Autoimmune Hepatitis Dig Dis 2015;33(suppl 2):47–52 DOI: 10.1159/000440709
Diagnostic Criteria for Autoimmune Hepatitis: Scores and More Ansgar W. Lohse I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
Abstract The diagnosis of autoimmune hepatitis is a clinical diagnosis that combines the patient’s history, clinical examination, laboratory and serological markers and the results of a liver biopsy. As the clinical spectrum of autoimmune hepatitis is very wide, making the diagnosis can sometimes be difficult, especially in non-expert hands. Diagnostic scores can help in making the diagnosis, and the simplified diagnostic score of the International Autoimmune Hepatitis Group has a sensitivity and specificity of around 90% in the different populations that have been studied. Therefore, it can be very helpful in everyday use, but nonetheless for some patients the score is not good enough. Limitations are patients with very acute presentations as well as atypical cases. In such cases, a trial of monotherapy with steroids and quick tapering of the steroids is recommended. If the disease responds well to treatment, but recurs after tapering the steroids, the diagnosis of autoimmune hepatitis is confirmed. In addition to its clinical use, diagnostic scores can also be helpful in defining the unified criteria in order to make scientific studies compa© 2015 S. Karger AG, Basel rable.
© 2015 S. Karger AG, Basel 0257–2753/15/0338–0047$39.50/0 E-Mail [email protected] www.karger.com/ddi
Autoimmune hepatitis is a disease with a fairly poor prognosis if undiagnosed and untreated, but with a very good and mostly excellent prognosis if diagnosed in time and treated properly [1, 2]. Therefore, making a reliable diagnosis of autoimmune hepatitis is the essential prerequisite for good medical care of affected patients. However, diagnosing autoimmune hepatitis can be quite challenging. The challenges are multiple. Most importantly, the disease is extremely heterogeneous with a clinical picture covering the whole range of asymptomatic, very mild disease, often with periods of spontaneous remission, up to very acute and even fulminant hepatitis. Similarly, the age range at clinical presentation is extremely wide. Occasionally, the disease can manifest in the first 2 years of life, sometimes very acutely, while other patients only present in the 8th or even in the 9th decade. In addition, the disease may for a long time run a totally subclinical course and a fair proportion of patients will only present at the stage of advanced fibrosis or even decompensated cirrhosis and have never previously been found to have liver disease. In view of the heterogeneity of the disease, and in the absence of a simple universal laboratory test making or excluding the diagnosis of autoimmune hepatitis, it essentially remains a clinical diagnosis that needs to take into account the personal history of the patient, clinical Prof. Dr. med. Ansgar W. Lohse I. Medizinische Klinik und Poliklinik Universitätsklinikum Hamburg-Eppendorf Martinistrasse 52, DE–20246 Hamburg (Germany) E-Mail alohse @ uke.de
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Key Words Simplified diagnostic criteria · Autoantibodies · IgG · International Autoimmune Hepatitis Group
Table 1. Simplified diagnostic criteria for autoimmune hepatitis of the International Autoimmune Hepatitis
Group [6] Feature/parameter
Discriminator
Score
ANA or SMA+
≥1:40
+1*
ANA or SMA+
≥1:80
+2*
or LKM+
≥1:40
+2*
or SLA/LP+
Any titre
+2*
IgG or γ-globulins level
>Upper limit of normal >1.1 × upper limit
+1 +2
Liver histology (evidence of hepatitis is a necessary condition)
Compatible with AIH Typical of AIH Atypical
+1 +2 0
Absence of viral hepatitis
No Yes
0 +2
Definite autoimmune hepatitis: ≥7; probable autoimmune hepatitis: ≥6. * Addition of points achieved for all autoantibodies (maximum, 2 points). Typical liver histology for autoimmune hepatitis = each of the following features had to be present namely, interface hepatitis, lymphocytic/lymphoplasmocytic infiltrates in portal tracts and extending into the lobule, emperipolesis (active penetration by 1 cell into and through a larger cell), and hepatic rosette formation. Compatible liver histology for autoimmune hepatitis = chronic hepatitis with lymphocytic infiltration without all the features considered typical. Atypical = showing signs of another diagnosis, like steatohepatitis.
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Dig Dis 2015;33(suppl 2):47–52 DOI: 10.1159/000440709
duction or discontinuation of immunosuppressive therapy. These 2 criteria are very reliable criteria, as both features are characteristic of autoimmune hepatitis. However, these criteria are not in any way helpful to the clinician treating a patient with unknown liver disease, in whom the diagnosis of autoimmune hepatitis has to be considered among other alternative diagnoses, and for whom decision starting immunosuppression has to be made. In order to provide a diagnostic score that is simple to use and that will help the clinician in deciding, if a patient should be initially managed as autoimmune hepatitis, the International Autoimmune Hepatitis Group in 2008 presented a simplified score for the diagnosis of autoimmune hepatitis that is based on 4 criteria [6] (table 1): raised IgG-gammaglobulins, autoantibodies, absence of viral hepatitis and a liver biopsy demonstrating inflammatory hepatitis. A number of studies have since shown that these simple criteria have a very good sensitivity and specificity, both around 90%, in the wide variety of populations tested. These simplified criteria, like all diagnostic scores, have some limitations discussed below, but provide sufficient guidance for the vast majority of clinical situations. Lohse
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findings, laboratory results, serological testing and liver biopsy findings. Occasionally, only close observation of the response to therapy or observation of a relapse of hepatitis following a therapeutic trial will make the final diagnosis. In this complex situation, diagnostic algorithms and diagnostic scores can help in 2 ways [3]. First of all, diagnostic scores may help the general gastroenterologist and hepatologist in making the primary clinical diagnosis, and in weighing the different laboratory, serological and histological results. In addition, diagnostic scores are important in stratifying patients and in making clinical scientific studies from different centres comparable. The first attempts to provide a score of generally agreed diagnostic criteria dates back to 1992, when the International Autoimmune Hepatitis Group was founded at the meeting of the International Association for the Study of the Liver in Brighton in order to agree on a complex set of criteria [4]. This initial score helped enormously in focusing further work, and in 1999, a modified score of the International Autoimmune Hepatitis Group was published; this has been the basis for a majority of scientific studies on autoimmune hepatitis [5]. Key features of this score, however, are the response to steroid therapy, and the possible relapse of disease upon dose re-
Diagnostic Criteria for Autoimmune Hepatitis
Dig Dis 2015;33(suppl 2):47–52 DOI: 10.1159/000440709
Hypergammaglobulinemia was a characteristic feature in the very first descriptions of patients with autoimmune hepatitis, and very marked hypergammaglobulinemia can sometimes be observed in autoimmune hepatitis [7, 8]. In fact, most case series describe raised gammaglobulins in about 90% of all patients presenting with autoimmune hepatitis. A characteristic feature of autoimmune hepatitis is the usually very highly selective elevation of IgG and the presence of normal levels of IgA and IgM. Only in advanced cirrhosis, IgA and IgM are also elevated, but IgG elevation is almost always predominant. However, there are only a very few studies that have looked at the exact degree of elevation of IgG and the ratio of IgG to IgA and IgM. In addition, the normal range of IgG is very wide due to the genetic variability of IgG levels among healthy humans. It appears that the few patients with IgG levels within the normal range and autoimmune hepatitis have values within the upper range of normal, and their IgG levels fall upon immunosuppressive therapy. Thus, these patients have a relative increase of IgG in active autoimmune hepatitis that is not immediately apparent at diagnosis. Therefore, attention should be paid to the exact levels of IgG, especially in those patients in whom autoimmune hepatitis is suspected but the IgG levels appear to be normal. The degree of elevation of IgG can be extremely high with levels of up to 40 g/l or even higher. There is a debate as to what extent the degree of IgG elevation is a mark of histological disease activity. There is at least sufficient correlation to argue that normalisation of IgG should be as much a therapeutic aim as normalisation of transaminase levels. In fact, international societies have defined remission in autoimmune hepatitis as complete normalisation of both transaminase levels and IgG levels [9].
Autoantibodies
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A demonstration of autoantibodies is a key feature of making the diagnosis of autoimmune hepatitis. Nuclear antibodies were the first antibodies described in autoimmune hepatitis, and these are directed against a variety of nuclear antigens, most of them not defined on a molecular level. Up to 25% of patients demonstrate antibodies against double-stranded DNA, and indeed anti-dsDNA antibodies are highly specific for one of two diagnoses: systemic lupus erythematodes or autoimmune hepatitis. In the context of active hepatitis, demonstration of anti-
dsDNA antibodies is thus almost diagnostic for autoimmune hepatitis. Both homogeneous and speckled staining patterns of the nuclei can be observed on immunofluorescence testing for antinuclear antibodies. As discussed in detail elsewhere in this book, standard autoantibodies testing must be performed by immunofluorescence using both rodent tissues as well as Hep-2 cell lines, in order to have sufficient sensitivity and specificity [10]. While low titers of ANA can be nonspecific, high titers of ANA, particularly the presence of both ANA and SMA, are highly suspicious of autoimmune hepatitis. Antibodies against smooth muscle antigens (antiSMA) can be found with a similar frequency as antinuclear antibodies in autoimmune hepatitis. About 3 quarters of all patients have at least 1 of these 2 autoantibodies, and about half of the patients have both ANA and SMA antibodies. SMA antibodies in autoimmune hepatitis are often primarily directed against the F-actin component of the smooth muscles, and therefore, specific immunoserology can be improved by testing for F-actin [11, 12]. Like ANA, SMA antibodies are not specific for autoimmune hepatitis, can be found in a variety of other immune-mediated and infectious diseases may be present in low titers even in healthy individuals. Like in ANA, the level of SMA antibody titers as well as the coexistence of other autoantibodies is suggestive of the diagnosis autoimmune hepatitis. Antibodies against a liver kidney microsome antigen were described to be a characteristic feature of a small subgroup of patients of autoimmune hepatitis, which have since been named Type II autoimmune hepatitis. LKMantibodies are directed against the specific iso-enzyme of cytochrome P450, CYP450–2D6, and therefore highly specific immunoassays such as ELISA are available to test for these autoantibodies. LKM-positive autoimmune hepatitis is more common in childhood, where it can present as a very aggressive disease, while in adults LKM-positive autoimmune hepatitis appears to be very similar to type I autoimmune hepatitis. Even though LKM-autoantibodies are rare, testing for LKM is essential, as more than half of the patients with LKM-autoantibodies are negative for ANA, SMA and SLA/LP autoantibodies. Antibodies to soluble liver antigen and antibodies to a liver pancreas antigen were described separately >30 years ago, and were described to be highly specific for autoimmune hepatitis. Identification of the exact autoantigen of these autoantibodies as an enzyme involved in selenocysteine-tRNA showed that these were indeed 1 and the same autoantibody system, and therefore named anti-
Raised IgG/Hypergammaglobulinemia
Probable or possible AIH
1 mg/kg prednisolone Response (= AIH likely)
Non-response
Taper steroids
Consider alternative diagnoses
Relapse
Remission
Definite AIH
Withdraw steroids and observe closely >1 year
No relapse
Fig. 1. Management algorithm for patients
AIH unlikely
with suspected autoimmune hepatitis [2].
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Dig Dis 2015;33(suppl 2):47–52 DOI: 10.1159/000440709
included in the diagnostic score. ANCA on the other hand is so non-specific with positivity also demonstrated in cholestatic liver diseases, inflammatory bowel diseases and other immune-mediated diseases, that inclusion in a diagnostic score was not considered helpful.
Absence of Viral Hepatitis
Generally demonstration of viral hepatitis is considered diagnostic and excludes a diagnosis of autoimmune hepatitis. However, in view of a prevalence of viral hepatitis B and C of up to 10% in Southeast Asia and Africa, and in some regions up to 40%, up to 10% of these regions may have both viral hepatitis and autoimmune hepatitis. However, in a patient with viral markers, all other criteria have to very clearly hint towards a diagnosis of autoimmune hepatitis in order to score positive on the simplified score. Viral hepatitis can induce autoantibodies and can lead to an elevation of gammaglobulins, especially in the presence of advanced fibrosis and cirrhosis. On the other hand, demonstration of elevated gammaglobulins, autoantibodies and inflammatory hepatitis on histology and the absence of viral hepatitis are highly suggestive of autoimmune hepatitis, and therefore the absence of viral Lohse
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SLA/LP-autoantibodies [13, 14]. The molecular identification of the target antigen has allowed the development of highly specific and reliable immunoassays [15]. Two features are important about SLA/LP-autoantibodies: First, they usually do not show up on standard immunofluorescence, because of the concentration of target antigen in the cytosol is so low and so diluted that specific staining is usually not visible. Second, SLA/LP-autoantibodies are the only antibodies with diagnostic specificity for autoimmune hepatitis, as they generally do not occur in any other diseases. Therefore, demonstration of SLA/ LP-autoantibodies in reliable immunoassays can almost be considered diagnostic for autoimmune hepatitis. Nonetheless, there may be very few exceptions, or there may be technical problems with false positive results, and therefore even in SLA/LP-positive patients a histological demonstration of hepatitis to prove autoimmune hepatitis is generally advised. The diagnostic specificity probably also depends on the titer, which can be measured reliably in immunoassays. Other autoantibodies, such as LC1 or LKM3 as well as ANCA may also be of diagnostic significance in autoimmune hepatitis [10]. However, LC1 and LKM3 autoantibodies are so uncommon, that they could not be evaluated for their diagnostic value and therefore could not be
Histology
The value of liver biopsy in making the diagnosis of autoimmune hepatitis is discussed in detail in the chapter by Professor Dina Tiniakos. It only should be stressed here that the simplified diagnostic score was developed on the assumption that every patient receives a liver biopsy [6]. Especially, in the increasing number of patients with NASH, liver biopsy is essential to either exclude NASH or recognize comorbidity of NASH and autoimmune hepatitis. In NASH-cirrhosis, hypergammaglobulinemia and significant levels of autoantibodies may also occur, and as these patients do not have markers of viral hepatitis, they may have a false positive score unless liver biopsy is assessed carefully. It may be necessary to have the liver biopsy assessed by an expert liver pathologist in order to recognise the characteristic features of autoimmune hepatitis, namely emperipolesis, interface hepatitis, rosetting and plasma cell infiltration.
Limitation of Diagnostic Score in Acute Hepatitis and DILI
In patients presenting with acute hepatitis of unknown cause, liver histology as discussed in the chapter by Dina Tiniakos may not show the characteristic features of chronic autoimmune hepatitis, but may show centralobular necrosis with no or little periportal interface hepatitis. These histological features are normally considered diagnostic for drug-induced liver injury (DILI). However, several reports have shown that acute autoimmune hepatitis may show exactly the same histological picture as immune mediated DILI [16]. In addition, patients with acute autoimmune hepatitis may not (yet) have significant levels of autoantibodies and IgG; these patients provide a particular diagnostic challenge. For these patients, the algorithm summarised in figure 1 should be applied Diagnostic Criteria for Autoimmune Hepatitis
[2]. Patients need to be submitted to a therapeutic trial of steroid monotherapy, which appears to be effective both in immunologic DILI and in autoimmune hepatitis [2]. Steroids should be quickly tapered upon treatment response. Patients with DILI will remain in complete remission, if they are no longer exposed to the offending drug. Patients with autoimmune hepatitis, however, will almost universally relapse upon reduction or withdrawal of steroids, and will thus demonstrate the diagnosis of autoimmune hepatitis. If in doubt, a follow-up biopsy will then demonstrate the characteristic features of autoimmune hepatitis. It is important to remember that relapse may be delayed, and therefore all patients, in whom the differential diagnosis of DILI versus autoimmune hepatitis has been considered, need regular follow-up for about 3 years with measurements of their liver enzymes and IgG levels about every 3 months in order to recognize a possibly delayed relapse of the inflammatory liver disease. In the absence of renewed exposure to the same drug, the diagnosis of autoimmune hepatitis can be considered true.
Overlap with Cholestatic Liver Diseases
Both primary sclerosing cholangitis and primary biliary cirrhosis may co-occur with autoimmune hepatitis [17]. These patients may either have aggressive forms of PSC or PBC, or have genuine coexistence of 2 autoimmune liver diseases. While in the 1990 revised criteria for autoimmune hepatitis, cholestatic features excluded the diagnosis of autoimmune hepatitis, the simplified score includes these patients. This difference was by design. Patients with features of autoimmune hepatitis thoroughly need immunosuppression, and the simplified diagnostic score aims at identifying the required immunosuppression. However, the pathogenesis of secondary autoimmune hepatitis in PSC and PBC may be different from genuine autoimmune hepatitis, and therefore, in scientific study it is important to distinguish between typical autoimmune hepatitis and autoimmune hepatitis associated with 1 of these 2 cholestatic liver diseases. Like in the differentiation from DILI, differentiating aggressive PSC or aggressive PBC from genuine autoimmune hepatitis can often only be done in due course by closely observing treatment response in the long run.
Disclosure Statement Nothing to disclose.
Dig Dis 2015;33(suppl 2):47–52 DOI: 10.1159/000440709
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hepatitis is included in the simplified score. In patients presenting with acute disease, other forms of viral hepatitis also need to be assessed such as hepatitis A, hepatitis E, EBV, CMV and in selected cases, HSV, adenovirus and pavovirus B19 have to be assessed. On the other hand, it must be remembered that patients with marked hypergammaglobulinemia may score false positive on viral serology. False positive results, however, will usually be limited to IgG testing and not to IgM testing and thus acute viral hepatitis can usually be excluded from serology.
References
52
7 Kunkel HG, Ahrens EJ Jr, Eigenmenger WJ, Bongiovanni AM, Slater RJ: Extreme hypergammaglobulinemia in young women with liver disease of unknown etiology (abstract). J Clin Invest 1951;30:654. 8 Cowling DC, Mackay IR, Taft LI: Lupoid hepatitis. Lancet 1956;271:1323–1326. 9 Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, et al: Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193–2213. 10 Vergani D, Alvarez F, Bianchi FB, Cançado EL, Mackay IR, Manns MP, et al: Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the international autoimmune hepatitis group. J Hepatol 2004;41:677–683. 11 Frenzel C, Herkel J, Lüth S, Galle PR, Schramm C, Lohse AW: Evaluation of F-actin ELISA for the diagnosis of autoimmune hepatitis. Am J Gastroenterol 2006;101:2731–2736. 12 Granito A, Muratori L, Muratori P, Pappas G, Guidi M, Cassani F, et al: Antibodies to filamentous actin (F-actin) in type 1 autoimmune hepatitis. J Clin Pathol 2006; 59: 280– 284.
Dig Dis 2015;33(suppl 2):47–52 DOI: 10.1159/000440709
13 Wies I, Brunner S, Henninger J, Herkel J, Kanzler S, Meyer zum Büschenfelde KH, et al: Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis. Lancet 2000;355:1510–1515. 14 Palioura S, Sherrer RL, Steitz TA, Söll D, Simonovic M: The human SepSecS-tRNASec complex reveals the mechanism of selenocysteine formation. Science 2009;325:321–325. 15 Baeres M, Herkel J, Czaja AJ, Wies I, Kanzler S, Cancado EL, et al: Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics. Gut 2002; 51:259–264. 16 Manns MP, Lohse AW, Vergani D: Autoimmune hepatitis – update 2015. J Hepatol 2015; 62(1 suppl):S100–S111. 17 Chazouillères O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R: Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 1998;28:296–301.
Lohse
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1 Kanzler S, Löhr H, Gerken G, Galle PR, Lohse AW: Long-term management and prognosis of autoimmune hepatitis (AIH): a single center experience. Z Gastroenterol 2001; 39: 339– 341, 344–348. 2 Lohse AW, Mieli-Vergani G: Autoimmune Hepatitis. J Hepatol 2011;55:171–182. 3 Wiegard C, Schramm C, Lohse AW: Scoring systems for the diagnosis of autoimmune hepatitis: past, present, and future. Semin Liver Dis 2009;29:254–261. 4 Johnson PJ, McFarlane IG: Meeting report: international autoimmune hepatitis group. Hepatology 1993;18:998–1005. 5 Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al: International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929–938. 6 Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, et al: Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169–176.
Diagnostic Criteria for Autoimmune Hepatitis: Scores and More Ansgar W. Lohse I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
Abstract The diagnosis of autoimmune hepatitis is a clinical diagnosis that combines the patient’s history, clinical examination, laboratory and serological markers and the results of a liver biopsy. As the clinical spectrum of autoimmune hepatitis is very wide, making the diagnosis can sometimes be difficult, especially in non-expert hands. Diagnostic scores can help in making the diagnosis, and the simplified diagnostic score of the International Autoimmune Hepatitis Group has a sensitivity and specificity of around 90% in the different populations that have been studied. Therefore, it can be very helpful in everyday use, but nonetheless for some patients the score is not good enough. Limitations are patients with very acute presentations as well as atypical cases. In such cases, a trial of monotherapy with steroids and quick tapering of the steroids is recommended. If the disease responds well to treatment, but recurs after tapering the steroids, the diagnosis of autoimmune hepatitis is confirmed. In addition to its clinical use, diagnostic scores can also be helpful in defining the unified criteria in order to make scientific studies compa© 2015 S. Karger AG, Basel rable.
© 2015 S. Karger AG, Basel 0257–2753/15/0338–0047$39.50/0 E-Mail [email protected] www.karger.com/ddi
Autoimmune hepatitis is a disease with a fairly poor prognosis if undiagnosed and untreated, but with a very good and mostly excellent prognosis if diagnosed in time and treated properly [1, 2]. Therefore, making a reliable diagnosis of autoimmune hepatitis is the essential prerequisite for good medical care of affected patients. However, diagnosing autoimmune hepatitis can be quite challenging. The challenges are multiple. Most importantly, the disease is extremely heterogeneous with a clinical picture covering the whole range of asymptomatic, very mild disease, often with periods of spontaneous remission, up to very acute and even fulminant hepatitis. Similarly, the age range at clinical presentation is extremely wide. Occasionally, the disease can manifest in the first 2 years of life, sometimes very acutely, while other patients only present in the 8th or even in the 9th decade. In addition, the disease may for a long time run a totally subclinical course and a fair proportion of patients will only present at the stage of advanced fibrosis or even decompensated cirrhosis and have never previously been found to have liver disease. In view of the heterogeneity of the disease, and in the absence of a simple universal laboratory test making or excluding the diagnosis of autoimmune hepatitis, it essentially remains a clinical diagnosis that needs to take into account the personal history of the patient, clinical Prof. Dr. med. Ansgar W. Lohse I. Medizinische Klinik und Poliklinik Universitätsklinikum Hamburg-Eppendorf Martinistrasse 52, DE–20246 Hamburg (Germany) E-Mail alohse @ uke.de
Downloaded by: Gazi Üniversitesi 198.143.58.1 - 1/21/2016 6:59:58 PM
Key Words Simplified diagnostic criteria · Autoantibodies · IgG · International Autoimmune Hepatitis Group
Table 1. Simplified diagnostic criteria for autoimmune hepatitis of the International Autoimmune Hepatitis
Group [6] Feature/parameter
Discriminator
Score
ANA or SMA+
≥1:40
+1*
ANA or SMA+
≥1:80
+2*
or LKM+
≥1:40
+2*
or SLA/LP+
Any titre
+2*
IgG or γ-globulins level
>Upper limit of normal >1.1 × upper limit
+1 +2
Liver histology (evidence of hepatitis is a necessary condition)
Compatible with AIH Typical of AIH Atypical
+1 +2 0
Absence of viral hepatitis
No Yes
0 +2
Definite autoimmune hepatitis: ≥7; probable autoimmune hepatitis: ≥6. * Addition of points achieved for all autoantibodies (maximum, 2 points). Typical liver histology for autoimmune hepatitis = each of the following features had to be present namely, interface hepatitis, lymphocytic/lymphoplasmocytic infiltrates in portal tracts and extending into the lobule, emperipolesis (active penetration by 1 cell into and through a larger cell), and hepatic rosette formation. Compatible liver histology for autoimmune hepatitis = chronic hepatitis with lymphocytic infiltration without all the features considered typical. Atypical = showing signs of another diagnosis, like steatohepatitis.
48
Dig Dis 2015;33(suppl 2):47–52 DOI: 10.1159/000440709
duction or discontinuation of immunosuppressive therapy. These 2 criteria are very reliable criteria, as both features are characteristic of autoimmune hepatitis. However, these criteria are not in any way helpful to the clinician treating a patient with unknown liver disease, in whom the diagnosis of autoimmune hepatitis has to be considered among other alternative diagnoses, and for whom decision starting immunosuppression has to be made. In order to provide a diagnostic score that is simple to use and that will help the clinician in deciding, if a patient should be initially managed as autoimmune hepatitis, the International Autoimmune Hepatitis Group in 2008 presented a simplified score for the diagnosis of autoimmune hepatitis that is based on 4 criteria [6] (table 1): raised IgG-gammaglobulins, autoantibodies, absence of viral hepatitis and a liver biopsy demonstrating inflammatory hepatitis. A number of studies have since shown that these simple criteria have a very good sensitivity and specificity, both around 90%, in the wide variety of populations tested. These simplified criteria, like all diagnostic scores, have some limitations discussed below, but provide sufficient guidance for the vast majority of clinical situations. Lohse
Downloaded by: Gazi Üniversitesi 198.143.58.1 - 1/21/2016 6:59:58 PM
findings, laboratory results, serological testing and liver biopsy findings. Occasionally, only close observation of the response to therapy or observation of a relapse of hepatitis following a therapeutic trial will make the final diagnosis. In this complex situation, diagnostic algorithms and diagnostic scores can help in 2 ways [3]. First of all, diagnostic scores may help the general gastroenterologist and hepatologist in making the primary clinical diagnosis, and in weighing the different laboratory, serological and histological results. In addition, diagnostic scores are important in stratifying patients and in making clinical scientific studies from different centres comparable. The first attempts to provide a score of generally agreed diagnostic criteria dates back to 1992, when the International Autoimmune Hepatitis Group was founded at the meeting of the International Association for the Study of the Liver in Brighton in order to agree on a complex set of criteria [4]. This initial score helped enormously in focusing further work, and in 1999, a modified score of the International Autoimmune Hepatitis Group was published; this has been the basis for a majority of scientific studies on autoimmune hepatitis [5]. Key features of this score, however, are the response to steroid therapy, and the possible relapse of disease upon dose re-
Diagnostic Criteria for Autoimmune Hepatitis
Dig Dis 2015;33(suppl 2):47–52 DOI: 10.1159/000440709
Hypergammaglobulinemia was a characteristic feature in the very first descriptions of patients with autoimmune hepatitis, and very marked hypergammaglobulinemia can sometimes be observed in autoimmune hepatitis [7, 8]. In fact, most case series describe raised gammaglobulins in about 90% of all patients presenting with autoimmune hepatitis. A characteristic feature of autoimmune hepatitis is the usually very highly selective elevation of IgG and the presence of normal levels of IgA and IgM. Only in advanced cirrhosis, IgA and IgM are also elevated, but IgG elevation is almost always predominant. However, there are only a very few studies that have looked at the exact degree of elevation of IgG and the ratio of IgG to IgA and IgM. In addition, the normal range of IgG is very wide due to the genetic variability of IgG levels among healthy humans. It appears that the few patients with IgG levels within the normal range and autoimmune hepatitis have values within the upper range of normal, and their IgG levels fall upon immunosuppressive therapy. Thus, these patients have a relative increase of IgG in active autoimmune hepatitis that is not immediately apparent at diagnosis. Therefore, attention should be paid to the exact levels of IgG, especially in those patients in whom autoimmune hepatitis is suspected but the IgG levels appear to be normal. The degree of elevation of IgG can be extremely high with levels of up to 40 g/l or even higher. There is a debate as to what extent the degree of IgG elevation is a mark of histological disease activity. There is at least sufficient correlation to argue that normalisation of IgG should be as much a therapeutic aim as normalisation of transaminase levels. In fact, international societies have defined remission in autoimmune hepatitis as complete normalisation of both transaminase levels and IgG levels [9].
Autoantibodies
49
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A demonstration of autoantibodies is a key feature of making the diagnosis of autoimmune hepatitis. Nuclear antibodies were the first antibodies described in autoimmune hepatitis, and these are directed against a variety of nuclear antigens, most of them not defined on a molecular level. Up to 25% of patients demonstrate antibodies against double-stranded DNA, and indeed anti-dsDNA antibodies are highly specific for one of two diagnoses: systemic lupus erythematodes or autoimmune hepatitis. In the context of active hepatitis, demonstration of anti-
dsDNA antibodies is thus almost diagnostic for autoimmune hepatitis. Both homogeneous and speckled staining patterns of the nuclei can be observed on immunofluorescence testing for antinuclear antibodies. As discussed in detail elsewhere in this book, standard autoantibodies testing must be performed by immunofluorescence using both rodent tissues as well as Hep-2 cell lines, in order to have sufficient sensitivity and specificity [10]. While low titers of ANA can be nonspecific, high titers of ANA, particularly the presence of both ANA and SMA, are highly suspicious of autoimmune hepatitis. Antibodies against smooth muscle antigens (antiSMA) can be found with a similar frequency as antinuclear antibodies in autoimmune hepatitis. About 3 quarters of all patients have at least 1 of these 2 autoantibodies, and about half of the patients have both ANA and SMA antibodies. SMA antibodies in autoimmune hepatitis are often primarily directed against the F-actin component of the smooth muscles, and therefore, specific immunoserology can be improved by testing for F-actin [11, 12]. Like ANA, SMA antibodies are not specific for autoimmune hepatitis, can be found in a variety of other immune-mediated and infectious diseases may be present in low titers even in healthy individuals. Like in ANA, the level of SMA antibody titers as well as the coexistence of other autoantibodies is suggestive of the diagnosis autoimmune hepatitis. Antibodies against a liver kidney microsome antigen were described to be a characteristic feature of a small subgroup of patients of autoimmune hepatitis, which have since been named Type II autoimmune hepatitis. LKMantibodies are directed against the specific iso-enzyme of cytochrome P450, CYP450–2D6, and therefore highly specific immunoassays such as ELISA are available to test for these autoantibodies. LKM-positive autoimmune hepatitis is more common in childhood, where it can present as a very aggressive disease, while in adults LKM-positive autoimmune hepatitis appears to be very similar to type I autoimmune hepatitis. Even though LKM-autoantibodies are rare, testing for LKM is essential, as more than half of the patients with LKM-autoantibodies are negative for ANA, SMA and SLA/LP autoantibodies. Antibodies to soluble liver antigen and antibodies to a liver pancreas antigen were described separately >30 years ago, and were described to be highly specific for autoimmune hepatitis. Identification of the exact autoantigen of these autoantibodies as an enzyme involved in selenocysteine-tRNA showed that these were indeed 1 and the same autoantibody system, and therefore named anti-
Raised IgG/Hypergammaglobulinemia
Probable or possible AIH
1 mg/kg prednisolone Response (= AIH likely)
Non-response
Taper steroids
Consider alternative diagnoses
Relapse
Remission
Definite AIH
Withdraw steroids and observe closely >1 year
No relapse
Fig. 1. Management algorithm for patients
AIH unlikely
with suspected autoimmune hepatitis [2].
50
Dig Dis 2015;33(suppl 2):47–52 DOI: 10.1159/000440709
included in the diagnostic score. ANCA on the other hand is so non-specific with positivity also demonstrated in cholestatic liver diseases, inflammatory bowel diseases and other immune-mediated diseases, that inclusion in a diagnostic score was not considered helpful.
Absence of Viral Hepatitis
Generally demonstration of viral hepatitis is considered diagnostic and excludes a diagnosis of autoimmune hepatitis. However, in view of a prevalence of viral hepatitis B and C of up to 10% in Southeast Asia and Africa, and in some regions up to 40%, up to 10% of these regions may have both viral hepatitis and autoimmune hepatitis. However, in a patient with viral markers, all other criteria have to very clearly hint towards a diagnosis of autoimmune hepatitis in order to score positive on the simplified score. Viral hepatitis can induce autoantibodies and can lead to an elevation of gammaglobulins, especially in the presence of advanced fibrosis and cirrhosis. On the other hand, demonstration of elevated gammaglobulins, autoantibodies and inflammatory hepatitis on histology and the absence of viral hepatitis are highly suggestive of autoimmune hepatitis, and therefore the absence of viral Lohse
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SLA/LP-autoantibodies [13, 14]. The molecular identification of the target antigen has allowed the development of highly specific and reliable immunoassays [15]. Two features are important about SLA/LP-autoantibodies: First, they usually do not show up on standard immunofluorescence, because of the concentration of target antigen in the cytosol is so low and so diluted that specific staining is usually not visible. Second, SLA/LP-autoantibodies are the only antibodies with diagnostic specificity for autoimmune hepatitis, as they generally do not occur in any other diseases. Therefore, demonstration of SLA/ LP-autoantibodies in reliable immunoassays can almost be considered diagnostic for autoimmune hepatitis. Nonetheless, there may be very few exceptions, or there may be technical problems with false positive results, and therefore even in SLA/LP-positive patients a histological demonstration of hepatitis to prove autoimmune hepatitis is generally advised. The diagnostic specificity probably also depends on the titer, which can be measured reliably in immunoassays. Other autoantibodies, such as LC1 or LKM3 as well as ANCA may also be of diagnostic significance in autoimmune hepatitis [10]. However, LC1 and LKM3 autoantibodies are so uncommon, that they could not be evaluated for their diagnostic value and therefore could not be
Histology
The value of liver biopsy in making the diagnosis of autoimmune hepatitis is discussed in detail in the chapter by Professor Dina Tiniakos. It only should be stressed here that the simplified diagnostic score was developed on the assumption that every patient receives a liver biopsy [6]. Especially, in the increasing number of patients with NASH, liver biopsy is essential to either exclude NASH or recognize comorbidity of NASH and autoimmune hepatitis. In NASH-cirrhosis, hypergammaglobulinemia and significant levels of autoantibodies may also occur, and as these patients do not have markers of viral hepatitis, they may have a false positive score unless liver biopsy is assessed carefully. It may be necessary to have the liver biopsy assessed by an expert liver pathologist in order to recognise the characteristic features of autoimmune hepatitis, namely emperipolesis, interface hepatitis, rosetting and plasma cell infiltration.
Limitation of Diagnostic Score in Acute Hepatitis and DILI
In patients presenting with acute hepatitis of unknown cause, liver histology as discussed in the chapter by Dina Tiniakos may not show the characteristic features of chronic autoimmune hepatitis, but may show centralobular necrosis with no or little periportal interface hepatitis. These histological features are normally considered diagnostic for drug-induced liver injury (DILI). However, several reports have shown that acute autoimmune hepatitis may show exactly the same histological picture as immune mediated DILI [16]. In addition, patients with acute autoimmune hepatitis may not (yet) have significant levels of autoantibodies and IgG; these patients provide a particular diagnostic challenge. For these patients, the algorithm summarised in figure 1 should be applied Diagnostic Criteria for Autoimmune Hepatitis
[2]. Patients need to be submitted to a therapeutic trial of steroid monotherapy, which appears to be effective both in immunologic DILI and in autoimmune hepatitis [2]. Steroids should be quickly tapered upon treatment response. Patients with DILI will remain in complete remission, if they are no longer exposed to the offending drug. Patients with autoimmune hepatitis, however, will almost universally relapse upon reduction or withdrawal of steroids, and will thus demonstrate the diagnosis of autoimmune hepatitis. If in doubt, a follow-up biopsy will then demonstrate the characteristic features of autoimmune hepatitis. It is important to remember that relapse may be delayed, and therefore all patients, in whom the differential diagnosis of DILI versus autoimmune hepatitis has been considered, need regular follow-up for about 3 years with measurements of their liver enzymes and IgG levels about every 3 months in order to recognize a possibly delayed relapse of the inflammatory liver disease. In the absence of renewed exposure to the same drug, the diagnosis of autoimmune hepatitis can be considered true.
Overlap with Cholestatic Liver Diseases
Both primary sclerosing cholangitis and primary biliary cirrhosis may co-occur with autoimmune hepatitis [17]. These patients may either have aggressive forms of PSC or PBC, or have genuine coexistence of 2 autoimmune liver diseases. While in the 1990 revised criteria for autoimmune hepatitis, cholestatic features excluded the diagnosis of autoimmune hepatitis, the simplified score includes these patients. This difference was by design. Patients with features of autoimmune hepatitis thoroughly need immunosuppression, and the simplified diagnostic score aims at identifying the required immunosuppression. However, the pathogenesis of secondary autoimmune hepatitis in PSC and PBC may be different from genuine autoimmune hepatitis, and therefore, in scientific study it is important to distinguish between typical autoimmune hepatitis and autoimmune hepatitis associated with 1 of these 2 cholestatic liver diseases. Like in the differentiation from DILI, differentiating aggressive PSC or aggressive PBC from genuine autoimmune hepatitis can often only be done in due course by closely observing treatment response in the long run.
Disclosure Statement Nothing to disclose.
Dig Dis 2015;33(suppl 2):47–52 DOI: 10.1159/000440709
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hepatitis is included in the simplified score. In patients presenting with acute disease, other forms of viral hepatitis also need to be assessed such as hepatitis A, hepatitis E, EBV, CMV and in selected cases, HSV, adenovirus and pavovirus B19 have to be assessed. On the other hand, it must be remembered that patients with marked hypergammaglobulinemia may score false positive on viral serology. False positive results, however, will usually be limited to IgG testing and not to IgM testing and thus acute viral hepatitis can usually be excluded from serology.
References
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