Autoimmune Hepatitis

Updated: Oct 20, 2021
  • Author: David C Wolf, MD, FACP, FACG, AGAF, FAASLD; Chief Editor: BS Anand, MD  more...
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Practice Essentials

Autoimmune hepatitis is a chronic disease of unknown cause. It is characterized by continuing hepatocellular inflammation and necrosis, and it has the potential to progress to cirrhosis.

Signs and symptoms

Autoimmune hepatitis may present as acute or chronic hepatitis or as well-established cirrhosis. Occasionally, it may present as acute liver failure.

Approximately one third of patients present with symptoms of acute hepatitis marked by fever, hepatic tenderness, and jaundice. Some patients go on to develop signs and symptoms of chronic liver disease, while others rapidly progress to acute liver failure, as marked by coagulopathy and jaundice.

Symptoms and physical examination findings may stem from extrahepatic diseases associated with autoimmune hepatitis. Common symptoms include the following:

  • 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)

Common findings on physical examination are as follows:

  • Hepatomegaly (83%)

  • Jaundice (69%)

  • Splenomegaly (32%)

  • Spider angiomata (58%)

  • Ascites (20%)

  • Encephalopathy (14%)

Pediatric patients

A study of children with autoimmune hepatitis recorded the following clinical findings and their prevalence [1] :

  • Jaundice (58%)

  • Nonspecific weakness (57%)

  • Anorexia (47%)

  • Abdominal pain (38%)

  • Pallor (26%)

See Presentation for more detail.


Laboratory studies

Laboratory findings in autoimmune hepatitis include the following:

  • Elevated serum aminotransferase levels (1.5-50 times reference values)

  • Elevated serum immunoglobulin (Ig) levels, primarily IgG

  • Mild to moderately elevated serum bilirubin and alkaline phosphatase: Marked hyperbilirubinemia can be seen in patients with acute severe autoimmune hepatitis

  • Positive tests for antinuclear antibodies (ANAs) and anti-smooth-muscle antibodies (ASMAs): Tests for antibodies to liver-kidney microsome type 1 (anti-LKM-1), soluble liver antigen (anti-SLA), and liver cytosol type 1 (anti-LC1) may be helpful if ANA and ASMA test results are negative.

  • Prolongation of the international normalized ratio (INR) and hypoalbuminemia: These markers of severe hepatic synthetic dysfunction may be observed in patients with acute severe autoimmune hepatitis or decompensated cirrhosis.

Other hematologic abnormalities may include the following:

  • Mild leukopenia

  • Normochromic anemia

  • Coombs-positive hemolytic anemia

  • Thrombocytopenia

  • Elevated erythrocyte sedimentation rate

  • Eosinophilia (uncommon)


Liver biopsy remains an important part of the diagnostic workup of patients with suspected autoimmune hepatitis.

See Workup for more detail.


For more than four decades, corticosteroids, either alone or in combination with azathioprine, have been the mainstays of drug therapy for patients with autoimmune hepatitis. [2] Budesonide (in combination with azathioprine) is now considered to be first-line therapy for autoimmune hepatitis. [3]

Patients can have highly variable responses to immunosuppressive treatment. Some patients can achieve a long-term biochemical remission and never need retreatment. Other patients relapse after an attempt at treatment withdrawal and may need life-long immunosuppressive therapy. Still others have a disease that is refractory to medical therapy and may experience more rapid progression to cirrhosis than patients who had an adequate response to treatment. [4]

Liver transplantation can save the lives of patients dying from decompensated cirrhosis caused by autoimmune hepatitis. It can also be used to rescue patients with acute liver failure caused by autoimmune hepatitis.

See Treatment and Medication for more detail.



Autoimmune hepatitis is a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis. Progressive fibrosis may lead to cirrhosis. Frequently, immune serum markers are present, including autoantibodies against liver-specific and non–liver-specific antigens and increased immunoglobulin G (IgG) levels. The disease often is associated with other autoimmune diseases, but autoimmune hepatitis cannot be explained on the basis of chronic viral infection, alcohol consumption, or exposure to hepatotoxic medications or chemicals.

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 and hepatic encephalopathy). The workup of such patients should include testing for serum autoantibodies, serum protein electrophoresis, and quantitative immunoglobulins. Urgent liver biopsy, transjugular if appropriate, may help to confirm the clinical suspicion of acute autoimmune hepatitis. (See Workup.)

Rapid institution of treatment with high-dose corticosteroids may rescue patients whose autoimmune hepatitis ultimately would have progressed to either acute liver failure or cirrhosis (see Treatment). Other patients continue to deteriorate in spite of immunosuppressant therapy. Accordingly, a low threshold should exist for transferring patients with acute liver failure to tertiary care hospitals that are capable of performing emergent liver transplantation.

For patient education information, see the Infections Center and Digestive Disorders Center, as well as Hepatitis A (HAV, Hep A), Hepatitis B (HBV, Hep B), Hepatitis C(HCV, Hep C), and Cirrhosis of the Liver.

Historical background

In 1950, Waldenstrom first described a form of chronic hepatitis in young women. [5] This condition was characterized by cirrhosis and plasma cell infiltration of the liver, and it was marked by hypergammaglobulinemia. Kunkel (1950) and Bearn (1956) described other features of the disease, including hepatosplenomegaly, jaundice, acne, hirsutism, cushingoid facies, pigmented abdominal striae, obesity, arthritis, and amenorrhea. [6, 7]

In 1955, Joske first reported the association of the lupus erythematosus (LE) cell phenomenon in active chronic viral hepatitis. [8] This association led to the introduction of the term lupoid hepatitis by Mackay and associates in 1956. [9] However, researchers currently know that no direct link exists between systemic lupus erythematosus (SLE) syndrome and autoimmune hepatitis. Thus, lupoid hepatitis is not associated with SLE and this term is no longer used.

The development of viral serologic tests represented another important step forward. These tests permitted hepatologists to differentiate chronic viral hepatitis from other types of chronic liver disease, including autoimmune hepatitis.

Autoimmune hepatitis now is recognized as a multisystem disorder that can occur in males and females of all ages. It can coexist with other liver diseases (eg, chronic viral hepatitis), and it can also be triggered by certain viral infections (eg, hepatitis A) and chemicals (eg, minocycline).

The histopathologic description of autoimmune hepatitis has undergone several revisions over the years. In 1992, an international panel codified the diagnostic criteria. [10] The term autoimmune hepatitis was selected to replace terms such as "autoimmune liver disease" and "autoimmune chronic active hepatitis." The panel waived the requirement of 6 months of disease activity to establish chronicity, expanded the histologic spectrum to include lobular hepatitis, and reaffirmed the nonviral nature of the disease. The panel also designated incompatible histologic features, such as cholestatic histology, the presence of bile duct injury, and ductopenia.



The proposed pathogenesis of autoimmune hepatitis involves the combination of genetic predisposition and environmental triggers. The genetic predisposition may relate to several defects in immunologic control of autoreactivity. An environmental agent may trigger the autoimmune response against liver antigens, causing necroinflammatory liver damage, fibrosis, and, eventually, cirrhosis, if left untreated.

Genetic predisposition

Genetic susceptibility to developing autoimmune hepatitis has been associated with the human leukocyte antigen (HLA) haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients. [11] HLA-DR3–positive patients are more likely than other patients to have aggressive disease, which is less responsive to medical therapy and more often results in liver transplantation. In addition, these patients are younger than other patients at the time of their initial presentation. HLA-DR4–positive patients are more likely to develop extrahepatic manifestations of their disease. [12]

Patients with autoimmune hepatitis have low levels of T lymphocytes that express the CD8 marker and a specific defect in a subpopulation of T cells that controls the immune response to specific liver cell membrane antigens.

Autoimmune hepatitis has also been associated with the complement allele C4AQO, resulting in a partial deficiency of complement component C4. C4 has a well-known role in virus neutralization; failure to eliminate viruses may lead to immune reaction against antigens on the infected cells.

Environmental triggers

Among several viruses implicated as triggering agents are rubella, Epstein-Barr, and hepatitis A and B.

Drugs may also trigger autoimmune hepatitis; however, no specific drug has been identified as an etiologic agent for this disease. Drug-metabolizing enzymes of phase 1 and phase 2 (ie, cytochrome P-450, uridine diphosphate glucuronosyltransferase proteins) are targets of virus-induced and drug-induced autoimmunity, as well as autoimmune hepatitis.


Autoimmune hepatitis appears to arise a consequence of the breakdown of immune tolerance. Typically, regulatory T cells help to maintain immune homeostasis. A decrease in their number and function may permit unimpeded presentation of liver autoantigen peptides by professional antigen presenting cells (APCs) to CD4+ helper T (Th) cells. This, in turn, may stimulate naïve T cells to differentiate into other T-cell lineages (eg, Th1, Th2, Th17). CD4 Th1 cells produce cytokines such as tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) that stimulate the proliferation of CK8 cytotoxic T lymphocytes (CTLs) and the activation of macrophages. CD4 Th2 cells produce cytokines such as interleukin (IL)-4, IL-5, IL-10, and IL-13 that stimulate B lymphocytes to produce immunoglobulins. Subsequent immunologic reactions ultimately lead to liver cell damage. [3, 13, 14]

Evidence for an autoimmune pathogenesis includes the following [15, 16, 17] :

  • 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 (RF)

  • 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 (ASGPR) or hepatic lectin

  • Antimitochondrial antibody (AMA): AMA is the sine qua non of primary biliary cholangitis (PBC) but may be observed in the so-called overlap syndrome with autoimmune hepatitis.

  • Antiphospholipid antibodies [18]


Based on autoantibody markers, autoimmune hepatitis is recognized as a heterogeneous disorder and has been subclassified into three types. The distinguishing features of these types are noted below in Table 1.

Type 1 autoimmune hepatitis is the most common type in the United States, accounting for 96% of autoimmune hepatitis cases in adults and about 90% of cases in children. [3]

Type 2 autoimmune hepatitis is uncommon in the United States but more frequently described in Europe. For example, type 2 autoimmune hepatitis accounts for 9-12% of autoimmune hepatitis cases in US children, as opposed to 38% of cases in children in the United Kingdom. [3]

Note that patients with type 3 autoimmune hepatitis have the same histologic features as patients with type 1 autoimmune hepatitis. Similarly, type 3 autoimmune hepatitis is typically responsive to steroid therapy. Some authors have questioned whether type 3 autoimmune hepatitis actually represents a separate and distinct disease phenotype. [19]

Autoantibody-negative hepatitis, also called 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. [20]


Table 1. Clinical Characteristics of Autoimmune Hepatitis [21] (Open Table in a new window)

Clinical Features

Type 1

Type 2

Type 3

Diagnostic autoantibodies





P-450 IID6

Synthetic core motif peptides 254-271

Soluble liver-kidney antigen

Cytokeratins 8 and 18


10 y - elderly

Pediatric (2-14 y)

Rare in adults

Adults (30-50 y)

Women (%)




Concurrent immune disease (%)




Gamma globulin elevation




Low IgA




HLA association

B8, DR3, DR4

B14, Dr3, C4AQO


Steroid response




Progression to cirrhosis (%)




ANA = antinuclear antibody; anti-LKM = anti-liver-kidney microsomal antibody; ASMA = anti-smooth muscle antibody; HLA = human leukocyte antigen; IgA = immunoglobulin A.



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.

Some cases of drug-induced liver disease have an immune-mediated basis. A number of drugs (eg, methyldopa, nitrofurantoin, minocycline, [22] adalimumab, [23] infliximab [24] ) can produce an illness with 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. [25]

Casswall et al found Helicobacter species DNA in 50% of liver biopsies from patients with autoimmune hepatitis and ulcerative colitis. [26] The significance of this finding is unclear.



The prevalence of autoimmune hepatitis is estimated at 31.2 cases per 100,000 persons in the United States. This is comparable to prevalence rates that are reported in Europe. [27] The prevalence of autoimmune hepatitis is as high as 43 cases per 100,000 persons in a native Alaskan population. [28] Autoimmune hepatitis is more common in Whites, compared to Blacks, Asians, and Hispanics. [27]

Autoimmune hepatitis is more prevalent in women than men, although men may be affected more commonly than women in older age groups. Amongst adults, 71-95% of patients are women. Amongst children, 60-76% of patients are girls. [3] In patients with type 2 autoimmune hepatitis, more than 90% of patients are female.

Classically, the new onset of autoimmune hepatitis was most commonly reported in the 10-30 and 40-60 age ranges. A study from New Zealand, however, reported that 72% of patients presented after age 40, with a peak age of presentation in the sixth decade of life. [29] Autoimmune hepatitis may occur in people of any age, including infants and older adults. [30, 31, 32] The diagnosis should not be overlooked in individuals older than 70 years. [33]



The prognosis of autoimmune hepatitis is excellent for many patients, particularly those who present with minimal or mild liver inflammation and fibrosis. Unfortunately, many patients experience more aggressive disease and have a worse prognosis.

Factors associated with a worse prognosis include the following:

  • Young age at presentation

  • Acute presentation

  • Hyperbilirubinemia

  • Human leukocyte antigen (HLA) DRB1*03 positivity [34]

Patients with type 2 autoimmune hepatitis appear to have a worse prognosis than patients with type 1 autoimmune hepatitis.

Patients with a severe initial presentation or severe inflammation on liver biopsy tend to have a worse long-term outlook than patients whose initial disease is mild. Similarly, the inability to enter remission or the development of multiple relapses, either during therapy or after treatment withdrawal, implies a worse long-term prognosis. [4]

About 25-34% of patients are asymptomatic at the time of presentation. [3] Some patients present with symptoms similar to those of acute viral hepatitis (eg, fatigue, nausea, vomiting, anorexia, abdominal pain).

Up to 50% of patients are jaundiced at the time of their presentation. About 30% of adults and 38% of children with type 2 autoimmune hepatitis have cirrhosis on liver biopsy at time of initial presentation. [35, 36] Some, but not all, studies suggest that patients who experience the new onset of autoimmune hepatitis with cirrhosis have a worse prognosis than those without cirrhosis. [37]

Acute severe autoimmune hepatitis is defined as autoimmune hepatitis of less than 26 weeks of duration, in which patients experience jaundice and coagulopathy (ie, international normalized ratio [INR] ≥1.5] but do not have evidence of hepatic encephalopathy. Its precise incidence is not well established. Some cases of acute severe autoimmune hepatitis will progress to acute liver failure, which is characterized by the new onset of coagulopathy and hepatic encephalopathy. A German study found that 9% of 565 patients with autoimmune hepatitis experienced acute liver failure as their initial presentation. [38]

The impact of immunosuppressant therapy on prognosis

Prior to the 1970s, most individuals diagnosed with autoimmune hepatitis (then termed “chronic active hepatitis”) died from their disease. Multiple studies in the early 1970s demonstrated the positive impact of corticosteroid therapy on disease outcomes. Sherlock and colleagues looked at the long-term impact of prednisolone therapy on survival and found that 63% of treated patients were alive at 10 years compared with only 27% of untreated patients in the control group (log rank test, P = 0.03). [39] The median survival in the treatment group was 12.2 years versus 3.3 years in the control group.

More recent literature described markedly improved outcomes with immunosuppressive treatment. Czaja and colleagues reported a 90% transplant-free survival at 10 years for patients without cirrhosis at presentation and 89% for patients with cirrhosis at presentation. [40] These survival rates were similar to those of the general population. [41]

Studies utilizing serial liver biopsies have demonstrated how successful immunosuppressive therapy can improve both liver inflammation and fibrosis, potentially preventing the development of cirrhosis. [42]

Potential outcomes of immunosuppressant therapy

The goal of treatment is disease remission. In remission, patients experience the improvement of symptoms, the normalization of abnormal liver chemistries and gamma globulin levels, and the reduction or elimination of inflammatory activity on liver biopsy.

Most patients who embark on a course of immunosuppressant therapy respond well initially. More than 90% of adults started on corticosteroid treatment experience improvements in liver chemistries and gamma globulin levels within 2 weeks. [40]

Remission, if it is to be achieved, typically requires 18-24 months of immunosuppressant therapy. Remission can be achieved in about 65% of patients within 18 months and 80% of patients within 3 years. [43] Once a drug-induced remission is achieved, an attempt should be made to withdraw immunosuppression. However, a sustained remission after total drug withdrawal is seen in 13% of patients at 5 years. [43] Patients who relapse need to restart long-term immunosuppressant therapy in an effort to normalize their biochemical abnormalities and to delay the progression of liver disease. Many such patients are maintained on chronic maintenance therapy with azathioprine.

About 13% of patients experience an incomplete response to treatment, without worsening of their condition. Most incomplete responders need long-term immunosuppression in an attempt to stabilize levels of aspartate transaminase (AST) and alanine aminotransferase (ALT) and—by extension—prevent disease progression.

Treatment failure occurs in about 9% of patients. In this setting, patients experience deterioration in their clinical, biochemical, or histologic status despite immunosuppressant therapy. A trial of high-dose prednisone in conjunction with azathioprine may be warranted. Alternative medications like cyclosporine and tacrolimus may be employed as well. However, aggressive medical therapy should not be employed indefinitely. Patients whose condition failed conventional treatment are at increased risk progression of their disease to decompensated cirrhosis. [44]

If cirrhosis is suspected in a patient with autoimmune hepatitis, that individual should be entered into a surveillance program to rule out the development of hepatocellular carcinoma as a complication of cirrhosis. Typically, hepatocellular carcinoma arises in about 3% of cirrhotic patients each year. In patients whose cirrhosis was caused by autoimmune hepatitis, the 10-year likelihood of developing hepatocellular carcinoma is 2.9%. [44]

Even with excellent immunosuppression management, the long-term mortality for patients with autoimmune hepatitis is higher than that of the general population. [45] A 2019 review reported that the percentage of patients who required liver transplant or died was a median of 13% (range, 5-26%) at 10 years after diagnosis and a median of 31% (range, 18-53%) at 20 years after diagnosis. [46] The prognosis is more grim for patients with acute severe autoimmune hepatitis and acute liver failure. As few as 7-15% of these patients respond to medical therapy, and they will either go on to undergo liver transplantation or die. [47]