Approach

Corticosteroids and immunosuppressants form the mainstay of treatment. Clinical judgement forms the basis of any decision to treat and, due to the potential toxicity of the drugs used, treatment may not always be indicated.

Patients with cirrhosis, post-menopausal osteopenia or vertebral compression, emotional lability or psychosis, poorly controlled hypertension, or brittle diabetes are at increased risk of adverse effects with corticosteroids (and may therefore have a poorer outcome).[1]

Indications for treatment

All individuals with autoimmune hepatitis (AIH) should be considered as candidates for therapy except those with inactive disease based on clinical, laboratory, and histological assessment.[1]

Treatment is mandated when symptoms or disease activity are severe, and in the presence of severe AIH.

Severe disease

Patients are considered to have severe disease if they present with:[1][26][36]

  • serum aminotransferase levels greater than 10-fold the upper limit of normal, or

  • serum aminotransferase levels 5-fold the upper limit of normal with a serum gamma-globulin level at least twice the upper limit of normal, or

  • bridging necrosis or multi acinar necrosis on liver histology.

Acute severe AIH

There are different clinical entities of acute severe AIH:[26]

  • the acute exacerbation of chronic AIH, and

  • true acute AIH without histological findings of chronic liver disease.

The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) define acute severe AIH as:[1][26]

  • jaundice

  • international normalised ratio (INR) >1.5 to <2

  • no encephalopathy

  • no previously recognised liver disease.

These patients should be treated unless other considerations (e.g., high risk of drug intolerance due to comorbidities, advanced inactive cirrhosis) apply.[1]

Patients who do not satisfy criteria for severe disease

Treatment must be individualised and the decision to treat or to monitor is based on the presence of symptoms (fatigue, arthralgia, jaundice); levels of serum aminotransferase, gamma-globulins, or both; and the presence of interface hepatitis on liver histology.[1]

Treatment should not be initiated in patients with cirrhosis that has become inactive and can also be deferred in patients with minimally active disease who have comorbidities.[1] These patients should be followed closely with assessment at intervals of 3 to 6 months.[26]

Patients who are antinuclear antibody (ANA)-negative, but have biopsy findings suggestive of AIH, may require treatment. The treatment approach would be dictated by the same parameters that inform management of an ANA-positive patient.

Management of acute severe AIH

Patients with acute severe AIH should be treated with high-dose corticosteroid monotherapy as early as possible.[26]

If there is a lack of improvement within 7 to 14 days, the patient should be evaluated for emergency liver transplantation.[1][26]

Patients with acute severe AIH and acute liver failure should be evaluated for liver transplantation immediately.[1]

Initial treatment regimens for active disease

Recommended initial treatments for AIH include a corticosteroid alone or in combination with immunosuppressant therapy.[1][26][36]

Corticosteroid monotherapy

The AASLD recommends corticosteroid monotherapy as one possible initial treatment for patients with AIH who do not have acute severe hepatitis or acute liver failure.[1]

The British Society of Gastroenterology (BSG) and EASL recommend that corticosteroid monotherapy is reserved for patients who have a contraindication to immunosuppressant therapy (e.g., cytopenia, active malignancies, or thiopurine methyltransferase [TPMT] deficiency), or when the presumed treatment course will be short (i.e., less than 6 months).[26][36]

Corticosteroid monotherapy is contraindicated in post-menopausal women and patients with osteoporosis, diabetes, glaucoma, cataracts, hypertension, major depression, and emotional lability.[1][26][36]

Prednisolone is an active metabolite of prednisone and either may be used; however, advanced cirrhosis can significantly impair the conversion of prednisone to prednisolone, although this impairment is usually insufficient to alter treatment response or justify the preferential administration of prednisolone.[1][41][42]

Budesonide is recommended as an alternative to prednisone or prednisolone in non-cirrhotic patients who have experienced, or are at increased risk for, severe side effects on prednisone or prednisolone (e.g., poorly controlled diabetes, osteoporosis, psychosis).[26][36] The majority of studies are favourable and report a good treatment response.[43][44][45][46]​​​[47] Budesonide monotherapy has demonstrated normalisation of transaminases, but histological responses to treatment have not been well studied thus far; therefore, budesonide is contraindicated in patients with cirrhosis and patients who present with acute severe AIH.[1]

Corticosteroid plus immunosuppressant therapy

The AASLD recommends the combination of a corticosteroid plus azathioprine as an alternative initial treatment for patients with AIH who do not have acute severe hepatitis or acute liver failure.[1]

The BSG and the EASL recommend the combination of a corticosteroid plus azathioprine as an initial treatment option when the presumed treatment course is >6 months, as it is considered to result in fewer side effects and better efficacy compared with corticosteroid monotherapy.[26][36]

Azathioprine should be started 2 weeks after corticosteroid treatment to confirm corticosteroid responsiveness, evaluate TPMT status, and assess treatment response by excluding the possibility of azathioprine-induced hepatitis.[1][26] Some people have reduced TPMT enzyme activity, which mediates elimination of mercaptopurine (the active metabolite of azathioprine). Those with a lower activity of TPMT are at a higher risk of toxicity from azathioprine; therefore, it is recommended that all patients should be routinely tested for TPMT activity.[1][26][36] Azathioprine should be avoided or used at a lower dose in those with a lower activity of TPMT.

Azathioprine is not recommended for patients with decompensated cirrhosis.[1]

Azathioprine can be continued throughout pregnancy.[1][26] Adverse effects of azathioprine include cholestatic hepatitis, veno-occlusive disease, pancreatitis, nausea, vomiting, and bone marrow suppression.

Prednisolone is an active metabolite of prednisone and either may be used; however, advanced cirrhosis can significantly impair the conversion of prednisone to prednisolone, although this impairment is usually insufficient to alter treatment response or justify the preferential administration of prednisolone.[1][41][42]

Budesonide is recommended as an alternative option to prednisone or prednisolone in non-cirrhotic patients who have experienced, or are at increased risk for, severe side effects on prednisone or prednisolone (e.g., poorly controlled diabetes, osteoporosis, psychosis).[26][36] Budesonide should not be used in patients who have cirrhosis or who present with acute severe AIH.[1]

One study of paediatric patients with AIH compared the combination of prednisone and azathioprine versus budesonide and azathioprine and found no statistically significant difference in response and adverse effects.[48] Non-significant trends were observed, including lower weight in the budesonide group and modestly improved rate of biochemical remission in the prednisone group.

Mycophenolate and ciclosporin may be considered as alternative immunosuppressants to azathioprine for patients who are intolerant to azathioprine or have a contraindication to its use.[1]

Mycophenolate combined with prednisone has been reported by systematic review evidence as superior to azathioprine with prednisone in the normalisation of alanine aminotransferase, aspartate aminotransferase, and immunoglobulin G levels and in the rate of non-response in patients with AIH.[49][50] Mycophenolate is contraindicated in pregnancy.[1]

Studies have shown that ciclosporin normalises serum transaminase levels and improves histology in AIH patients without significant adverse effects requiring cessation of therapy.[51][52] However, its high toxicity profile may limit its use due to increased risk of hypertension, renal insufficiency, hyperlipidaemia, hirsutism, opportunistic infection, and malignancy.

Management of AIH with primary biliary cholangitis (overlap syndrome)

Patients with histological features of AIH but serological findings of primary biliary cirrhosis (i.e., antimitochondrial antibodies [AMA] directed towards enzymes in the 2-oxoacid dehydrogenase family) can rapidly progress to cirrhosis, so even asymptomatic patients should be treated.

A combination of a corticosteroid plus an immunosuppressant is usually preferred.[1] Patients with contraindications to immunosuppressant therapy (e.g., cytopenia, active malignancies, or TPMT deficiency) are treated with corticosteroid monotherapy.[3]

Ursodeoxycholic acid should be given in combination with immunosuppressive therapy in patients with overlap syndrome.[1]

Second-line treatment regimens (management of treatment failure, incomplete response, and drug intolerance)

Second-line therapies are used to manage treatment failure, incomplete response, and drug intolerance.[1]

Treatment failure is defined as worsening of clinical, laboratory, and histological features despite compliance with therapy.[1] An elevation of aminotransferase values by at least 67% is usually considered a sign of treatment failure, as well as development of jaundice, ascites, or hepatic encephalopathy. At least 9% of adult patients and 5% to 15% of children experience treatment failure with standard treatment schedules.

Incomplete response is defined as failure to achieve remission after 3 years of therapy, with some or no improvement in clinical, laboratory, and histological features, but with no worsening of the condition. This outcome is seen in approximately 15% of patients.[1]

Treatment intolerance indicates the inability to continue therapy due to adverse effects of the drug.[1]

The AASLD recommends a trial of mycophenolate or tacrolimus for children and adults with AIH who have treatment failure, incomplete response, or drug intolerance to first-line agents. Based on ease of use and adverse effect profile, the AASLD suggests mycophenolate over tacrolimus as the initial second-line agent.[1] Mycophenolate is contraindicated in pregnancy.[1]

The EASL and BSG recommend a standard approach to managing treatment failure with very high doses of a corticosteroid or a combination of a corticosteroid with azathioprine for at least 1 month.[26][36] The dose of the corticosteroid and azathioprine is reduced after each month of clinical and laboratory improvement, and dose reduction is continued until conventional maintenance levels of medications are achieved.

Maintenance therapy

Maintenance therapy should be continued until remission, treatment failure, incomplete response, or drug toxicity.[1]

Corticosteroids are used either alone or in combination with an immunosuppressant (e.g., azathioprine, mercaptopurine). Drug preference is informed as per initial treatment options, and depends on comorbid conditions and intolerance. Possible complications of long-term immunosuppressive therapy include oncogenicity and teratogenicity.

Decompensated liver disease

Combination therapy is not recommended for patients with decompensated liver disease; high-dose corticosteroid monotherapy is advised before evaluation for transplantation.[1][26] Whether medical therapy with corticosteroids affects the natural history, or reduces the need for liver transplantation, remains controversial.

Overall, liver transplantation is largely successful with a 5-year-survival rate of 80% to 90%.[1]​ Patients who receive liver transplants for AIH, however, have a greater risk of developing acute cellular and ductopenic rejection compared with patients who receive liver transplants for other conditions.[53]

Long-term prevention of relapse

Relapse is defined as the exacerbation of disease activity after induction of remission and drug withdrawal, and occurs in up to 87% of adults and 80% of children.[1] It is commonly asymptomatic.

Liver tissue examination prior to drug withdrawal may help to exclude unsuspected inflammation and reduce the frequency of relapse.[1]

Patients who relapse subsequent to drug withdrawal typically respond to the original regimen.[1] A long-term maintenance regimen can be implemented when biochemical remission is achieved.

Treatment endpoints

Remission is associated with disappearance of symptoms, improvement of serum aminotransferase levels to normal, normalisation of serum bilirubin and gamma-globulin levels, and improvement of liver histology to normal or with minimal inflammation but no interface hepatitis.[1]

Normalisation of indices prior to treatment termination confers a relative risk reduction of relapse between 3-fold and 11-fold, with 87% of patients who achieve sustained remission having had normal values prior to treatment discontinuation. Approximately 65% of patients enter remission within 18 months of therapy and 80% within 3 years, with a mean duration of treatment to remission being 22 months.[1] Adults rarely achieve remission in less than 12 months and the probability of remission diminishes after 2 years.[1] Histological improvement lags behind clinical and laboratory improvement by 3 to 6 months, which is important when considering repeated liver biopsy.[3]

Relapse occurs in 20% to 100% of patients who enter remission, depending on the histological findings before drug withdrawal.[1] Patients with normal histology have a 20% frequency of relapse, while patients with portal hepatitis at termination have a 50% frequency of relapse within 6 months.[1] Those who progress to cirrhosis during treatment or who have interface hepatitis at drug withdrawal commonly relapse.[1]

Drug toxicity requires premature discontinuation or alteration of conventional therapy in 13% of patients.[1]

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