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Guinea Pig Transglutaminase Immunolinked Assay Does Not Predict Coeliac Disease in Patients with Chronic Liver Disease

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Guinea Pig Transglutaminase Immunolinked Assay Does Not Predict Coeliac Disease in Patients with Chronic Liver Disease 506 Gut 2001;49:506–511 Guinea pig transglutaminase immunolinked assay does not predict coeliac disease in patients with Gut: first published as 10.1136/gut.49.4.506 on 1 October 2001. Downloaded from chronic liver disease A Carroccio, L Giannitrapani, M Soresi, T Not, G Iacono, C Di Rosa, E Panfili, A Notarbartolo, G Montalto Abstract patients with atrophy of the intestinal Background—It has been suggested that mucosa were positive for anti-tTG while serological screening for coeliac disease all others were negative, including those (CD) should be performed in patients false positive in the ELISA based on with chronic unexplained hypertransami- guinea pig tTG as the antigen. nasaemia. Conclusions—In patients with elevated Aims—To evaluate the specificity for CD transaminases and chronic liver disease diagnosis of serum IgA antitissue trans- there was a high frequency of false glutaminase (tTG) determination in con- positive anti-tTG results using the ELISA secutive patients with chronic based on tTG from guinea pig as the anti- hypertransaminasaemia using the most gen. Indeed, the presence of anti-tTG did widely utilised ELISA based on tTG from not correlate with the presence of EmA or guinea pig as the antigen. CD. These false positives depend on the Patients and methods—We studied 98 presence of hepatic proteins in the com- patients with chronic hypertransamina- mercial tTG obtained from guinea pig saemia, evaluated for the first time in a liver and disappear when human tTG is hepatology clinic. Serum anti-tTG and used as the antigen in the ELISA system. antiendomysial (EmA) assays were per- We suggest that the commonly used tTG formed. Patients positive for EmA and/or ELISA based on guinea pig antigen should anti-tTG were proposed for intestinal not be used as a screening tool for CD in biopsy. Finally, all sera were reassayed for patients with chronic liver disease. ( 2001; :506–511) anti-tTG using an ELISA based on human Gut 49 recombinant tTG as the antigen. Keywords: liver disease; coeliac disease; antitissue http://gut.bmj.com/ Results—A total of 94/98 hypertransami- transglutaminase antibodies; antiendomysial nasaemic patients were positive for hepa- antibodies; autoimmunity; intestinal histology titis virus markers, with 82/98 (83%) positive for anti-hepatitis C virus. Liver histology showed that most patients had Hepatic damage is a frequent finding in mild or moderate chronic hepatitis while patients with coeliac disease (CD) on a gluten severe fibrosis or overt liver cirrhosis was containing diet; in fact, hypertransaminasae- found in 20/98. CD screening showed that mia has been reported in 10–54% of patients at on September 29, 2021 by guest. Protected copyright. CD diagnosis.1–4 As a consequence, it has been Internal Medicine, 15/98 (16%) hypertransaminasaemic sub- University Hospital of jects had anti-tTG values in the same suggested that serological screening for CD Palermo, Palermo, should be performed in patients with chronic range as CD patients; however, IgA EmA 5 Italy were positive in only 2/98 (2%). Distal unexplained hypertransaminasaemia. In this A Carroccio respect, a previous study revealed that the duodenal biopsy, performed in nine pa- L Giannitrapani serum antiendomysial antibody (EmA) assay is tients, showed subtotal villous atrophy in M Soresi the optimum test for predicting CD in patients C Di Rosa the two EmA+/anti-tTG+ patients but was with chronic liver disease6 but this indirect A Notarbartolo normal in 7/7 EmA−/anti-tTG+ subjects. immunofluorescence test is not easy to apply in G Montalto The presence of anti-tTG+ values in large scale screening. However, tissue trans- I Pediatric Division, EmA− patients was unrelated to particu- glutaminase (tTG) has recently been identified “Di Cristina lar gastrointestinal symptoms, other asso- as the main (or sole) autoantigen recognised by Hospital”, Palermo, ciated diseases, severity of liver histology, EmA in CD patients7 and this has permitted Italy or distribution of viral hepatitis markers. G Iacono the use of an ELISA test, based on commercial There was a significantly higher frequency guinea pig tissue transglutaminase, to detect Pediatric Division, of positive serum autoantibodies (anti- the presence of anti-tTG autoantibodies in IRCCS Burlo nuclear, antimitochondrial, antismooth Garofolo, Trieste, Italy muscle, and anti-liver-kidney microsomal Abbreviations used in this paper: CD, coeliac T Not antibodies) in anti-tTG+/EmA− patients disease; EmA, antiendomysial antibody; tTG, tissue E Panfili than in the other subjects (9/13 v 10/83; transglutaminase; AST, aspartate aminotransferase; p<0.003). Also, a correlation was found ALT, alanine aminotransferase; HCV, hepatitis C virus; Correspondence to: ANA, antinuclear antibodies; AMA, antimitochondrial Dr A Carroccio, Via CoVaro between serum gamma globulin and anti- 25, 90124 Palermo, Italy. tTG values (p<0.01). When sera were antibodies; ASMA, antismooth muscle antibodies; [email protected] anti-LKM, anti-liver-kidney microsomal antibodies; tested with the ELISA based on human h-tTG, human recombinant tissue transglutaminase; Accepted for publication tTG as the antigen, no false positive PBS, phosphate buVered saline; IEL, intraepithelial 26 February 2001 results were observed: only the two EmA+ lymphocyte. www.gutjnl.com Anti-tTG autoantibodies in chronic liver diseases 507 serum, specific for the diagnosis of CD.7–11 tTG (h-tTG) as antigen, according to the Previous studies on the clinical utility of methods described below. anti-tTG determination have reported no or Control sera for evaluation of anti-tTG anti- Gut: first published as 10.1136/gut.49.4.506 on 1 October 2001. Downloaded from very rare false positive results for CD bodies were obtained from two diVerent diagnosis,7–11 and when positive results have groups: the first group included 20 EmA posi- been found in patients with normal intestinal tive coeliac patients on a gluten containing diet histology, the hypothesis of latent CD has been with total or subtotal intestinal villous atrophy, advanced.89However, as in the case of patients diagnosed according to the criteria of the with chronic liver disease (primary biliary European Society of Pediatric Gastroenterol- cirrhosis), the occurrence of false positive anti- ogy and Nutrition15; the second group of tTG antibody results has been found.12 control sera was obtained from 35 EmA nega- In the present study, we evaluated serum tive healthy subjects who were members of the anti-tTG and EmA in consecutive patients medical and laboratory personnel of our clinic. with chronic hypertransaminasaemia due to Subjects in these control groups were sex and various causes. age matched with the hypertransaminasaemic patients. Patients and methods All subjects gave informed consent and the The study included 98 consecutive subjects protocol was approved by the ethics committee (66 males; age range 18–64 years, median 36) of our hospital. with chronic hypertransaminasaemia (serum aspartate aminotransferase (AST) and alanine SERUM ANTIENDOMYSIAL ANTIBODY aminotransferase (ALT) levels >40 IU/l for DETERMINATION more than two months) who attended the out- As previously described,16 IgA class EmA patient clinic for liver disease at the Internal values were determined using a commercially Medicine Division of the University Hospital available indirect immunofluorescence tech- of Palermo for the first time between Septem- nique (Anti-endomisio; Eurospital Pharma, ber 1998 and May 1999. Patients previously Trieste, Italy). hospitalised in our division or examined in our outpatient clinics for liver or gastrointestinal SERUM ANTI-tTG ELISA DETERMINATION USING diseases were excluded; we also excluded sub- tTG FROM GUINEA PIG AS ANTIGEN jects with known CD and those who in the past This assay was performed by an inhouse had undergone complete serological evaluation ELISA in accordance with the method de- for CD diagnosis. scribed by Troncone and colleagues,9 adding In all patients, alcohol intake, use of drugs, 5 mmol/l CaCl2 to U bottomed microtitre and exposure to potential hepatic toxins were plates according to Sulkanen and colleagues.8 investigated. Laboratory investigations in- Values were expressed as a percentage of posi- cluded routine liver and kidney function tests. tive reference sera, obtained from untreated http://gut.bmj.com/ Immunoglobulin levels were evaluated to coeliac patients diagnosed according to the exclude IgA deficiency. Furthermore, all sub- criteria of the European Society of Pediatric jects underwent serological screening for viral Gastroenterology and Nutrition,15 showing in hepatitis B and C (HCV); anti-HCV immuno- all cases the presence of EmA. Anti-tTG values reactivity was confirmed by a third generation greater than the 95th percentile of the control immunoblot assay (RIBA 3; Chiron Corpora- group, including over 100 healthy controls tion, Emeryville, California, USA, and Ortho negative for serum EmA, were considered on September 29, 2021 by guest. Protected copyright. Diagnostic Systems). Sera were also tested for positive (8% of the reference serum). The hepatitis B surface antigen using a commercial intra-assay coefficient of variation for the IgA ELISA (Abbott Diagnostic, North Chicago, t-TG autoantibody ELISA was 8.7% (n=22), Illinois, USA). In all subjects the presence of and the inter-assay coeYcient of variation was antinuclear (ANA), antimitochondrial (AMA), 10.3% (n=18). antismooth muscle (ASMA), and anti-liver- kidney microsomal (anti-LKM) antibodies was HUMAN RECOMBINANT
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