ai hepatitis dr rintu
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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.
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