Guideline sources The following summarized guidelines for the evaluation and management of autoimmune hepatitis are prepared by our editorial team based on guidelines from the American Association for the Study of Liver Diseases (AASLD 2020), the Hellenic Association for the Study of the Liver (HASL 2019), the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN 2018), the American College of Gastroenterology (ACG 2016; 2015), the Italian Association for the Study of the Liver (AISF 2016), and the European Association for the Study of the Liver (EASL 2015). 1 2 3 4 5 6 7 8 9 10 11 Definition AIH is a chronic liver disease of unknown etiology characterized by interface hepatitis, hypergammaglobulinaemia, and circulating autoantibodies. 8 Epidemiology https://web.pathway.md/diseases/recy694asCYrsgEzB 1/12 6/23/23, 3:16 AM Autoimmune hepatitis Pathway The cause of AIH is primarily unknown, but there is a complex interplay of genetic (HLA haplotype) and environmental factors. 9 Disease course The immunological reaction against autologous liver antigens in genetically predisposed individuals results in AIH, which may an asymptomatic, acute, or acute severe (fulminant) presentation. Disease progression may lead to hepatic encephalopathy, cirrhosis, and a need for the liver transplantation. 10 Prognosis and risk of recurrence All-cause mortality/liver transplant rates for AIH over a period of 10 years is 13%. 11 CalculatorHistology activity index HAI Guidelines 1. Screening and diagnosis Clinical presentation: As per AASLD 2020 guidelines, suspect the diagnosis of AIH in all patients presenting with acute or chronic liver disease, including patients with asymptomatic liver test abnormalities, ALF, and autoantibody-negative hepatitis. E As per EASL 2015 guidelines, suspect AIH in any patient with acute or chronic liver disease, particularly in the context of hypergammaglobulinemia. B Show 2 more Diagnostic criteria: As per AASLD 2020 guidelines, diagnose AIH based on compatible histological findings and further support the diagnosis by the following features: elevated serum aminotransferase levels elevated serum IgG level and/or positive serological markers exclusion of viral, hereditary, metabolic, cholestatic, and drug-induced diseases potentially resembling AIH. E Show 4 more As per HASL 2019 guidelines, suspect AIH in any patient with acute or chronic hepatitis, particularly in the presence of high IgG levels, as it has a global distribution at any age in both sexes and in all ethnic groups. B https://web.pathway.md/diseases/recy694asCYrsgEzB 2/12 6/23/23, 3:16 AM Autoimmune hepatitis Pathway Show 6 more As per EASL 2015 guidelines, diagnose AIH based on the presence of autoantibodies, hypergammaglobulinemia and typical or compatible histology. B 2. Classification and risk stratification Classification: Classify the diagnosis of acute AIH as one of the following two clinical forms of presentation: acute worsening of previously undiagnosed or misdiagnosed AIH real (original) acute onset of AIH without chronic lesions on liver histology. B Consider classifying AIH into two types: AIH-1: ANA, smooth muscle antibodies and/or anti-SLA/LP positive AIH-2: anti-LKM1, anti-LKM3 and/or anti-LC1 positive. C 3. Diagnostic investigations Immunoglobulin levels: As per HASL 2019 guidelines, do not exclude the diagnosis of AIH in patients with normal IgG levels, even though a selective high serum IgG is an important AIH characteristic. D As per EASL 2015 guidelines, recognize that: elevated IgG, especially in the absence of cirrhosis, is suggestive of AIH B elevated IgG in the absence of IgA and IgM elevation is particularly suggestive of AIH B normal IgG or gamma-globulin do not preclude the diagnosis of AIH most of patients with normal IgG demonstrate a fall of IgG levels upon treatment. B Autoantibody titers: As per AASLD 2020 guidelines: Obtain ANA and ASMA in adults and ANA, ASMA, and anti-LKM1 in children in the initial serological testing for AIH. E Consider obtaining additional autoantibody tests if warranted to secure the diagnosis. E As per HASL 2019 guidelines, use IDIF, preferably on freshly frozen rodent substrates, for routine screening in the detection of most autoantibodies and use ELISA and immunoblotting as the tests for anti-SLA/LP and anti-LC1 autoantibodies. B As per EASL 2015 guidelines, recognize that circulating non-organ specific antibodies are present in the vast majority of AIH patients. B Show 2 more Cholangiography: As per AASLD 2020 guidelines, obtain cholangiography to evaluate for large-duct PSC for AIH- PSC overlap syndrome in patients with AIH, cholestatic laboratory findings, histological features https://web.pathway.md/diseases/recy694asCYrsgEzB 3/12 6/23/23, 3:16 AM Autoimmune hepatitis Pathway of bile duct injury or loss, and concurrent chronic ulcerative colitis. E As per HASL 2019 guidelines, consider obtaining MRCP in adult patients with AIH only when cholestatic laboratory manifestations are present. C As per ACG 2015 guidelines, obtain MRCP for patients < 25 years of age with AIH who have elevated serum ALP (usually > 2 times the ULN). B As per EASL 2015 guidelines: Consider obtaining magnetic resonance cholangiography to exclude autoimmune sclerosing cholangitis in adult patients with AIH and cholestatic pattern of laboratory abnormalities. C Obtain magnetic resonance cholangiography to exclude autoimmune sclerosing cholangitis in all pediatric patient with AIH. B Screening for drug-induced liver injury: Include drug-induced AIH-like liver injury in the differential diagnosis of AIH. E Withdraw the offending agent and maintain monitoring to ensure laboratory resolution. E Screening for liver cirrhosis: As per AASLD 2020 guidelines: Do not obtain serum-based biomarker panels for hepatic fibrosis in patients with AIH. D Defer obtaining vibration-controlled transient elastography for the detection of advanced fibrosis or cirrhosis for at least 6 months after successful treatment of AIH in order to avoid the confounding effects of hepatic inflammation. E As per HASL 2019 guidelines, assess for cirrhosis at diagnosis of AIH, as almost 33% of adult patients and 50% of pediatric patients with AIH are first diagnosed at the stage of cirrhosis, indicating that they have had subclinical disease for a long time. B Evaluation for concomitant diseases: As per AASLD 2020 guidelines, screen patients with AIH for celiac and thyroid diseases at diagnosis. E Show 2 more As per HASL 2019 guidelines, recognize that coexistence of AIH features and cholestatic diseases can be observed at both diagnosis and follow-up, but their diagnosis may be problematic because of the lack of internationally accepted criteria. B Show 2 more As per EASL 2015 guidelines: Obtain diagnostic tests for primary biliary cirrhosis and PSC in patients showing features of cholestasis. B Recognize that AIH is associated with a wide variety of other autoimmune diseases. B Psychosocial assessment: As per AASLD 2020 guidelines, monitor for manifestations of depression and changes in the quality of life throughout management of AIH. Consider using structured and validated questionnaires for objective assessment. E https://web.pathway.md/diseases/recy694asCYrsgEzB 4/12 6/23/23, 3:16 AM Autoimmune hepatitis Pathway As per EASL 2015 guidelines, address psychosocial needs in the management of patients with AIH, recognizing the associated decreased quality of life. B 4. Diagnostic procedures Liver biopsy: perform liver biopsy in the initial diagnostic work-up of AIH, as it is a prerequisite for the confirmation of diagnosis. B Show 2 more 5. Medical management General principles: As per HASL 2019 guidelines, treat all patients with active disease, even with advanced fibrosis or cirrhosis. A Show 2 more As per EASL 2015 guidelines, initiate treatment in all patients with active AIH. A Show 4 more Treatment targets: As per HASL 2019 guidelines, aim to achieve complete biochemical and histological remission in an attempt to prevent potential disease progression. B Show 2 more As per EASL 2015 guidelines, aim to obtain complete biochemical and histological resolution of the disease in order to prevent further progression of liver disease. B Show 2 more Corticosteroids: As per AASLD 2020 guidelines, initiate corticosteroids in patients with drug-induced AIH-like injury when symptoms or disease activity are severe (fulfilling Hy's law) or if symptoms and laboratory tests fail to improve or worsen after discontinuation of the offending drug. E Show 3 more As per HASL 2019 guidelines, initiate prednisolone 0.5-1 mg/kg/day at one oral dose in the morning, combined with azathioprine at an initial morning dose of 50 mg/day usually after 2 weeks, if bilirubin is < 6 mg/dL, as first-line therapy in patients with AIH. A Show 2 more As per EASL 2015 guidelines, initiate prednisone or prednisolone, followed by the addition of azathioprine after 2 weeks of corticosteroids, as first-line therapy in patients with AIH. A Show 5 more Immunosuppressive agents: As per AASLD 2020 guidelines: https://web.pathway.md/diseases/recy694asCYrsgEzB 5/12 6/23/23, 3:16 AM Autoimmune hepatitis Pathway Consider screening patients with AIH for absent or near-absent TPMT activity before initiating treatment with azathioprine. E Consider initiating a trial of mycophenolate mofetil rather than tacrolimus as the initial second- line agent in patients with AIH. C As per HASL 2019 guidelines, initiate mycophenolate mofetil as second-line therapy in patients intolerant to azathioprine. B Consider initiating mercaptopurine or thioguanine as an alternative. B As per EASL 2015 guidelines, consider initiating azathioprine whenever bilirubin levels are < 6 mg/dl (100 mcmol/L) and ideally 2 weeks after the initiation of corticosteroid treatment. Administer azathioprine at an initial dose of 50 mg/day and increase depending on toxicity and response up until a maintenance dose of 1-2 mg/kg. C Show 3 more Biologics: consider initiating anti-TNF or anti-CD20 therapy as an alternative after first-line and second-line regimens have failed. E Duration of treatment: As per AASLD 2020 guidelines: Consider withdrawing treatment and achieving a long-term treatment-free remission of AIH in patients with normalized serum aminotransferase and IgG levels for at least 2 years. E Consider performing liver tissue examination before drug withdrawal for excluding unsuspected inflammation and reducing the frequency of relapse. E As per HASL 2019 guidelines, perform liver biopsy before treatment discontinuation in patients with AIH in persistent complete biochemical remission for at least the last 2 years of immunosuppression. B Show 2 more As per EASL 2015 guidelines, continue immunosuppressive treatment for 3 years in total and for 2 years following complete normalization of transaminases and IgG. B Show 3 more Maintenance therapy: As per HASL 2019 guidelines, increase azathioprine dose up to 1-2 mg/kg/day (maintenance dose). B Show 7 more As per EASL 2015 guidelines, recognize that only a small minority of patients stay in remission without maintenance therapy. B Show 2 more 6. Surgical interventions Liver transplantation: As per AASLD 2020 guidelines, evaluate patients with AIH for liver transplantation in the following circumstances: https://web.pathway.md/diseases/recy694asCYrsgEzB 6/12 6/23/23, 3:16 AM Autoimmune hepatitis Pathway ALF failed to improve laboratory tests within 1-2 weeks of corticosteroid therapy clinical deterioration within 1-2 weeks of corticosteroid therapy. E Show 4 more As per HASL 2019 guidelines, manage patients with AIH after liver transplantation, either recurrent or de novo, by the basic treatment principles of AIH. B As per EASL 2015 guidelines: List patients with acute severe AIH for emergency liver transplantation after lack of improvement with higher doses of corticosteroids ( 1 mg/kg) within 7 days. B Follow standard management principles for the treatment of AIH (recurrent or de novo) after liver transplantation. B 7. Specific circumstances Pediatric patients, diagnosis: As per HASL 2019 guidelines, obtain at least MRCP in pediatric patients with AIH to exclude autoimmune sclerosing cholangitis. B As per ESPGHAN 2018 guidelines, diagnose autoimmune liver disease in pediatric patients based on presence of serum autoantibodies, elevated IgG, compatible liver histology, positive family history for autoimmune conditions, and exclusion of other causes of pediatric chronic liver disease. E Show 5 more Pediatric patients, treatment: As per HASL 2019 guidelines, transit patients from childhood to adult care based on a multidisciplinary approach by special transition services. B As per ESPGHAN 2018 guidelines, initiate prednisolone/prednisone (2 mg/kg/day, up to 60 mg/day) as first-line therapy in pediatric patients with AIH, weaned down over 6-8 weeks to a maintenance dose of 5-7.5 mg/day, with monitoring of biochemical response (AST/ALT). Avoid using budenoside over the standard treatment as first-line therapy. E Show 8 more Pregnant patients: As per AASLD 2020 guidelines, include the goal of achieving biochemical remission of AIH for 1 year before conception in the family planning. E Show 5 more As per HASL 2019 guidelines, counsel female patients with AIH in remission that they have no contraindication for pregnancy or breastfeeding. B Show 3 more As per ACG 2016 guidelines, continue treatment with corticosteroids and/or azathioprine in pregnant patients with AIH. B https://web.pathway.md/diseases/recy694asCYrsgEzB 7/12 6/23/23, 3:16 AM Autoimmune hepatitis Pathway As per AISF 2016 guidelines, discuss treatment options before pregnancy in patients with AIH. Recognize that the dose of corticosteroids required to maintain remission will likely be lower if the patient is receiving corticosteroid monotherapy. Consider increasing the corticosteroid dose shortly before the expected date of delivery and monitoring liver enzymes and IgG closely in the weeks following delivery as pregnancy-related flare may occur. B Show 2 more As per EASL 2015 guidelines, recognize that controlled AIH is not a contraindication for pregnancy or breastfeeding. B Show 3 more Elderly patients: Initiate treatment in elderly patients with at least moderate necroinflammatory activity. Decide on the type of corticosteroid therapy and the tapering schedule carefully in all ages in the presence of other comorbidities. B Obtain close long-term follow-up in asymptomatic elderly patients with mild interface activity and comorbidities. B Patients with overlap syndromes: As per AASLD 2020 guidelines, consider adding UDCA to prednisone or prednisolone in combination with azathioprine in patients with AIH and overlap syndromes. E As per HASL 2019 guidelines: Initiate a combination of immunosuppression with UDCA in patients with AIH-PBC. Initiate immunosuppression if AIH is the dominant compartment and consider adding UDCA if remission is not achieved. B Consider adding UDCA to immunosuppressive treatment in patients with AIH-PSC. C As per EASL 2015 guidelines, initiate combined therapy with UDCA and immunosuppressants in patients with AIH and features of PBC. B Show 2 more Patients with viral hepatitis: As per AASLD 2020 guidelines: Obtain periodic serological testing (HBsAg, HBV DNA) during conventional therapy with prednisone or prednisolone in conjunction with azathioprine to detect HBV reactivation and the need for on-demand antiviral therapy in patients with AIH being HBsAg-negative/anti-HBcAg- positive during the diagnostic phase of their evaluation. E Consider initiating preemptive antiviral therapy in patients with serological evidence of previous HBV infection treated with high-dose corticosteroids or other immunomodulators, especially B-cell-depleting agents, because they at moderate risk for HBV reactivation. E As per HASL 2019 guidelines, do not screen for anti-liver kidney microsomal antibodies in patients with HCV before direct acting antivirals therapy. D Show 2 more Patients with HIV: individualize treatment in patients with AIH and human immunodeficiency virus, as standard immunosuppression seems to be safe and effective but carries a risk of life- https://web.pathway.md/diseases/recy694asCYrsgEzB 8/12 6/23/23, 3:16 AM Autoimmune hepatitis Pathway threatening infections. B Patients with fatty liver disease: ensure strict adherence to nonalcoholic fatty liver disease/NASH guidelines and use the lowest effective dose of cortiocosteroids for AIH in patients with nonalcoholic fatty liver disease/NASH, recognizing that the impact of nonalcoholic fatty liver disease/NASH on treatment outcome and response in AIH is unknown. B 8. Patient education General counseling: As per AASLD 2020 guidelines, identify potential barriers to long-term medication compliance and address at the start of treatment and monitor thereafter. E As per EASL 2015 guidelines, consider advising UV-protective measures in patients on immunosuppressants. C 9. Preventative measures Routine immunizations: As per AASLD 2020 guidelines: Provide routine immunizations in all susceptible patients with AIH according to the age-specific guidelines of the CDC. E Provide vaccination against HAV and HBV infections in unprotected patients, preferably before immunosuppressive therapy. E As per HASL 2019 guidelines, offer vaccination against hepatitis A, hepatitis B, pneumococcus (particularly in patients with cirrhosis) along with yearly influenza vaccination in all patients with AIH. B As per EASL 2015 guidelines: Provide hepatitis A and B immunization in all patients with AIH. B Provide influenza immunization on an annual basis in all patients with AIH. B Prevention of osteoporosis: As per AASLD 2020 guidelines, obtain bone mineral densitometry at baseline in all adult patients with AIH having risk factors for osteoporosis. Repeat bone mineral densitometry every 2-3 years of continuous corticosteroid treatment. E Show 3 more As per HASL 2019 guidelines, obtain bone density determination at treatment initiation in all patients receiving corticosteroids. Initiate vitamin D supplementation and advise adequate calcium intake. B As per EASL 2015 guidelines: Obtain bone density measurement at the initiation of corticosteroid therapy. B https://web.pathway.md/diseases/recy694asCYrsgEzB 9/12 6/23/23, 3:16 AM Autoimmune hepatitis Pathway Initiate vitamin D supplementation and ensure adequate calcium intake in all patients receiving corticosteroid therapy. B 10. Follow-up and surveillance Assessment of treatment response: As per AASLD 2020 guidelines, reevaluate the accuracy of the original diagnosis and medication adherence in patients with AIH not responding to first-line therapy. E As per EASL 2015 guidelines, reconsider the diagnosis of AIH and reevaluate treatment adherence in patients with failure of adequate response. B Management of incomplete response: As per HASL 2019 guidelines, increase azathioprine dose to 2 mg/kg/day in combination with 5- 10 mg/kg/day prednisolone in patients partially responding to conventional regimen. B Show 8 more As per EASL 2015 guidelines, consider replacing budesonide with prednisone or prednisolone (> 20 mg/day) in patients with incomplete response on budesonide-based regimen. C Show 3 more Monitoring for relapse: As per AASLD 2020 guidelines, obtain close monitoring for relapse with regular laboratory assessments during the first 12 months after treatment withdrawal and annually thereafter to cover for lifelong risk. E As per EASL 2015 guidelines, obtain close follow-up at 3-6-month intervals in patients with (spontaneous) remission. B Show 3 more Management of relapse: As per AASLD 2020 guidelines: Reinstitute original treatment in patients with a relapse until biochemical remission and subsequently switch to a long-term maintenance regimen. E Consider initiating mycophenolate mofetil or tacrolimus to achieve and maintain biochemical remission in patients with AIH with treatment failure, incomplete response, or drug intolerance to first-line agents. C As per HASL 2019 guidelines, recognize that IgG elevation usually precedes transaminase increase in patients with AIH relapse, but do not perform liver biopsy. B Show 2 more As per EASL 2015 guidelines: Consider administering corticosteroids in patients with a relapse or flare with doses similar to the induction regimen. Recognize that earlier detection of relapse allows lower doses of immunosuppressants to re-induce full remission. C https://web.pathway.md/diseases/recy694asCYrsgEzB 10/12 6/23/23, 3:16 AM Autoimmune hepatitis Pathway Keep patients on immunosuppression permanently if they have received adequate immunosuppression and have relapsed during drug withdrawal, or experienced a flare during adequate maintenance therapy. B Surveillance for malignancy: As per AASLD 2020 guidelines, obtain liver ultrasound, with or without serum AFP level, every 6 months for cancer surveillance in patients with cirrhosis, and adhere to standard guidelines for detection of extrahepatic malignancy. E As per HASL 2019 guidelines, obtain liver ultrasound every 6 months for early HCC detection in patients with AIH-related cirrhosis, as in cirrhosis of other etiologies. B As per EASL 2015 guidelines: Obtain liver ultrasound every 6 months for HCC screening in patients with AIH and cirrhosis. B Consider monitoring for non-melanoma skin cancer in patients on immunosuppressants. C References 1. Dalekos GN, Koskinas J, Papatheodoridis GV. Hellenic Association for the Study of the Liver Clinical Practice Guidelines: Autoimmune hepatitis. Ann Gastroenterol. 2019 Jan-Feb;32 1 1 23. Open 2. Cara L Mack, David Adams, David N Assis et al. 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