History
Autoimmune hepatitis may present as acute hepatitis, chronic hepatitis, or well-established cirrhosis. Occasionally, it may present as acute liver failure.
Acute autoimmune hepatitis is common, accounting for 25-75% of new autoimmune hepatitis cases. [3] Patients who present with acute hepatitis may experience fever, hepatic tenderness, and jaundice. In some patients, the acute illness may appear to resolve spontaneously; however, patients invariably develop signs and symptoms of chronic liver disease. A small percentage of patients present with acute severe autoimmune hepatitis, which can progress rapidly to acute liver failure. True acute liver failure (as marked by the new onset of coagulopathy and hepatic encephalopathy) is uncommon. It is seen in 3-6% of new autoimmune hepatitis cases in the United States and Europe. [3]
Cirrhosis is seen in 28-33% of adult patients with autoimmune hepatitis at time of presentation and in about 38% of children at time of presentation. [3] Up to 45% of patients have signs of liver decompensation at time of presentation. [48]
The fact that patients may present with cirrhosis—either well-compensated or decompensated—suggests that patients may be suffering from subclinical autoimmune hepatitis for months or years prior to presentation.
Symptoms of chronic autoimmune hepatitis
The chronic hepatitis associated with autoimmune hepatitis may range in severity from a subclinical illness with abnormal liver chemistries and no symptoms to a disabling chronic liver disease. Symptoms and physical examination findings may stem from the various extrahepatic diseases associated with autoimmune hepatitis. Common symptoms include the following:
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Fatigue
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Upper abdominal discomfort
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Mild pruritus
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Anorexia
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Myalgia
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Diarrhea
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Cushingoid features
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Arthralgias
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Skin rashes (including acne)
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Edema
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Hirsutism
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Amenorrhea
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Chest pain from pleuritis
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Weight loss and intense pruritus (unusual)
Patients with cirrhosis may experience classic symptoms of portal hypertension, namely variceal bleeding, ascites, and hepatic encephalopathy. Patients with complications of cirrhosis should be referred for consideration of liver transplantation.
Associated disease
Autoimmune hepatitis, especially type 2, is associated with a wide variety of other disorders. Involvement of other systems may present at disease onset or may develop during the course of the active liver disease. Most of these conditions are immunologic in origin.
Patients may present with manifestations of the following hematologic disorders:
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Hypersplenism (usually attributable to cirrhosis and portal hypertension)
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Autoimmune hemolytic anemia
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Coombs-positive hemolytic anemia
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Pernicious anemia
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Idiopathic thrombocytopenic purpura
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Eosinophilia
Gastrointestinal disease associated with autoimmune hepatitis includes inflammatory bowel disease, which is seen in 6% of cases. The presence of ulcerative colitis in patients with autoimmune hepatitis should prompt performance of magnetic resonance cholangiopancreatography (MRCP) to exclude a diagnosis of primary sclerosing cholangitis (PSC). A study of 140 pediatric patients with autoimmune hepatitis, autoimmune cholangitis, and overlap syndrome identified 23 patients with celiac disease. [49]
Associated endocrinologic conditions include Graves disease (6%) and autoimmune thyroiditis (12%).
The American Association for the Study of Liver Diseases (AASLD) recommends that patients with a new diagnosis of autoimmune hepatitis undergo serologic testing to rule out thyroid disease and celiac disease. [3]
Associated rheumatologic complications include the following:
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Rheumatoid arthritis and Felty syndrome
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Sjögren syndrome
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Systemic sclerosis
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Mixed connective-tissue disease
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Erythema nodosum
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Leukocytoclastic vasculitis (Patients may present with leg ulcers.)
Other associated conditions are as follows:
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Proliferative glomerulonephritis
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Fibrosing alveolitis
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Pericarditis and myocarditis
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Febrile panniculitis
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Lichen planus
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Uveitis
Autoimmune hepatitis in children
Juvenile autoimmune hepatitis is typically a more aggressive disease than that seen in adults. Its incidence appears to have been on the rise over the last few decades. [50]
A 2018 position statement by the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) summarized how children may present with autoimmune hepatitis, [36] as follows:
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Acute presentation, similar to acute viral hepatitis, is seen in 40-50% of children with autoimmune hepatitis type 1 (AIH-1) or AIH-2.
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Acute liver failure is seen in about 3% of children with AIH-1 and about 25% of children with AIH-2.
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Insidious onset, characterized by nonspecific symptoms (eg, fatigue), is seen in about 40% of children with AIH-1 and about 25% of children with AIH-2.
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Cirrhosis, either well-compensated or decompensated, is seen in at least one-third of patients.
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An incidental finding of abnormal liver chemistries may be present, with or without symptoms. [36]
The symptoms of autoimmune hepatitis in children may include the following [1] :
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Jaundice (58%)
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Nonspecific weakness (57%)
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Anorexia (47%)
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Abdominal pain (38%)
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Pallor (26%)
As in adults, pediatric patients with the following characteristics have a poor prognosis [35] :
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Young age at presentation
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Type 2 autoimmune hepatitis
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Coagulopathy
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Elevated bilirubin
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Severe histologic activity on initial biopsy
Typically, children with autoimmune hepatitis respond well—at least initially—to immunosuppression. Guidelines published by the British Society of Gastroenterology (BSG) in 2011 stated that children with autoimmune hepatitis should receive immunosuppressive treatment to prevent or delay cirrhosis, even if the patient did not have markedly elevated aminotransferases or an elevated gamma globulin. [37]
Treatment failure is seen in about 10% of pediatric patients. [51] Sometimes, these patients respond to an alternative immunosuppressant therapy (eg, mycophenolate mofetil, tacrolimus, rituximab, infliximab); sometimes, liver transplantation is needed to rescue them. [36]
Treatment withdrawal can be achieved successfully in about 19% of pediatric patients with AIH-1 but rarely or never in patients with AIH-2. [52]
Additional autoimmune disorders often occur in children with autoimmune hepatitis. In children with AIH-1, associated autoimmune disorders include the following:
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Ulcerative colitis
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Sclerosing cholangitis
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Arthritis
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Vasculitis
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Glomerulonephritis
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Diabetes mellitus
In children with AIH-2, associated autoimmune disorders include the following:
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Polyendocrinopathy [53]
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Alopecia areata
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Diabetes mellitus
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Thyroiditis
Physical Examination
Common findings on physical examination in patients with autoimmune hepatitis are as follows:
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Hepatomegaly (83%)
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Jaundice (69%)
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Splenomegaly (32%)
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Spider angiomata (58%)
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Ascites (20%)
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Encephalopathy (14%)
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Malnutrition (with poor growth in children)
All of these findings may be observed in patients with disease that has progressed to cirrhosis with ensuing portal hypertension. However, hepatomegaly, jaundice, splenomegaly, and spider angiomata also may be observed in patients who do not have cirrhosis.
Tables
Clinical Features |
Type 1 |
Type 2 |
Type 3 |
Diagnostic autoantibodies |
ASMA ANA Anti-actin |
Anti-LKM P-450 IID6 Synthetic core motif peptides 254-271 |
Soluble liver-kidney antigen Cytokeratins 8 and 18 |
Age |
10 y - elderly |
Pediatric (2-14 y) Rare in adults |
Adults (30-50 y) |
Women (%) |
78 |
89 |
90 |
Concurrent immune disease (%) |
41 |
34 |
58 |
Gamma globulin elevation |
+++ |
+ |
++ |
Low IgA |
No |
Occasional |
No |
HLA association |
B8, DR3, DR4 |
B14, Dr3, C4AQO |
Uncertain |
Steroid response |
+++ |
++ |
+++ |
Progression to cirrhosis (%) |
45 |
82 |
75 |
ANA = antinuclear antibody; anti-LKM = anti-liver-kidney microsomal antibody; ASMA = anti-smooth muscle antibody; HLA = human leukocyte antigen; IgA = immunoglobulin A. |
|||
Absolute Indications |
Relative Indications |
Serum aspartate transaminase (AST) ≥10-fold the upper limit of normal (ULN) |
Symptoms (eg, fatigue, arthralgia, jaundice) |
Serum AST ≥5-fold the ULN and gamma-globulin level ≥2-fold the ULN |
Serum AST and/or gamma-globulin less than absolute criteria |
Bridging necrosis or multiacinar necrosis on histologic examination |
Interface hepatitis |
|
Prednisone Only (mg/d) |
Combination Therapy |
|
Prednisone (mg/d) |
Azathioprine (mg/d) |
||
Week 1 |
60 |
30 |
50 |
Week 2 |
40 |
20 |
50 |
Week 3 |
30 |
15 |
50 |
Week 4 |
30 |
15 |
50 |
Maintenance until end point |
20 |
10 |
50 |
Reasons for preference |
Cytopenia
Thiopurine methyltransferase deficiency
Pregnancy
Malignancy
Short course (≤6 months) |
Postmenopausal state
Osteoporosis
Brittle diabetes
Obesity
Acne
Emotional lability
Hypertension |
|
Initial Regimen |
Maintenance Regimen |
End Point |
Prednisone, 1-2 mg/kg/day (up to 60 mg/day), for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/day |
a. Prednisone taper over 6-8 weeks to 0.1-0.2 mg/kg daily or 5 mg daily
b. Azathioprine at constant dose if added initially
c. Continue daily prednisone dose with or without azathioprine, or switch to alternate day prednisone dose adjusted to response with or without azathioprine |
a. Normal liver tests for 1-2 years during treatment
b. No flare during entire interval
c. Liver biopsy examination discloses no inflammation |
