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

Immunity

AUTOIMMUNE HEPATITISChronic hepatitis of unknown etiologyCan progress to cirrhosisCharacteristics include:

presence of autoimmune antibodyevidence of hepatitis (interface being

characteristic)elevation of serum globulinsContinuing/unresolving hepatocellular

inflammation and necrosis

OTHER NAMESActive chronic hepatitis or chronic active

hepatitisChronic aggressive hepatitisLupoid hepatitisPlasma cell hepatitisAutoimmune chronic active hepatitis

Cases in which hepatotropic viruses, metabolic / genetic derrangements and hepatotoxic drugs have been excluded represent a spectrum of heterogenous liver disorders of unknown cause, a proportion of which are most likely autoimmune 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

EPIDEMIOLOGYFrequency of AIH among patients with

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

Accounts for 5.6% of liver transplants in the US

Prevalence greatest among northern European white persons

Japenese have a lower frequency

PATHOGENESISUnknown mechanism but several proposed

mechanismsGenetically predisposed individual with exposure

to an environmental agent triggers the autoimmune pathogenic process

Genetic predisposing factors:HLA-DR3: early onset, severe formHLA-DR4: caucasian, late onset, better response to

steroids, higher incidence of extrahepatic manifestations IgG: part of the IgG molecule (mainly the heavy chain)T-Cell receptors

PATHOGENESISEVIDENCE SUPPORTING AUTOIMMUNE

PATHOGENESISHistopathological lesions composed of cytotoxic

Tcells and plama cellsCirculating autoantibodiesHyperglobulinemiaOther autoimmune disorders: thyroiditis, RA ,

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

Hitocompatibility haplotypes assosciationsResponse to steroids and immunosuppression.

PATHOGENESISEnvironmental Triggers: presumed to be

certain viruses, toxins, drugsDrugs:

OxyphenisatinMethyldopaNitrofurantoinDiclofenacMinocyclinestatins

CLASSIFICATIONTYPE 1TYPE 2OVERLAP 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 populationDLA 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 ControversialAntibodies to soluble liver antigen / liver

pancreas antigenLack ANA and anti- LKM 1 antibodiesMore in women, part of spectrum of type 1

AIH

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

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

presntation; history of recurrent boutsAsymptomatic in 34%-45% casesSymptoms: malaise, fatigue, anorexia,

amenorrhea, acne, arthralgias, jaundice, nausea, vomiting, abdominal pain, myalgias , fever

Arthritis, maculopapular eruptions, erythema nodosum, colitis, pleurisy, pericarditis, anemia, azotemia, sicca syndrome

SignsHepatomegalyJaundiceStigmata of chronic liver diseaseSplenomegalyConcurrent immune diseaseAscitesEncephalopathy

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

severityElevated AST and ALT (100-1000 IU/L)Serum bilirubin, ALP may be normal or

raisedElevated PTHypergammaglobulinemia (>2.5 gn/dl)Immunoserological markers: SMA,ANA, anti-

LKM1, pANCA, AAA, anti-liver cytosol, anti-soluble liver antigen, anti-asialoglycoprotein

CourseSevere disease in 20% cases6-month mortality without therapy may be as

high as 40%Spontaneous remissions and exacerbationsPoor prognostic signs: multilobular collapse histologically at

presentation failure of bilirubin to improve after 2 weeks of

therapyHCC may be a late complication

DIAGNOSISElevated AST and ALTElevated IgGRule out other causes:

Wilsons diseaseAlpha 1 antitrypsin deficiencyViral hepatitis (A, B, C)Drug induced liver disease (alcohol, minocycline,

nitrofurantoin, INH, PTU, methyldopa, etc) NASHPBC, PSC, autoimmune cholangitis

Presence of autoimmune antibodiesLiver biopsy

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 diseaseAlcoholic 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

TREATMENTCorticosteroidsAzathioprineChildren: azathioprine or 6MP

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

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 ? 1 week 40mg ? 1 week

15mg ? 2 weeks 30mg ? 2 weeks

10mg until the end point

20mg until the end point

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: d/c azathioprine and taper prednisone

TREATMENT FAILUREWorsening clinical, laboratory and histologic

findings despite compliance with therapy Onset of ascites or encephalopathyIncrease in aminotransferases by >67%Action: increase prednisone to 60mg daily

and azathioprine to 150mg daily for one month

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: 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

LIVER TRANSPLANTPatients with ascites and hepatic

encephalopathy (generally will have a poor prognosis, but consider liver transplant if they have failed glucocorticoid therapy.

Considered in patients with multilobar necrosis and have at least one laboratory parameter which does not normalize within 2 weeks of treatment (theses patients have a high immediate mortality rate)

LIVER TRANSPLANTATIONConsidered in pts who worsen while on

glucocorticoid therapy. Recurrence of disease after transplant is

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

PROGNOSIS

PROGNOSIS40% of all pts with AIH develop cirrhosis54% develop esophageal varices within 2 yearsPoor prognosis if has presence of ascites or

hepatic encephalopathy13-20% of patients can have spontaneous

resolutionOf 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.