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Management of autoimmune hepatitis

Management of autoimmune hepatitis
Literature review current through: Jan 2024.
This topic last updated: May 17, 2023.

INTRODUCTION — Autoimmune hepatitis is an uncommon, inflammatory liver disease that is characterized by circulating autoantibodies and elevated serum immunoglobulin G (IgG) levels (table 1). Initial therapy usually consists of oral glucocorticoids with or without a thiopurine, and most patients achieve biochemical remission with pharmacologic treatment. However, some patients may not respond to therapy and develop progressive disease and cirrhosis.

This topic will discuss management of autoimmune hepatitis. The pathogenesis, clinical features, and diagnosis of autoimmune hepatitis are discussed separately. (See "Autoimmune hepatitis: Pathogenesis" and "Overview of autoimmune hepatitis".)

The overlap of autoimmune hepatitis with other immune-mediated disorders (eg, primary biliary cholangitis) is discussed separately. (See "Autoimmune hepatitis variants: Definitions and treatment".)

PRETREATMENT EVALUATION — The goals of the pretreatment evaluation are to assess risk for adverse effects related to therapy. Prior to initiating therapy, we measure the following:

Thiopurine methyltransferase (TPMT) enzyme activity. We assess TPMT enzyme activity because thiopurines (ie, azathioprine or 6-mercaptopurine) have been associated with bone marrow suppression in patients with low or absent TPMT activity (which leads to the preferential production of 6-thioguanine) (figure 1). Testing for TPMT activity and thiopurine drug metabolism are discussed in more detail separately. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease".)  

Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), and hepatitis B core antibody (HBcAb).

Patients with serologic evidence of hepatitis B virus (HBV) infection (HBsAg-positive or anti-HBc-positive) are at risk for HBV reactivation if they receive immunosuppressive therapy. Prevention, diagnosis, and treatment of HBV reactivation are discussed separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Bone density testing. The evaluation for low bone mass in patients with autoimmune hepatitis is similar to the evaluation for any patient at risk for osteoporosis and includes assessment of fracture risk, bone mineral density testing, and laboratory evaluation. These issues are discussed separately. (See "Osteoporotic fracture risk assessment" and "Screening for osteoporosis in postmenopausal women and men".)

The diagnostic evaluation of patients with suspected autoimmune hepatitis including laboratory studies (eg, serum aminotransferases, IgG level) is discussed separately. (See "Overview of autoimmune hepatitis", section on 'Diagnostic evaluation'.)

TREATMENT GOALS — Goals of drug therapy for autoimmune hepatitis are to improve symptoms, reduce liver inflammation, normalize aminotransferase and immunoglobulin G (IgG) levels, and prevent disease progression [1,2].

In a consensus statement by the International Autoimmune Hepatitis Group, treatment response and remission were defined as follows [2]:

Complete biochemical response (CBR) – CBR is the normalization of serum aminotransferases and IgG (ie, levels below the upper limit of normal) within six months after initiating treatment.

Patients who do not meet these criteria after six months are regarded as insufficient responders.

Histologic remission – Histologic remission on liver biopsy is defined as Hepatitis Activity Index (HAI) <4 (table 2) [3]. (See "Histologic scoring systems for chronic liver disease", section on 'Ishak score (modified Knodell score)'.)

INITIAL MANAGEMENT

General measures — The following measures apply to patients with autoimmune hepatitis:

Referral to a specialist — Many patients with autoimmune hepatitis are under the care of a hepatologist when the diagnosis is made, and we generally encourage long-term management by a hepatologist. However, initial treatment by a primary care clinician who is familiar with the management of autoimmune hepatitis is reasonable. In addition, patients with any of the following should be referred to a hepatologist:

Patients with cirrhosis

Patients with acute liver failure; such patients should be hospitalized and referred to a liver transplantation center for evaluation (see 'Patients with acute liver failure' below)

Patients who do not respond to therapy (see 'Assessing response' below)

Abstain from alcohol We suggest that patients refrain from alcohol, and in particular, we recommend avoiding heavy alcohol use (ie, >14 drinks per week or >4 drinks on a given day for males and >7 drinks per week or >3 drinks on a given day for females) [4].  

Immunizations Vaccination for hepatitis A virus and hepatitis B virus should be given to patients without serologic evidence of immunity. Additional vaccines for patients with chronic liver disease include pneumococcal vaccination and standard immunizations that are given to the general population (eg, influenza, tetanus boosters). Immunization schedules are described separately. (See "Immunizations for adults with chronic liver disease".)

Indications for drug therapy — The decision to begin drug therapy for autoimmune hepatitis is informed by severity of symptoms, magnitude of the serum aminotransferase and IgG elevations, histologic findings, and risk of adverse effects.

We use pharmacologic therapy for patients with any of the following clinical features (table 3) [5]:

Serum aminotransferase levels (ie, alanine aminotransferase and aspartate aminotransferase) greater than 10-fold the upper limit of normal

Serum IgG greater than twice the upper limit of normal

Serum aminotransferase levels greater than twice the upper limit of normal along with:

Symptoms

An elevated IgG level, even if less than twice the upper limit of normal

An elevated conjugated bilirubin level

Interface hepatitis on liver biopsy

Cirrhosis with any degree of inflammation on biopsy (see 'Patients with cirrhosis' below)

Age <18 years (see 'Pediatric patients' below)

Histologic features of bridging necrosis or multiacinar necrosis. However, it is also reasonable to use drug therapy for patients with histologic findings limited to interface hepatitis (without bridging necrosis or multiacinar necrosis), particularly if the patient is young (ie, age <50 years).

For patients who do not meet any of these criteria (ie, asymptomatic patients with normal or near-normal serum aminotransferase and IgG levels who have minimal or no inflammatory activity on liver biopsy), observation with laboratory monitoring is a reasonable approach [6]. Such patients are at low risk for disease progression. (See 'Patients without indications for therapy' below.)

In addition, we do not initiate drug therapy for patients with cirrhosis and inactive disease (ie, no inflammation on histology) [1,5]. The benefit of therapy is uncertain for such patients who may be at increased risk for glucocorticoid-related side effects. (See 'Patients with cirrhosis' below.)

Selecting initial therapy — For most patients with autoimmune hepatitis, a glucocorticoid is the cornerstone of initial therapy, and we typically initiate an oral glucocorticoid (eg, prednisone 40 to 60 mg once daily, followed by a taper) (algorithm 1). For patients with mildly active disease (ie, asymptomatic patients with aminotransferase levels <10 times the upper limit of normal), initiating glucocorticoid therapy at a lower dose (eg, prednisone 20 to 30 mg daily) is an alternative.

For patients who are at increased risk for adverse effects from glucocorticoids (eg, uncontrolled diabetes or hypertension, osteoporosis, history of psychosis), we typically use a combination of a glucocorticoid and a thiopurine. By adding a thiopurine, we are able to use lower doses of prednisone while maintaining efficacy. Thus, we initiate prednisone at a lower dose (eg, 30 mg daily) and then begin a thiopurine (eg, azathioprine 50 mg daily) two weeks later, provided that thiopurine methyltransferase (TPMT) enzyme activity is normal or intermediate. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease", section on 'Assessing TPMT enzyme activity'.)

By initiating each drug separately, we avoid the potential for diagnostic uncertainty if aminotransferases rise or if new symptoms develop after starting therapy given the small risk of thiopurine-related drug-induced liver injury. For patients who do not have cirrhosis, budesonide is an alternative glucocorticoid, and it is usually used in combination with a thiopurine. (See 'Investigational therapies' below.)

Most patients have improvement in serum aminotransferases and IgG within four weeks of initiating glucocorticoid therapy. However, patients with aminotransferases that decrease by <50 percent of the baseline values after four weeks are regarded as nonresponders [2]. (See 'Administration and monitoring' below and 'Assessing response' below.)

Early treatment trials for autoimmune hepatitis suggested that glucocorticoid-based therapy resulted in a survival benefit. Mortality rates for patients given glucocorticoid therapy were 14 percent, whereas the mortality rate for untreated patients was as high as 56 percent during 30 to 72 months of follow-up [7-11].

While glucocorticoid monotherapy has not been directly compared with combination therapy in large trials with long-term follow-up, limited data and clinical experience suggested that efficacy of these initial regimens were similar. In a systematic review of five trials including 363 patients with autoimmune hepatitis who were treatment-naïve, there were no significant differences in rates of symptomatic, biochemical, and histologic remission between glucocorticoid monotherapy compared with a glucocorticoid plus azathioprine [12].

Administration and monitoring

Glucocorticoid monotherapy — Approximately 90 percent of patients have improvement in serum aminotransferases, bilirubin, and IgG within four weeks of initiating glucocorticoid therapy [13].

Dosing – For most patients, we initiate prednisone 40 to 60 mg daily for the first one to two weeks of treatment. We then taper prednisone by 5 to 10 mg every one to two weeks until a dose of 20 mg daily is reached. Next, we taper prednisone by 5 mg every one to two weeks to a target dose of 10 mg daily. Patients usually remain at this dose until achieving complete biochemical response (CBR). (See 'Treatment goals' above.)

We may adjust the glucocorticoid taper based on the patient's response to therapy. As an example, for patients whose aminotransferases are trending downward but have not yet achieved CBR, we may reduce the prednisone dose to 7.5 mg daily until CBR is achieved. In addition, for patients with slower initial biochemical improvement (ie, requiring >4 weeks), we use a slower glucocorticoid taper (eg, dose adjustments every two to four weeks).

For patients with mild hepatitis (eg, asymptomatic patients with aminotransferase levels <10 times the upper limit of normal), initiating prednisone at a lower dose (20 to 30 mg per day) is a reasonable alternative. Observational data suggested that clinical response rates were not significantly different for patients given higher-dose compared with lower-dose glucocorticoid therapy [14]. However, the possibility of selection bias cannot be excluded.

In the United States, prednisone is typically used, whereas in Europe, prednisolone is used. The dosing regimen for prednisolone is similar to prednisone dosing.

Monitoring – We measure serum aminotransferases, IgG level, and total bilirubin once weekly during the first four weeks and then every two to four weeks until CBR is achieved.

For patients who develop recurrent symptoms or worsening laboratory values during the prednisone taper, we resume the lowest dose that controlled symptoms and was associated with biochemical improvement. This may require increasing the dose of prednisone (eg, to 40 to 60 mg daily) and gradually tapering while monitoring for biochemical response and side effects. (See 'Nonresponders' below.)

We monitor patients on long-term glucocorticoid therapy (ie, >6 months) for adverse effects related to glucocorticoid use:

Bone disease – We obtain bone density testing as part of pretreatment testing and then repeat bone density testing every one to two years. Strategies for preventing or treating bone disease include a regular weight-bearing exercise program, supplementation with vitamin D and calcium, and where appropriate, bone active agents such as bisphosphonates. These issues are discussed in detail separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Eye disease – We screen patients annually for glaucoma and cataracts.

In adults, autoantibody levels are not used to monitor disease activity because they do not correlate with disease activity.

Adverse effects – Adverse effects associated with systemic glucocorticoids include hyperglycemia, hypertension, Cushingoid appearance, osteoporosis, and cataracts (table 4). Side effects of systemic glucocorticoids are discussed in detail separately. (See "Major adverse effects of systemic glucocorticoids".)  

Glucocorticoid plus a thiopurine — The addition of a thiopurine (azathioprine or 6-mercaptopurine) to glucocorticoid therapy allows for lower glucocorticoid doses and may reduce the risk of glucocorticoid-related side effects:

Dosing – When using combination therapy, the typical initial dosing is prednisone 30 mg daily and azathioprine 50 mg daily. However, we delay starting a thiopurine until TPMT testing is available and until glucocorticoid therapy has been given for two weeks. By initiating each drug separately, we avoid potential diagnostic uncertainty if aminotransferases rise or if new symptoms develop after starting therapy, given the small risk of thiopurine-related drug-induced liver injury.

We typically taper prednisone by 5 to 10 mg per week until a dose of 10 mg daily is reached while maintaining an azathioprine dose of 50 mg for the first one to two months of therapy to ensure tolerability.

The dose of azathioprine can be gradually increased to 1 to 2 mg/kg daily (maximum dose, 200 mg daily) if needed to achieve symptomatic improvement and biochemical response. The pharmacology, dosing, and monitoring of thiopurines are discussed in more detail separately. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease".)

For patients with mild adverse effects (eg, gastrointestinal disturbances) related to azathioprine, we may switch to 6-mercaptopurine at one-half of the azathioprine dose [15]. However, we do not substitute 6-mercaptopurine for azathioprine in patients who do not respond to azathioprine or who develop other side effects such as bone marrow suppression or pancreatitis.  

Monitoring – For patients on a glucocorticoid plus a thiopurine, laboratory monitoring during the first month includes measuring serum aminotransferases, total bilirubin, IgG level, complete blood cell count, and amylase once weekly. We then measure laboratory studies every two to four weeks until CBR is achieved [5].

We monitor complete blood count in all patients on thiopurine therapy because bone marrow suppression can occur in patients with normal TPMT enzyme activity.

We do not routinely monitor thiopurine metabolite levels (6-thioguanine and 6-methylmercaptopurine) in adults who respond to therapy because metabolite levels do not correlate well with therapeutic response. As an example, patients may have sustained remission despite having subtherapeutic levels of 6-thioguanine [16]. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease", section on 'Therapeutic drug monitoring'.)

We generally avoid the use of allopurinol in patients on thiopurine therapy. Allopurinol inhibits the enzyme xanthine oxidase and the combination of allopurinol and a thiopurine can potentially lead to life-threatening bone marrow suppression. However, for patients with thiopurine resistance, investigational use of allopurinol has been reported, and this is discussed separately. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease", section on 'Patients with thiopurine resistance'.)

Adverse effects – In addition to the risk of bone marrow suppression and cytopenia, other adverse effects associated with thiopurines include nausea, emesis, drug-induced liver injury (rare), infection, pancreatitis, and malignancy. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)

Previous history of malignancy is not an absolute contraindication to thiopurine use. However, population-based data from Denmark suggested that patients with autoimmune hepatitis on immunosuppressive therapy had a higher 10-year risk for developing colorectal cancer (risk ratio [RR] 2.1, 95% CI 1.3-3.5) and non-melanoma skin cancer (RR 1.8, 95% CI 1.3-2.5) compared with age- and sex-matched controls [17]. In another population-based cohort, patients with autoimmune hepatitis had higher risk for lymphoma (hazard ratio [HR] 1.89, 95% CI 1.25-2.86) compared with a reference population [18]. Whether malignancy risk was related to autoimmune disease or its treatment has been uncertain.

For patients who do not tolerate azathioprine, options include treating with glucocorticoid alone or replacing the thiopurine with an alternative antimetabolite agent such as mycophenolate. (See 'Investigational therapies' below.)

Assessing response — Most adult patients have symptomatic and biochemical improvement within four weeks of starting glucocorticoid-based therapy [2]. To assess response to therapy, we measure serum aminotransferase and IgG levels. Patients with an initial response have ≥50 percent decrease in aminotransferases within four weeks of treatment. The time to achieve CBR (ie, normalization of serum aminotransferases and IgG) is usually longer (ie, within six months), whereas improvement in histology (ie, Hepatitis Activity Index [HAI] <4) does not typically occur before 12 months [2,19]. (See 'Treatment goals' above.)

However, confirmation of histologic remission in patients with CBR is not required. Thus, follow-up liver biopsy is not consistently performed in clinical practice.

Patients with <50 percent decrease of aminotransferases within four weeks of treatment are nonresponders. Patients who do not respond to therapy may have ongoing biochemical and histologic activity that may lead to cirrhosis, complications of portal hypertension, and liver transplantation. In addition, lack of therapeutic response raises the possibility of an alternative or coexisting diagnosis. (See 'Nonresponders' below.)

SUBSEQUENT MANAGEMENT — Subsequent therapy is informed by the patient's response to initial therapy. (See 'Assessing response' above.)

Among patients who achieve CBR, some patients will tolerate complete withdrawal of drug therapy, whereas others require long-term maintenance to avoid disease relapse. (See 'Withdrawing therapy' below.)

Patients with complete biochemical response (CBR)

Transitioning to maintenance therapy — We use maintenance therapy for most patients who achieve CBR to reduce the risk of disease relapse while minimizing the risk of adverse drug effects. Although glucocorticoids and thiopurines are effective for controlling disease activity, use of a thiopurine alone for maintenance avoids the risks associated with long-term glucocorticoid therapy (eg, osteoporosis, cataracts, infection) [20-22]. (See "Major adverse effects of systemic glucocorticoids".)

Transitioning to maintenance therapy is also informed by the existing drug regimen, patient preferences, and clinician preferences:

Glucocorticoid monotherapy – For patients who achieved CBR with glucocorticoid monotherapy, we usually taper prednisone to a daily dose ranging from 2.5 mg to 7.5 mg and continue it as maintenance therapy for a minimum of 18 months before evaluating for drug withdrawal. We use the lowest dose of glucocorticoid that maintains disease remission (eg, biochemical response and absence of symptoms).

The approach to tapering glucocorticoid monotherapy to achieve drug withdrawal is discussed below. (See 'Withdrawing therapy' below.)

Glucocorticoid plus thiopurine – For patients with CBR on an oral glucocorticoid plus a thiopurine, we taper prednisone and then discontinue it while continuing azathioprine long-term. When the prednisone dose is >20 mg, we taper prednisone by 5 to 10 mg every one to two weeks until a dose of 20 mg per day is reached. We then taper prednisone by 5 mg every one to two weeks until a dose of 10 mg per day is reached. Next, we taper prednisone by 2.5 mg every one to two weeks until the drug is withdrawn. Biochemical and clinical response to dose adjustments also guides the glucocorticoid taper. If laboratory tests worsen or symptoms recur, we stop the taper and resume the previous dose.

Thiopurine monotherapy – For patients with CBR on thiopurine monotherapy, we continue thiopurine at the existing dose. After 6 to 12 months of sustained CBR, we taper the dose of azathioprine by 50 mg per day each month until a dose of 50 mg per day is reached.

During the transition to maintenance therapy with a drug taper, we monitor laboratory studies (serum aminotransferases, IgG, total bilirubin, serum glucose, complete blood count, amylase) every one to three months. If a patient loses biochemical response during the drug taper, we resume the drug regimen that initially resulted in CBR. After reestablishing CBR, we transition the patient to maintenance therapy, usually with thiopurine alone.

Data suggested that thiopurine monotherapy was associated with high rates of long-term remission. In a study including 72 patients with autoimmune hepatitis who achieved remission with prednisolone and azathioprine and then continued azathioprine alone (2 mg/kg daily) for maintenance, 60 patients (83 percent) had sustained remission after a median of 67 months [20].

Monitoring during maintenance therapy — For patients with sustained CBR on maintenance therapy, we monitor serum aminotransferases, bilirubin, and IgG levels every three to six months.

Increasingly, the role of liver biopsy is limited to determining the need to change therapeutics, re-evaluating diagnosis where doubt exists, assessing disease activity or steatosis, assessing for overlap syndrome or prior to withdrawing treatment. (See 'Withdrawing therapy' below.)

The use of noninvasive evaluation for liver fibrosis (eg, ultrasound-based transient elastography) for monitoring has been increasingly adopted in clinical practice with a decrease in liver stiffness linked to complete biochemical remission [23].

Withdrawing therapy — The decision to discontinue maintenance therapy is informed by duration of sustained CBR, the estimated likelihood of relapse, severity of liver disease, risk of adverse drug effects, and patient preferences. We typically attempt to withdraw treatment for patients with sustained CBR for at least 18 months who also have the following clinical features [1,5,24]:

Anti-liver kidney microsomal-1-antibody negative

Anti-soluble liver antigen/liver pancreas antibodies negative

Age >16 years

No interface hepatitis on liver biopsy

We typically obtain a liver biopsy to exclude interface hepatitis or other features of active disease because studies suggested that persistent histologic activity was common despite biochemical remission. In a study including 120 patients in biochemical remission (defined by normal serum alanine aminotransferase and gamma globulin), 55 patients (46 percent) had persistent histologic activity (histologic activity index ≥4) [25]. Persistent histologic activity was associated with lower rates of fibrosis regression (32 versus 60 percent) and higher mortality (standardized mortality ratio 1.4 versus 0.7) compared with histologic remission.

We discuss the risk of disease relapse and potential benefits of withdrawing therapy with patients who participate in shared decision-making. In particular, we discuss that long-term follow-up studies suggested that rates of sustained remission following drug withdrawal ranged from 20 to 40 percent [1,7,26].

For patients who remained on an oral glucocorticoid for maintenance, we begin drug withdrawal by tapering prednisone. The maintenance prednisone dose is typically ≤10 mg daily; thus, we decrease the dose by 2.5 mg per day every two weeks until the drug is withdrawn. We monitor serum aminotransferases, total bilirubin, and IgG levels every two weeks during drug withdrawal and at three months after completing withdrawal. We then monitor these laboratory studies every six months for one year, and yearly thereafter.

For patients on glucocorticoid plus a thiopurine (typically azathioprine), we usually begin tapering the azathioprine after the glucocorticoid has been discontinued.

The approach to withdrawing thiopurine therapy is informed by the existing dose. For patients taking azathioprine 50 mg daily, we simply stop the azathioprine. For patients taking higher doses, we reduce the dose by 50 mg per day every three months with laboratory monitoring (serum aminotransferases, total bilirubin, and IgG levels) every three months. We then monitor laboratory studies every six months for one year, and yearly thereafter. Treatment should be reinstituted if a relapse occurs.

Nonresponders

Risk factors — Approximately 10 to 20 percent of patients with autoimmune hepatitis do not respond to initial therapy [27]. Risk factors for lack of response to therapy include [28,29]:

Cirrhosis

Age at diagnosis: Younger (<20 years) or older (>60 years)

Human leukocyte antigens (HLA)-B8 and/or HLA-DR3 phenotypes

The frequency of HLA-B8 has been noted to be higher in patients who are refractory to treatment and in those referred for liver transplantation [28,30]. As a result, the HLA phenotypes HLA-B8 and/or HLA-DR3 may serve as markers for severity of disease rather than a risk factor for limited treatment response. Genetic risk factors are discussed in more detail separately. (See "Autoimmune hepatitis: Pathogenesis".)

Management — For patients who do not respond to initial therapy (ie, those with <50 percent decrease of aminotransferases within four weeks of treatment), we first confirm that the patient is adhering to therapy and that other etiologies of liver disease have been excluded [2]. As an example, some patients may have overlap of autoimmune hepatitis with primary sclerosing cholangitis. The differential diagnosis of autoimmune hepatitis and management of overlap syndromes are discussed in more detail separately. (See "Overview of autoimmune hepatitis", section on 'Differential diagnosis' and "Autoimmune hepatitis variants: Definitions and treatment".)

The next steps are informed by the patient's initial drug regimen:

For patients on glucocorticoid monotherapy and normal or intermediate thiopurine methyltransferase (TPMT) enzyme activity, we add a thiopurine (eg, azathioprine 50 mg daily). (See 'Glucocorticoid monotherapy' above.)

For patients on lower-dose glucocorticoid therapy plus azathioprine, we gradually increase the dose of azathioprine to 2 mg/kg daily (maximum dose, 200 mg daily), provided that the patient does not develop adverse effects (eg, leukopenia [white blood cell count ≤4000 cells/microL]). If this is not effective, we increase the prednisone dose to 40 to 60 mg daily. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Dosing and monitoring' and 'Glucocorticoid plus a thiopurine' above.)

For patients who respond to treatment with a glucocorticoid and azathioprine, we taper the dose of prednisone by 10 mg per day each month until a dose of 10 mg daily is achieved or to the lowest dose associated with biochemical response. We continue azathioprine at the existing dose for up to one year before considering a dose reduction. After one year of sustained CBR, we taper the dose of azathioprine by 50 mg per day each month until a dose of 50 mg per day is reached.

After sustaining CBR for 18 to 24 months, we evaluate patients for treatment withdrawal. However, patients with a history of initial nonresponse often require long-term maintenance therapy. (See 'Patients with complete biochemical response (CBR)' above.)

For patients already on azathioprine who have not achieved biochemical response, measuring thiopurine metabolite levels (6-MMP and 6-thioguanine) can be helpful [31]. If 6-thioguanine levels are low, we typically increase the thiopurine dose while monitoring complete blood count for toxicity. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease", section on 'Therapeutic drug monitoring'.)

Treatment for patients who do not respond to initial glucocorticoid-based therapy is not well established [27]. Subsequent options include mycophenolate and other alternative immunosuppressive agents. (See 'Investigational therapies' below.)

Patients who do not respond to therapy and develop cirrhosis and complications of portal hypertension are typically evaluated for liver transplantation. (See 'Liver transplantation' below.)

DISEASE RELAPSE

Incidence and risk factors — Reported rates of disease relapse (ie, loss of complete biochemical response [CBR] within 12 months of drug withdrawal) have ranged from 45 to 80 percent following drug withdrawal [21,32,33].

Risk factors for disease relapse include [21]:

Histologic activity prior to drug withdrawal – Patients who achieved histologic remission have a 20 to 30 percent chance of relapse after treatment is withdrawn, whereas those who had evidence of interface hepatitis have a 75 to 90 percent chance of relapse in one year [32,34,35].

Liver biochemistries – Higher IgG and alanine aminotransferase levels (>2 times the upper limit of normal) have been associated with increased risk of relapse following drug withdrawal [33,34]. In a report including 107 patients with autoimmune hepatitis, patients who relapsed had higher baseline gamma globulin level compared with those who maintained remission (3.3 versus 2.8 g/dL) [34].

Human leukocyte antigen (HLA) phenotype – In one report, HLA-A1, HLA-B8, or HLA-DR3 phenotype was a risk factor for relapse [36].

Patient sex – Male sex has been associated with higher risk for disease relapse [37].

Duration of immunosuppressive therapy – Shorter duration of therapy has been associated with lower rates of sustained remission following drug withdrawal. In one study, continuous immunosuppressive therapy for one to two years or for two years prior to drug withdrawal was associated with lower rates of sustained remission compared with four years of therapy (10 and 17 percent, respectively, versus 67 percent) [36].

Clinical presentation — Patients who develop disease relapse may be asymptomatic or complain of fatigue, arthralgias, and/or anorexia. Laboratory abnormalities include a rise in serum aminotransferase levels and/or an increase in IgG levels. A rise in serum aminotransferases to more than three times the upper limit of normal or a rise in IgG to more than 2 g/dL correlates strongly with histologic activity [38].

Management — We typically restart the drug regimen that initially resulted in CBR for patients who relapse. We usually begin a glucocorticoid with or without a thiopurine and use dosing that is similar to dosing for initial therapy. (See 'Administration and monitoring' above.)  

Most patients respond to restarting therapy and achieve CBR in four to six months and histologic remission in 6 to 12 months [26]. After CBR is achieved, attempts can be made to withdraw immunosuppressive therapy. Limited data suggested that some patients who relapse will have sustained remission following drug withdrawal [1,34]. In a study including 107 patients with autoimmune hepatitis, rates of achieving long-term remission were not significantly different for patients with history of relapse after drug withdrawal compared with no relapse (28 versus 21 percent) [34].

We typically attempt to withdraw drug therapy after the patient has sustained biochemical response for 18 to 24 months, provided there is no interface hepatitis seen on biopsy. However, if relapse recurs, we discuss with the patient that life-long therapy is warranted and that any further attempts to withdraw immunosuppression will require repeat liver biopsy to confirm there is no interface hepatitis or other histologic disease activity.

INVESTIGATIONAL THERAPIES — For patients who do not respond to or do not tolerate glucocorticoid-based therapy, alternative drug regimens have been studied, and they include:

Mycophenolate – We typically use an antimetabolite, mycophenolate mofetil (MMF) for patients who do not respond to initial treatment or do not tolerate thiopurine therapy. The dose of MMF is 1 g twice daily. Some patients experience adverse effects (eg, gastrointestinal symptoms, bone marrow suppression) that limit its use [39-43]. MMF acts by blocking de novo purine synthesis, and the pharmacology, dosing, and adverse effects related to MMF are discussed in more detail separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Adverse effects' and "Liver transplantation in adults: Initial and maintenance immunosuppression", section on 'Mycophenolate (commonly-used)'.)

Use of MMF for autoimmune hepatitis is supported by observational studies demonstrating biochemical and histologic improvement. However, response to MMF has been more favorable in patients who did not tolerate, rather than lacked response, to initial therapy. In a meta-analysis of 12 studies including 397 patients, the pooled rate of response to MMF therapy was 58 percent, whereas the response rate was numerically higher for patients who did not tolerate azathioprine compared with patients who did not respond (82 versus 38 percent) [41]. The pooled rate of adverse events related to MMF was 14 percent, with a pooled discontinuation rate of 8 percent. In a subsequent study including 105 patients with autoimmune hepatitis who did not tolerate or did not respond to glucocorticoids with or without a thiopurine, mycophenolate rescue therapy was associated with biochemical remission in 63 patients (60 percent) [42].

Data from randomized trials that evaluate liver histology before and after treatment are needed before MMF is used routinely as first-line therapy.

Budesonide – Budesonide is an alternative to prednisone for patients without cirrhosis who are at increased risk for glucocorticoid side effects [24]. We do not use budesonide in patients with cirrhosis because budesonide undergoes extensive first-pass hepatic metabolism [44]. In addition, budesonide is not effective for patients who did not respond to traditional glucocorticoids (eg, prednisone); thus, budesonide should not be used as rescue therapy [45,46].

Budesonide is often used in combination with a thiopurine. The initial dose of budesonide is 3 mg three times daily. The dosing frequency is subsequently reduced to twice daily when the patient has biochemical response.

Data from case series and randomized trials suggested that budesonide was effective for treating autoimmune hepatitis in adults and had fewer side effects than prednisone [45,47-52]. However, additional studies with long-term follow-up are needed before budesonide is used routinely for autoimmune hepatitis. In a trial of 208 patients with autoimmune hepatitis without cirrhosis, budesonide plus azathioprine resulted in higher rates of complete biochemical response (CBR) after six months compared with prednisone plus azathioprine (47 versus 18 percent). Patients receiving budesonide also had lower rates of glucocorticoid-related side effects (28 versus 53 percent). On subgroup analysis, budesonide resulted in higher rates of complete biochemical response in adults (60 versus 39 percent), but response rates in pediatric patients were not significantly different. In a trial comparing budesonide/azathioprine therapy with prednisone/azathioprine that included 46 pediatric patients with autoimmune hepatitis, there were no statistically significant differences in rates of biochemical response or glucocorticoid-related side effects between the groups [51].

Calcineurin inhibitors – We do not typically use calcineurin inhibitors for treating autoimmune hepatitis because data from randomized trials are limited and because of potential adverse effects (eg, hypertension, renal insufficiency, hyperlipidemia, infection) [53-55]. (See "Pharmacology of cyclosporine and tacrolimus".)

However, limited data suggested that tacrolimus was effective for treating autoimmune hepatitis, including patients who did not respond to glucocorticoid therapy [56-59]. In a retrospective study of 93 patients with autoimmune hepatitis who did not respond to prednisone with or without azathioprine, tacrolimus was associated with higher rates of clinical response compared with MMF (57 versus 34 percent) [59]. The rates of liver-related deaths or liver transplantation were not significantly different between the groups.

Other therapies – Other treatments that have been studied include sirolimus [60], methotrexate [61], infliximab [62], and rituximab [63]. However, we do not routinely use any of these agents because data on efficacy and safety in patients with autoimmune hepatitis are limited.

SPECIAL POPULATIONS

Patients with acute liver failure — Patients with autoimmune hepatitis complicated by acute liver failure have severe liver injury with impaired synthetic function (ie, international normalized ratio [INR] ≥1.5) and encephalopathy within 26 weeks of disease onset. The clinical manifestations and diagnosis of acute liver failure are discussed separately. (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

For some patients, treatment for acute liver failure is liver transplantation [64]. Whether glucocorticoids prevent disease progression to liver transplantation is uncertain, and glucocorticoid therapy may increase the risk of infectious complications. Our approach is to evaluate patients for liver transplantation and begin a short trial of glucocorticoids (ie, <2 weeks) while closely monitoring the patient's clinical status and Model for End-stage Liver Disease (MELD) score [65]. (See "Model for End-stage Liver Disease (MELD)" and "Acute liver failure in adults: Management and prognosis".)

We use prednisone (or prednisolone), 1 mg/kg daily (maximum dose 60 mg daily), for treating patients with autoimmune hepatitis complicated by acute liver failure [64,66,67].

We reserve liver transplantation for patients without clinical or biochemical (ie, INR) improvement within one to two weeks of initiating glucocorticoid therapy.

Data on glucocorticoid therapy for severe autoimmune hepatitis with acute liver failure are mixed and limited by varied definitions of severe disease. Observational studies reported rates of clinical response with glucocorticoid therapy ranging from 20 to 80 percent [64,66-69]. In a series of 32 patients with severe autoimmune hepatitis, glucocorticoid therapy was associated with lower rates of liver transplantation compared with no glucocorticoids (48 versus 100 percent) [64]. However, mortality rates were not significantly different between the groups. In a study of 16 patients with severe autoimmune hepatitis (most with encephalopathy), rates of liver transplantation were not significantly different for those receiving glucocorticoid therapy compared with no glucocorticoids [68]. In addition, severe septic complications were common among patients receiving glucocorticoids (30 percent).

Studies have attempted to identify factors that predict a favorable response to glucocorticoids. However, methods for predicting response are limited because the threshold values for prognostic scores remain uncertain [7]. In a study including 72 patients with acute severe autoimmune hepatitis, higher MELD, MELD-Na, and United Kingdom End-stage Liver Disease (UKELD) scores were risk factors for lack of therapeutic response [66]. As an example, the median MELD score in patients who did not respond to glucocorticoids was higher compared with those who responded (median MELD: 26 versus 20). (See "Model for End-stage Liver Disease (MELD)".)

Patients with cirrhosis — Cirrhosis is common in patients who are diagnosed with autoimmune hepatitis, and some patients progress to decompensated cirrhosis that may require liver transplantation [70,71]. We typically use drug therapy (ie, prednisone [or prednisolone]-based initial regimen) for patients with cirrhosis and active disease (ie, active inflammation on liver biopsy). (See 'Initial management' above.)

Most patients with cirrhosis, including those with complications of portal hypertension (eg, ascites), respond well to drug therapy [72,73]. In a study including 128 patients with autoimmune hepatitis treated with glucocorticoid therapy, survival rates after 10 years of follow-up were not significantly different for patients with cirrhosis compared with no cirrhosis (89 versus 90 percent) [72].

However, we generally do not use drug therapy for patients with cirrhosis and inactive disease (ie, no active inflammation on liver biopsy).

For patients with cirrhosis due to autoimmune hepatitis, management is similar to management of cirrhosis due to other causes and includes screening for hepatocellular carcinoma, managing complications of portal hypertension, and liver transplant evaluation for patients with decompensated cirrhosis [74]. (See "Portal hypertension in adults" and "Surveillance for hepatocellular carcinoma in adults".)

General management of cirrhosis is presented separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

Patients with hepatitis C virus (HCV) infection — Patients with chronic hepatitis C virus (HCV) infection rarely develop autoimmune hepatitis. However, in patients with HCV infection and autoimmune hepatitis, we do not delay initiating direct-acting antiviral therapy. Management of HCV infection is discussed separately. (See "Overview of the management of chronic hepatitis C virus infection".)

Pregnancy — Issues related to pregnancy in patients with autoimmune hepatitis include:

Patient counseling – When counseling patients with autoimmune hepatitis, we emphasize that maintaining biochemical remission with drug therapy has been linked to favorable pregnancy outcomes [75,76]. Although some studies suggested that autoimmune hepatitis was associated with increased maternal and perinatal risks, whether these risks are related to disease activity or glucocorticoid use remains uncertain [77-80]. In a study using data from the United States National Inpatient Sample, pregnant patients with autoimmune hepatitis had higher risk of gestational diabetes (adjusted odds ratio [aOR] 2.4, 95% CI 1.6-3.6), hypertensive complications (aOR 2.4, 95% CI 1.3-4.1), and preterm birth (aOR 2.0, 95% CI 1.2-3.5) compared with no chronic liver disease, after adjusting for factors such as age, multiple gestation, and metabolic disease [77].

Medication adjustments – For patients who are planning to become or are pregnant, the use of glucocorticoids and thiopurines appears to be safe. However, we avoid the use of mycophenolate during pregnancy and for at least three months prior to conception because of an increased risk of pregnancy loss and of congenital anomalies with mycophenolate use [81]. The safety of immunosuppressive medications during pregnancy is discussed in more detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

Maintaining remission – We continue immunosuppressive therapy in pregnant patients because discontinuing therapy has been associated with disease relapse [82,83]. We monitor patients carefully during pregnancy and for several months postpartum because of the risk of disease flare. In general, we measure serum aminotransferases once during each trimester and approximately 12 weeks following delivery to screen for disease activity. The risk of a disease flare may be especially increased postpartum when estrogen levels return to normal.

Patients without indications for therapy — For patients who do not receive drug therapy, monitoring for disease progression includes the following:

Laboratory studies – We measure aminotransferases, total bilirubin, and IgG levels every three to six months.

Monitoring for fibrosis – We typically obtain transient elastography using an ultrasound to exclude hepatic fibrosis every two years or if there is an increase in aminotransferase level(s). An alternative is obtaining liver biopsy to reassess histologic disease activity. However, we rarely obtain liver biopsy because transient elastography is noninvasive and widely available.

Pediatric patients — We typically initiate therapy for all pediatric patients with autoimmune hepatitis to avoid disease progression [84,85]. Although studies have suggested that approximately 40 percent of pediatric patients have cirrhosis at the time of diagnosis, most pediatric patients respond to therapy and achieve long-term disease remission [86-89].

The principles of therapy in pediatric patients are [7,90]:

Goals of therapy – The goal is to achieve biochemical remission defined as normal aminotransferase and IgG levels as well as negative or low-titer autoantibodies (eg, anti-smooth muscle antibody). Autoantibody titers are associated with disease activity in pediatric patients (table 1) [91].

More specifically, we aim to achieve an 80 percent reduction in the aminotransferase levels during the first eight weeks of therapy. Normalization of aminotransferases occurs in 75 to 90 percent of pediatric patients after six to nine months of treatment.

Dosing and administration – We typically initiate a glucocorticoid (prednisone or prednisolone; 1 to 2 mg/kg daily, up to a maximum of 60 mg daily) and then add a thiopurine shortly thereafter (ie, two weeks after starting glucocorticoid therapy) [1,92,93]. We initiate a thiopurine as a glucocorticoid-sparing agent to lower the risks associated with glucocorticoid use (ie, bone disease, impacts on growth, acne). (See "Major adverse effects of systemic glucocorticoids".)

We taper the prednisone dose over four to eight weeks to achieve a dose of 2.5 to 5 mg daily. Initially, we measure aminotransferases weekly to inform prednisone dosing (ie, we do not lower the dose if aminotransferase levels are not improving).  

We initiate azathioprine, 0.5 mg/kg daily, and gradually increase the dose to 1.5 to 2 mg/kg daily (maximum dose 200 mg daily) if needed to achieve biochemical remission and if it is tolerated. We monitor aminotransferases, IgG, complete blood count, total bilirubin and amylase weekly during the first month and every one to three months thereafter. If azathioprine is used for long-term maintenance, it is typically given as 1 to 1.5 mg/kg daily. Azathioprine may be used as monotherapy or in combination with low-dose prednisone if a glucocorticoid is needed to maintain biochemical response. (See 'Administration and monitoring' above.)

Alternatives to systemic glucocorticoid-based therapy – Alternatives to systemic glucocorticoids that have been studied in pediatric patients include azathioprine monotherapy [93], cyclosporine [53,54], tacrolimus [94], budesonide [51], and mycophenolate mofetil (MMF) [95], but we do not routinely use these regimens as first-line therapy because their role in pediatric populations is uncertain. In a meta-analysis of 15 studies involving pediatric patients with refractory autoimmune hepatitis, response rates at six months for cyclosporine (15 patients), tacrolimus (4 patients), and MMF (34 patients) were 83, 50, and 36 percent, respectively [96]. Adverse effects were most frequently reported in cyclosporine-treated patients with 64 percent of patients experiencing at least one adverse effect followed by tacrolimus (54 percent) and MMF (48 percent). (See 'Investigational therapies' above.)

Withdrawing therapy – We typically treat pediatric patients for two to three years after achieving biochemical and histologic remission before evaluating them for drug withdrawal [92]. In addition, we do not withdraw therapy during puberty because relapses are more common during this period of adolescence.

Approximately 20 to 40 percent of pediatric patients with type 1 autoimmune hepatitis have long-term remission in the absence of maintenance therapy, whereas most pediatric patients with type 2 autoimmune hepatitis develop disease relapse without therapy [97,98].

The classification of disease subtypes (ie, type 1 or type 2 autoimmune hepatitis) is discussed separately. (See "Overview of autoimmune hepatitis", section on 'Disease classification'.)

DISEASE COURSE

Survival — The overall prognosis for patients who are treated for autoimmune hepatitis is good with 10-year survival rates of approximately 90 percent [99]. However, studies have suggested that for patients with autoimmune hepatitis, mortality risk was higher than the general population [100-103]. In a population-based study including over 6000 patients with autoimmune hepatitis, the 10-year cumulative incidence of mortality was higher in patients with autoimmune hepatitis compared with a reference population (32 versus 14 percent, hazard ratio [HR] 2.29, 95% CI 2.17-2.41) [102]. In addition, cirrhosis at baseline has been associated with higher mortality rates after 10 years of follow-up [101].

Cirrhosis — Approximately one-third of adult patients with autoimmune hepatitis have cirrhosis at the time of diagnosis, and cirrhosis develops in another 30 to 50 percent of patients during the course of their disease [71,74,104]. Risk factors for progression to cirrhosis include histologic findings of bridging necrosis at diagnosis and lack of sustained biochemical remission [72,105]. (See 'Patients with cirrhosis' above.)

Hepatocellular carcinoma — We screen for hepatocellular carcinoma (HCC) using transabdominal ultrasound in patients with autoimmune hepatitis complicated by cirrhosis because such patients are at risk for HCC [18,74,106]. Routine surveillance intervals, imaging tests, and management of imaging results are discussed separately. (See "Surveillance for hepatocellular carcinoma in adults".)

In a meta-analysis of 25 studies, including over 6500 patients with autoimmune hepatitis who were followed for a median of eight years, the incidence rate of hepatocellular carcinoma was 3.1 (95% CI 2.2-4.2) per 1000 person-years [74]. In a meta-analysis of 16 studies of patients with autoimmune hepatitis and cirrhosis at diagnosis, the incidence rate of hepatocellular carcinoma was 10.1 (95% CI 6.9-14.7) per 1000 patient-years [74].

Liver transplantation — Studies have suggested that approximately 10 to 20 percent of patients with autoimmune hepatitis develop progressive disease requiring liver transplantation [5]. We evaluate patients for liver transplantation who have any of the following:

Decompensated cirrhosis.

A Model for End-stage Liver Disease (MELD)-Na score ≥15. The MELD-Na score can be calculated online. (See "Model for End-stage Liver Disease (MELD)".)

Hepatocellular carcinoma meeting criteria for transplantation. (See "Liver transplantation for hepatocellular carcinoma", section on 'Indications for transplantation'.)

Acute liver failure. (See 'Patients with acute liver failure' above.)

In addition, recurrent autoimmune hepatitis is common among liver transplant recipients [107,108]. In a study including 736 patients with autoimmune hepatitis who underwent liver transplantation, the rate of disease recurrence was 20 percent at five years and 31 percent at 10 years. Risk factors included younger age at transplant (ie, ≤42 years), use of mycophenolate, donor and recipient sex mismatch, and high IgG level prior to transplant [108].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Autoimmune hepatitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Autoimmune hepatitis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

General measures – The following general measures apply to all patients with autoimmune hepatitis (see 'General measures' above):

Standard, age-appropriate immunizations, in addition to vaccination for hepatitis A virus and hepatitis B virus for patients without serologic evidence of immunity. (See "Immunizations for adults with chronic liver disease".)

We advise patients to refrain from alcohol and, in particular, to avoid heavy alcohol use (ie, >14 drinks per week or >4 drinks on a given day for males and >7 drinks per week or >3 drinks on a given day for females).

Hepatology consultation for long-term management.

Goals of drug therapy – Goals of drug therapy are to improve symptoms, reduce liver inflammation, normalize aminotransferase and immunoglobulin G (IgG) levels, and prevent disease progression. (See 'Treatment goals' above.)

Pretreatment testing – Pretreatment evaluation includes testing for thiopurine methyltransferase (TPMT) enzyme activity, hepatitis B virus serologies, and bone density testing. (See 'Pretreatment evaluation' above.)

Initial management Indications for drug therapy are listed in the table (table 3).

For asymptomatic adults who have minimal or no elevation in serum aminotransferases and IgG levels and no active inflammation on liver biopsy, we suggest not initiating immunosuppressive therapy (Grade 2C).

For adults with autoimmune hepatitis who are selected for treatment, we suggest glucocorticoid monotherapy rather than other immunosuppressive agents (algorithm 1) (Grade 2C). Glucocorticoids reduce mortality compared with expectant management in these patients. The combination of a lower-dose glucocorticoid plus azathioprine is a reasonable alternative for patients at increased risk for glucocorticoid-associated adverse effects. (See 'Glucocorticoid monotherapy' above.)

We initiate prednisone (or prednisolone) 40 to 60 mg daily, followed by a gradual glucocorticoid taper. For patients with mild disease (eg, asymptomatic patients with aminotransferase levels <10 times the upper limit of normal), initiating prednisone at a lower dose (20 to 30 mg daily) is an alternative.

For patients who are at increased risk for side effects from glucocorticoids (eg, uncontrolled diabetes or hypertension), initiating a glucocorticoid at a lower dose (eg, prednisone 30 mg daily) as monotherapy or in combination with a thiopurine (eg, azathioprine, 50 mg daily) is a reasonable alternative. (See 'Glucocorticoid plus a thiopurine' above.)

Subsequent management – For most patients with autoimmune hepatitis who achieve complete biochemical response (CBR) with drug therapy, we suggest maintenance therapy with a thiopurine (eg, azathioprine) rather than chronic glucocorticoid use (Grade 2C). Maintenance therapy reduces the risk of disease relapse, and choosing azathioprine avoids long-term side effects associated with chronic glucocorticoid use.

The transition to long-term maintenance therapy is informed by the existing drug regimen, risk of drug-associated adverse effects, patient preferences, and clinician preferences. (See 'Subsequent management' above.)

Prognosis The overall prognosis for patients who are treated for autoimmune hepatitis is good with 10-year survival rates of approximately 90 percent. However, some patients develop progressive disease and cirrhosis, and management includes (see 'Disease course' above):

Screening for hepatocellular carcinoma. (See "Surveillance for hepatocellular carcinoma in adults".)

Managing complications of portal hypertension. (See "Portal hypertension in adults".)

Liver transplant evaluation for patients with decompensated cirrhosis. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)

Special populations:

Pediatric patients – For pediatric patients with autoimmune hepatitis, we suggest using a glucocorticoid plus a thiopurine rather than glucocorticoid monotherapy (Grade 2C). Combination therapy lowers the risk of adverse effects associated with glucocorticoid use (eg, bone disease, impacts on growth and puberty, acne). (See 'Pediatric patients' above.)

We use oral prednisone or prednisolone (1 to 2 mg/kg daily, up to a maximum of 60 mg daily), followed by a taper. Approximately two weeks after starting a glucocorticoid, we add a thiopurine (eg, azathioprine 0.5 mg/kg daily, maximum dose 200 mg daily). By initiating each drug separately, we avoid potential diagnostic uncertainty if aminotransferases rise or if new symptoms develop after starting drug therapy given the small risk of drug-induced liver injury associated with thiopurine use.

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Topic 3659 Version 46.0

References

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