Autoimmune hepatitis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Overview

Mainstay treatment of autoimmune hepatitis is pharmacotherapy. Corticosteroids alone or in combination with immunosuppressants are commonly used. Immunosuppressive treatment should be based on serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum gamma-globulin levels, and histological features. Regimens are different for adults and children. According to course of immunosupressants, further management is planned.

Medical Therapy

Mainstay treatment of autoimmune hepatitis is pharmacotherapy. Corticosteroids alone or in combination with immunosuppressants are commonly used.

Acute Pharmacotherapies

• Pharmacologic medical therapies for autoimmune hepatitis include prednisone alone and combination of azathioprine and prednisone

According to American Association for the Study of Liver Diseases indications for immunosuppressive treatment:

Indications for Immunosuppressive Treatment
Absolute Indications	Relative Indications	None
Serum AST >10 fold upper limit of normal range(ULN)	Symptoms like fatigue, arthralgia, jaundice	Asymptomatic with normal or near normal serum AST and gamma globulin levels
Serum AST >5 fold ULN	Serum AST and/or gamma globulin less than absolute criteria	Inactive cirrhosis or mild portal inflammation (portal hepatitis)
Gamma globulin level>2 fold ULN	Interface hepatitis	Severe cytopenia (white blood cell counts <2.5 x109/L or platelet counts <50 x 109/L)
Bridging necrosis or multiacinar necrosis on histological examination	Osteopenia, emotional instability, hypertension, diabetes, or cytopenia (white blood cell counts <2.5 x109/L or platelet counts <50 x109/L)	Complete deficiency of TPMT activity precludes treatment with azathioprine
Incapacitating symptoms such as fatigue and arthralgia		Vertebral compression, psychosis, brittle diabetes, uncontrolled hypertension, known intolerances to prednisone or azathioprine

Recommendations for the Treatment of Autoimmune Hepatitis

• Immunosuppressive treatment should be based on serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum gamma-globulin levels, and histological features.Various treatment used for adults and children:
  • Prednisone or prednisolone with azathioprine (adults)
  • Prednisone with azathioprine or 6-mercaptopurine (children)
  • Prednisone or prednisolone alone
• Monitoring for bone disease
• Adjunctive therapies for bone disease (weight-bearing exercise program, vitamin D and calcium supplementation, bisphosphonates)
• Pretreatment vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV)
• Management of treatment side effects and risks, including during pregnancy
• Alternative drug therapies for suboptimal response (cyclosporine, tacrolimus, or mycophenolate mofetil)
• Hepatic ultrasonography to detect hepatocellular carcinoma (HCC)
• Liver transplantation, management of recurrent disease after transplant with drug therapy and/or retransplantation in certain patients

According to American Association for the Study of Liver Diseases, Immunosuppressive Treatment Regimens for Adults with Autoimmune Hepatitis

• Preferred regimen (1):
  • Prednisone 60mg PO q24h for 7 days ( Preference:Cytopenia, Thiopurine methyltransferase deficiency, Pregnancy, Malignancy, Short-course (<6 months)
  • Tapering of prednisone should be done as follow:
    • Prednisone 40mg PO q24h for next 7 days
    • Prednisone 30mg PO q24h for next 7 days
    • Prednisone 30mg PO q24h for next 7 days
    • Prednisone 20mg and below PO q 24h for maintenance until endpoint
• Preferred regimen (2): Combination Therapy which includes Prednisone and Azathioprine:
  • Tapering of prednisone should be done as follow:
    • Prednisone 30mg PO q24h for 7 days and Azathioprine 50mg q24h for 7 days
    • Prednisone 20mg PO q24h for 7 days and Azathioprine 50mg q24h for next 7 days
    • Prednisone 15mg PO q24h for 7 days and Azathioprine 50mg q24h for next 7 days
    • Prednisone 10mg PO q24h for 7 days and Azathioprine 50mg q24h for maintenance until endpoint

Immunosuppressive Treatment Regimens for Adults in Autoimmune Hepatitis
Monotherapy Prednisone only* (mg/day)		Combination Therapy
Weeks	Dosage	Prednisone	Azathioprine USA (mg/day) EU (mg/kg/day)
First	60	30	50	12
Second	40	20	50	12
Third	30	15	50	12
Fourth	30	15	50	12
Maintenance until endpoint	20 and below	10	50	12
Reasons for Preference	Cytopenia, Thiopurine methyltransferase deficiency, Pregnancy, Malignancy, Short-course (<6 months)		Postmenopausal state, Brittle diabetes, Obesity, Acne, Emotional lability, Hypertension

Adjunctive therapies:

• Adjunctive therapy is based on medication and complication occurs due to medication

• The regular weight-bearing exercise program, vitamin D, calcium supplementation and bisphosphonates should be taken by patient who is taking corticosteroids for long-term
• Vaccination against hepatitis B virus (HBV) and hepatitis A virus (HAV) should be done as early as possible even before immunosuppression

According to American Association for the Study of Liver Diseases, Immunosuppressive Treatment Regimens for Children in Autoimmune Hepatitis

Pediatric:

• Preferred regimens:
  • Initial regimen (1): Prednisone 1- 2 mg/kg (upto60mg/day) PO q24h for 14 days either alone or in combination with azathioprine, 1- 2 mg/kg q24h
  • Maintenance regimen (2): Prednisone taper to 0.1 -0.2 mg/kg q24h or 5 mg q24h for 6 -8 weeks
    • if added initially, azathioprine at constant dose
    • Continue daily prednisone dose with or without azathioprine or switch to alternate day prednisone dose adjusted in response with or without azathioprine

Immunosuppressive Treatment Regimens for Children with Autoimmune Hepatitis
Initial Regimen	Maintenance Regimen	Endpoint
Prednisone, 1- 2 mg/kg daily (up to 60 mg/day), for two weeks either alone or in combination with azathioprine, 1- 2 mg/kg daily	Prednisone taper over 6 -8 weeks to 0.1 -0.2 mg/kg daily or 5 mg daily Azathioprine at constant dose if added initially Continue daily prednisone dose with or without azathioprine or switch to alternate day prednisone to adjust to response with or without azathioprine	Normal liver tests for 1- 2 years during treatment No flare during entire interval Liver biopsy examination discloses no inflammation

Frequency and Nature of Side Effects Associated with Treatment in Adults with Autoimmune Hepatitis
Prednisone-Related Side Effects		Azathioprine-Related Side Effects
Type	Frequency	Type	Frequency
Cosmetic (usually mild) Facial rounding Weight gain Dorsal hump striae Hirsutism Alopecia	80% (after 2 years)	Hematologic (mild) Cytopenia	46% (especially with cirrhosis)
Somatic (usually mild) Emotional instability Glucose intolerance Cataracts	13% (treatment ending)	Hematologic (severe) Leucopenia Thrombocytopenia	6% (treatment ending)
Somatic (severe) Osteopenia Vertebral compression Diabetes (brittle) Psychosis Hypertension (labile)	13% (treatment ending)	Somatic (usually mild) Nausea Rash Fever Arthralgias	5%
Inflammatory/neoplastic Pancreatitis Opportunistic infection Malignancy	Rare	Neoplastic Non-hepatic cell types	3% (after 10 years)
		Hematologic/enteric Rare (treatment ending) Bone marrow failure Villous Atrophy Malabsorption Teratogenic during pregnancy	Rare

Immunosuppressive treatment with course of action in AIH

Drug treatment includes: •Corticosteroids •Azathioprine

Remission: •Absence of symptoms •Normal Serum Transaminase •Normal bilirubin •Normal gamma globulin level •Normal histology or inactive cirrhosis

Incomplete response: •Some or no improvement in clinical, laboratory,and histological features despite compliance with therapy after 2-3 year

Treatment failure: •Worsening clinical laboratory and histological features despite compliance with therapy Development ofjaundice ,ascites or hepatic encephalopathy

Drug toxicity: •Development of intolerable cosmetic changes, symptomatic osteopenia, emotional instability, poorly controlled hypertension, brittle diabetes or progressive cytopenia

•Gradual taper ofprednisone over 6 week period •Serum AST orALT , total bilirubin , and gamma globulin levels every 3 weeks during tapering then every 3-6 months after stopping

•Reduction in doses of prednisone by 2.5 mg/month until lowest level possible (<10 mg daily) to prevent worsening of serum ASTor ALT abnormalities •Indefinite azathioprine therapy (2 mg/kg daily) as an alternative treatment if corticosteroid intolerance

•Prednisone, 60 mg daily , or prednisone, 30 mg daily • Azathioprine , 150 mg daily, for at least 1 month Dose reduction of prednisone by 10mg •Azathioprine by 50 mg for each month of improvement until standard treatment doses are achieved

•Reduction in dose or discontinuation of offending drug Maintenance on tolerated drug in adjusted dose

Relapse: Restart corticosteroid and Azathioprine

Inactive disease: Monitor lab test

Liver transplant

Empiric cyclosporine/Tacrolimus

Empiric Mycophenolate Mofetil

Long-Term Follow up

• Perform liver function tests weekly during the first 6-8 weeks of treatment and then every 2-3 months depends upon results
• Abdominal imaging studies (e.g, ultrasound, CT, MRI) every 6 months
• Alpha-fetoprotein testing is done every 6 months

Treatment of overlap syndrome

Overlap Syndrome is diagnosed when patients who present with the features of primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) along with the features of AIH, PBC-AIH or PSC-AIH

Treatment of overlap syndrome
Types	Drugs
AIH-PBC	Prednisone or prednisolone 30 mg OD × 7days 20 mg OD × 7days 15 mg OD × 15days 10 mg thereafter Combined with azathioprine 50 mg OD from start, or 1 mg/kg/day to 2 mg/kg/day
AIH-PBC	Prednisone or prednisolone in combination with azathioprine as above combined with Ursodeoxycholic acid: 13 mg/kg/day to 15 mg/kg/day
AIH-PSC	Prednisone or prednisolone 0.5 mg/kg/day tapered to 10 mg/day to 15 mg/day Combined with azathioprine 50 mg/day to 75 mg/day Combined with Ursodeoxycholic acid 13 mg/kg/day to 15 mg/kg/day
AIH-cholestatic syndrome	Prednisone or prednisolone in combination with azathioprine as above combined with Ursodeoxycholic acid: 13 mg/kg/day to 15 mg/kg/day