Autoimmune Hepatitis Treatment & Management

For more than 3 decades, corticosteroids, either alone or in combination with azathioprine, have been the mainstays of drug therapy for patients with autoimmune hepatitis.^[41] 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 in order to document histologic remission, prior to attempting withdrawal of immunosuppression?
• Should patients receive life-long low-dose maintenance therapy with azathioprine?

Azathioprine is metabolized to 6-mercaptopurine. 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. High 6-thioguanine levels, in turn, may predispose the patient to bone marrow suppression. Some authors recommend that patients undergo TPMT genotyping prior to the initiation of azathioprine therapy.^[42]

Approximately 65% of patients respond to initial therapy and enter histological remission; however, 80% of these patients relapse after drug withdrawal. The practice guideline of the American Association for the Study of Liver Diseases (AASLD) provides recommendations for therapy.^[43] See Table 2, below.

Table 2. Indications for Treatment of Autoimmune Hepatitis in Adults (Open Table in a new window)

Treatment might not be indicated in patients with inactive cirrhosis, preexistent comorbid conditions, or drug intolerances. On the other hand, patients with a histologic diagnosis of cirrhosis may respond well to therapy and should be offered treatment in an attempt to slow disease progression.

Treatment might not be appropriate in patients with decompensated liver disease. Such individuals might be better served by undergoing liver transplantation.

The AASLD guidelines suggest 2 potential initial treatment regimens for adults (see Table 3, below). Recently, the British Society of Gastroenterology (BSG) has put forth their recommendations on treatment of autoimmune hepatitis. Essentially, the recommendations of both AASLD and BSG are the same and the differences are only in the wording. While BSG "strongly recommends" combination therapy with prednisone and azathioprine, AASLD recommends this option as "preferred."

Table 3. Treatment Regimens for Adults (Open Table in a new window)

BSG guidelines strongly recommend the combination of prednisolone and azathioprine as initial therapy, whereas the AASLD notes that combination therapy is preferred to prednisone alone.^{[43, 30]}

Patients whose liver chemistries normalize after initial therapy then require maintenance therapy. In the authors' opinions, prednisone dosing can be further reduced after achieving normalization of liver chemistries. The authors commonly use azathioprine alone as a maintenance drug. Azathioprine therapy is withdrawn approximately 1 year after the patient's liver chemistries have normalized.

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

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

Prednisolone rather than prednisone may be used, at a dosage of 2 mg/kg/d (not to exceed 60 mg/d). The BSG guidelines assume use of prednisolone.^[30] Taper over 4-8 weeks, if testing of transaminase levels demonstrates gradual improvement, then administer the minimum maintenance dose required to sustain reference levels of liver enzymes.

Frequently check liver enzyme levels during the initial period of treatment (ie, first 6-8 wk). Liver enzyme levels are usually checked weekly to fine-tune the treatment and avoid adverse effects from the steroids.

Liver enzymes levels may require several months to return to reference range values. In patients with autoimmune hepatitis type 1 (AIH-1), transaminase levels took a median of 0.5 years (range, 0.2-7 y) to return to reference values; in patients with autoimmune hepatitis type 2 (AIH-2), transaminase levels took a median of 0.8 years (range, 0.02-3.2 y) to return to reference values.

If liver enzyme levels do not return to reference values during the first 4-8 weeks of treatment or if improvement requires high doses of steroids, initiate azathioprine administration at 0.5 mg/kg/d and gradually increase to 2 mg/kg/d until transaminase levels return to reference values. Some authors recommend starting azathioprine with prednisone at disease onset.

Budesonide may offer an alternative to prednisone. In a prospective, double-blind randomized trial by Manns et al, 60% of budesonide-treated patients had normalized liver chemistries 6 months after initiating treatment, compared with 39% of prednisone-treated patients.^[44] Furthermore, steroid-specific side effects were seen in only 28% of the budesonide-treated patients but in 53% of the prednisone-treated patients.

Budesonide was given in a dosage of 3 mg three times daily or twice daily to prednisone. The initial prednisone dose was 40 mg daily, tapered to 10 mg daily. Patients also received azathioprine 1-2 mg/kg/d.^[44] Longer-term follow-up is needed to better assess the efficacy and safety of budesonide.

Based on moderate-quality evidence, the 2011 BSG guidelines strongly recommend use of budesonide for prednisolone-intolerant patients.^[30]

Cyclosporine has been used successfully to avoid high steroid doses in both adult and pediatric patients. In a study in children by Alvarez et al, cyclosporine induced biochemical remission of the hepatic inflammatory process in children with autoimmune hepatitis while causing few and well-tolerated adverse effects.^[45] In this study, cyclosporine was administered for 6 months alone, followed by combined low doses of prednisone and azathioprine for 1 month, then cyclosporine was discontinued.

A study in children and adolescents by Sciveres et al found that cyclosporine may be considered as a safe treatment for all autoimmune liver diseases and as an effective alternative for front-line therapy.^[46] This study included patients with autoimmune hepatitis, autoimmune cholangitis, and giant cell hepatitis.

Patients may achieve 1 of 4 treatment endpoints^[43] :

• Remission
• Treatment failure
• Incomplete response
• Drug toxicity

Remission

Remission is indicated by the absence of symptoms, normalization of aminotransferases, and histologic improvement to normal or minimal inflammatory activity on liver biopsy. Patients achieving remission may be able to taper off prednisone over a 6-week period. Azathioprine can be discontinued after the withdrawal of prednisone.

Patients in acute liver failure whose liver chemistries improve rapidly after starting prednisone have an excellent short-term prognosis. Many such patients ultimately achieve clinical remission on immunosuppressant therapy.

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 medications. Indeed, adults infrequently achieve clinical, laboratory, and histologic remission in less than 12 months. Immunosuppressant therapy can achieve remission in 65% of patients within 18 months and in 80% of patients by 3 years.

Histologic remission tends to lag behind clinical and laboratory remission by 3-6 months. Many clinicians—and the current practice guidelines of the AASLD^[43] —recommend that a follow-up liver biopsy be performed. This is done in an effort to avoid medication withdrawal in a patient who is not yet in histologic remission.

Treatment failure

Treatment failure is defined as deterioration in a patient's clinical condition, laboratory tests, or histologic features during therapy. This is seen in approximately 9% of patients.^[43] Some patients will have a response to reinstitution of treatment with high-dose prednisone, with or without combined azathioprine.

Patients with severe disease (eg, acute liver failure due to autoimmune hepatitis) have a high short-term mortality rate if they fail to show normalization of at least 1 laboratory parameter after starting prednisone-based therapy or if pretreatment hyperbilirubinemia fails to improve during a 2-week treatment trial. Early liver transplantation should be considered in such individuals.

High-dose prednisone (60 mg/d) alone or prednisone (30 mg/d) plus azathioprine (150 mg/d) 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.^{[47, 48, 49]} However, the potential toxicity of these calcineurin inhibitors must be assessed carefully before initiating treatment.

Similarly, a few studies have supported the use of mycophenolate mofetil in patients whose disease was refractory to standard therapy.^{[50, 51, 52, 53]} In these studies, a dose of 1 g orally twice per day was employed initially.

The authors have seen a number of patients who experienced treatment failure with prednisone plus azathioprine but achieved treatment success with low-dose prednisone plus mycophenolate mofetil. However, mycophenolate mofetil has not been subjected to a randomized trial in patients with autoimmune hepatitis.

Aw et al concluded that mycophenolate mofetil is an effective rescue therapy for children with autoimmune hepatitis, but not for those with autoimmune sclerosing cholangitis (ASC).^[54] Inclusion criteria this study included failure to achieve/maintain remission with prednisolone/azathioprine or significant treatment side effects. Of the 26 children recruited, 16 had AIH type 1, 2 had AIH type 2, and 8 had ASC. Of the 26 children, 18 responded to mycophenolate mofetil and 8 (6 with ASC) did not respond.

There are no clear guidelines as to how mycophenolate mofetil should be tapered if a therapeutic response has been achieved. The authors have used doses as low as 500 mg twice per day to maintain patients in a drug-induced remission.

Budesonide has been has been used with variable success in patients who had treatment failures.^{[55, 56]} Limited data are available regarding the use of tacrolimus, methotrexate, and other agents.

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.^[43] Many such patients will require indefinite treatment with as low an immunosuppressant dose as is needed to prevent clinical deterioration.

A prednisone schedule similar to that used after relapse (10 mg/d) is reasonable. The goal of therapy is to control disease activity on the lowest dose of medication possible. Azathioprine may help to serve as a steroid-sparing agent.

Patients should be referred for consideration of liver transplantation if they manifest signs of hepatic decompensation (eg, new onset of hypoalbuminemia, coagulopathy, variceal bleeding, ascites, hepatic encephalopathy).

Drug toxicity

Drug toxicity may occur. Patients must be tapered off from the culprit medication. Some patients successfully achieve treatment goals on alternative medications.

Cushingoid features, acne, and hirsutism develop in 80% of patients after 2 years of prednisone-based therapy. Osteoporosis with vertebral compression, diabetes, cataracts, severe emotional lability, and hypertension may develop in patients who are treated with prolonged courses of high-dose prednisone. Premature treatment withdrawal is justified in patients who develop intolerable obesity, cosmetic changes, or osteoporosis.

Azathioprine can function as a steroid-sparing agent. The authors have had great success and minimal drug-related adverse effects using a regimen of prednisone 10 mg/d plus azathioprine 50 mg/d.

Patients should be co-treated with calcium and vitamin D in order to prevent the development of steroid-induced osteoporosis. Regular exercise should be encouraged. Bone densitometry performed every 1-2 years should be used to monitor patients. Signs of early osteoporosis may warrant the institution of treatment with alendronate.

Azathioprine therapy can be complicated by cholestatic hepatotoxicity, nausea, vomiting, rash, cytopenia, and pancreatitis. These complications occur in fewer than 10% of patients treated with azathioprine at 50 mg/d.

To date, most studies of azathioprine efficacy in autoimmune hepatitis have used a dose of 50 mg/d. 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/8x10⁸ erythrocytes.^[57] 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.

Cytopenias, particularly leukopenia, may occur at any time after the initiation of azathioprine therapy. All patients undergoing treatment with azathioprine should undergo routine interval testing of the complete blood count.

Teratogenicity has been ascribed to treatment with azathioprine; however, the gastroenterology literature is replete with references that describe the safe use of azathioprine and 6-mercaptopurine in pregnant women with inflammatory bowel disease. Whether this observation can be extended to pregnant women with autoimmune hepatitis and whether azathioprine can be employed safely in these patients is unclear.

The 2011 BSG guidelines include a weak recommendation to maintain combination treatment with as little change as possible during pregnancy, whereas the AASLD guideline suggests discontinuing azathioprine in pregnant patients. Both guidelines warn of postpartum exacerbation and recommend a prompt return to standard therapy; the BSG recommends this return immediately after delivery, whereas the AASLD recommends a return 2 weeks prior to the expected delivery date.^{[43, 30]}

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.

Relapse occurs in 50% of patients within 6 months of treatment withdrawal and in 80% of patients within 3 years of treatment. Reinstitution of the original treatment regimen usually induces another remission; however, relapse commonly recurs after a second attempt at terminating therapy. The major consequence of relapse and re-treatment is the development of drug-related complications, which occurs in 70% of patients.

Patients who relapse twice require indefinite therapy with either prednisone or azathioprine. The dose is titrated as low as possible in order to prevent symptoms and to maintain an AST level 5-fold below the reference range. The median dose of prednisone required to achieve this is 7.5 mg/d.

Some authors advocate indefinite treatment with azathioprine only. In one study, 60 of 72 patients (83%) receiving long-term therapy with azathioprine at a dose of 2 mg/kg/d remained in remission, with a median follow-up period of 67 months (range, 12-128 mo).^[58]

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.

This procedure is an effective form of therapy for patients in whom medical therapy has failed, or those with decompensated cirrhosis caused by autoimmune hepatitis. Liver transplantation also may be used to rescue patients who present with fulminant hepatic failure secondary to autoimmune hepatitis. A low threshold should exist for transferring patients with acute liver failure to tertiary care hospitals that are capable of performing emergent liver transplantation. Approximately 10-20% of patients require liver transplantation.

The long-term outlook after liver transplantation is excellent, with 10-year survival rates reported as greater than 70%.^[59] Positive autoantibodies and hypergammaglobulinemia tend to disappear within 2 years of transplantation.^[60]

Recurrence of autoimmune hepatitis is described after liver transplantation. It has been reported primarily in inadequately immunosuppressed patients. It may occur more often in HLA DR3–positive recipients of livers from HLA-DR3–negative donors.

Recurrent disease is seen in 10-35% of patients undergoing transplantation for autoimmune hepatitis. Although such recurrences are often mild events, one paper described a need for retransplantation in one half of patients experiencing recurrent disease.^{[59, 61, 62]}

Montano-Loza et al concluded that recurrence risk factors include concomitant autoimmune disease and high levels of aspartate aminotransferase, alanine aminotransferase, and IgG prior to the transplant.^[62] The presence of moderate to severe inflammatory activity or plasma cell infiltration in the liver explant also was said to increase the recurrence risk. According to the authors, their findings suggest that incomplete suppression of disease activity before liver transplantation promotes autoimmune hepatitis recurrence.

Treatment combining ursodiol and immunosuppressants may be advisable in patients with the autoimmune hepatitis–primary biliary cirrhosis (PBC) overlap syndrome. In one study, of noncirrhotic patients, fibrosis progression was seen in 4 of 8 patients treated with ursodiol monotherapy, versus 0 of 6 patients treated with combination therapy.^[63] The mean duration of follow-up was 7.5 years.

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), 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 unnecessary, but patients may feel better with restricted physical activity.

Perform liver function tests in patients with autoimmune hepatitis (AIH) weekly during the first 6-8 weeks of treatment and then every 2-3 months, based on results. Schedule regular follow-up visits to assess disease activity and to search for signs and symptoms of chronic liver disease.

Surveillance abdominal imaging studies (eg, ultrasound, CT, MRI) and alpha-fetoprotein testing are typically performed every 6 months in patients with most types of cirrhosis. The optimal interval for surveillance and the best type of abdominal imaging study have not yet been determined for patients with autoimmune hepatitis–induced cirrhosis. Detection of a small hepatocellular carcinoma on imaging studies should prompt immediate referral for consideration of liver transplantation.