autoimmune hepatitis

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  • 1. CHAIRED BY : Dr. Raminderpal Singh Sibia PRESENTED BY : Dr. Rintu Sharma Immunity

2. Case scenarios HISTORY 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. 3. 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)++ 4. AUTOIMMUNE HEPATITIS Continuing/unresolving hepatocellular inflammation and necrosis of unknown etiology Can progress to cirrhosis Exclusion of other chronic liver diseases Characteristics include: presence of autoimmune antibody evidence of hepatitis (interface being characteristic) elevation of serum globulins 5. OTHER NAMES Active chronic hepatitis or chronic active hepatitis Chronic aggressive hepatitis Lupoid hepatitis Plasma cell hepatitis Autoimmune chronic active hepatitis 6. BACKGROUND First described in 1950s Accounts for 5.6% of liver transplants in the US Affects women more than men (3.6:1) If untreated approximately 40% die within 6 months 40% develop cirrhosis 54% develop esophageal varices 20% die of hemorrhage 7. EPIDEMIOLOGY Incidence: 1.9 cases per 100,000 persons per yr Frequency 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 Scand J Gastroenterol1998;33:99. 8. PATHOGENESIS Unknown 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 9. Triggering factors Infections (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 cells IL-4 and IL-10: proliferation of B cells 10. Evidence supporting autoimmune pathogenesis Histopathological lesions composed of cytotoxic Tcells and plama cells Circulating autoantibodies Hyperglobulinemia Other autoimmune disorders: thyroiditis, RA , autoimmune hemolytic anemia, ulcerative colitis, membranoproliferative glomerulonephritis, diabetes mellitus, celiac disease, sjogrens syndrome Histocompatibility haplotypes assosciations Response to steroids and immunosuppression. 11. CLASSIFICATION TYPE 1 TYPE 2 TYPE 3 OVERLAP SYNDROMES 12. TYPE 1 Classically in young females ANA or Anti-Smooth Muscle antibody positive Titer usually > 1:100 10% 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 13. TYPE 1 Bimodal Age distribution (ages 10-20 and 45-70) Female:male (3.6:1) HLA DR3 or DR4 assosciation Associated with extrahepatic manifestations(38%): Autoimmune thyroiditis, Graves disease, Chronic UC Less 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 14. TYPE 2 Seen in children (2-14 years)in Meditteranean population HLA DR1 or DQB1 assosciation Presence 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 15. 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 16. OVERLAP SYNDROMES Primary Biliary Cirrhosis Primary 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 17. Autoimmune hepatitis and Chronic hepatitis C 8% of white North American adults have Concurrent infection with HCV 52% of chronic hepatitis C patients have autoantibodies Interferon therapy can enhance immune manifestations of AIH and concurrent HCV infection Immunosuppressive treatment can increase serum viral levels in patients with chr hepatitis C Treatment should be appropriate for predominant disease , based on nature of concurrent immune disease 18. Autoimmune hepatitis and Chronic hepatitis C 19. CLINICAL PRESENTATION Similar as chronic hepatitis May be confused with acute hepatitis Can hav acute severe or fulminant presntation; history of recurrent bouts Asymptomatic in 34%-45% cases 20. Symptoms: Fatigue, Malaise- 86% Jaundice- 77% abdominal pain- 48% Pruritis 36% Anorexia- 30% Amenorrhea Arthralgias nausea, vomiting myalgias Fever Arthritis maculopapular eruptions erythema nodosum, colitis anemia Features of concurrent immune disease 21. Signs Hepatomegaly- 78% Jaundice- 69% Splenomegaly -32% Concurrent immune disease- < 38% Ascites- 20 % Encephalopathy 14% Stigmata of chronic liver disease 22. Lab findings Similar to chronic viral hepatitis May not corelate with clinical or histological severity Elevated AST 100% Hypergammaglobulinemia 92% Inc immunoglobulin G level 91% Hyperbilirubinemia 83% Alk Phos >2 times 33% 23. 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 % 24. Clinical criteria Presence of characteristic clinical features Liver histology Exclusion of other diseases Scoring criteria Assess the strength of the diagnosis Pretreatment and post-treatment Helpful with variant or atypical forms of AIH Diagnostic criteria 25. Diagnostic criteria 26. Simplified scoring system Greater 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 %) 27. DIAGNOSTIC ALGORITHM FOR AUTOIMMUNE HEPATITIS 28. HISTOLOGY Chronic hepatitis with marked piecemeal necrosis and lobular involvement Numerous plasma cells Interface hepatitis: hallmark finding Necroinflammatory activity Evidence of hepatocellular regeneration (rosette formation , regenerative pseudolobules) Bile duct injuries and granulomas are uncommon 29. DIFFERENTIAL DIAGNOSIS Primary biliary cirrhosis Post-necrotic cryptogenic cirrhosis Primary sclerosing cholangitis Acute viral hepatitis Mild chronic viral hepatitis Wilsons disease Haemochromatosis Alcoholic hepatitis Non alcoholic fatty liver disease 30. TREATMENT Should be based on: Severity of symptoms Degree of elevation in transaminases and IgG Histologic findings Potential side effects of treatment 31. AASLD RECOMMENDATIONS Treat if serum aminotransferases are greater than 10 times normal Treat 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) 32. INDICATIONS FOR TREATMENT Absolute 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 AST5 fold ULN Gammaglobulin >2fold AST>5 fold ULN Gammaglobulin 3 folds ULN Cirrhosis develops commonly Reinstitute original treatment: azathioprine continued indefinitely Liver transplantation 43. Alternative medications Cyclosporine 6MP ursodeoxycholic acid Budesonide methotrexate cyclophosphamide mycophenolate mofetil 44. LIVER TRANSPLANT: Indications Patients with ascites and hepatic encephalopathy Failed glucocorticoid therapy. HCC MELD score >15 Multilobar necrosis and have at least one laboratory parameter which does not normalize within 2 weeks of treatment Worsen while on glucocorticoid therapy 45. LIVER TRANSPLANTATION Recurrence 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 46. PROGNOSIS 4

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