AUTOANTIBODIES IN PAEDIATRIC LIVER DISEASE
Diego Vergani *
Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London. *
The juvenile form of autoimmune hepatitis (AIH) typically affects children and young adults. AIH is subdivided on the basis of marker autoantibodies into two serologically and clinically distinct forms. The diagnosis of either form is made only after fulfilling several positive and negative criteria. Classically autoantibodies are detected by indirect immunofluorescence using fresh rat liver and kidney and rat or human stomach as a composite block substrate. The reason for using different tissues derives from the fact that laboratory diagnosis is achieved only with the analysis of three tissues. Type 1 AIH Hepatitis is diagnosed if antinuclear (ANA) and/or anti-smooth muscle antibody (SMA) are present. ANA of AIH does not have specific features, though the homogeneous immunofluorescent pattern prevails. SMA is said to have the 'actin-like' appearance, but whether its target is actin is hotly debated. In contrast to type 1 AIH, type 2 AIH is characterized by a powerful identifier, namely liver kidney microsomal type 1 (LKM 1) antibody. Sadly and with severe clinical consequences, this antibody is often neglected and misdiagnosed. Due to the pattern similarity with AMA on rodent kidney, LKM 1 has been and is frequently incorrectly diagnosed as antimitochondrial antibody (AMA). The consequences of this will be discussed. A clinically significant level of autoantibody positivity in adults starts at the arbitrary dilution of 1/40. In contrast, for healthy children up to the age of 18 years, any level of autoantibody reactivity in serum is infrequent, so that dilutions of 1/20 for ANA and SMA and even 1/10 for anti-LKM 1 could be clinically relevant. Hence the laboratory should report any level of positivity from 1/10, and allow the clinician to interpret the result within the clinical context and the age of the patient. The basic technique of choice at present for the routine testing of autoantibodies relevant to AIH is indirect immunofluorescence on a rodent multi-organ substrate panel that should include kidney, liver and stomach. This multi-tissue combination allows the detection of several specificities relevant to AIH, including ANA, SMA, anti-LKM 1 as well as anti-LC1 and anti-mitochondrial antibody (AMA), this latter characteristic of primary biliary cirrhosis. Fortunately, molecular targets are being identified for the various autoantibodies enabling their detection through objective techniques. Amongst the antibodies classically detected by immunofluorescence, AMA targets the E2 component of pyruvate dehydrogenase complex while LKM 1 recognizes cytochrome P4502D6. Two other autoantibodies are specific for AIH, namely liver cytosol type 1 (LC1), and anti-soluble liver antigen ( SLA ). LC1 is difficult to detect by immunofluorescence, often occurring simultaneously with and obscured by - LKM 1: its molecular target has been identified as formiminotransferase cyclodeaminase (FTCD); anti-SLA is not detectable by immunofluorescence, targets UGA tRNA suppressor associated antigenic protein [t-RNP (Ser) Sec] and can predict disease severity.
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