Gastroenterology Case Conference Wednesday, March 18, 2009

Hendra Nurjadin

Autoimmune hepatitis
An unresolving inflammation of the liver of unknown cause.  Characterized by the presence of :

 interface

hepatitis on histologic examination  Hypergammaglobulinemia  autoantibodies

Diagnosis requires the exclusion of other chronic liver diseases:

   

Wilson disease chronic viral hepatitis α1-anti-trypsin deficiency Hemochromatosis drug-induced liver disease

nonalcoholic steatohepatitis  primary biliary cirrhosis (PBC)  primary sclerosing cholangitis (PSC)  autoimmune cholangitis

populations are susceptible to AIH : African Americans.000 population   Alaskan natives :   white Norwegian:   AIH among patients with chronic liver disease in North America: 11% .9 per 100.9 cases per 100.000 persons per year prevalence : 16. . 43 per 100. Argentinians.6% of the transplantations in the European Liver Transplant Registry and 5.000 to 200.000 persons per year.000 population 16. AIH affects 100.9 cases per 100.EPIDEMIOLOGY  white northern Europeans:    United States:   incidence :1. Arabs. Brazilians.23%. and Indians.000 persons 2.9% in the National Institutes of Health Liver Transplantation Database. Japanese.

and toxins. or a combination of both mechanisms  constellation of interactive factors : triggering agent. genetic predisposition.  Liver cell destruction : cell-mediated cytotoxicity or antibody-dependent cell-mediated cytotoxicity. and various determinants of autoantigen display. and effector cell expansion.  Triggering factors : infectious agents.PATHOGENESIS  The pathogenic mechanisms of AIH are unknown. immunocyte activation. .  The CD4+ helper T cell is the principal effector cell and its activation is the initial step in the pathogenic pathway. drugs.






SCORING CRITERIA of AIH  Pre-treatment score  Definite diagnosis  Probable diagnosis  >15 10-15 >17 12-17 Post-treatment score  Definite diagnosis  Probable diagnosis .

Czaja. and the simplified system is better at excluding the diagnosis in diseases with concurrent immune manifestations  Sensivity : 100% vs 95%  Specifity : 90% vs 73%  excluding the diagnosis in other diseases with concurrent immune features : 83% vs 64% Albert J. The revised original scoring system performs better in patients with few or atypical features of AIH. May 2008 .

asialoglycoprotein receptor (ASGPR).DIAGNOSTIC CRITERIA  The serologic tests essential for diagnosis are assays for antinuclear antibodies (ANA). and relapse after drug withdrawal   . poor treatment response. smooth muscle antibodies (SMA). and liver cytosol type 1 (anti-LC1)  associated with severe disease. and antibodies to liver-kidney microsome type 1 (antiLKM1). chromatin (anti-chromatin). Peri-nuclear anti-neutrophil cytoplasmic antibodies (pANCAs) are common in type 1 AIH Antibodies to soluble liver antigen/liver pancreas (antiSLA/LP). actin (anti-actin).

CLINICAL CRITERIA  The definite diagnosis : exclusion of other similar diseases   laboratory findings that indicate substantial immunoreactivity histologic features of interface hepatitis  A probable diagnosis : findings are compatible with AIH but insufficient for a definite diagnosis .

CLASSIFICATION Three types of AIH : on the basis of serologic markers.  Variant forms : Patients who have atypical features of AIH currently lack an official designation and confident treatment strategy:    manifestations of AIH and another type of chronic liver disease  overlap syndrome findings that are incompatible with AIH by current diagnostic criteria outlier syndrome . but only two types have distinctive serologic profiles.

Classification of Autoimmune Hepatitis Based on Autoantibodies .

Variant Forms of Autoimmune Hepatitis .

drug-related hepatitis. hepatitis.Conventional Repertoire of Autoantibodies ANA can be found in primary biliary cirrhosis. chronic viral. primary sclerosing cholangitis. nonalcoholic steatohepatitis and alcohol-induced liver disease  ANA are the traditional markers of AIH : present alone (13%) or with SMA (54%) in 67% of patients with the disease  .

 . either as the sole marker of the disease (33%) or in conjunction with ANA (54%)  Anti-LKM1 typically occur in the absence of SMA and ANA.SMA are present in 87% of patients with AIH.

 .  Less severe laboratory abnormalities  better prognosis  Spontaneous resolution is possible in 13% to 20% of patients regardless of disease activity.  Sustained severe derangements  poor outcome unless therapy is started.LABORATORY INDICES Serum AST and gamma globulin levels  the severity of disease and immediate prognosis.

 Hepatocellular carcinoma also can occur in patients with cirrhosis (small risk)  . pattern of liver cell injury  prognostic implication  Inactive cirrhosis develops in 41%.HISTOPATHOLOGIC FINDINGS The histologic findings : indices of disease severity.

2. YOSHIHIRO FUKUDA1. and OSAMU YOKOSUKA .Precise histological evaluation of liver biopsy specimen is indispensable for diagnosis and treatment of acute-onset autoimmune hepatitis J Gastroenterol 2008. we should evaluate liver biopsy specimens precisely and should be ready for a timely initiation of corticosteroid therapy to improve the prognosis. 43:951–958  Histological examination of the liver is necessary for early diagnosis of acute-onset AIH. KEIICHI FUJIWARA1. Moreover.2.

PROGNOSTIC INDICES  the severity of liver inflammation at the initial medical consultation :  the laboratory indices and the histologic findings  HLA status and ethnicity influence disease occurrence. clinical phenotype. and treatment outcome .

Prognosis of Autoimmune Hepatitis .

Treatment Indications in Autoimmune Hepatitis .

Preferred Treatment Regimens in Autoimmune Hepatitis .

Improvement to portal hepatitis alone  50% frequency of relapse. The presence of plasma cells within the portal tract  persistent immune reactivity and the propensity for relapse . incomplete response.TREATMENT END POINTS  Glucocorticoid therapy  until remission. treatment failure. or drug toxicity occurs Liver biopsy examination before drug withdrawal ensures an optimal end point. Progression to cirrhosis or persistence of interface hepatitis 100% frequency of relapse.      Improvement of the liver tissue to normal: relapse  only 20% after cessation of treatment.

End Points of Initial Treatment and Courses of Action .

resolution of inflammatory indices and histologic improvement to normal or minimal activity. .Remission  the absence of symptoms.

TREATMENT FAILURE  deterioration during therapy (9%)  It is characterized by worsening of the serum AST or bilirubin levels by at least 67% of previous values. progressive histologic activity. . or onset of ascites or encephalopathy. and a high-dose regimen should be instituted.  Conventional glucocorticoid therapy should be stopped.

 The goal of treatment is to reduce and stabilize disease activity  .INCOMPLETE RESPONSE 13% : clinical improvement but the findings do not satisfy remission criteria  A low-dose prednisone regimen and the administration of azathioprine (2 mg/kg daily) as the sole drug are reasonable approaches.

treatment usually can be continued with the single tolerated drug (prednisone or azathioprine) in an adjusted dose  Cyclosporine.DRUG TOXICITY For patients with serious side effects from therapy. 6-mercaptopurine. and cyclophosphamide also have been used successfully after drug toxicity in isolated cases  .

and AIH develops de novo in 3% to 5% of patients undergoing transplantation for nonautoimmune liver disease. glucocorticoid-resistant rejection. and chronic rejection occur more commonly in patients undergoing transplantation for AIH . and the actuarial 10-year survival rate after transplantation is 75%.LIVER TRANSPLANTATION     Liver transplantation is effective in the treatment of decompensated AIH Five-year survival rates for patients and grafts range from 83% to 92%. Autoimmune hepatitis recurs in at least 17% of patients. Acute rejection.

83% remain in remission for up to 10 years .RELAPSE    Relapse occurs in 50% within 6 months.  87% can be managed long term on prednisone at less than 10 mg per day (median dose. The major consequence of relapse and retreatment is the development of drug-related complications (70% of those who have multiple relapses and retreatments) Patients who have had at least two relapses should be given either low-dose prednisone or azathioprine as the sole drug   Continuous azathioprine therapy (2 mg/kg per day) is an alternative strategy that can be used in patients who are not severely cytopenic. and most patients (70% to 86%) experience exacerbation within 3 years. 7.5 mg per day).

Recurrent AIH typically is mild and develops in patients who are inadequately immunosuppressed.  Dose adjustments usually are sufficient to suppress the disease. but progression to cirrhosis and graft failure have been reported  .