AA

1. AUTOIMMUNE HEPATITIS
Autoimmune hepatitis is a chronic disease of unknown cause, characterized by
continuing hepatocellular inflammation and necrosis and tending to progress to cirrhosis.
Frequently, immune serum markers are present; they include autoantibodies against
liver-specific and non–liver-specific antigens and increased immunoglobulin G (IgG)
levels. The disease often is associated with other autoimmune diseases. Autoimmune
hepatitis cannot be explained on the basis of chronic viral infection, alcohol consumption,
or exposure to hepatotoxic medications or chemicals.
Autoimmune hepatitis now is recognized as a multisystem disorder
that can occur in males and females of all ages. This condition can
coexist with other liver diseases (eg, chronic viral hepatitis) and
also may be triggered by certain viral infections (eg, hepatitis A)
and chemicals (eg, minocycline).

2. ETIOLOGY
 The etiology of autoimmune hepatitis is unknown. Several factors (eg, viral infection,
drugs, environmental agents) may trigger an autoimmune response and
autoimmune disease.
 In a few patients with autoimmune hepatitis, illness onset follows acute hepatitis A,
hepatitis B, or Epstein-Barr virus infections. Autoantibodies are common in patients
with chronic hepatitis C virus (HCV) infection. Some patients with chronic HCV
infection exhibit liver-kidney microsomal type 1 (LKM-1) antibody.
 Some cases of drug-induced liver disease have an immune-mediated basis. A number
of drugs (eg, methyldopa, nitrofurantoin, minocycline, [20] adalimumab, [21] infliximab [22] )
can produce an illness with the clinical features of autoimmune hepatitis. Although
most cases improve when the drug is stopped, chronic cases of autoimmune hepatitis
may be seen, even after drug withdrawal. [23]
 Casswall et al found Helicobacter species DNA in 50% of liver biopsies from patients
with autoimmune hepatitis and ulcerative colitis.

3. EPIDEMIOLOGY
1. The disease is most common in whites of northern European ancestry
with a high frequency of HLA-DR3 and HLA-DR4 markers.
2. Autoimmune hepatitis has a bimodal age distribution, with a first peak of
incidence at age 10-20 years and a second at age 45-70 years.
Approximately one half of the affected individuals are younger than 20
years; incidence peaks in premenstrual girls. (but still can occur in any
age).
3. AIH type 2 is more predominant in Europe and Canada .
4. In the USA AIH type 1 is the predominant type .
5. Autoimmune hepatitis accounts for about 3% of liver transplantations in
Europe and about 6% in the USA .

4. PATHOPHYSIOLOGY
 Current evidence suggests that liver injury in a patient with autoimmune hepatitis is the result of a cell-
mediated immunologic attack. Aberrant display of human leukocyte antigen (HLA) class II on the surface
of hepatocytes facilitates the exposure of normal liver cell membrane constituents to antigen-presenting
cells (APCs).
 APCs present hepatic antigens to uncommitted helper T lymphocytes (TH 0). APCs and helper T
lymphocytes interact at the ligand-ligand level, which, in turn, activates TH 0. This activation is followed
by functional differentiation into helper T cell 1 (TH 1) or helper T cell 2 (TH 2), according to the cytokines
prevailing in the tissue and the nature of the antigen. TH 1 primarily secretes interleukin 2 (IL-2) and
interferon gamma, which activate macrophages and enhance the expression of HLA classes I and II,
thus perpetuating the immune recognition cycle.
 TH 2 cells primarily produce interleukins 4, 5, and 10, which stimulate autoantibody production by B
lymphocytes.
 So the cells and molecules responsible for this in order are: 1. HLA II 2.TH0 , TH1 and
TH2 3. Cytokines(INF-gamma, IL-2) and macrophages 4. HLA I 5. Cytotoxic cells.

5. EVIDENCE OF AUTOIMMUNITY
 Evidence for an autoimmune pathogenesis includes the following:
• Hepatic histopathologic lesions composed predominantly of cytotoxic T cells and plasma cells
• Circulating autoantibodies (ie, nuclear, smooth muscle, thyroid, liver-kidney microsomal, soluble liver antigen,
hepatic lectin)
• Association with hypergammaglobulinemia and the presence of a rheumatoid factor
• Association with other autoimmune diseases
• Response to steroid and/or immunosuppressive therapy
 The autoantibodies described in these patients include the following:
• Antinuclear antibody (ANA), primarily in a homogeneous pattern
• Anti–smooth muscle antibody (ASMA) directed at actin
• Anti–liver-kidney microsomal antibody (anti–LKM-1)
• Antibodies against soluble liver antigen (anti-SLA) directed at cytokeratins types 8 and 18
• Antibodies to liver-specific asialoglycoprotein receptor or hepatic lectin
• Antimitochondrial antibody (AMA) - AMA is the sine qua non of primary biliary cirrhosis (PBC) but may be observed
in the so-called overlap syndrome with autoimmune hepatitis.
• Antiphospholipid antibodies .

6. TYPES AND AUTO ANTIBODIES INVOLVEMENT
Autoimmune hepatitis is characterized by positive
findings on autoantibody tests, as follows:
• AIH-1 - ASMA and ANA
• AIH-2 - Anti–LKM-1 antibody , Anti-LKM-2 Ab.
• AIH-3 - Antibodies to soluble liver antigen (anti-SLA)

7.  Most cases have an insidious onset. Patients may be asymptomatic or have
nonspecific symptoms (eg, fatigue, anorexia, weight loss, behavioral
changes, amenorrhea). Systemic or cutaneous abnormalities occur in 25% of
patients. Epistaxis, bleeding gums, and bruises with minimal trauma are
frequent complaints.
 Autoimmune hepatitis may present as acute hepatitis, chronic hepatitis, or well-
established cirrhosis.
Fatigue
• Upper abdominal discomfort
• Mild pruritus
• Anorexia
• Myalgia
• Diarrhea
• Cushingoid features
• Arthralgias
• Skin rashes
(including acne)
• Edema
• Hirsutism
• Amenorrhea
• Chest pain from
pleuritis
• Weight loss and
intense pruritus
(unusual)

8. DDX
 1. Cryptogenic autoimmune hepatitis is characterized by a clinical picture that is indistinguishable
from autoimmune hepatitis. Here, the diagnosis is made by liver biopsy. ANA, ASMA, and anti–LKM-1
are negative at disease onset and may appear late in the disease course, as might anti-SLA. The
disease usually is responsive to steroid therapy.
 2. Overlap syndromes
 Patients with autoimmune hepatitis may present with features that overlap with those classically
associated with patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).
3. virtually all viral hepatitis ( A, B , C ,D, E ).
4. Alcoholic liver disease .
5. NAFLD .
6. Toxicities , including drugs .

9. WORK UP IN AIH
 Clinicians must consider the diagnosis of autoimmune hepatitis in any patient who has acute
hepatitis or acute liver failure (defined by the new onset of coagulopathy). In addition to
aminotransferase levels and other liver function studies, the workup of such patients should include the
following assays:
• Serum antinuclear antibody (ANA)
• Anti–smooth muscle antibody (ASMA)
• Liver-kidney microsomal type 1 (LKM-1) antibody
• Serum protein electrophoresis (SPEP)
• Quantitative immunoglobulins
 Urgent liver biopsy, transjugular if appropriate, may help to confirm the clinical suspicion of
autoimmune hepatitis.
 Laboratory findings in autoimmune hepatitis include the following:
• Elevated serum aminotransferase levels (1.5-50 times reference values), with average of 200-300.
• Elevated serum immunoglobulin levels, primarily immunoglobulin G (IgG)
• Seropositive results for ANAs, SMAs, or LKM-1 or anti–liver cytosol 1 (anti-LC1) antibodies
 In 50% of patients, abnormal results on liver function tests include decreased albumin levels and prolonged
prothrombin time.

10. CBC IN AIH
Complete Blood Count and Other Blood Studies
Other hematologic abnormalities may include the
following:
• Mild leukopenia.
• Normochromic anemia.
• Coombs-positive hemolytic anemia.
• Thrombocytopenia.
• Elevated erythrocyte sedimentation rate.

11. Liver biopsy is the most important diagnostic
procedure in patients with autoimmune hepatitis. This
procedure can be performed percutaneously, with or
without ultrasound guidance, or by the transjugular route.
The latter is preferred if the patient has coagulopathy or
severe thrombocytopenia. A transjugular liver biopsy also
may be preferable if ascites is present or if the liver is
small, shrunken, and difficult to reach percutaneously.
 Biopsy can help in differentiating AIH from other causes as viral infections mainly A , B
,C and D . Also can show degree of fibrosis .

12. OTHER GUIDELINES
1. All children with AIH should undergo magnetic resonance
cholangiopancreatography (MRCP) at minimum to rule out
autoimmune sclerosing cholangitis.
Patients who have AIH with cholestatic features should undergo
testing for primary biliary cholangitis (PBC).
2. Patients with AIH-related cirrhosis should undergo
ultrasonography every 6 months to monitor for hepatocellular
carcinoma (HCC).

13. TREATMENT
 The goal of AIH therapy is to achieve complete biochemical and histological remission to prevent
disease progression.
 All patients with active disease, including those with advanced fibrosis or cirrhosis, should undergo
treatment.
 Induction treatment
 First-line therapy for AIH should be prednisolone 0.5-1 mg/kg/day PO given in one dose in the morning
plus azathioprine at an initial morning dose of 50 mg/dL, usually after 2 weeks, if bilirubin levels are < 6
mg/dL.
 Afterward, azathioprine should be increased up to 1-2 mg/kg/day (maintenance dose).
 In patients with noncirrhotic AIH who are not candidates for conventional corticosteroid therapy (eg,
serious comorbidities), budesonide 9 mg/day plus azathioprine may be used as induction treatment.

14.  Maintenance treatment:
 Corticosteroid-free azathioprine monotherapy (mycophenolate mofetil [MMF] is an
alternative) is the optimal maintenance treatment.
 In patients with mild AIH and azathioprine intolerance who have a complete response
after induction therapy, low-dose long-term prednisolone monotherapy may be used to
maintain remission.
 Maintenance dosing should be adjusted so that persistent biochemical response
(normalization of aspartate aminotransferase [AST], alanine aminotransferase [ALT],
and IgG) is maintained.
 Immunosuppression should be administered for at least 3 years and for at least 2
years after a complete biochemical response is achieved.
 Maintenance therapy should not be discontinued without a complete biochemical or
histological response (hepatitis activity index [HAI] score >3).

15.  Monitoring
 Close long-term monitoring should be maintained after treatment is discontinued, since relapses are most common
during the first 6-12 months posttreatment but may occur many years afterward.
 Relapses should be treated in a manner similar to that of the initial treatment schedule; this schedule is also
effective in re-inducing full remission.
 Long-term (probably life-long) maintenance treatment is suggested in patients whose AIH relapses during drug-
withdrawal or maintenance treatment despite adequate treatment (≥4 years of immunosuppression).
 Liver biopsy is recommended before treatment discontinuation in patents with AIH who have been in complete
biochemical remission for at least the last 2 years of immunosuppression.
 Bone density should be measured upon treatment initiation and vitamin D supplementation and adequate calcium
intake recommended in all patients receiving corticosteroid treatment.
 If primary complete biochemical remission does not occur despite adequate treatment, misdiagnosis or
therapy noncompliance should be suspected.
 Treatment adherence is vital for optimal outcomes, especially in children, adolescents, and young adults.
 In patients with azathioprine intolerance, MMF be considered an alternative.

16.  Absolute
 Serum AST 10-fold or more greater than the
upper limit of normal
 Serum AST 5-fold or more greater than the
upper limit of normal and gamma-globulin
level 2-fold or more greater than normal
 Bridging necrosis or multiacinar necrosis on
histologic examination.
 Relative
 Symptoms (eg, fatigue, arthralgia, jaundice)
 Serum AST and/or gamma-globulin less than
absolute criteria
 interface hepatitis .