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FeedbackAutoimmune hepatitis (AIH) is a chronic autoimmune liver disease (ALD) that is characterized by hypergammaglobulinemia. If diagnosed and treated promptly, patients can expect a normal or nearly normal life expectancy. However, if untreated, AIH leads to cirrhosis and liver failure, with a high mortality rate. As many as one-third of patients with AIH are asymptomatic at diagnosis, which most often follows the unexplained elevation of serum transaminases. Patients may also present with nonspecific symptoms such as fatigue, nausea, weight loss, and jaundice. In about 25% of patients, onset of AIH is acute and presentation is similar to that of acute hepatitis that arises from other causes. AIH may be separated into two types, type 1 (AIH-1) and type 2 (AIH-2). A diagnosis of AIH is usually determined based on the presence of a typical phenotype and the exclusion of other chronic liver diseases, which may present in a similar manner as AIH. Laboratory tests for the diagnosis of AIH include liver biopsy, liver biochemistry tests, immunoglobulin G (IgG) titers, and tests for various autoantibodies.
Quick Answers for Clinicians
Autoimmune hepatitis (AIH) has been divided into at least two specific types, characterized by different autoantibody profiles, AIH type 1 (AIH-1) and AIH type 2 (AIH-2).
| Subtype | Frequency | Associated Antibodies | Clinical Significance |
|---|---|---|---|
|
AIH-1 |
Accounts for nearly 90% of AIH cases |
ANAs, SMAs, anti-SLA/LP |
Varying disease severity and relapse rates Treatment failure is rare |
|
AIH-2 |
Accounts for up to 10% of AIH cases |
Anti-LKM1, anti-LKM3, anti-LC1 |
Onset usually occurs in childhood or early adulthood More severe disease course, with acute or advanced disease common at diagnosis and with treatment failure and relapse occurring often Long-term maintenance therapy often required |
|
ANAs, antinuclear antibodies; LC1, liver cytosol type 1; LKM1, liver kidney microsome type 1; SLA/LP, soluble liver antigen/liver-pancreas; SMAs, smooth muscle antibodies |
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Patients with overlapping features of two different diseases, such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and/or primary sclerosing cholangitis (PSC), have often been classified as having “overlap syndromes,” although universally accepted criteria for defining these syndromes are lacking. The relationship between the two disorders suggested by these overlapping features is uncertain. Several possibilities have been described, including the simultaneous presentation of two different disorders and overlap syndromes as distinct diagnoses. However, the understanding most commonly supported by researchers is that overlap syndromes represent one primary disorder that simply has characteristics of another. As such, the term “variant form” may be a more appropriate way to describe these cases.
The presence of a variant form or overlap syndrome may have an impact on the therapeutic approach. A diagnosis of the AIH-PSC variant form may be made in an individual with various features of AIH (biochemical, serologic, and histologic) and cholangiographic or histologic features strongly associated with PSC but without antimitochondrial antibodies (AMAs). The “Paris criteria” are the most common criteria used to diagnose the AIH-PBC variant form ; these criteria have a sensitivity of 92% and a specificity of 97%. Immunosuppressant therapy should be considered for patients with either of these variant forms. For more information on the diagnostic criteria for the AIH-PBC variant form, see Primary Biliary Cholangitis on ARUP Consult.
About 25% of patients present with acute-onset autoimmune hepatitis (AIH), which has a very similar clinical presentation to that of acute hepatitis caused by other etiologies. These patients may have normal immunoglobulin G (IgG) levels and may test negative for antinuclear antibodies (ANAs) and smooth muscle antibodies (SMAs), which may lead to a failure to consider AIH as a possible diagnosis. A more sensitive and/or extensive assessment for autoantibodies related to autoimmune liver disease may be useful in these cases because a delay in diagnosis, and thus treatment, results in a poorer prognosis. Additionally, in cases of acute hepatitis, autoantibody testing should be repeated after 3-6 months if initial tests were negative because autoantibodies can develop over the course of the disease.
A liver biopsy with compatible histologic findings is required for the diagnosis of autoimmune hepatitis (AIH). Although no particular morphologic feature is specific to AIH, interface hepatitis is the most common finding. Other suggestive features include periportal necrosis, emperipolesis, and rosetting of hepatocytes. Panlobular hepatitis, bridging necrosis, and massive necrosis may also be present, particularly in cases of acute disease onset.
Indications for Testing
Testing for AIH should be considered in all individuals who present with acute or chronic liver disease (including acute liver failure) or abnormal liver function tests (elevated aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), particularly when hypergammaglobulinemia or features of other autoimmune disorders are present.
Testing is also indicated in patients with AIH to monitor the disease before, during, and after treatment.
Criteria for Diagnosis
The heterogeneous presentation seen in AIH creates a diagnostic challenge. The simplified International Autoimmune Hepatitis Group (IAIHG) diagnostic criteria can be used in clinical settings to help address this challenge. These criteria have a reported sensitivity of >80% and a reported specificity of >95% (with a cutoff of ≥7 points). These criteria are not always necessary, and their clinical utility is limited to assisting in diagnosis of challenging cases.
| Variable | Cutoff | Points | |
|---|---|---|---|
|
IgG |
Above upper limit |
1 |
|
|
>1.10 times upper limit of normal |
2 |
||
|
Liver histology |
Compatible with AIH |
1 |
|
|
Typical of AIH |
2 |
||
|
Absence of viral hepatitis |
Yes |
2 |
|
|
ANAs or SMAsa |
≥1:40 |
1 |
|
|
≥1:80 |
2 |
||
|
Anti-LKMa |
≥1:40 |
2 |
|
|
Anti-SLAa |
Positive |
2 |
|
|
|
|||
| Diagnosis | Cutoff (Points) | ||
|
Probable AIH |
6 |
||
|
Definite AIH |
≥7 |
||
|
aAutoantibodies may account for a maximum of 2 points. ANAs, antinuclear antibodies; LKM, liver kidney microsome; SLA, soluble liver antigen; SMAs, smooth muscle antibodies |
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Laboratory Testing
Diagnosis
The diagnosis of AIH is based on a combination of biochemical testing, autoantibody testing, and histology in addition to the exclusion of other liver diseases.
Biochemistry Tests
AIH is associated primarily with hypergammaglobulinemia, which is found in approximately 85% of patients with AIH and may be detected by either IgG testing or serum protein electrophoresis. Although IgG levels are usually elevated in AIH, IgA and IgM concentrations typically remain at normal levels. Elevated IgA levels may suggest alcoholic steatohepatitis, whereas elevated IgM levels may suggest primary biliary cholangitis (PBC).
Many patients with AIH present with persistently elevated bilirubin and aminotransferases (specifically AST and ALT). The concentrations in individuals with AIH range from just above the upper limit of normal to >50 times that amount. Gamma-glutamyl transferase (GGT) may also be elevated in AIH. An important consideration during the diagnostic process is that AST, ALT, and GGT may spontaneously return to normal levels while inflammatory activity persists, which can delay diagnosis, and thus treatment.
Autoantibody Tests
AIH is associated with various autoantibodies; however, most of these autoantibodies are not specific to AIH, and their presence is not necessary for an AIH diagnosis. Autoantibody expression often varies over the course of the disease and may be detected later in patients who were initially seronegative.
An initial autoantibody assessment tailored for AIH includes ANAs, SMAs, LKM type 1 (LKM1) autoantibodies, liver cytosol type 1 (anti-LC1) autoantibodies, and SLA/liver-pancreas (LP) autoantibodies. Antimitochondrial antibodies (AMAs) may also be included to assist in differentiating AIH from PBC or to assess for the AIH-PBC variant form. According to the IAIHG, immunofluorescence (IFL) using rodent tissue is the preferred methodology for AIH antibody testing, with the exception of tests for anti-SLA/LP autoantibodies. However, this method is not standardized, and although commercial substrates exist, their quality varies. Thus, other methods of testing, such as enzyme-linked immunosorbent assay (ELISA), are gaining popularity.
ANAs and SMAs
ANAs are a marker of AIH-1 and are found in nearly half of patients with AIH-1. Although the homogeneous fluorescence pattern is most common in AIH, no particular staining pattern is consistently indicative of AIH, and the specific staining pattern does not appear to have clinical relevance. Thus, HEp-2 staining is not needed when screening for AIH. SMAs are also a marker of AIH-1 and are detected in about half of diagnosed patients. Because SMA with reactivity against F-actin is more specific for AIH, testing for SMA/antiactin by ELISA is a useful diagnostic tool, although IFL is still preferred. In North America, the majority of patients with AIH have ANAs, SMAs, or both ; the two autoantibodies are frequently found together, which can improve the diagnostic strength.
Anti-LKM1 and Anti-LC1
Anti-LKM1 and anti-LC1 autoantibodies are markers for AIH-2 that are often found in conjunction with one another. The prevalence of anti-LKM1 and anti-LC1 autoantibodies in AIH-2 has been reported at 66% and 53%, respectively, although they are not specific to AIH, and both have been detected in patients with hepatitis C virus (HCV). The specific target of each autoantibody has been determined; anti-LKM1 acts against cytochrome P450 2D6 (CYP2D6), and anti-LC1 acts against formininotransferase cyclodeaminase (FTCD). Because anti-LKM1 autoantibodies can be mistaken for AMAs when using IFL, ELISA testing should be used to confirm positivity.
Anti-SLA/LP
Anti-SLA/LP autoantibodies are highly specific to AIH and thus have a high diagnostic value. These autoantibodies are detected in about 30% of patients with AIH but cannot be detected by IFL, so ELISA or Western blot testing must be used.
Other Autoantibody Tests
If initial autoantibody tests are negative, but clinical suspicion for AIH remains high, antineutrophil cytoplasmic antibody (ANCA) testing may be useful. Atypical perinuclear ANCAs (p-ANCAs), originally thought to be specific to PSC and inflammatory bowel disease (IBD), are now recognized as common in patients with AIH-1.
When anti-LKM1 autoantibodies are not detected, testing for anti-LKM3 autoantibodies (also associated with AIH-2) may be considered.
Prognosis
Autoantibodies
Of the autoantibodies assessed for diagnostic purposes, anti-LC1 (associated with AIH-2), anti-SLA/LP, and antiactin (a subset of SMAs) also have prognostic implications. Anti-LC1 autoantibodies are associated with severe liver inflammation and a rapid progression to cirrhosis. Anti-SLA/LP autoantibodies are associated with more severe histologic changes, as well as a higher likelihood of relapse, treatment dependence, and transplantation. Antiactin autoantibodies are associated with higher likelihoods of treatment dependence, poorer treatment response, and liver failure.
Antiasialoglycoprotein receptor autoantibodies (anti-ASGPR) can be detected in some patients with AIH and are associated with increased interface hepatitis and more frequent relapse in patients. (6-Sebode 2018) When these autoantibodies disappear during treatment, a sustained remission after treatment withdrawal is more likely.
Other autoantibodies that may indicate more severe disease, treatment resistance, or long-term treatment dependence are antichromatin autoantibodies, anti-double-stranded DNA (anti-dsDNA) autoantibodies, and anticyclic citrullinated peptide (anti-CCP) autoantibodies.
Other Tests
Biochemical assessment is more useful in diagnosis than in monitoring, but recent studies have indicated that elevated GGT levels may be useful as an independent predictor of treatment outcome.
Histology reveals cirrhosis in 28-33% of patients at AIH diagnosis, and these patients, as well as those with bridging necrosis at diagnosis, have a poorer prognosis than those with neither. However, patients with cirrhosis do usually have treatment-responsive disease.
Monitoring
In adults, autoantibody titers only roughly correlate with disease activity and are thus not useful in monitoring the disease. However, in children, autoantibody titers (particularly in the case of anti-LC1) are biomarkers of disease activity and may be a useful tool in monitoring treatment response.
For adults, the frequency of monitoring depends on the clinical situation of the patient.
| Clinical Situation | Tests Performed | Frequency |
|---|---|---|
|
No treatment indicated |
ALT, IgG Perform biopsy if either increases |
Every 3 mos |
|
During treatment |
ALT, AST, IgG |
Closely during first 4 wks Every 1-3 mos as steroid dose tapers |
|
After remission is reacheda |
ALT, AST, IgG, bilirubin |
Every 3 wks for the first 3 mos, then every 6 mos for the first yr, and once per yr thereafter |
|
During maintenance therapy |
ALT, AST, IgG |
Every 3-6 mos |
|
aBiochemical remission is defined as normal AST, ALT, and IgG levels; histologic remission is defined as a biopsy result that is normal or indicates only minimal hepatitis. |
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Treatment-Related Testing
Because azathioprine therapy can cause severe myelosuppression in those with thiopurine methyltransferase (TPMT) deficiency, phenotyping or genotyping testing should be considered to assess the risk of such complications before initiating treatment.
ARUP Laboratory Tests
Initial screening for hepatobiliary inflammation
Quantitative Enzymatic Assay/Quantitative Spectrophotometry
Use to detect hypergammaglobulinemia
May assist in the diagnosis and monitoring of AIH
Quantitative Immunoturbidimetry
Quantitative Capillary Electrophoresis/Colorimetry
May assist in the diagnosis and monitoring of AIH
Quantitative Spectrophotometry
May assist in the diagnosis and monitoring of AIH
Quantitative Enzymatic Assay
Quantitative Enzymatic Assay
May assist in the diagnosis of AIH and in the prediction of treatment outcome
Quantitative Enzymatic Assay
Recommended first-line panel for the evaluation of ALD
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
Components: AMA, IgG; LKM-1 antibody, IgG; F-actin SMA, IgG; SMA, IgG titer; SLA antibody, IgG; ANA with HEp-2 substrate, IgG
Use to detect ANA
May assist in the diagnosis of AIH-1
Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Multiplex Bead Assay/Qualitative Immunoblot
Use to detect SMA
May assist in the diagnosis of AIH-1
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
Semi-Quantitative Indirect Fluorescent Antibody
Use to detect anti-LKM1 autoantibodies by ELISA
May assist in the diagnosis of AIH-2
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Use to detect anti-LKM autoantibodies by IFL
Does not differentiate among the four types of anti-LKM autoantibodies
May assist in the diagnosis of AIH-2
Semi-Quantitative Indirect Fluorescent Antibody
Use to detect anti-LC1 autoantibodies
May assist in the diagnosis and prognosis of AIH-2
Qualitative Immunoblot
Use to detect anti-SLA autoantibodies
Highly suggestive of AIH; may assist in the prognosis of AIH
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Use to detect p-ANCAs
May assist in the diagnosis of AIH when other antibody tests are negative
Semi-Quantitative Indirect Fluorescent Antibody (IFA)
Use to assess risk for severe myelosuppression with standard dosing of thiopurine drugs
Polymerase Chain Reaction (PCR)/Fluorescence Monitoring
Enzymatic Assay/Quantitative Liquid Chromatography-Tandem Mass Spectrometry
References
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Medical Experts
Nandakumar
Components: albumin; alkaline phosphatase (ALP); AST; ALT; bilirubin, direct; protein, total; and bilirubin, total