Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Autoimmune Hepatitis Treatment & Management

  • Author: David C Wolf, MD, FACP, FACG, AGAF, FAASLD; Chief Editor: BS Anand, MD  more...
 
Updated: Feb 18, 2016
 

Approach Considerations

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.[2, 17] Treatment must be individualized for patients with autoimmune hepatitis,[16] as 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.[47]

Italian investigators indicate that patients with autoimmune hepatitis who are asymptomatic should undergo the same treatment strategy as symptomatic patients because both groups experience a similar course of disease progression and clinical response to immunosuppressive medication.[48] In addition, subclinical disease appears to be more common in those with thyroid or dermatologic conditions and routine evaluation is advised in the setting of these disorders.

Next

Initial Therapy for Adults

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.[49] See Table 2, below.

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

Absolute Relative
Serum AST 10-fold or more greater than the upper limit of normal Symptoms (eg, fatigue, arthralgia, jaundice)
Serum AST 5-fold or more greater than the upper limit of normal and gamma-globulin level 2-fold or more greater than normal Serum AST and/or gamma-globulin less than absolute criteria
Bridging necrosis or multiacinar necrosis on



histologic examination



Interface hepatitis
AST = aspartate aminotransferase.

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 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)

  Prednisone only (mg/d) Combination
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 mo or less)



Postmenopausal state



Osteoporosis



Brittle diabetes



Obesity



Acne



Emotional lability



Hypertension



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.[36, 49]

Patients whose liver chemistries normalize after initial therapy require maintenance therapy. In the authors' opinion, 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.

Previous
Next

Initial Therapy for Children

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)

Initial Regimen Maintenance Regimen End Point
Prednisone, 1-2 mg/kg/d (up to 60 mg/d), for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/d 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



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.[36] 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, 0.02-3.2y) 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.

Previous
Next

Alternative Agents

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.[50] 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. The initial prednisone dose was 40 mg daily, tapered to 10 mg daily. Patients also received azathioprine 1-2 mg/kg/d.[50] 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.[36]

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.[51] 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.[52] This study included patients with autoimmune hepatitis, autoimmune cholangitis, and giant cell hepatitis.

Previous
Next

Treatment Endpoints

Patients may achieve 1 of 4 treatment endpoints[49] :

  • 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[49] —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.[49] Some patients will have a response to reinstitution of treatment with high-dose prednisone, with or without 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.[17] The use of these medications is supported by a number of small case series.[53, 54, 55] However, the potential toxicity of these calcineurin inhibitors must be assessed carefully before initiating treatment.

In a more recent study that evaluated the clinical, biochemical, immunologic profiles, treatment response, and side effects of tacrolimus therapy in 17 patients with treatment-refractory type 1 autoimmune hepatitis who were followed for over a median of 60 months, Than et al reported that tacrolimus treatment was safe and effective, with improvements seen in liver biochemistry as well as levels of immunglobulin G and aspartate transaminase.[56] Their results support the use of tacrolimus as an option for compliant patients with difficult-to-treat autoimmune hepatitis in experienced centers. However, the investigators note that lack of an immunomodulatory effect remains.[56]

Similarly, a few studies have supported the use of mycophenolate mofetil in patients whose disease was refractory to standard therapy.[17, 57, 58, 59, 60] 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).[61] Inclusion criteria for 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.[62, 63] 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.[49] 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 at 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.[64] 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.[36, 49]

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.

Previous
Next

Relapse

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 down to 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).[65]

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.

Previous
Next

Liver Transplantation

Liver transplantation is an effective form of therapy for patients in whom medical therapy has failed, or those with decompensated cirrhosis caused by autoimmune hepatitis.[66] 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%.[67] Positive autoantibodies and hypergammaglobulinemia tend to disappear within 2 years of transplantation.[68]

Recurrence of autoimmune hepatitis is described after liver transplantation.[66] 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, one study described the need for retransplantation in half of patients experiencing recurrent disease.[67, 69, 70]

Montano-Loza et al concluded that the risk factors associated with recurrence include concomitant autoimmune disease and high levels of aspartate aminotransferase, alanine aminotransferase, and IgG prior to the transplant.[70] 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.

Previous
Next

Treatment of Overlap Syndrome

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.[71] The mean duration of follow-up was 7.5 years.

Previous
Next

Diet and Activity

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.

Previous
Next

Long-Term Monitoring

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.

Previous
 
 
Contributor Information and Disclosures
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<br/>Received research grant from: Vital Therapies.

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

Disclosure: Nothing to disclose.

Robert Baldassano, MD Director, Center for Pediatric Inflammatory Bowel Disease, Children's Hospital of Philadelphia; Professor, Department of Pediatrics, Division of Gastroenterology and Nutrition, University of Pennsylvania School of Medicine

Robert Baldassano, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Nothing to disclose.

Carmen Cuffari, MD Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine

Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Mohammad F El-Baba, MD Associate Professor of Pediatrics, Division of Pediatric Gastroenterology, Wayne State University School of Medicine; Divison Chief of Pediatric Gastroenterology, Children's Hospital of Michigan

Mohammad F El-Baba, MD is a member of the following medical societies: American Gastroenterological Association and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Nothing to disclose.

Husam H Sukerek, MD Consulting Staff, Department of Gastroenterology, Sabine Medical Center

Husam H Sukerek, MD is a member of the following medical societies: American Academy of Pediatrics and American Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
  1. Oettinger R, Brunnberg A, Gerner P, Wintermeyer P, Jenke A, Wirth S. Clinical features and biochemical data of Caucasian children at diagnosis of autoimmune hepatitis. J Autoimmun. 2005 Feb. 24(1):79-84. [Medline].

  2. Strassburg CP, Manns MP. Treatment of autoimmune hepatitis. Semin Liver Dis. 2009 Aug. 29(3):273-85. [Medline].

  3. Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012 Aug 17. 61:1-32. [Medline]. [Full Text].

  4. Waldenstrom J. The diagnostic importance of ACTH. Acta Endocrinol (Copenh). 1950. 5(3):235-42. [Medline].

  5. Kunkel HG, Ahrens EH, Eisenmenger WJ. Extreme hypergammaglobulinemia in young women with liver disease of unknown etiology. J Clin Invest. 1950. 30:654.

  6. Bearn AG, Kunkel HG, Slater RJ. The problems of chronic liver disease in young women. Am J Med. 1956. 21:3-15.

  7. Joske RA, King WE. The L.E.-cell phenomenon in active chronic viral hepatitis. Lancet. 1955 Sep 3. 269(6888):477-80. [Medline].

  8. Cowling DC, Mackay IR, Taft LI. Lupoid hepatitis. Lancet. 1956 Dec 29. 271(6957):1323-6. [Medline].

  9. Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology. 1993 Oct. 18(4):998-1005. [Medline].

  10. Scully LJ, Toze C, Sengar DP, et al. Early-onset autoimmune hepatitis is associated with a C4A gene deletion. Gastroenterology. 1993 May. 104(5):1478-84. [Medline].

  11. Czaja AJ, Carpenter HA, Santrach PJ, et al. Genetic predispositions for the immunological features of chronic active hepatitis. Hepatology. 1993 Oct. 18(4):816-22. [Medline].

  12. Longhi MS, Ma Y, Mieli-Vergani G, Vergani D. Aetiopathogenesis of autoimmune hepatitis. J Autoimmun. 2009 Sep 17. [Medline].

  13. Vento S, Cainelli F. Is there a role for viruses in triggering autoimmune hepatitis?. Autoimmun Rev. 2004 Jan. 3(1):61-9. [Medline].

  14. Wen L, Peakman M, Lobo-Yeo A, McFarlane BM, Mowat AP, Mieli-Vergani G, et al. T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis. Lancet. 1990 Dec 22-29. 336(8730):1527-30. [Medline].

  15. Umemura T, Ota M. Genetic factors affect the etiology, clinical characteristics and outcome of autoimmune hepatitis. Clin J Gastroenterol. 2015 Dec. 8 (6):360-6. [Medline].

  16. Wang Q, Yang F, Miao Q, Krawitt EL, Gershwin ME, Ma X. The clinical phenotypes of autoimmune hepatitis: A comprehensive review. J Autoimmun. 2015 Nov 21. [Medline].

  17. Czaja AJ. Diagnosis and management of autoimmune hepatitis. Clin Liver Dis. 2015 Feb. 19 (1):57-79. [Medline].

  18. Pathmakanthan S, Kay EW, Murray FE. Autoimmune chronic active hepatitis associated with the presence of antiphospholipid antibodies. Eur J Gastroenterol Hepatol. 1998 Feb. 10(2):155-7. [Medline].

  19. Czaja AJ. Autoimmune hepatitis. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 6th ed. Philadelphia, Pa: WB Saunders Company; 1998. 1265-1274.

  20. Ramakrishna J, Johnson AR, Banner BF. Long-term minocycline use for acne in healthy adolescents can cause severe autoimmune hepatitis. J Clin Gastroenterol. 2009 Sep. 43(8):787-90. [Medline].

  21. Adar T, Mizrahi M, Pappo O, Scheiman-Elazary A, Shibolet O. Adalimumab-induced autoimmune hepatitis. J Clin Gastroenterol. 2010 Jan. 44(1):e20-2. [Medline].

  22. Fairhurst DA,Sheehan-Dre R. Autoimmune hepatitis associated with infliximab in a patient with palmoplanter pustular psoriasis. Clin Exp Dermatol. 2009/04. 34(3):421-2.

  23. Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis. 2002 Aug. 6(3):755-74. [Medline].

  24. Casswall TH, Németh A, Nilsson I, Wadström T, Nilsson HO. Helicobacter species DNA in liver and gastric tissues in children and adolescents with chronic liver disease. Scand J Gastroenterol. 2010. 45(2):160-7. [Medline].

  25. Michitaka K, Nishiguchi S, Aoyagi Y, Hiasa Y, Tokumoto Y, Onji M. Etiology of liver cirrhosis in Japan: a nationwide survey. J Gastroenterol. 2009 Sep 30. [Medline].

  26. Seki T, Kiyosawa K, Inoko H, et al. Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients. Hepatology. 1990 Dec. 12(6):1300-4. [Medline].

  27. Boberg KM. Prevalence and epidemiology of autoimmune hepatitis. Clin Liver Dis. 2002 Aug. 6(3):635-47. [Medline].

  28. Czaja AJ. Special clinical challenges in autoimmune hepatitis: the elderly, males, pregnancy, mild disease, fulminant onset, and nonwhite patients. Semin Liver Dis. 2009 Aug. 29(3):315-30. [Medline].

  29. McFarlane IG, Heneghan MA. Autoimmunity and the female liver. Hepatol Res. 2004 Apr. 28(4):171-176. [Medline].

  30. Mieli-Vergani G, Vergani D. Autoimmune hepatitis in children: what is different from adult AIH?. Semin Liver Dis. 2009 Aug. 29(3):297-306. [Medline].

  31. Haider AS, Kaye G, Thomson A. Autoimmune hepatitis in a demographically isolated area of Australia. Intern Med J. 2009 Aug 27. [Medline].

  32. Czaja AJ, Carpenter HA. Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly. Hepatology. 2006 Mar. 43(3):532-8. [Medline].

  33. Kirk AP, Jain S, Pocock S, et al. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut. 1980 Jan. 21(1):78-83. [Medline].

  34. Ferreira AR, Roquete ML, Toppa NH, de Castro LP, Fagundes ED, Penna FJ. Effect of treatment of hepatic histopathology in children and adolescents with autoimmune hepatitis. J Pediatr Gastroenterol Nutr. 2008 Jan. 46(1):65-70. [Medline].

  35. Greene MT, Whitington PF. Outcomes in pediatric autoimmune hepatitis. Curr Gastroenterol Rep. 2009 Jun. 11(3):248-51. [Medline].

  36. Gleeson D, Heneghan MA. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis. Gut. 2011 Jul 13. [Medline].

  37. Gregorio GV, Portmann B, Reid F, Donaldson PT, Doherty DG, McCartney M, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology. 1997 Mar. 25(3):541-7. [Medline].

  38. Caprai S, Vajro P, Ventura A, et al. Autoimmune liver disease associated with celiac disease in childhood: a multicenter study. Clin Gastroenterol Hepatol. 2008 Jul. 6(7):803-6. [Medline].

  39. Mieli-Vergani G, Vergani D. Autoimmune paediatric liver disease. World J Gastroenterol. 2008 Jun 7. 14(21):3360-7. [Medline]. [Full Text].

  40. Czaja AJ. Autoimmune hepatitis and viral infection. Gastroenterol Clin North Am. 1994 Sep. 23(3):547-66. [Medline].

  41. Floreani A, Rizzotto ER, Ferrara F, et al. Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol. 2005 Jul. 100(7):1516-22. [Medline].

  42. Czaja AJ, Cassani F, Cataleta M, Valentini P, Bianchi FB. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology. 1996 Nov. 24(5):1068-73. [Medline].

  43. Czaja AJ, Carpenter HA. Sensitivity, specificity, and predictability of biopsy interpretations in chronic hepatitis. Gastroenterology. 1993 Dec. 105(6):1824-32. [Medline].

  44. Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999 Nov. 31(5):929-38. [Medline].

  45. Wiegard C, Schramm C, Lohse AW. Scoring systems for the diagnosis of autoimmune hepatitis: past, present, and future. Semin Liver Dis. 2009 Aug. 29(3):254-61. [Medline].

  46. Tucker SM, Jonas MM, Perez-Atayde AR. Hyaline droplets in Kupffer cells: a novel diagnostic clue for autoimmune hepatitis. Am J Surg Pathol. 2015 Jun. 39 (6):772-8. [Medline].

  47. Lichtenstein GR. Use of laboratory testing to guide 6-mercaptopurine/azathioprine therapy. Gastroenterology. 2004 Nov. 127(5):1558-64. [Medline].

  48. Muratori P, Lalanne C, Barbato E, et al. Features and progression of asymptomatic autoimmune hepatitis in Italy. Clin Gastroenterol Hepatol. 2016 Jan. 14 (1):139-46. [Medline].

  49. [Guideline] Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, et al. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010 Jun. 51(6):2193-213. [Medline].

  50. Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology. 2010 Oct. 139(4):1198-206. [Medline].

  51. Alvarez F, Ciocca M, Cañero-Velasco C, Ramonet M, de Davila MT, Cuarterolo M, et al. Short-term cyclosporine induces a remission of autoimmune hepatitis in children. J Hepatol. 1999 Feb. 30(2):222-7. [Medline].

  52. Sciveres M, Caprai S, Palla G, Ughi C, Maggiore G. Effectiveness and safety of ciclosporin as therapy for autoimmune diseases of the liver in children and adolescents. Aliment Pharmacol Ther. 2004 Jan 15. 19(2):209-17. [Medline].

  53. Fernandes NF, Redeker AG, Vierling JM, et al. Cyclosporine therapy in patients with steroid resistant autoimmune hepatitis. Am J Gastroenterol. 1999 Jan. 94(1):241-8. [Medline].

  54. Aqel BA, Machicao V, Rosser B, et al. Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis. J Clin Gastroenterol. 2004 Oct. 38(9):805-9. [Medline].

  55. Van Thiel DH, Wright H, Carroll P, et al. Tacrolimus: a potential new treatment for autoimmune chronic active hepatitis: results of an open-label preliminary trial. Am J Gastroenterol. 1995 May. 90(5):771-6. [Medline].

  56. Than NN, Wiegard C, Weiler-Normann C, et al. Long-term follow-up of patients with difficult to treat type 1 autoimmune hepatitis on tacrolimus therapy. Scand J Gastroenterol. 2016 Mar. 51 (3):329-36. [Medline].

  57. Devlin SM, Swain MG, Urbanski SJ, et al. Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory to standard therapy. Can J Gastroenterol. 2004 May. 18(5):321-6. [Medline].

  58. Inductivo-Yu I, Adams A, Gish RG, et al. Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy. Clin Gastroenterol Hepatol. 2007 Jul. 5(7):799-802. [Medline].

  59. Richardson PD, James PD, Ryder SD. Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine. J Hepatol. 2000 Sep. 33(3):371-5. [Medline].

  60. Wolf DC, Bojito L, Facciuto M, Lebovics E. Mycophenolate mofetil for autoimmune hepatitis: a single practice experience. Dig Dis Sci. 2009 Nov. 54(11):2519-22. [Medline].

  61. Aw MM, Dhawan A, Samyn M, Bargiota A, Mieli-Vergani G. Mycophenolate mofetil as rescue treatment for autoimmune liver disease in children: a 5-year follow-up. J Hepatol. 2009 Jul. 51(1):156-60. [Medline].

  62. Czaja AJ, Lindor KD. Failure of budesonide in a pilot study of treatment-dependent autoimmune hepatitis. Gastroenterology. 2000 Nov. 119(5):1312-6. [Medline].

  63. Zandieh I, Krygier D, Wong V, Howard J, Worobetz L, Minuk G, et al. The use of budesonide in the treatment of autoimmune hepatitis in Canada. Can J Gastroenterol. 2008 Apr. 22(4):388-92. [Medline]. [Full Text].

  64. Osterman MT, Kundu R, Lichtenstein GR, et al. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology. 2006 Apr. 130(4):1047-53. [Medline].

  65. Johnson PJ, McFarlane IG, Williams R. Azathioprine for long-term maintenance of remission in autoimmune hepatitis. N Engl J Med. 1995 Oct 12. 333(15):958-63. [Medline].

  66. Faisal N, Renner EL. Recurrence of autoimmune liver diseases after liver transplantation. World J Hepatol. 2015 Dec 18. 7 (29):2896-905. [Medline].

  67. Tripathi D, Neuberger J. Autoimmune hepatitis and liver transplantation: indications, results, and management of recurrent disease. Semin Liver Dis. 2009 Aug. 29(3):286-96. [Medline].

  68. Reich DJ, Fiel I, Guarrera JV, et al. Liver transplantation for autoimmune hepatitis. Hepatology. 2000 Oct. 32(4 Pt 1):693-700. [Medline].

  69. Duclos-Vallee JC, Sebagh M, Rifai K, et al. A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence. Gut. 2003 Jun. 52(6):893-7. [Medline].

  70. Montano-Loza AJ, Mason AL, Ma M, Bastiampillai RJ, Bain VG, Tandon P. Risk factors for recurrence of autoimmune hepatitis after liver transplantation. Liver Transpl. 2009 Sep 29. 15(10):1254-1261. [Medline].

  71. Chazouillères O, Wendum D, Serfaty L, et al. Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. J Hepatol. 2006 Feb. 44(2):400-6. [Medline].

  72. Douglas D. Budesonide Helpful in Pediatric Autoimmune HepatitisMedscape. July 10, 2013. Available at http://www.medscape.com/viewarticle/807623. Accessed: July 22, 2013.

  73. Woynarowski M, Nemeth A, Baruch Y, Koletzko S, Melter M, Rodeck B, et al. Budesonide versus Prednisone with Azathioprine for the Treatment of Autoimmune Hepatitis in Children and Adolescents. J Pediatr. 2013 Jun 27. [Medline].

 
Previous
Next
 
Table 1. Clinical Characteristics of Autoimmune Hepatitis [19]
Clinical Features Type 1 Type 2 Type 3
Diagnostic autoantibodies ASMA



ANA



Antiactin



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
*Immunoglobulin A
Table 2. Indications for Treatment of Autoimmune Hepatitis in Adults
Absolute Relative
Serum AST 10-fold or more greater than the upper limit of normal Symptoms (eg, fatigue, arthralgia, jaundice)
Serum AST 5-fold or more greater than the upper limit of normal and gamma-globulin level 2-fold or more greater than normal Serum AST and/or gamma-globulin less than absolute criteria
Bridging necrosis or multiacinar necrosis on



histologic examination



Interface hepatitis
AST = aspartate aminotransferase.
Table 3. Treatment Regimens for Adults
  Prednisone only (mg/d) Combination
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 mo or less)



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/d (up to 60 mg/d), for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/d 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



Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.