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Autoimmune Hepatitis Workup

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

Approach Considerations

Clinicians must consider the diagnosis of autoimmune hepatitis in any patient who has acute hepatitis or acute liver failure (defined by the new onset of coagulopathy). In addition to aminotransferase levels and other liver function studies, the workup of such patients should include the following assays:

  • Serum antinuclear antibody (ANA)
  • Anti–smooth muscle antibody (ASMA)
  • Liver-kidney microsomal type 1 (LKM-1) antibody
  • Serum protein electrophoresis (SPEP)
  • Quantitative immunoglobulins

Urgent liver biopsy, transjugular if appropriate, may help to confirm the clinical suspicion of autoimmune hepatitis.

Laboratory findings in autoimmune hepatitis include the following:

  • Elevated serum aminotransferase levels (1.5-50 times reference values)
  • Elevated serum immunoglobulin levels, primarily immunoglobulin G (IgG)
  • Seropositive results for ANAs, SMAs, or LKM-1 or anti–liver cytosol 1 (anti-LC1) antibodies

In 50% of patients, abnormal results on liver function tests include decreased albumin levels and prolonged prothrombin time.

In August 2012, the Centers for Disease Control and Prevention (CDC) expanded their existing, risk-based testing guidelines to recommend a 1-time blood test for hepatitis C virus (HCV) infection in baby boomers—the generation born between 1945 and 1965, who account for approximately three fourths of all chronic HCV infections in the United States—without prior ascertainment of HCV risk (see Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965).[3] One-time HCV testing in this population could identify nearly 808,600 additional people with chronic infection. All individuals identified with HCV should be screened and/or managed for alcohol abuse, followed by referral to preventative and/or treatment services, as appropriate.

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Autoantibody Assays

Autoimmune hepatitis is characterized by positive findings on autoantibody tests, as follows:

  • AIH-1 - ASMA and ANA
  • AIH-2 - Anti–LKM-1 antibody
  • AIH-3 - Antibodies to soluble liver antigen (anti-SLA)

SMAs are present in 90-100% of patients with autoimmune hepatitis type 1 (AIH-1). ANAs are present in 10% of patients with AIH-1 and in association with SMAs in 40-60% of patients with AIH-1. Titers range from 1:100-500,000. SMAs occur in low titers in healthy children and patients with viral hepatitis and other diseases that do not affect the liver.

LKM-1 antibodies are present in 40-45% of patients with AIH-2 and are associated with anti-LC1 antibodies in 50% of patients. Anti-LC1 antibodies occur alone in 30% of patients with AIH-2; these antibodies recognize formiminotransferase cyclodeaminase, a liver-specific 58kD metabolic enzyme. Anti-asialoglycoprotein receptor antibodies occur more often in patients with AIH-1 and may serve as a marker of inflammatory activity.

Other autoantibodies may be evident. Atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) are frequently present. Czaja et al have shown that patients with autoimmune hepatitis who have positive test results for actin antibody are younger, more commonly test positive for human leukocyte antigen (HLA)–DR3, and required transplantation more frequently than patients with ANAs who test negative for actin antibody.[42]

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Serum Proteins and Immunoglobulins

An IgG-predominant polyclonal hypergammaglobulinemia is a common finding in patients with untreated autoimmune hepatitis. Gamma globulin values typically range from 3-4 g/dL and frequently are as high as 5-6 g/dL. Cases of hyperviscosity syndrome secondary to high IgG levels are reported. Autoimmune hepatitis is an unlikely diagnosis in patients who have acute hepatitis without hypergammaglobulinemia.

The gamma globulin or the IgG level may be followed on a regular basis as a marker of disease responsiveness to therapy.

Patients with AIH-2 commonly have partial immunoglobulin A (IgA) deficiency.[39]

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Aminotransferases

Serum aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are elevated in 100% of patients at initial presentation, with average values of 200-300 U/L. Aminotransferase values correlate poorly with the degree of hepatic necrosis; however, values in the thousands may indicate acute hepatitis or a severe flare of preexisting disease.

Continued elevation of the aminotransferases in the face of ongoing therapy is a reliable marker for ongoing inflammatory activity in the liver. Normalization of the aminotransferase levels during therapy is an encouraging sign, but active liver inflammation is present in more than 50% of patients with normalized liver chemistries. Indeed, biochemical remission may precede true histologic remission by 3-6 months.

Typically, patients are treated for at least 1 year after documentation of normal liver chemistries. Liver biopsy is recommended by some experts to confirm that the patient is in histologic remission. Drug withdrawal may be attempted at this time (see Treatment).

Worsening of aminotransferase levels in a patient undergoing treatment or in a patient who is in remission may signal a resurgence of disease activity.

Other liver chemistries

Serum bilirubin and alkaline phosphatase values are mildly to moderately increased in 80-90% of patients. A sharp increase in the alkaline phosphatase values during the course of autoimmune disease might reflect the development of PSC or the onset of hepatocellular carcinoma as a complication of cirrhosis.

Hypoalbuminemia and prolongation of prothrombin time are markers of severe hepatic synthetic dysfunction, which may be observed in active disease or decompensated cirrhosis.

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Complete Blood Count and Other Blood Studies

Other hematologic abnormalities may include the following:

  • Mild leukopenia
  • Normochromic anemia
  • Coombs-positive hemolytic anemia
  • Thrombocytopenia
  • Elevated erythrocyte sedimentation rate

Eosinophilia is uncommon, but counts ranging from 9% to 48% are described. Autoimmune hepatitis has even been described as the sole presenting feature of idiopathic hypereosinophilic syndrome.

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Hepatic Imaging Studies

Imaging studies, in general, are not helpful in reaching a definitive diagnosis of autoimmune hepatitis; however, the presence of heterogeneous hepatic echotexture on abdominal ultrasound or abnormal contrast enhancement on abdominal CT imaging may suggest the presence of active inflammation or necrosis.

The appearance of an irregular nodular liver may confirm the presence of cirrhosis. Furthermore, these imaging studies may be used to rule out the presence of hepatocellular carcinoma, a potential complication of autoimmune hepatitis–induced cirrhosis.

When alkaline phosphatase levels are 7-8 times reference values or gamma glutamyl transferase levels are 2-3 times reference values, a patient with autoimmune hepatitis and ulcerative colitis may require endoscopic retrograde cholangiopancreatography (ERCP) to rule out coexisting primary sclerosing cholangitis (PSC).

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Liver Biopsy

Liver biopsy is the most important diagnostic procedure in patients with autoimmune hepatitis. This procedure can be performed percutaneously, with or without ultrasound guidance, or by the transjugular route. The latter is preferred if the patient has coagulopathy or severe thrombocytopenia. A transjugular liver biopsy also may be preferable if ascites is present or if the liver is small, shrunken, and difficult to reach percutaneously.

Liver biopsy routinely is performed in the outpatient setting to investigate abnormal liver chemistries. Liver biopsy should be performed as early as possible in patients with acute hepatitis who are thought to have autoimmune hepatitis. Confirmation of the diagnosis enables initiation of treatment at an early stage in the disease process.

The role of biopsy in patients presenting with well-established cirrhosis secondary to autoimmune hepatitis is less clear. As an example, the initiation of treatment in a patient with cirrhosis, normal aminotransferase levels, and a minimally elevated gamma globulin level is not expected to influence the disease outcome.

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Histologic Findings

Histopathologic findings on liver biopsy specimens are crucial to determining the diagnosis of autoimmune hepatitis and the disease's severity. Liver biopsy findings can help to differentiate autoimmune hepatitis from chronic hepatitis C virus (HCV) infection, alcohol-induced hepatitis, drug-induced liver disease, primary biliary cirrhosis, and PSC.[43]

Autoimmune hepatitis is characterized by a portal mononuclear cell infiltrate that invades the limiting plate surrounding the portal triad and permeates the surrounding lobule (ie, periportal infiltrate) and beyond. A plasma cell infiltrate sometimes occurs, which, in the past, led to use of the term plasma cell hepatitis.

Biopsies may show evidence for interface hepatitis (ie, piecemeal necrosis), bridging necrosis, and fibrosis. Interface hepatitis essentially spares the biliary tree but may involve most of the lobule. Lobular collapse, best identified by reticulin staining, is a common finding.

Interface hepatitis does not predict a progressive disease course. By contrast, a strong likelihood exists that cirrhosis will develop when bridging necrosis is present. The presence or absence of cirrhosis on liver biopsy is an important determinant of the patient's prognosis.

Fibrosis is present in most patients with autoimmune hepatitis. Without effective therapy, fibrosis starts to connect the portal and central areas, which ultimately leads to cirrhosis.

In 1999, the International Autoimmune Hepatitis Group established a scoring system that is particularly helpful in establishing the diagnosis of autoimmune hepatitis in problematic cases.[44, 45]

Histopathologic findings in patients with autoimmune hepatitis are characteristic but nonspecific; autoimmune hepatitis has findings in common with chronic viral hepatitis, drug-associated chronic hepatitis, and several other chronic liver disorders. Multinucleated giant hepatocytes are found in 10-20% of biopsy specimens; their occurrence after the neonatal period may suggest a diagnosis of autoimmune hepatitis.

Tucker et al indicate that the presence of characteristic hyaline droplets in the cytoplasm of Kupffer cells on routine hematoxylin and eosin (H&E) from biopsy specimens in pediatric patients with autoimmune hepatitis may provide a useful diagnostic clue to distinguish this disease from other forms of chronic hepatitis.[46]

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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.

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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



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