Autoimmune Hepatitis

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.

Diagnosis

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)

Biopsy

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

See Workup for more detail.

Management

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.

• References

Background

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.

• References

Pathophysiology

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.

Pathogenesis

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]

Classification

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]

View Table

See Table

• References

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.

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.

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Epidemiology

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]

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Prognosis

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]

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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:

• 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)

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:

• Hypersplenism (usually attributable to cirrhosis and portal hypertension)
• Autoimmune hemolytic anemia
• Coombs-positive hemolytic anemia
• Pernicious anemia
• Idiopathic thrombocytopenic purpura
• 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:

• Rheumatoid arthritis and Felty syndrome
• Sjögren syndrome
• Systemic sclerosis
• Mixed connective-tissue disease
• Erythema nodosum
• Leukocytoclastic vasculitis (Patients may present with leg ulcers.)

Other associated conditions are as follows:

• Proliferative glomerulonephritis
• Fibrosing alveolitis
• Pericarditis and myocarditis
• Febrile panniculitis
• Lichen planus
• 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:

• Acute presentation, similar to acute viral hepatitis, is seen in 40-50% of children with autoimmune hepatitis type 1 (AIH-1) or AIH-2.
• Acute liver failure is seen in about 3% of children with AIH-1 and about 25% of children with AIH-2.
• 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.
• Cirrhosis, either well-compensated or decompensated, is seen in at least one-third of patients.
• 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] :

• Jaundice (58%)
• Nonspecific weakness (57%)
• Anorexia (47%)
• Abdominal pain (38%)
• Pallor (26%)

As in adults, pediatric patients with the following characteristics have a poor prognosis^[35] :

• Young age at presentation
• Type 2 autoimmune hepatitis
• Coagulopathy
• Elevated bilirubin
• 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:

• Ulcerative colitis
• Sclerosing cholangitis
• Arthritis
• Vasculitis
• Glomerulonephritis
• Diabetes mellitus

In children with AIH-2, associated autoimmune disorders include the following:

• Polyendocrinopathy^[53]
• Alopecia areata
• Diabetes mellitus
• Thyroiditis

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Physical Examination

Common findings on physical examination in patients with autoimmune hepatitis are as follows:

• Hepatomegaly (83%)
• Jaundice (69%)
• Splenomegaly (32%)
• Spider angiomata (58%)
• Ascites (20%)
• Encephalopathy (14%)
• 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.

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Approach Considerations

Clinicians must consider the diagnosis of autoimmune hepatitis in any patient who presents with abnormal liver chemistries, acute hepatitis, or acute liver failure (defined by the new onset of coagulopathy and hepatic encephalopathy).

In addition to aminotransferase levels and other liver function studies (albumin, bilirubin, alkaline phosphatase, international normalized ratio [INR]), the workup of such patients should include the following assays:

• Serum antinuclear antibody (ANA)
• Anti–smooth muscle antibody (ASMA)
• Anti-mitochondrial antibody (AMA)
• Quantitative immunoglobulins (IgG, IgA, IgM)

Additional testing may include the following:

• Liver-kidney microsomal type 1 (LKM-1) antibody
• Anti-soluble liver antigen (anti-SLA): This test should be considered if tests for ASMA and AMA are negative.
• Serum protein electrophoresis (SPEP)

Other tests that may be considered, particularly in the setting of acute severe autoimmune hepatitis include the following:

• Anti-hepatitis A virus (anti-HAV) total and IgM
• Hepatitis B core (HBc) IgG and IgM, hepatitis B surface Ag (HBsAg), hepatitis B surface Ab (HBsAb)
• Anti-HCV, HCV RNA [Note: One-time anti-HCV testing is now recommended by the Centers for Disease Control and Prevention (CDC) for all US adults]
• Anti-hepatitis E virus (anti-HEV) IgM (and HEV RNA if anti-HEV IgM results are positive)
• Anti-herpes simplex virus (anti-HSV) IgM
• Epstein Barr Virus (EBV) DNA
• Cytomegalovirus (CMV) DNA
• Anti-varicella zoster virus (anti-VZV) IgM
• Parvovirus B19 IgG and IgM

Laboratory findings in autoimmune hepatitis include the following:

• Elevated serum aminotransferase levels (1.5-50 times reference values)
• Elevated serum immunoglobulin levels, primarily IgG
• Seropositive results for ANA, ASMA, anti-LKM-1, anti-SLA, or anti–liver cytosol 1 (anti-LC1)

While serologic tests may help the clinician make a correct a diagnosis of autoimmune hepatitis, it should be recalled that liver biopsy plays a pivotal role in the evaluation. The 2019 American Association for the Study of Liver Diseases (AASLD) practice guideline states: “The diagnosis of autoimmune hepatitis cannot be made without liver biopsy and compatible histologic findings.”^[3]

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Autoantibody Assays

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 antinuclear antibody (ANA) and anti–smooth muscle antibody (ASMA) test results are negative.

Autoimmune hepatitis is characterized by positive findings on autoantibody tests, as follows:

• AIH-1: ASMA and ANA
• AIH-2: Anti-LKM-1 antibody
• AIH-3: Anti-SLA

The 2019 AASLD Practice Guidelines indicate the following findings in White North American adults at time of presentation with autoimmune hepatitis^[3] :

• ANA is positive in 80%. Note that ANA may be positive in other chronic liver diseases and in healthy adults.
• ASMA is positive in 63%. Note that ASMAs occur in low titers in healthy children and patients with viral hepatitis and other diseases that do not affect the liver.
• Anti-LKM1 is positive in 3%.
• Anti-SLA is positive in 7-22%.

In patients with type 2 autoimmune hepatitis, note the following:

• Anti-LKM1 antibodies are positive in 40-45%.
• Anti-LC1 antibodies occur alone in 30% of patients with autoimmune hepatitis type 2 (AIH-2).

Other autoantibodies may be evident. Atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) are frequently present. Anti-asialoglycoprotein receptor antibodies (anti-ASGPR) occur more often in patients with AIH-1 and may serve as a marker of inflammatory activity.

Of the multiple forms of ASMAs, antibodies against filamentous (F) actin may have the highest sensitivity for identifying patients with autoimmune hepatitis. They are seen in upward of 86% of patients.^[55]

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Serum Proteins and Immunoglobulins

An immunoglobulin G (IgG)-predominant polyclonal hypergammaglobulinemia is a common finding in patients with untreated autoimmune hepatitis. Gamma globulin values typically range from 3 to 4 g/dL and frequently are as high as 5-6 g/dL. Cases of hyperviscosity syndrome secondary to high IgG levels have been reported. Autoimmune hepatitis is an unlikely diagnosis in patients who have acute hepatitis without hypergammaglobulinemia.

The gamma globulin or the IgG level may be followed on a regular basis as a marker of disease responsiveness to therapy.

Patients with autoimmune hepatitis type 2 (AIH-2) commonly have partial IgA deficiency.^[53]

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Aminotransferases

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. Aminotransferase values correlate poorly with the degree of hepatic necrosis; however, values in the thousands may indicate acute severe autoimmune hepatitis or a severe flare of preexisting disease.

Continued elevation of the aminotransferases in the face of continuing therapy is a reliable marker for ongoing inflammatory activity in the liver. 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 3-8 months.

Typically, patients are treated for at least 1 year after documentation of normal liver chemistries. Liver biopsy is recommended by some experts to confirm that the patient is in histologic remission. Drug withdrawal may be attempted at this time (see Treatment).

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

Serum bilirubin and alkaline phosphatase (ALP) values are mildly to moderately increased in 80-90% of patients. Marked hyperbilirubinemia can be seen in patients with acute severe autoimmune hepatitis. A sharp increase in the ALP values over the course of autoimmune disease might reflect the development of primary sclerosing cholangitis (PSC) or the onset of hepatocellular carcinoma as a complication of cirrhosis.

Hypoalbuminemia and prolongation of the prothrombin time are markers of severe hepatic synthetic dysfunction, which may be observed in severe acute autoimmune hepatitis or decompensated cirrhosis.

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Complete Blood Cell 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 (ESR)

Eosinophilia is uncommon, but counts ranging from 9% to 48% are described. Autoimmune hepatitis has even been described as the sole presenting feature of idiopathic hypereosinophilic syndrome (HES).

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Hepatic Imaging Studies

Imaging studies, in general, are not helpful in reaching a definitive diagnosis of autoimmune hepatitis. However, the presence of heterogeneous hepatic echotexture on abdominal ultrasonography or abnormal contrast enhancement on abdominal computed tomography (CT) imaging may suggest the presence of active inflammation or necrosis.

The appearance of an irregular, nodular liver may confirm the presence of cirrhosis. Patients with suspected cirrhosis due to autoimmune hepatitis should undergo routine surveillance to rule out the development of hepatocellular carcinoma as a complication of cirrhosis. Typically, this involves the performance of a hepatic sonogram every 6 months, as well as blood testing for alpha fetoprotein (AFP). Abdomen CT scanning or magnetic resonance imaging (MRI) should be performed if a liver mass is discovered on ultrasonography.

Primary sclerosing cholangitis (PSC) needs to be ruled out in autoimmune hepatitis patients with either a rising alkaline phosphatase (ALP) level or a concomitant diagnosis of ulcerative colitis. MRI with MR cholangiopancreatography (MRCP) is an excellent noninvasive test to investigate the possibility of PSC.

• References

Liver Biopsy

Liver biopsy is the most important diagnostic procedure in patients with autoimmune hepatitis. This procedure can be performed percutaneously, with or without ultrasonographic 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, if the liver is small and shrunken, or if the liver is difficult to reach percutaneously.

Liver biopsy routinely is performed in the outpatient setting to investigate abnormal liver chemistries. 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.

The role of biopsy in patients presenting with well-established cirrhosis secondary to autoimmune hepatitis is less clear. For example, the initiation of treatment in a patient with cirrhosis, normal aminotransferase levels, and a minimally elevated gamma globulin level is not expected to influence the disease outcome.

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Histologic Findings

Histopathologic findings on liver biopsy specimens are crucial to determining the diagnosis of autoimmune hepatitis and the disease severity. Liver biopsy findings can help to differentiate autoimmune hepatitis from chronic hepatitis C virus (HCV) infection, alcohol-induced hepatitis, drug-induced liver disease, primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).^[56]

Key histologic features defined in the 2008 “simplified criteria” published by the International Autoimmune Hepatitis Group (IAHIG) include the following^[57] :

• Interface hepatitis: Lymphocytes and plasma cells infiltrate the portal tract and expand beyond its limiting plate to permeate the surrounding liver lobule. The infiltrate is commonly plasma cell predominant.
• Emperipolesis: Lymphocytes may penetrate the cytoplasm of damaged hepatocytes.
• Hepatocyte rosette formation: Small groups of hepatocytes appear to be arranged around a small central lumen.

Lobular hepatitis and perivenulitis (involving the terminal hepatic venule) also may be seen.

Fibrosis is present in most patients with autoimmune hepatitis. Without effective therapy, fibrosis starts to connect the portal and central areas, ultimately leading to cirrhosis.

Simplified criteria for making a diagnosis of autoimmune hepatitis

The IAHIG published its initial diagnostic scoring system for making a diagnosis of autoimmune hepatitis in 1993.^[10] The system was initially designed for research purposes. A revised version was published in 1999, but it was still felt to be cumbersome by some users.^{[58, 59]} The simplified system was introduced in 2008 and was found to be highly reliable.^[57]

The simplified IAHIG diagnostic scoring system is as follows^[57] :

• If the antinuclear antibody (ANA) or smooth muscle antibody (SMA) cutoff is ≥1:40, assign 1 point
• If the ANA or SMA cutoff is ≥1:80 ---
• Or, soluble liver antigen (SLA) is positive ---
• Or, if the liver-kidney microsome (LKM) cutoff is ≥1:40, assign 2 points (addition of points achieved for all autoantibodies, for a maximum of 2 points)
• If immunoglobulin G (IgG) is over the upper limit of normal (ULN), assign 1 point; if it is over 1.10 times the ULN, assign 2 points
• If the liver histology (evidence of hepatitis is required) is compatible with autoimmune hepatitis, assign 1 point; if it is typical of autoimmune hepatitis, assign 2 points
• If viral hepatitis is absent, assign 2 points

If the total score is at least 6 points, autoimmune hepatitis is probable. If it is at least 7, then autoimmune hepatitis is definite.

• References

Approach Considerations

After making a diagnosis of autoimmune hepatitis, it is incumbent upon the physician to educate the patient as to their risk of progressing to advanced liver disease. It is important to review the following goals of treatment with the patient:

• Improvement of liver inflammation
• Improvement of liver chemistries
• Improvement of symptoms
• Prevention of disease progression (eg, to cirrhosis)
• Minimization of risks of immunosuppressive therapy

Patients should also be informed that while some individuals can achieve a drug-free remission after only a year or two of treatment, many patients need life-long monitoring and treatment.

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, 17]} Treatment must be individualized for patients with autoimmune hepatitis.^[16] Considerable variation in practice style exists when answering the following common clinical questions:

• How high a dose of prednisone should be used when initiating therapy?
• When should azathioprine be added to the patient's treatment regimen?
• When should a reduction in steroid dosing be considered?
• How long should treatment continue beyond biochemical remission?
• Should liver biopsy be performed to document histologic remission, prior to attempting withdrawal of immunosuppression?
• Should patients receive life-long low-dose maintenance therapy with azathioprine?

Patients with autoimmune hepatitis who are asymptomatic should undergo the same treatment strategy as symptomatic patients, because both groups experience a similar course of disease progression and clinical response to immunosuppressive medications.^[60]

Azathioprine is metabolized to 6-mercaptopurine (6-MP). One of the enzymes responsible for this is thiopurine methyltransferase (TPMT). About 0.3% of the population possesses mutations of the genes coding for TPMT. These individuals, with low or no TPMT activity, may develop excess levels of the metabolite 6-thioguanine (6-TG). High 6-TG levels, in turn, may predispose the patient to bone marrow suppression. Many authors—and the 2019 American Association for the Study of Liver Diseases (AASLD) Practice Guideline—recommend that patients undergo TPMT genotyping prior to the initiation of azathioprine therapy.^{[44, 3]}

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Initial Therapy for Adults and Children

The American Association for the Study of Liver Diseases (AASLD) published detailed guidelines regarding the management of autoimmune hepatitis in 2010 and 2019.^{[44, 3]}

The 2010 AASLD guideline delineated absolute and relative indications for immunosuppressive treatment.^[44]  See Table 2, below.

Table 2. Indications for Treatment of Autoimmune Hepatitis in Adults

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Note that many patients with cirrhosis and active autoimmune hepatitis respond well to immunosuppression.

The 2010 AASLD guideline also described the following contraindications to treatment^[44] :

• Asymptomatic patients with normal or near normal aspartate aminotransferase (AST) and gamma globulin levels
• Inactive cirrhosis (with minimal or no portal inflammation)
• Severe osteoporosis, psychosis, brittle diabetes, or uncontrolled hypertension (precluding treatment with prednisone)
• Severe cytopenias or patients with complete deficiency of thiopurine methyltransferase (TPMT) (precluding treatment with azathioprine)

In addition, treatment might not be appropriate in patients with decompensated liver disease (eg, a patient with massive ascites or severe hepatic encephalopathy). Such individuals might be better served by liver transplantation.

The 2010 AASLD guideline also recommended initial treatment strategies for adults as shown in Table 3, below.^[44]

Table 3. Treatment Regimens for Adults

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The AASLD guideline also propose an initial treatment regimen for children (see Table 4, below).

Table 4. Treatment Regimens for Children

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See Table

In the authors’ opinions, the recommendations from the 2010 AASLD guideline had a major weakness: The dosages of prednisone recommended for adults and children may have been appropriate for patients with acute severe autoimmune hepatitis, but they were too high for most outpatients with mild or moderately severe disease. This weakness was remedied in the 2019 guideline.

The 2019 guideline stated the starting dosage of prednisone in adults could be as low as 20 mg. In addition, it recommended routine TPMT testing prior to embarking on azathioprine therapy. It acknowledged the utility of budesonide as a potential initial treatment for adults and children with autoimmune hepatitis without cirrhosis. It also acknowledged the safety of using azathioprine throughout pregnancy.^[3]

The 2019 guideline recommendations for initial treatment of autoimmune hepatitis can be summarized as follows^[3] :

Initial treatment for autoimmune hepatitis without cirrhosis

• Adults can initiate treatment with prednisone 20-40 mg/day.
• Children can initiate treatment with prednisone 1-2 mg/kg/day.
• As an alternative, both adults and children can initiate treatment with budesonide 9 mg per day. Budesonide treatment has the potential advantage of reducing steroid-specific side effects.
• Azathioprine (at a dose of 50-150 mg/day) can be initiated after 2 weeks, provided that TPMT testing has ruled out a complete deficiency of TPMT activity.
• Laboratory tests should be followed every 1-2 weeks.
• Response to treatment should be assessed at 4-8 weeks. For patients with a biochemical response, prednisone can be tapered to 5-10 mg daily (and budesonide to 3 mg daily) over the next 6 months. Treatment with azathioprine should be maintained. For patients without a biochemical response, either the diagnosis of autoimmune hepatitis should be reconsidered or second-line drugs (eg, mycophenolate mofetil or tacrolimus) can be employed.

Initial treatment for autoimmune hepatitis with cirrhosis

• Budesonide should be avoided, due to concerns that the portosystemic shunting of cirrhosis might permit budesonide to bypass the liver, thereby reducing drug efficacy.
• Adults can initiate treatment with prednisone 20-40 mg/day.
• Children can initiate treatment with prednisone 1-2 mg/kg/day.
• In patients with well-compensated cirrhosis, azathioprine (at a dose of 50-150 mg/day) can be initiated after 2 weeks, providing that TPMT testing has ruled out a complete deficiency of TPMT activity.
• In patients with decompensated cirrhosis, azathioprine should not be used.
• Laboratory tests should be followed every 1-2 weeks.
• Response to treatment should be assessed at 4-8 weeks. For patients with a biochemical response, prednisone can be tapered to 5-10 mg daily over the next 6 months. If started, azathioprine should be maintained. For patients without a biochemical response, either the diagnosis of autoimmune hepatitis should be reconsidered or second-line drugs (eg, mycophenolate mofetil or tacrolimus) can be employed.

Maintenance therapy for autoimmune hepatitis, with or without cirrhosis, who have achieved biochemical remission

• Laboratory tests should be followed every 3-4 months.
• Steroid withdrawal may be attempted while continuing azathioprine.
• If patients achieve a prolonged biochemical remission (eg, 24 months)—perhaps after performance of a second liver biopsy—immunosuppression withdrawal may be attempted. Laboratory tests should continue to be followed every 4-6 months.

Initial treatment for acute severe autoimmune hepatitis

• Adults can initiate treatment with prednisone 60 mg/day.
• Children can initiate treatment with prednisone 2 mg/kg/day or intravenous (IV) steroids.
• Neither budesonide nor azathioprine should be used.
• Laboratory tests should be followed every 12-24 hours.
• Response to treatment should be assessed at 7-14 days. For patients with a biochemical response, the prednisone dose can be reduced cautiously. Azathioprine can be introduced after jaundice resolves (providing that TPMT testing has ruled out a complete deficiency of TPMT activity). Laboratory tests should continue to be followed every 1-2 weeks. For patients without a biochemical response, either the diagnosis of autoimmune hepatitis should be reconsidered, or second-line drugs (eg, tacrolimus) can be used. Liver transplant evaluation should be initiated. Patients should undergo urgent liver transplantation if hepatic encephalopathy develops.

Maintenance therapy for acute severe autoimmune hepatitis patients who have achieved biochemical remission

• Laboratory tests should be followed every 3-4 months.
• Patients should be maintained on the lowest immunosuppression doses necessary to maintain remission.
• Immunosuppression should not be withdrawn.

In 2010, Manns et al conducted a randomized trial of 203 noncirrhotic patients with noncirrhotic autoimmune hepatitis.^[61] Patients were treated with azathioprine at a dose of 1-2 mg/kg/day and randomized to receive either budesonide 3 mg (2-3 times per day) or prednisone (40 mg tapering to 10 mg daily) for 6 months. At 6 months, 60% of the budesonide-treated patients achieved a complete biochemical response as opposed to 39% of the prednisone-treated patients (P = 0.001).^[61] Budesonide-treated patients had fewer steroid-specific side effects than prednisone-treated patients (28% vs 53%, P< 0.001).

Budesonide plus azathioprine had equivalent efficacy to prednisone plus efficacy in a trial of 46 children and adolescents.^[62]

Budesonide therapy also offers the promise of less weight gain and other steroid side effects. A trial conducted in patients with Crohn disease showed less of a reduction in bone mineral density in patients treated with budesonide than with prednisolone.^[63]

Alternative first-line treatments

A few studies have investigated alternatives to the classical regimens of corticosteroids plus azathioprine. Mycophenolate mofetil,^[64] cyclosporine,^{[65, 66]} and tacrolimus^[67] all showed promising early results.

Treatment of overlap syndromes

A little more than 10% of autoimmune hepatitis patients have an overlap syndrome with either primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC). There is a paucity of data on how best to treat such patients.

Treatment combining immunosuppressants and ursodiol may be advisable in patients with the autoimmune hepatitis-PBC overlap syndrome. In a study of noncirrhotic patients, fibrosis progression was seen in 0 of 6 patients treated with combination therapy, versus 4 of 8 patients treated with ursodiol monotherapy.^[68] The mean duration of follow-up was 7.5 years.

Another study looked at 7 patients with autoimmune hepatitis-PSC overlap syndrome, comparing them to 34 patients with “classical” PSC.^[69] All patients were treated with ursodiol 15-20 mg/kg/day. The patients with autoimmune hepatitis-PSC also received prednisolone in combination with azathioprine. Survival rates were superior in the autoimmune hepatitis-PSC overlap syndrome group.^[69] The median duration of follow-up was 8 years.

• References

Treatment Endpoints

Patients may achieve 1 of 4 treatment end points, as follows^[44] :

• Remission
• Treatment failure
• Incomplete response
• Drug toxicity

Remission

Definition

Remission is defined as a combination of the following:

• Resolution of symptoms
• Normalization of aminotransferases, bilirubin, and gamma globulin (ie, biochemical remission)
• Resolution inflammation on liver biopsy (ie, histologic remission)

In adults, clinical, biochemical, and histologic remission can be achieved in about 65% of patients within 18 months and 80% of patients within 3 years.^[43] In children, remission is achieved in 60-90% of patients.^[36]

Treatment withdrawal

There are no firm guidelines regarding the duration of therapy in either adults or children. However, most patients need relatively long courses of immunosuppressant therapy. It is common for treatment to continue for 1.5-2 years or longer before an attempt is made to withdraw all immunosuppression medications. Provided that the patient is maintained on azathioprine, corticosteroid withdrawal can be attempted after the patient achieves a biochemical remission.

Histologic remission tends to lag behind biochemical remission by 3-8 months.^[44] The persistence of portal plasma cell infiltration on liver biopsy has been associated with an increased risk of disease relapse after the discontinuation of corticosteroid therapy.^[70] Accordingly, many clinicians in the past recommended the routine performance of a liver biopsy prior to attempting to withdraw treatment. This practice is no longer routinely recommended in adults.^{[3, 71]} However, the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) continues to recommend liver biopsy prior to treatment withdrawal in children.^[36]

Relapse after treatment withdrawal

Relapse occurs in 50-85% of adults and 60-80% of children after treatment withdrawal.^[3] One-half of relapses occur within the first 6 months after stopping medications.^[43] Encouragingly, the vast majority of patients who relapse respond to retreatment with their original treatment regimen.^[3]

Most patients who relapse require indefinite therapy with either prednisone or azathioprine. Medication doses should be titrated down to as low as possible to maintain aminotransferase levels within the reference range.

Some authors advocate indefinite treatment with azathioprine only. In a study by Johnson et al, 60 of 72 patients (83%) receiving long-term therapy with azathioprine at a dose of 2 mg/kg/day remained in remission, with a median follow-up period of 67 months (range, 12-128 months).^[72]

Patients should be cautioned against premature withdrawal of drug therapy. Abrupt discontinuation of medical therapy is not infrequently complicated by an acute flare of disease activity. Such flares may be severe and potentially life-threatening.

Treatment failure

Treatment failure is defined as deterioration in a patient's clinical condition, laboratory test results, or histologic features after starting standard therapy. It is a serious condition that is seen in about 9% of patients.^[44] Treatment failure may be noted in as little as 3-6 weeks after initiating therapy for autoimmune hepatitis.

High-dose prednisone (60 mg/day) alone or prednisone (30 mg/day) plus azathioprine (150 mg/day) are alternative approaches when standard therapy fails. Patients whose condition is resistant to steroids can be treated with cyclosporine or tacrolimus. The use of these medications is supported by a number of small case series.^{[17, 73, 74, 67]} Rituximab has been used in a some patients as well.

Although many patients with initial treatment failure will respond to more aggressive therapy, other patients will continue to deteriorate despite treatment. They may require early liver transplantation to survive.^[44]

Incomplete response

Incomplete response is defined as an improvement that is insufficient to satisfy remission criteria. It is estimated to occur in 13% of patients.^[44] Many such patients require indefinite treatment with as low an immunosuppressant dose as is needed to prevent clinical deterioration. Long-term treatment options include prednisone at doses of up to and including 10 mg/day and azathioprine at a dose of 2 mg/kg/day.^[44]

A few studies have supported the use of mycophenolate mofetil in patients whose disease was refractory to standard therapy.^{[17, 75, 76, 77, 78, 79]} Mycophenolate 1 g twice per day was a typical starting dose. There are no clear guidelines as to how mycophenolate mofetil should be tapered if a therapeutic response has been achieved. Limited data are available regarding the use of budesonide, tacrolimus,^[80] methotrexate, and other agents in patients who were incomplete responders.

Drug toxicity

Drug toxicity is not uncommon during treatment for autoimmune hepatitis. Up to 13% of patients discontinue corticosteroids due to their side effects. Up to 10% of patients discontinue azathioprine due to its side effects.^[44] Most clinicians view long-term use of azathioprine more favorably than they do corticosteroids; they consider azathioprine to be a steroid-sparing agent.

Patients should be counselled regarding potential drug-related side-effects before starting treatment. Classic dermatologic and systemic side-effects of corticosteroids include facial rounding, striae, acne, alopecia, facial hirsutism, weight gain and cataracts. Classic endocrinologic and orthopedic complications include diabetes, vascular joint necrosis, osteopenia, osteoporosis, and vertebral compression fractures. [The authors advise the routine institution of treatment with calcium and vitamin D when corticosteroid therapy is begun. Regular exercise should be encouraged. Bone densitometry should be performed routinely to monitor patients. Signs of early osteoporosis might warrant the institution of treatment with alendronate.] Other potential side effects include emotional lability, hypertension, and pancreatitis.

Azathioprine is commonly associated with cytopenias, which may improve with dose reduction. Cytopenias, particularly leukopenia, may occur at any time after initiation of azathioprine therapy. All patients undergoing treatment with azathioprine should receive routine testing of the complete blood cell (CBC) count with differential count at least once every 3 months. Severe bone marrow failure is seen infrequently. It is hoped that routine thiopurine methyltransferase (TPMT) testing prior to starting azathioprine treatment might reduce the incidence of this dreaded side effect.

Other common side effects of azathioprine include nausea, vomiting, and rash. These symptoms may prompt the early, premature discontinuation of azathioprine therapy. Less common side effects include pancreatitis and cholestatic hepatitis.

To date, most studies of azathioprine efficacy in autoimmune hepatitis have used a dose of 50 mg/day. In contrast, many authors in the field of inflammatory bowel disease (IBD) suggest individualizing the dose so that patients achieve a 6-thioguanine level of 230-400 pmol per 8 × 10⁸ erythrocytes.^[81] This level has been associated with optimal clinical outcomes for patients with IBD. It remains to be determined whether such an approach should be applied to azathioprine dosing in patients with autoimmune hepatitis.

Hematologic malignancy has been reported in patients undergoing treatment with azathioprine; however, the risk of malignancy is thought to be low in patients with autoimmune hepatitis who are treated with low doses of the drug.

The gastroenterology literature is replete with references that describe the safe use of azathioprine and 6-mercaptopurine (6-MP) in pregnant women with IBD. The 2019 AASLD guidelines state that both corticosteroids and azathioprine can be continued during pregnancy. However, mycophenolate mofetil has been associated with spontaneous abortions and birth defects; therefore, its use contraindicated in pregnancy.^[3]

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Liver Transplantation

Liver transplantation is a life-saving therapy for many severely ill patients with autoimmune hepatitis. The classic signs and symptoms of liver decompensation include the new onset of hypoalbuminemia, coagulopathy, variceal bleeding, ascites, or hepatic encephalopathy. Patients with decompensated cirrhosis and acute liver failure due to autoimmune hepatitis—as well as many patients with acute severe autoimmune hepatitis—have a poor prognosis unless liver transplantation is performed. The clinicians caring for such patients should strongly consider transferring them to a tertiary care hospital capable of performing liver transplantation. Autoimmune hepatitis is the indication for about 4-6% of liver transplants performed in adults and 2-3% of liver transplants performed in children.^[44]

Patients transplanted due to autoimmune hepatitis appear to have a higher incidence of acute T-cell mediated rejection than patients transplanted for other diagnoses. Recurrence of autoimmune hepatitis is described in 36-68% of patients transplanted for the disease.^[3] Potential risk factors for recurrence include human leukocyte antigen (HLA) DR3-positive recipients of HLA DR3-negative donor organs,^[82] the presence of moderate to severe inflammation in the liver explant, and an elevated immunoglobulin G (IgG) level prior to the transplant.^[83]

Despite this, the long-term outlook after liver transplantation is excellent, with 10-year survival reported as greater than 70%.^[84] The precise incidence of graft failure necessitating re-transplant is not clear, but it appears to be low.^[85] In years past, chronic prednisone therapy was advocated after liver transplant to help protect against recurrent autoimmune hepatitis. This is no longer the case.^[3]

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Diet and Activity

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 daily) is mandatory in these individuals. Patients should continue to consume protein (ie, >1.3 g protein per kg body weight per day), given the catabolic nature of the disease and the 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 not recommended, but patients may feel better with restricted physical activity.

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Long-Term Monitoring

See Initial Therapy for Adults and Children for specific recommendations for the frequency of laboratory testing.

Surveillance abdominal imaging studies (eg, ultrasonography, computed tomography [CT] scanning, magnetic resonance imaging [MRI]) and alpha-fetoprotein (AFP) testing are routinely performed every 6 months as part of routine hepatocellular carcinoma surveillance in patients with cirrhosis. This includes patients whose cirrhosis was induced by autoimmune hepatitis. The detection of a small hepatocellular carcinoma on imaging studies should prompt immediate referral for consideration of curative liver transplantation.

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Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Treatment with corticosteroids and azathioprine is the cornerstone of achieving remission. Initiating azathioprine with prednisone at the beginning of treatment enables a faster decrease in the prednisone dose.

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Prednisone

• Dosing, Interactions, etc.

Clinical Context:  Prednisone is an immunosuppressant for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity. It stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

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Prednisolone

• Dosing, Interactions, etc.

Clinical Context:  Prednisolone decreases autoimmune reactions, possibly by suppressing key components of the immune system. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

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Budesonide (Entocort EC, Ortikos, Uceris)

• Dosing, Interactions, etc.

Clinical Context:  Budesonide is an anti-inflammatory corticosteroid with potent glucocorticoid activity but weak mineralocorticoid activity. It offers the promise of fewer steroid-specific side effects. Because of its high first-pass metabolism, the majority of the orally absorbed drug does not reach the systemic circulation.

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Class Summary

Corticosteroids induce immunosuppression through a number of mechanisms. Most notably, they help to block T-cell-derived and antigen-presenting cell (APC)-derived cytokine expression.^[86] Corticosteroids can suppress lymphocyte activity and decrease antibody production. They can also suppress the production of prostaglandins and leukotrienes, helping to reduce inflammation.

The rapid institution of treatment with high-dose corticosteroids may rescue patients whose disease ultimately would have progressed to either acute liver failure or cirrhosis. Long-term treatment with corticosteroids has been shown to improve the chances for survival significantly.

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Azathioprine (Imuran, Azasan)

• Dosing, Interactions, etc.

Clinical Context:  Azathioprine antagonizes purine metabolism and helps to block DNA replication in T and B lymphocytes.^[108] This, in turn, results in decreased autoimmune activity. Azathioprine has been used in the treatment of autoimmune hepatitis since the early 1970s.^[109]

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Mycophenolate (CellCept, MMF, Myfortic)

• Dosing, Interactions, etc.

Clinical Context:  Mycophenolate mofetil and mycophenolic acid inhibit the production of inosine phosphate dehydrogenase and the production of guanosine nucleotides. This, in turn, leads to the blockade of DNA replication in T and B lymphocytes.^[108] Mycophenolate is utilized in patients who are intolerant to azathioprine, as well as in patients who had either an incomplete response or a treatment failure after combination therapy with corticosteroids plus azathioprine.^[78]

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Cyclosporine (Gengraf, Sandimmune, Neoral)

• Dosing, Interactions, etc.

Clinical Context:  Calcineurin stimulates the expression of interleukin-2 (IL-2)—amongst other cytokines—by T lymphocytes. IL-2, in turn, stimulates the proliferation of T lymphocytes. By inhibiting calcineurin’s function, both cyclosporine and tacrolimus inhibit the production of IL-2, with resulting suppression of T cell-mediated immunity. The dosing of both drugs is based upon the patient’s body weight. Most experts recommend the routine follow-up of patients’ trough drug levels.

• References