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Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group

Published:August 26, 2004DOI:https://doi.org/10.1016/j.jhep.2004.08.002
      The diagnosis of autoimmune hepatitis (AIH) has been advanced by the criteria developed by the International Autoimmune Hepatitis Group (IAIHG) [
      • Johnson P.J.
      • McFarlane I.G.
      Meeting report: International Autoimmune Hepatitis Group.
      ,
      • Alvarez F.
      • Berg P.A.
      • Bianchi F.B.
      • Bianchi L.
      • Burroughs A.K.
      • Cancado E.L.
      • et al.
      International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis.
      ]. 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 [
      • Johnson P.J.
      • McFarlane I.G.
      Meeting report: International Autoimmune Hepatitis Group.
      ,
      • Alvarez F.
      • Berg P.A.
      • Bianchi F.B.
      • Bianchi L.
      • Burroughs A.K.
      • Cancado E.L.
      • et al.
      International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis.
      ], 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 [
      • Gregorio G.V.
      • Portmann B.
      • Reid F.
      • Donaldson P.T.
      • Doherty D.G.
      • McCartney M.
      • et al.
      Autoimmune hepatitis in childhood: a 20-year experience.
      ,
      • Homberg J.C.
      • Abuaf N.
      • Bernard O.
      • Islam S.
      • Alvarez F.
      • Khalil S.H.
      • et al.
      Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of autoimmune hepatitis.
      ]. Also, consideration is needed of ‘overlap’ syndromes [
      • Taylor S.L.
      • Dean P.J.
      • Riely C.A.
      Primary autoimmune cholangitis. An alternative to antimitochondrial antibody-negative primary biliary cirrhosis.
      ,
      • Gregorio G.V.
      • Portmann B.
      • Karani J.
      • Harrison P.
      • Donaldson P.T.
      • Vergani D.
      • et al.
      Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
      ], 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 [
      • Pratt D.S.
      • Kaplan M.M.
      Evaluation of abnormal liver-enzyme results in asymptomatic patients.
      ]. 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 [
      • Bonifacio E.
      • Bingley P.J.
      • Shattock M.
      • Dean B.M.
      • Dunger D.
      • Gale E.A.
      • et al.
      Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes.
      ,
      • Lernmark A.
      • Molenaar J.L.
      • van Beers W.A.
      • Yamaguchi Y.
      • Nagataki S.
      • Ludvigsson J.
      • et al.
      The Fourth International Serum Exchange Workshop to standardize cytoplasmic islet cell antibodies. The immunology and diabetes workshops and participating laboratories.
      ,
      • Mire-Sluis A.R.
      • Das R.G.
      • Lernmark A.
      The development of a World Health Organisation international standard for islet cell antibodies: the aims and design of an international collaborative study.
      ]. 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.
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