Hospital Medicine

Autoimmune hepatitis (lupoid hepatitis, chronic active hepatitis)

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Autoimmune hepatitis (lupoid hepatitis, chronic active hepatitis)

I. What every physician needs to know.

Autoimmune hepatitis (AIH) is also known historically as chronic aggressive hepatitis, plasma cell hepatitis, lupoid hepatitis and chronic active hepatitis. It is a form of chronic hepatitis that is characterized by immunologic and autoimmunologic features; two types have been identified on the basis of autoantibody patterns.

II. Diagnostic Confirmation: Are you sure your patient has autoimmune hepatitis?

Laboratory testing should show evidence of abnormal liver chemistry tests, increased total immunoglobulin G (IgG) or gamma-globulin levels and autoantibodies. Histology demonstrates lymphoplasmacytic portal infiltrate. Other etiologies of chronic hepatitis should be excluded.

A. History Part I: Pattern Recognition:

There is a variable presentation ranging from asymptomatic to chronic liver disease to acute liver failure. There may also be non-specific symptoms like fatigue, malaise, nausea, abdominal discomfort, itching, and arthralgia’s particularly in the small joints.

B. History Part 2: Prevalence:

AIH is seen in all the ethnic groups and can occur at any age, though it is often diagnosed in patients in their forties or fifties, including patients with graft dysfunction after liver transplantation. AIH is more common in woman than men for both type 1 and type 2; additionally, type 2 is usually seen in children and young adults. The disease is often seen in association with other autoimmune processes including type I diabetes, thyroiditis, celiac disease, rheumatoid arthritis, and ulcerative colitis.

C. History Part 3: Competing diagnoses that can mimic autoimmune hepatitis.

  • Primary biliary cirrhosis (PBC), which may be characterized by isolated presence of anti-mitochondrial antibodies (AMA). Liver biopsy shows bile duct paucity with inflammation or periductular fibrosis.

  • Primary sclerosing cholangitis (PSC).

  • Overlap syndromes account for 7% of PBC/AIH and 6% of PSC/AIH cases. The nomenclature and diagnostic criteria for these variant forms of AIH have not been standardized yet.

  • Acute viral hepatitis secondary to hepatitis A to D, hepatitis E in some parts of the world, cytomegalovirus, Epstein-Barr virus and herpes virus.

  • Chronic hepatitis C. Antibodies to hepatitis C may not develop until 6 to 12 months after infection so carry out a measurement of circulating hepatitis C virus ribonucleic acid (RNA) by polymerase chain reaction (PCR). Approximately 5 % of patients with chronic hepatitis C have antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA) and anti-liver kidney microsomal (ALKM-1) antibody titers of 1:100 or greater which can confound the diagnosis. In case of patient having both AIH and hepatitis C, it is prudent to first treat the AIH.

  • Liver disease associated with lupus. ANA are seen in both conditions but ASMA and AMA are rare in lupus.

  • Non-alcoholic steatohepatitis. Liver biopsy for this condition typically shows fatty infiltration, presence of polymorphonuclear leukocytes and central fibrosis.

  • Hemochromatosis (HFE). Exclude by measurement of hepatic iron concentration and HFE mutations.

  • Wilson's disease.

D. Physical Examination Findings.

Physical exam may be normal. However, one should look for hepatosplenomegaly, features of cirrhosis and jaundice.

E. What diagnostic tests should be performed?

Lab testing is most important as diagnosis can be made on the basis of biochemical and autoantibody tests combined with clinical picture. The autoantibodies are not believed to be involved in the pathogenesis of autoimmune hepatitis and are not predictive of histologic severity or the treatment response.

Liver biopsy is not essential as there are no findings specific for AIH. However, a histologic picture compatible with the diagnosis, in which one may see mononuclear infiltrate in the portal areas and an abundance of plasma cells. The periportal lesion, referred to as piecemeal necrosis or interface hepatitis, essentially spares the biliary tree but may involve more of the lobule.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The criteria used are: serum aminotransferase levels greater than 10 fold the upper normal limit, serum gamma globulin level greater than twice the upper normal limit, elevated conjugated bilirubin, interface hepatitis on biopsy.

Autoantibody testing includes ANA (at least 1:80 titer), ASMA with titers of 1:320 or greater generally reflective of the presence of specific antiactin antibodies which are usually not measured in most clinical laboratories, atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA), soluble liver antigen and liver-pancreas antigen (SLA/LP) which is seen in 30% of patients, liver-kidney microsomal antibody type 1 (LKM-1), and anti-liver cytosol antibody type 1 (ALC-1). AMA may sometimes be seen although are typically seen in primary biliary cirrhosis.

Type 1 AIH is typically characterized by positive (+) smooth muscle antibodies (SMA), +pANCA, +ANA, and +SLA/LP antibodies (most specific for type 1, but only found in 10-30% of cases). Type 2 is usually characterized by antibodies to ALKM-1 and ALC-1. However, autoantibody testing alone is not diagnostic as positive testing can be seen in other liver disease. Additionally, circulating antibodies are absent in about 10% of patients.

Serologies for viral hepatitides should be ordered to exclude these from the diagnosis.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are no imaging studies that would help establish the diagnosis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

None

III. Default Management.

  • Assess severity of disease and degree of liver impairment through history, physical exam and testing (serum aminotransferases, immunoglobulin levels, liver function, histologic testing).

  • Consultation with gastrointestinal (GI)/hepatology specialist for help with initiation or adjustment of treatment, which is typically prednisone with or without azathioprine.

  • Monitor progress with aminotransferase and IgG levels and liver biopsy.

  • Diseases commonly seen with autoimmune hepatitis include hemolytic anemia, immune thrombocytopenia, type 1 diabetes mellitus, thyroiditis, celiac sprue, ulcerative colitis, primary biliary cirrhosis and primary sclerosing cholangitis.

A. Immediate management.

Approximately 90% of patients have improvement in serum aminotransferases, bilirubin and gamma globulin within two weeks. However, histologic improvement lags behind biochemical improvement by three to eight months. In adults, autoantibody levels do not appear to parallel disease activity and should not be used to monitor activity.

B. Physical Examination Tips to Guide Management.

Evaluate for signs of acute liver failure by assessing mentation. Evaluate complications of chronic liver disease by looking for ascites, skin findings or hepatic encephalopathy. Ensure that there are not infectious complications related to immunosuppressive therapy by looking for fever, oral thrush or rashes.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Aminotransferase and immunoglobulin levels are checked every several months. Histologic response usually lags behind biochemical response but may better reflect severity of disease. Liver biopsy may therefore be performed prior to reduction or withdrawal of maintenance drug therapy.

D. Long-term management.

Remission is usually not achieved until after 1 year, at which time an attempt can be made to withdraw maintenance drug therapy. Many patients require long-term maintenance therapy, particularly those who have cirrhosis at the time of initial diagnosis. In those who are refractory to therapy and have developed end-stage liver disease, liver transplantation should be considered as it’s the ultimate rescue therapy with 5 and 10 year survivals exceeding 70% in adults. Liver transplantation is indicated by Model for End Stage Liver Disease (MELD) score>16, acute decompensation, treatment intolerance or detection of liver cancer.

E. Common Pitfalls and Side-Effects of Management

Before initiating azathioprine, thiopurine methyltransferase (TPMT) levels should be checked (absent activity in 0.3% of population). Patients with decreased TPMT activity are at risk for azathioprine-related toxicity since TPMT is a key enzyme in azathioprine metabolism. Azathioprine is typically initiated under the advisement of a hepatologist and usually in the outpatient setting.

Long-term prednisone use has many side effects including immunosuppression, worsening of diabetes and bone health. Azathioprine has been associated with aplastic anemia as well as lesser degrees of bone marrow suppression, infection, pancreatitis and malignancy like lymphoma.

Drug treatment for autoimmune hepatitis

Prednisone 60 mg (milligrams) oral daily

OR

Prednisone 30 mg oral daily + azathioprine 50 mg oral daily (can help lower the frequency of steroid induced side effects- 10% versus 44%)

Patients should ultimately be tapered by 5 mg every week to maintain remission.

Investigational treatments include mycophenolate mofetil, budesonide, cyclosporine, tacrolimus and sirolimus. Their role has now started to expand as alternative frontline and salvage therapy. Infliximab and rituximab are also under evaluation for treatment of AIH.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

A dose reduction of azathioprine is recommended. Seventy-five percent of the usual dose should be given for creatinine clearance (CrCl) 10-50 milliliters/minute (ml/min), and 50% of the usual dose should be given for CrCl less than 10 ml/min.

B. Liver Insufficiency.

Azathioprine may worsen liver function due to hepatotoxicity versus progressive liver dysfunction that occurs in AIH refractory to therapy. No dose adjustments are necessary but patients with cirrhosis are felt to be more refractory to drug therapy for AIH and therefore higher doses of azathioprine may be attempted.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

Steroid use may exacerbate hyperglycemia and adjustments may need to be made in diabetes medications and insulin. Steroids also can result in deterioration in bone health and vigilance needs to be paid to bone density and vitamin D and calcium supplementation.

F. Malignancy

No change in standard management. Screening for hepatocellular carcinoma is performed in patients with cirrhosis from AIH. Patients using azathioprine are at increased risk for lymphoma.

G. Immunosuppression (HIV, chronic steroids, etc.).

No change in standard management but one should be cognizant that azathioprine and prednisone confer additional immunosuppression. Testing for latent tuberculosis with T-spot or gold interferon test should be performed before starting induction therapy along with vaccination against hepatitis A or B if not already immune.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

Azathioprine can result in nausea, vomiting and diarrhea that may exacerbate symptoms from pre-existing gastrointestinal disease. Prednisone in conjunction with non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin can predispose to peptic ulcer disease development.

J. Hematologic or Coagulation Issues

Azathioprine may result in cytopenias, particularly neutropenia, at toxic levels.

K. Dementia or Psychiatric Illness/Treatment

Patients initiated on steroids may experience increased agitation or mania.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

None

B. Anticipated Length of Stay.

Treatment may be initiated as an inpatient but typically is continued as an outpatient.

C. When is the Patient Ready for Discharge.

Not applicable as treatment can be pursued as an outpatient.

D. Arranging for Clinic Follow-up

N/A

1. When should clinic follow up be arranged and with whom.

Hepatology clinic follow-up should be arranged within 2-4 weeks after initiation of treatment.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Complete blood cell count, basic metabolic panel, liver biochemistries, and serum immunoglobulins.

E. Placement Considerations.

None

F. Prognosis and Patient Counseling.

AIH typically responds to immunosuppressive therapy. A patient may need to remain on this therapy long-term. Ultimately, liver transplantation has been successful in those who do not respond to medical therapy.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Because these patients are usually on immunosuppressant therapy, they should be up to date with vaccinations for seasonal influenza and pneumococcal infections. They should be vaccinated against hepatitis A and hepatitis B to prevent acute infection. Patients should watch closely for development of fever, sore throat, colds, rashes, and breathing difficulties and seek timely and appropriate care. Long-term, patients on chronic corticosteroids need to have assessment for bone health and hyperglycemia.

VII. What's the Evidence?

Krawitt, EL. "Autoimmune hepatitis". N Engl J Med. vol. 354. 2006. pp. 54.

Johnson, PJ, McFarlane, IG. "Meeting report: International Autoimmune Hepatitis Group". Hepatology. vol. 18. 1993. pp. 998.

Manns, MP, Czaja, AJ, Gorham, JD. "Diagnosis and management of autoimmune hepatitis". Hepatology. vol. 51. 2010. pp. 2193.

Boberg, KM, Aadland, E, Jahnsen, J. "Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population". Scand J Gastroenterol. vol. 33. 1998. pp. 99.

Werner, M, Prytz, H, Ohlsson, B. "Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study". Scand J Gastroenterol. vol. 43. 2008. pp. 1232.

Abe, M, Onji, M, Kawai-Ninomiya, K. "Clinicopathologic features of the severe form of acute type 1 autoimmune hepatitis". Clin Gastroenterol Hepatol. vol. 5. 2007. pp. 255.

Stravitz, RT, Lefkowitch, JH, Fontana, RJ. "Autoimmune acute liver failure: proposed clinical and histological criteria". Hepatology. vol. 53. 2011. pp. 517.

Hofer, H, Oesterreicher, C, Wrba, F. "Centrilobular necrosis in autoimmune hepatitis: a histological feature associated with acute clinical presentation". J Clin Pathol. vol. 59. 2006. pp. 246.

Bianchi, FB. "Autoimmune hepatitis: the lesson of the discovery of hepatitis C virus". J Hepatol. vol. 18. 1993. pp. 273.

Woynarowski, M, Nemeth, A, Baruch, Y. "Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents". J Pediatr. vol. 163. 2013. pp. 1347.

Boberg, KM, Chapman, RW, Hirschfield, GM. "Overlap syndromes: The International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue". J Hepatol. vol. 54. 2011. pp. 374.

Czaja, AJ. "Frequency and nature of the variant syndromes of autoimmune liver disease". Hepatology. vol. 28. 1998. pp. 360.

Mehendiratta, V, Mitroo, P, Bombonati, A. "Serologic markers do not predict histologic severity or response to treatment in patients with autoimmune hepatitis". Clin Gastroenterol Hepatol. vol. 7. 2009. pp. 98.

Czaja, AJ. "Autoantibody-negative autoimmune hepatitis". Dig Dis Sci. vol. 57. 2012. pp. 610.

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