INVESTIGATION

• Autoantibodies [161]:
Autoimmune hepatitis is characterized by positive findings on autoantibody tests. Autoimmune hepatitis type 1 is characterized by positive test results for ASMA and ANA. Type 2 disease is marked by a positive test result for anti–LKM-1 antibody. Type 3 is marked by a positive test result for anti-SLA antibody.
• Serum protein electrophoresis and quantitative immunoglobulins
o An immunoglobulin G (IgG)–predominant polyclonal hypergammaglobulinemia is a common finding in patients with untreated autoimmune hepatitis. Gamma globulin values typically range from 3-4 g/dL and frequently are as high as 5-6 g/dL. Cases of hyperviscosity syndrome secondary to high IgG levels are reported. Autoimmune hepatitis is an unlikely diagnosis in patients who have acute hepatitis without hypergammaglobulinemia.
o The gamma globulin or the IgG level may be followed on a regular basis as a marker of disease responsiveness to therapy.
• Aminotransferases [147]
o Serum aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are elevated in 100% of patients at initial presentation, with average values of 200-300 U/L and can reach upto 1000 U/L.
o Aminotransferase values correlate poorly with the degree of hepatic necrosis; however, values in the thousands may indicate acute hepatitis or a severe flare of preexisting disease.
o Continued elevation of the aminotransferases in the face of ongoing therapy is a reliable marker for ongoing inflammatory activity in the liver.
o Normalization of the aminotransferase levels during therapy is an encouraging sign, but active liver inflammation is present in more than 50% of patients with normalized liver chemistries. Indeed, biochemical remission may precede true histologic remission by 3-6 months.
o Worsening of aminotransferase levels in a patient undergoing treatment or in a patient who is in remission may signal a resurgence of disease activity.
• Other liver chemistries [161]
o Serum bilirubin and alkaline phosphatase values are mildly to moderately increased in 80-90% of patients. A sharp increase in the alkaline phosphatase values during the course of autoimmune disease might reflect the development of PSC or the onset of hepatocellular carcinoma as a complication of cirrhosis.
o Hypoalbuminemia and prolongation of prothrombin time are markers of severe hepatic synthetic dysfunction, which may be observed in active disease or decompensated cirrhosis.
• Other common laboratory abnormalities
Mild leukopenia
o Normochromic anemia
o Coombs-positive hemolytic anemia
Thrombocytopenia
Elevated sedimentation rate
o Eosinophilia (uncommon but counts ranging from 9-48% are described)
o Autoimmune hepatitis even has been described as the sole presenting feature of idiopathic hypereosinophilic syndrome.
• Imaging studies, in general, are not helpful in reaching a definitive diagnosis of autoimmune hepatitis; however, the presence of heterogeneous echotexture on abdominal ultrasound or abnormal contrast enhancement on abdominal CT imaging may suggest the presence of active inflammation or necrosis.
• Liver biopsy [161, 147]
o Liver biopsy is the most important diagnostic procedure in patients with autoimmune hepatitis. Liver biopsy should be performed as early as possible in patients with acute hepatitis who are thought to have autoimmune hepatitis. Confirmation of the diagnosis enables initiation of treatment at an early stage in the disease process.
o The role of biopsy in patients presenting with well-established cirrhosis secondary to autoimmune hepatitis is less clear.
o Liver biopsy findings can help to differentiate autoimmune hepatitis from chronic HCV infection, alcohol-induced hepatitis, drug-induced liver disease, PBC, and PSC
• Endoscopic retrograde cholangiopancreatography: Occasionally, a patient with autoimmune hepatitis and ulcerative colitis may require endoscopic retrograde cholangiopancreatography (ERCP) to rule out coexisting PSC.
TREATMENT
NON PHARMACOLOGICAL TREATMENT
• Patients with acute autoimmune hepatitis and symptoms of nausea and vomiting may require intravenous fluids and even total parenteral nutrition; however, most patients can tolerate a regular diet. A high caloric intake is desirable.
• Patients with cirrhosis secondary to autoimmune hepatitis may develop ascites. A low-salt diet (generally <2000 mg of sodium per d) is mandatory in these individuals. Patients should continue to consume protein (i.e., >1.3 g protein per kg body weight) given the catabolic nature of the disease and patients' high risk for developing muscle wasting.
• Most patients do not need hospitalization, although this may be required for clinically severe illness. Forced and prolonged bed rest is unnecessary, but patients may feel better with restricted physical activity

PHARMACOLOGICAL TREATMENT

Treatment indications
1. Treatment should be instituted in patients with serum aminotransferase levels greater than 10-fold the upper limit of normal.
2. Patients with serum aminotransferase levels that are 5-fold the upper limit of normal in conjunction with a serum gamma-globulin level at least twice the upper limit of normal should be treated.
3. Histologic features of bridging necrosis or multiacinar necrosis compel therapy.
4. Patients not satisfying the criteria in above 3 recommendations, they must be individualized and treatment should be based on clinical judgment. The presence of interface hepatitis without bridging necrosis or multiacinar necrosis on histologic examination does not compel treatment.
5. Treatment may not be indicated in patients with inactive cirrhosis, preexistent comorbid conditions, or drug intolerances.
6. Treatment is warranted in most children at the time of diagnosis.
Treatment regimens
1. Prednisone in combination with azathioprine or a higher dose of prednisone alone is the appropriate treatment for severe AIH in adults.
2. Prednisone in combination with azathioprine is the preferred initial treatment because of its lower frequency of side effects (10% vs. 44%)
3. Prednisone is appropriate as the sole medication in individuals with severe cytopenia,those undergoing a short treatment trial (duration of therapy, <6 months), individuals who are pregnant or contemplating pregnancy, patients with active malignancy,andindividuals with thiopurine methyltransferase deficiency
4. The combination regimen is appropriate in patients who will be treated continuously for at least 6 months or who are at increased risk for drug related complications, including postmenopausal women and individuals with emotional instability, osteoporosis, brittle diabetes, labile hypertension, and/or exogenous obesity
5. All patients treated with prednisone alone or in combination with azathioprine must be monitored for the development of drug-related side effects.
6. Azathioprine or 6-mercaptopurine is preferred as a corticosteroid-sparing agent in children, especially when high doses of prednisone are required for disease control.
Treatment in children
• Initial dose of prednisone in children is 2 mg/kg/d (up to 60 mg/d), for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/d
• For maintainance prednisone taper over 6-8 weeks to 0.1-0.2 mg/kg daily or 5 mg daily , azathioprine at constant dose if added initially and continue daily prednisone dose with or without azathioprine or switch to alternate day prednisone dose adjusted to response with or without azathioprine
• The occurrence of relapse in children justifies reinstitution of the original treatment regimen.
• Indefinite low-dose therapy can then be instituted after suppression of disease activity using prednisone in combination with azathioprine or 6-mercaptopurine
• The experience with azathioprine alone as maintenance therapy is limited in children

Treatment end points
1. Conventional treatment regimens should be continued in adults and children until remission, treatment failure, incomplete response, or drug toxicity. Once disease remission has been achieved, drug withdrawal should be attempted.
2. Remission is generally not observed before 12 months. Approximately 65 and 80 percent of patients achieve remission by 18 months and 3 years, respectively. The probability of remission decreases after two years.
3. Treatment in children should be adjusted to clinical and laboratory finding in an individualized fashion, recognizing that therapy is frequently long term.
4. Treatment end point in children is normal liver tests for 1-2 years during treatment, no flare during entire interval and liver biopsy examination disclosing no inflammation

Management of remission
Remission is defined as disappearance of symptoms, normal serum bilirubin and gamma globulin levels, serum aminotransferase level normal or less than twice normal and normal hepatic tissue or minimal inflammation and no interface hepatitis
Remission is managed as:
• Gradual withdrawal of prednisone over 6-week period
• Discontinuation of azathioprine
• Regular monitoring for relapse
Management of relapse after drug withdrawal
1. Relapse is common in adults and children after drug withdrawal, and patients should be monitored for this occurrence by regular determinations of serum aminotransferase, bilirubin, and gamma-globulin levels.
2. Adults who have relapsed more than once should be treated with combination prednisone and azathioprine therapy, low dose prednisone, or azathioprine only.
3. If patient relapse indefinite low-dose prednisone strategy employs the lowest dose of medication possible to prevent symptoms and maintain serum aminotransferase levels below fivefold normal [189].
4. The prednisone dose is reduced by 2.5 mg each month until the lowest dose is reached below which there is clinical and/or biochemical instability.
5. Serum aminotransferase levels must be checked each month as small decrements in prednisone dose can be associated with marked increases in the serum aminotransferase level [189,190].
6. This strategy is most appropriate in patients who are taking prednisone as their sole drug.
7. It can also be applied to individuals taking prednisone and azathioprine.
8. In these latter instances, the dose of prednisone is first reduced to the lowest dose to prevent biochemical instability. Azathioprine is then discontinued as the dose of prednisone is readjusted to compensate for the withdrawal
9. Patients taking prednisone only can be switched to the azathioprine schedule by adding azathioprine (2 mg/kg daily) and then reducing the prednisone dose by 2.5 mg each month.
Management of suboptimal responses to initial therapy
Treatment failure is defined as worsening clinical, laboratory, and histologic features despite compliance with therapy, increase of serum aminotransferase by 67 percent and development of jaundice, ascites, or hepatic encephalopathy.
Incomplete response is defined as some or no improvement in clinical, laboratory, and histologic features during therapy, failure to achieve remission after 3 years but no worsening of condition
• Treatment failure is managed with high doses of prednisone alone (60 mg daily) or prednisone (30 mg daily) in conjunction with azathioprine (150 mg daily)
• The regimen is continued for at least one month, and then the dose of prednisone is reduced by 10 mg and the dose of azathioprine is reduced by 50 mg after each month of clinical and laboratory improvement. Dose reduction is continued until conventional maintenance levels of medication are again achieved
• Alternative management strategies for treatment failure in adults have included the administration of cyclosporine, ursodeoxycholic acid, budesonide , 6-mercaptopurine, methotrexate , cyclophosphamide, and mycophenolate mofetil.
• Liver transplantation should be considered in the decompensated patient who is unable to undergo or be salvaged by drug therapy
• There are no findings prior to therapy that predict immediate and long-term outcome, and all decompensated patients with severe inflammation should be given a treatment trial of corticosteroids before proceeding with transplantation
• The likelihood of a significant response to corticosteroid treatment can be determined within two weeks
• Resolution of at least one laboratory abnormality, improvement in the pretreatment hyperbilirubinemia, and/or failure of any test to worsen during the treatment period indicates that therapy will be effective short term
• The presence of multiacinar necrosis and a hyperbilirubinemia that does not improve after two weeks identifies individuals who will not survive without urgent transplantation
• Inability to induce remission after four years of continuous treatment identifies a subgroup of adults at risk for liver failure.
• Liver transplantation should be considered in these individuals at the first sign of decompensation. The development of ascites is the most common indication
• Children who have treatment failure should be treated with high-dose corticosteroid regimens and considered for liver transplantation
• Drug toxicity compels immediate adjustments in therapy .
• Cytopenia, nausea, emotional lability, hypertension, cosmetic changes, and diabetes are typically dose related. These consequences can improve with dose reduction.
• Severe reactions, including psychosis, extreme cytopenia, and symptomatic osteopenia with or without vertebral compression, justify immediate discontinuation of the offending agent.
• In these patients, treatment can usually be continued with the single tolerated drug (prednisone or azathioprine) in adjusted dose