Autoimmune Hepatitis Treatment & Management

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

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]

Next:

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 (Open Table in a new window)

Absolute Indications

Relative Indications

Serum aspartate transaminase (AST) ≥10-fold the upper limit of

normal (ULN)

Symptoms (eg, fatigue, arthralgia, jaundice)

Serum AST ≥5-fold the ULN and gamma-globulin level ≥2-fold the ULN

Serum AST and/or gamma-globulin less than absolute criteria

Bridging necrosis or multiacinar necrosis on

histologic examination

Interface hepatitis

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 (Open Table in a new window)

 

Prednisone Only (mg/d)

Combination Therapy

Prednisone (mg/d)

Azathioprine (mg/d)

Week 1

60

30

50

Week 2

40

20

50

Week 3

30

15

50

Week 4

30

15

50

Maintenance until

end point

20

10

50

Reasons for preference

Cytopenia

 

Thiopurine methyltransferase deficiency

 

Pregnancy

 

Malignancy

 

Short course (≤6 months)

Postmenopausal state

 

Osteoporosis

 

Brittle diabetes

 

Obesity

 

Acne

 

Emotional lability

 

Hypertension

 

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

 

Table 4. Treatment Regimens for Children (Open Table in a new window)

Initial Regimen

Maintenance Regimen

End Point

Prednisone, 1-2 mg/kg/day (up to 60 mg/day), for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/day

a. Prednisone taper over 6-8 weeks to 0.1-0.2 mg/kg daily or 5 mg daily

 

b. Azathioprine at constant dose if added initially

 

c. Continue daily prednisone dose with or without azathioprine, or switch to alternate day prednisone dose adjusted to response with or without azathioprine

a. Normal liver tests for 1-2 years during treatment

 

b. No flare during entire interval

 

c. Liver biopsy examination discloses no inflammation

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.

Previous
Next:

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]

Previous
Next:

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]

Previous
Next:

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.

Previous
Next:

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.

Previous