AUTOIMMUNE HEPATITIS

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 1-anti-trypsin deficiency Hemochromatosis drug-induced liver disease

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

EPIDEMIOLOGY

white northern Europeans:

United States:

incidence :1.9 cases per 100,000 persons per year prevalence : 16.9 cases per 100,000 persons per year. AIH affects 100,000 to 200,000 persons 2.6% of the transplantations in the European Liver Transplant Registry and 5.9% in the National Institutes of Health Liver Transplantation Database. 43 per 100,000 population 16.9 per 100,000 population

Alaskan natives :

white Norwegian:

AIH among patients with chronic liver disease in North America: 11% - 23%. populations are susceptible to AIH : African Americans, Brazilians, Argentinians, Arabs, Japanese, and Indians.

PATHOGENESIS

The pathogenic mechanisms of AIH are unknown.

Triggering factors : infectious agents, drugs, and toxins. The CD4+ helper T cell is the principal effector cell and its activation is the initial step in the pathogenic pathway. Liver cell destruction : cell-mediated cytotoxicity or antibody-dependent cell-mediated cytotoxicity, or a combination of both mechanisms

constellation of interactive factors : triggering agent, genetic predisposition, and various determinants of autoantigen display, immunocyte activation, and effector cell expansion.

CLINICAL FEATURES

CLINICAL FEATURES

CLINICAL FEATURES

CLINICAL FEATURES

SCORING CRITERIA of AIH

SCORING CRITERIA of AIH

Pre-treatment score
Definite

diagnosis Probable diagnosis

>15 10-15
>17 12-17

Post-treatment score
Definite

diagnosis Probable diagnosis

The revised original scoring system performs better in patients with few or atypical features of AIH, 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. Czaja, May 2008

DIAGNOSTIC CRITERIA

The serologic tests essential for diagnosis are assays for antinuclear antibodies (ANA), smooth muscle antibodies (SMA), and antibodies to liver-kidney microsome type 1 (antiLKM1). 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), chromatin (anti-chromatin), asialoglycoprotein receptor (ASGPR), and liver cytosol type 1 (anti-LC1) associated with severe disease, poor treatment response, and relapse after drug withdrawal

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, but only two types have distinctive serologic profiles. 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

Classification of Autoimmune Hepatitis Based on Autoantibodies

Variant Forms of Autoimmune Hepatitis

Conventional Repertoire of Autoantibodies

ANA can be found in primary biliary cirrhosis, primary sclerosing cholangitis, chronic viral, hepatitis, drug-related hepatitis, 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

SMA are present in 87% of patients with AIH, 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.

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

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

Precise histological evaluation of liver biopsy specimen is indispensable for diagnosis and treatment of acute-onset autoimmune hepatitis
J Gastroenterol 2008; 43:951958

Histological examination of the liver is necessary for early diagnosis of acute-onset AIH. Moreover, we should evaluate liver biopsy specimens precisely and should be ready for a timely initiation of corticosteroid therapy to improve the prognosis.

KEIICHI FUJIWARA1,2, YOSHIHIRO FUKUDA1,2, and OSAMU YOKOSUKA

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

TREATMENT END POINTS

Glucocorticoid therapy until remission, treatment failure, incomplete response, or drug toxicity occurs Liver biopsy examination before drug withdrawal ensures an optimal end point.

Improvement of the liver tissue to normal: relapse only 20% after cessation of treatment. Improvement to portal hepatitis alone 50% frequency of relapse. Progression to cirrhosis or persistence of interface hepatitis 100% frequency of relapse. The presence of plasma cells within the portal tract persistent immune reactivity and the propensity for relapse

End Points of Initial Treatment and Courses of Action

Remission
the

absence of symptoms, resolution of inflammatory indices and histologic improvement to normal or minimal activity.

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. Conventional glucocorticoid therapy should be stopped, and a high-dose regimen should be instituted.

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. The goal of treatment is to reduce and stabilize disease activity

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

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%, and the actuarial 10-year survival rate after transplantation is 75%. Autoimmune hepatitis recurs in at least 17% of patients, and AIH develops de novo in 3% to 5% of patients undergoing transplantation for nonautoimmune liver disease. Acute rejection, glucocorticoid-resistant rejection, and chronic rejection occur more commonly in patients undergoing transplantation for AIH

RELAPSE

Relapse occurs in 50% within 6 months, and most patients (70% to 86%) experience exacerbation within 3 years. 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.

87% can be managed long term on prednisone at less than 10 mg per day (median dose, 7.5 mg per day).

83% remain in remission for up to 10 years

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

THANK YOU AND GOOD DAY