Autoimmune Hepatitis

Educational Objectives

The goal of this program is to improve diagnosis and treatment of hepatitis. After hearing and assimilating this program, the clinician will be better able to:

1. List risk factors for autoimmune hepatitis.
2. Identify patients with autoimmune hepatitis who need pharmacologic treatment or liver transplantation.

Summary

Epidemiology: autoimmune hepatitis (AIH) rare (16-18 persons per 100,000 in Europe, but 43 persons per 100,000 in Alaska); female-to-male ratio for AIH 3.6:1; age distribution at diagnosis bimodal, with peaks near age of puberty and at 40 to 60 yr of age

Clinical manifestations: two-thirds of patients asymptomatic at diagnosis but have abnormal liver function tests (LFTs); symptoms include fatigue, anorexia, pruritus, fluctuating jaundice, and arthritis of small joints; one-quarter of patients have acute hepatitis at diagnosis, which may be fulminant; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels may reach 50 times upper limit of normal (ULN); most patients have elevated immunoglobulins; occasionally, mild cholestasis present

Diagnosis: scoring system allows clinician to make definitive or probable diagnosis; diagnostic criteria include titers of standard autoantibodies; low titers do not exclude diagnosis; high titers do not establish diagnosis in absence of other findings; lower titers significant in children (healthy children should not have autoantibodies); indirect immunofluorescence testing used to detect antibodies; standard antibodies include antinuclear antibodies (ANA), which target centromeres and histones; smooth muscle antibodies (SMA) target actin and nonactinic components and have high specificity; presence of both types of autoantibodies confers higher diagnostic specificity (99%) and sensitivity (43%); type 1 liver-kidney microsomal (anti-LKM-1) autoantibodies target cytochrome P450 2D6 and have high specificity (99%) but low sensitivity; in study of 163 patients, ANA and anti-SMA tended to occur together; patients positive for anti-LKM-1 and liver-specific cytosolic antigen (LC1) usually negative for ANA, and vice versa

Subtypes: these mutually exclusive subtypes of autoantibodies used to classify AIH; type 1 — encompasses >90% of patients in North America; type 2 — patients positive for anti-LKM-1 and LC1; usually seen in young adults, in whom disease may be advanced; may be seen in children with partial deficiency of IgA; type 3 — previously defined as positivity for antibodies to soluble liver antigen/liver pancreas (anti-SLA/LP); however, 30% of patients with type 1 AIH have anti-SLA/LP; nonstandard autoantibodies — may be checked when AIH suspected and tests for standard autoantibodies negative; patients may have antibodies to actin, α-actinin, or SLA, perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), or antibodies to asialoglycoprotein receptor or LC1

Scoring of histology: interface hepatitis confers 3 points; other histologies lymphocytoplasmacytic infiltrates and rosette formation; points subtracted for biliary changes (other autoimmune cholestatic diseases should be ruled out)

Scoring systems: simplified system that relies on autoantibodies, immunoglobulins, histology, and viral markers has high sensitivity and specificity compared with original system

Indications for treatment: absolute indications — include AST level >10 times ULN, AST level >5 times ULN with IgG titer >2 times ULN, or bridging necrosis; relative indications — include symptoms with lesser elevations in AST and IgG levels or interface hepatitis; treatment not indicated — for asymptomatic patients with normal enzymes, normal IgG titer, and no disease activity on biopsy, or inactive cirrhosis without inflammation; however, such patients should be followed

Management: standard regimens include prednisone with or without azathioprine; combination treatment preferred; side effects of steroids (obesity, acne, emotional lability, and hypertension) limit duration of therapy; alternatives to steroids should be considered in patient with vertebral compression fracture, brittle diabetes, or psychosis; activity of thiopurine methyltransferase (TPMT) should be checked before starting azathioprine because 0.3% of population lacks TPMT and may develop myelosuppression while on azathioprine; 5% of patients taking azathioprine develop cytopenia; blood counts should be checked every 3 to 6 mo; other effects nausea, vomiting, rash, pancreatitis, and liver toxicity; azathioprine pregnancy category D, but no fetal complications reported in humans

Duration of treatment: 2 yr in Europe; 66% to 91% of patients have normal LFTs within 2 yr; remission unlikely if not achieved by 3 yr; liver biopsies used to document resolution, but clinician may forego biopsy if LFTs stable for 1 yr; histologic improvement lags by 3 to 6 mo; prednisone tapered over 6 wk; LFTs and IgG should be monitored every 3 wk for 3 mo, then every 6 mo to 1 yr

Failure of treatment: occurs in 7% of patients; characterized by worsening LFTs on therapy; 14% have incomplete response (LFTs improve but do not normalize); for treatment failure, clinician should increase doses and duration of steroids and azathioprine; patient with incomplete response may need low doses of steroids and azathioprine indefinitely

Alternative regimens: budesonide — in trial comparing budesonide-azathioprine with prednisone-azathioprine in ≈100 patients, budesonide group had lower rate of side effects (28% vs 53%) and more likely to achieve normal AST and ALT levels (50% vs 20% at 6 mo); mycophenolate mofetil (Cellcept) — reduces levels of AST, ALT, and IgG within 1 mo; effect maintained for 5 yr; side effects include cytopenia, teratogenic effects that preclude use during pregnancy, gastrointestinal effects, headache, and insomnia; calcineurin inhibitors — second- and third-line treatments; cyclosporine and tacrolimus may help patients with steroid-refractory AIH; both drugs equivalent to standard therapy in treatment-naive patients, but side effects preclude use in first line; more on budesonide — budesonide may be used as first-line treatment in patients who do not tolerate steroids, but drug not effective for treatment failure; switching from prednisone to budesonide often associated with flare; emerging rescue treatments — cyclophosphamide, methotrexate, rituximab, and infliximab studied in small groups of patients; sirolimus improved level of ALT in 80% of patients with refractory AIH

Liver transplantation: indications include mental status changes, worsening LFTs on treatment, cirrhosis, and hepatocellular carcinoma; 5- and 10-yr survival rates >75; however, 30% of patients develop recurrent AIH within 5 yr, which may lead to allograft cirrhosis and graft failure; posttransplantation AIH treated with tacrolimus, steroids, azathioprine, mycophenolate mofetil, sirolimus, or repeat transplantation

Pearls: patients should be immunized against hepatitis A and B and influenza; patients on steroids — should avoid live vaccines; supplementation with calcium and vitamin D and weight-bearing exercises recommended; bone density should be monitored and treated; prophylaxis against Pneumocystis pneumonia should be given

Readings

Alvarez F et al: International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999 Nov;31(5):929-38; Czaja AJ: Performance parameters of the diagnostic scoring systems for autoimmune hepatitis. Hepatology 2008 Nov;48(5):1540-8; Manns MP 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; Manns MP et al: Diagnosis and management of autoimmune hepatitis. Hepatology 2010 Jun;51(6):2193-213; Muratori P et al: Autoimmune hepatitis in Italy: the Bologna experience. J Hepatol 2009 Jun;50(6):1210-8; Zachou K et al: Mycophenolate for the treatment of autoimmune hepatitis: prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment-naïve patients. J Hepatol 2011 Sep;55(3):636-646.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Niu spoke at the 4th Annual Liver Disease Symposium, presented by the Sidney Kimmel Medical College at Thomas Jefferson University, Office of Continuing Medical Education, and held March 24, 2018, in Philadelphia, PA. For information on meetings presented by Thomas Jefferson University Office of Continuing Medical Education, please visit https://cme.jefferson.edu/. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

IM652702

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.