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Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Treatment with corticosteroids and azathioprine is the cornerstone of achieving remission. Initiating azathioprine with prednisone at the beginning of treatment enables a faster decrease in the prednisone dose.

Class Summary

Corticosteroids induce immunosuppression through a number of mechanisms. Most notably, they help to block T-cell-derived and antigen-presenting cell (APC)-derived cytokine expression.^[86]Corticosteroids can suppress lymphocyte activity and decrease antibody production. They can also suppress the production of prostaglandins and leukotrienes, helping to reduce inflammation.

The rapid institution of treatment with high-dose corticosteroids may rescue patients whose disease ultimately would have progressed to either acute liver failure or cirrhosis. Long-term treatment with corticosteroids has been shown to improve the chances for survival significantly.

Prednisone

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Prednisone is an immunosuppressant for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity. It stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

Prednisolone

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Prednisolone decreases autoimmune reactions, possibly by suppressing key components of the immune system. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Budesonide (Entocort EC, Ortikos, Uceris)

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Budesonide is an anti-inflammatory corticosteroid with potent glucocorticoid activity but weak mineralocorticoid activity. It offers the promise of fewer steroid-specific side effects. Because of its high first-pass metabolism, the majority of the orally absorbed drug does not reach the systemic circulation.

Azathioprine (Imuran, Azasan)

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Azathioprine antagonizes purine metabolism and helps to block DNA replication in T and B lymphocytes.^[108]This, in turn, results in decreased autoimmune activity. Azathioprine has been used in the treatment of autoimmune hepatitis since the early 1970s.^[109]

Mycophenolate (CellCept, MMF, Myfortic)

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Mycophenolate mofetil and mycophenolic acid inhibit the production of inosine phosphate dehydrogenase and the production of guanosine nucleotides. This, in turn, leads to the blockade of DNA replication in T and B lymphocytes.^[108]Mycophenolate is utilized in patients who are intolerant to azathioprine, as well as in patients who had either an incomplete response or a treatment failure after combination therapy with corticosteroids plus azathioprine.^[78]

Cyclosporine (Gengraf, Sandimmune, Neoral)

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Calcineurin stimulates the expression of interleukin-2 (IL-2)—amongst other cytokines—by T lymphocytes. IL-2, in turn, stimulates the proliferation of T lymphocytes. By inhibiting calcineurin’s function, both cyclosporine and tacrolimus inhibit the production of IL-2, with resulting suppression of T cell-mediated immunity. The dosing of both drugs is based upon the patient’s body weight. Most experts recommend the routine follow-up of patients’ trough drug levels.

Questions

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Table 1. Clinical Characteristics of Autoimmune Hepatitis ^[21]

Clinical Features	Type 1	Type 2	Type 3
Diagnostic autoantibodies	ASMA ANA Anti-actin	Anti-LKM P-450 IID6 Synthetic core motif peptides 254-271	Soluble liver-kidney antigen Cytokeratins 8 and 18
Age	10 y - elderly	Pediatric (2-14 y) Rare in adults	Adults (30-50 y)
Women (%)	78	89	90
Concurrent immune disease (%)	41	34	58
Gamma globulin elevation	+++	+	++
Low IgA	No	Occasional	No
HLA association	B8, DR3, DR4	B14, Dr3, C4AQO	Uncertain
Steroid response	+++	++	+++
Progression to cirrhosis (%)	45	82	75
ANA = antinuclear antibody; anti-LKM = anti-liver-kidney microsomal antibody; ASMA = anti-smooth muscle antibody; HLA = human leukocyte antigen; IgA = immunoglobulin A.

Table 2. Indications for Treatment of Autoimmune Hepatitis in Adults

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

Table 3. Treatment Regimens for Adults

	Prednisone Only (mg/d)	Combination Therapy
	Prednisone Only (mg/d)	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

Table 4. Treatment Regimens for Children

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

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Author

David C Wolf, MD, FACP, FACG, AGAF, FAASLD Medical Director of Liver Transplantation, Westchester Medical Center; Professor of Clinical Medicine, Division of Gastroenterology and Hepatobiliary Diseases, Department of Medicine, New York Medical College

David C Wolf, MD, FACP, FACG, AGAF, FAASLD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Salix; Gilead; Abbvie; Intercept; Merck.

Coauthor(s)

Unnithan V Raghuraman, MD, FACG, FACP, FRCP Consulting Staff, Department of Gastroenterology, St John Medical Center

Unnithan V Raghuraman, MD, FACG, FACP, FRCP is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy