Special articleLiver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group☆
Introduction
The diagnosis of autoimmune hepatitis (AIH) has been advanced by the criteria developed by the International Autoimmune Hepatitis Group (IAIHG) [1], [2]. A critical component of these criteria is detection by indirect immunofluorescence (IIF) of autoantibodies to components of the nuclei (anti-nuclear, ANA), smooth muscle (SMA) and liver kidney microsomes type 1 (anti-LKM-1). Detection not only assists in the diagnosis but also enables discrimination between two distinct subtypes of the disease [1], [2], AIH-1 and AIH-2. The differing serological reactivities for the two types (ANA, SMA vs anti-LKM-1) are virtually mutually exclusive; in the rare exceptions with ‘double positive’ serology, the clinical expression resembles AIH-2 [3], [4]. Also, consideration is needed of ‘overlap’ syndromes [5], [6], in particular types of cholangiopathy with autoimmune serological expressions. The relatively low prevalence of autoimmune liver diseases and the operator dependency of immunofluorescence, which still remains the mainstay of liver diagnostic autoimmune serology, explain the lack of agreement between laboratories on the frequency of particular reactivities in different liver diseases, particularly the less frequent specificities such as anti-LKM-1. Perceived inaccuracy of the methodology apparently led influential authors to suggest (misleadingly) that assessment of autoantibodies be disregarded in the diagnosis of AIH because of the low sensitivity and specificity of relevant serological tests [7]. This view also may have been motivated by assignment of autoantibody testing to commercial laboratories and use of kit-based semi-automated systems often with little contact between laboratory and clinician to assist in interpretation of results. Moreover, kit-based commercial assays may have been validated only ‘in-house’, such that the performance characteristics would not necessarily be available to the end-user. The problems that do exist between laboratory reporting and clinical interpretation of the serological results depend in part on insufficient standardisation of the basic tests, a problem common to autoimmune diagnostic serology in general, and in part on a degree of unfamiliarity of some clinicians with disease expressions of AIH. In regard to standardisation, a lead has been taken by the diabetes community in encouraging use of standardised methods by establishing ongoing serum exchange workshops since 1986 with calibrated reference sera containing autoantibodies to autoantigens relevant to type 1 diabetes mellitus [8], [9], [10]. Consequently, editors of major journals of diabetes now expect, in reports that cite reactivities of autoantibodies, that assays have been validated under international workshop conditions. Accordingly, the IAIHG established an internationally representative committee to define guidelines and develop procedures and reference standards for more reliable testing.
Although concerned with specific serological reactivity, emphasis is given to the importance for diagnosis and for monitoring treatment of a raised level of immunoglobulin (Ig) G measured by standard procedures, as noted in the IAIHG criteria.
Section snippets
Autoantibody testing by indirect immunofluorescence
The basic technique for the routine testing of autoantibodies relevant to AIH is IIF on a freshly removed rodent (usually rat) multi-organ substrate panel that should include kidney, liver and stomach. This allows for detection of ANA, SMA, anti-LKM-1 as well as anti-mitochondrial antibody (AMA), and also antibodies to liver cytosol type 1 (anti-LC1). For sera positive at the screening stage, further examination is required to assess the pattern of nuclear staining, by use of HEp2 cells, or to
Concluding remarks
Detection of autoantibodies plays a pivotal role in the diagnosis of liver disorders with an autoimmune pathogenesis and may be a useful tool in monitoring disease activity. However, both the laboratory personnel and the clinician need to become more familiar with the interpretation of the liver autoimmune serology to derive maximum benefit for the patient. Akin to what has already been achieved for other autoimmune diseases, especially type 1 diabetes, this can only be obtained through
Acknowledgements
We thank: Dimitrios Bogdanos, Ian McFarlane, Giorgina Mieli-Vergani, Yun Ma, Luigi Muratori and Senga Whittingham for helpful comments.
References (60)
- et al.
International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis
J Hepatol
(1999) - et al.
Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study
Hepatology
(2001) - et al.
Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes
Lancet
(1990) - et al.
Patterns of nuclear immunofluorescence and reactivities to recombinant nuclear antigens in autoimmune hepatitis
Gastroenterology
(1994) - et al.
Thermolabile and calcium-dependent serum factor interferes with polymerized actin, and impairs anti-actin antibody detection
J Autoimmun
(2001) - et al.
Frequency and significance of antibodies to liver/kidney microsome type 1 in adults with chronic active hepatitis
Gastroenterology
(1992) - et al.
Anti-mitochondrial autoantibodies
Clin Appl Immunol Rev
(2002) - et al.
Antibodies to soluble liver antigen, P450IID6, and mitochondrial complexes in chronic hepatitis
Gastroenterology
(1993) - et al.
Establishment of a novel radioligand assay using eukaryotically expressed cytochrome P4502D6 for the measurement of liver kidney microsomal type 1 antibody in patients with autoimmune hepatitis and hepatitis C virus infection
J Hepatol
(1997) - et al.
Anti-liver cytosolic antigen type 1 (LC1) antibodies in childhood autoimmune liver disease
Hepatology
(1995)
Detection of anti-liver cytosol antibody type 1 (anti-LC1) by immunodiffusion, counterimmunoelectrophoresis and immunoblotting: comparison of different techniques
J Immunol Methods
Formiminotransferase cyclodeaminase is an organ-specific autoantigen recognized by sera of patients with autoimmune hepatitis
Gastroenterology
Distinct epitopes on formiminotransferase cyclodeaminase induce autoimmune liver cytosol antibody type 1
Hepatology
Chronic active hepatitis associated with vitiligo, nail dystrophy, alopecia and a new variant of LKM antibodies
J Hepatol
Hepatic autoantigens in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
Gastroenterology
Cytochrome P450 2A6: a new hepatic autoantigen in patients with chronic hepatitis C virus infection
J Hepatol
Recognition of uridine diphosphate glucuronosyl transferases by LKM-3 antibodies in chronic hepatitis D
Lancet
Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis
Gastroenterology
Cytochromes P450 and uridine triphosphate-glucuronosyltransferases: model autoantigens to study drug-induced, virus-induced, and autoimmune liver disease
Hepatology
Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen
Lancet
Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis
Lancet
Soluble liver antigen: isolation of a 35-kd recombinant protein (SLA-p35) specifically recognizing sera from patients with autoimmune hepatitis
Hepatology
Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease
Hepatology
Antibodies to soluble liver antigen/liver pancreas and HLA risk factors for type 1 autoimmune hepatitis
Am J Gastroenterol
Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis
Lancet
High-titer antineutrophil cytoplasmic antibodies in type-1 autoimmune hepatitis
Gastroenterology
Atypical p-ANCA in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines
Gastroenterology
Meeting report: International Autoimmune Hepatitis Group
Hepatology
Autoimmune hepatitis in childhood: a 20-year experience
Hepatology
Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of autoimmune hepatitis
Hepatology
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The authors are the members of the committee for autoimmune serology of the International Autoimmune Hepatitis Group. DV is the chairman.