMay not corelate with clinical or

histological severityElevated AST 100%Hypergammaglobulinemia 92%Inc immunoglobulin G level 91%Hyperbilirubinemia 83%Alk Phos >2 times 33%

Immunoserological markers: SMA,ANA, anti-LKM1- 100 %pANCA- 92 % ( type 1 only)anti-asialoglycoprotein- 82 %AAA- 74 %anti-liver cytosol – 32% ( type 2 only )anti-soluble liver antigen- 11-17 %

Clinical criteriaPresence of characteristic clinical featuresLiver histologyExclusion of other diseases

Scoring criteriaAssess the strength of the diagnosisPretreatment and post-treatmentHelpful with variant or atypical forms of AIH

Diagnostic criteria

Diagnostic criteria

Simplified scoring systemGreater specificity vs original scoring system

( 90% vs 73%)Greater predictability ( 92% vs 82% )Useful for excluding AIH in patients with

other conditions and concurrent immune features

Less sensitivity (95% vs 100 %)

DIAGNOSTIC ALGORITHM FOR AUTOIMMUNE HEPATITIS

HISTOLOGYChronic hepatitis with marked piecemeal

necrosis and lobular involvementNumerous plasma cellsInterface hepatitis: hallmark findingNecroinflammatory activityEvidence of hepatocellular regeneration

(“rosette formation” , regenerative “pseudolobules”)

Bile duct injuries and granulomas are uncommon

DIFFERENTIAL DIAGNOSISPrimary biliary cirrhosisPost-necrotic cryptogenic cirrhosisPrimary sclerosing cholangitisAcute viral hepatitisMild chronic viral hepatitisWilsons diseaseHaemochromatosis Alcoholic hepatitisNon alcoholic fatty liver disease

TREATMENTShould be based on:

Severity of symptomsDegree of elevation in transaminases and IgGHistologic findingsPotential side effects of treatment

AASLD RECOMMENDATIONSTreat if serum aminotransferases are greater

than 10 times normalTreat if serum aminotransferases are greater

than 5 times normal and IgG is elevated to greater than 2 times normal, bridging fibrosis or multilobular necrosis, presence of symptoms

In patients with inactive cirrhosis , evaluate for preexisting comorbidities (hep C), pregnancy, and drug intolerances (increased risk of steroid side effects in pts with DM, osteoporosis, HTN)

INDICATIONS FOR TREATMENTAbsolute Relative None

CLINICAL Incapacitating symptoms

Mild or no symptoms

Asymptomatic with minimal lab changes; previous intolerance of prednisolone/ azathioprine

Relentless clinical progression

LABORATORY AST >10-foldULN

AST 3-9.9 ULN AST<3 ULN

AST>5 fold ULNGammaglobulin >2fold

AST>5 fold ULNGammaglobulin <2fold

AST <3 fold ULN

HISTOLOGIC Bridging necrosis

Interface hepatitis

Inactive cirrhosis

Multilobular necrosis

Portal hepatitis

Decompensated cirrhosis

Preferred treatment regimens

Combination therapy

Single drug therapy

Prednisolone (mg/day)

Azathioprine (mg/d)

Prednisolone (mg/day)

30mg 1 week 50 mg until the end point

60mg 1 week

20mg 2 week 40mg 2 week

15mg 3 weeks 30mg 3 weeks

10mg until the end point

20mg until the end point

PREDNISONE ONLYPrednisone 60mg PO daily with a taper down to

30mg at the 4th week into treatment and then maintenance of 20mg daily until reach endpoint

Reasons for Prednisone only: Cytopenia TPMT deficiency Malignancy PregnancyTherapy response expected in upto 80% of

cases

COMBINATION THERAPYPrednisone + AzathioprinePrednisone: start at 30mg daily and taper

down to 15mg at week 4, then maintain on 10mg daily until therapy endpoint

Azathioprine 50mg daily

Side effects : Prednisone

Side effects : Azathioprine

TREATMENT REMISSIONDisappearance of symptomsNormal serum bilirubin and IgGSerum aminotransferases normal or less than

twice normalNormal hepatic tissue or minimal

inflammation and no interface hepatitis.Action

Gradual withdrawal of prednisone Discontinuation of azathioprineRegular monitoring for relapse

TREATMENT FAILUREWorsening clinical, laboratory and histologic

findings despite compliance with therapy Onset of ascites or encephalopathyIncrease in aminotransferases by >67%Action

Pred 60 mg/d or pred 30 mg/d with aza 150 mg/d x 1 month

Reduction of the dose each month of improvement until maintenance levels

TREATMENT FAILURETreatment failures are frequent in patients

with established cirrhosis, HLA-DR3 or in patients who present with disease at a younger age and with a longer duration of symptoms

INCOMPLETE RESPONSESome or no improvement in clinical,

laboratory or histologic features that does not satisfy remission criteria

Failure to achieve remission after 3 yearsAction

Reduction of dose to lowest levels possible to prevent worsening

Indefinite treatment

RELAPSE An exacerbation after drug withdrawal in

patients who enter remissionReappearance of histological diseaseAST >3 folds ULNCirrhosis develops commonlyReinstitute original treatment: azathioprine

continued indefinitely Liver transplantation

Alternative medicationsCyclosporine6MPursodeoxycholic acidBudesonidemethotrexatecyclophosphamide mycophenolate mofetil

LIVER TRANSPLANT: IndicationsPatients with ascites and hepatic

encephalopathyFailed glucocorticoid therapy. HCCMELD score >15Multilobar necrosis and have at least one

laboratory parameter which does not normalize within 2 weeks of treatment

Worsen while on glucocorticoid therapy

LIVER TRANSPLANTATIONRecurrence of disease after transplant is

common in those with AIH but has only been described in patients who are not adequately immunosuppressed.

5 year patient & graft survival 83-92%Auto antibodies disappear within 1y

PROGNOSIS

SUMMARYChronic hepatocellular disease of unknown etiologyClinical presentation is variableDiagnosis based upon LFTs, serology, gamma

globulins, and histologyImmunosuppressive therapy is the mainstay of

treatmentTailor therapy based upon treatment endpointsOf patients who survive the most early and active

stage of disease, approximately 41% of them develop inactive cirrhosis.

Of patients who have severe initial disease and survive the first 2 years, typically survive long term.