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Overcoming a “Probable” Diagnosis in Antimitochondrial Antibody Negative Primary Biliary Cirrhosis: Study of 100 Sera and Review of the Literature

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Abstract

Serum anti-mitochondrial antibodies (AMA) are the serological hallmark of primary biliary cirrhosis (PBC), yet up to 15% of PBC sera are AMA negative at routine indirect immunofluorescence (IIF) while being referred to as “probable” cases. The diagnostic role of PBC-specific antinuclear antibodies (ANA) remains to be determined. We will report herein data on the accuracy of new laboratory tools for AMA and PBC-specific ANA in a large series of PBC sera that were AMA-negative at IIF. We will also provide a discussion of the history and current status of AMA detection methods. We included IIF AMA-negative PBC sera (n = 100) and sera from patients with other chronic liver diseases (n = 104) that had been independently tested for IIF AMA and ANA; sera were blindly tested with an ELISA PBC screening test including two ANA (gp210, sp100) and a triple (pMIT3) AMA recombinant antigens. Among IIF AMA-negative sera, 43/100 (43%) manifested reactivity using the PBC screening test. The same test was positive for 6/104 (5.8%) control sera. IIF AMA-negative/PBC screen-positive sera reacted against pMIT3 (11/43), gp210 (8/43), Sp100 (17/43), both pMIT3 and gp210 (1/43), or both pMIT3 and Sp100 (6/43). Concordance rates between the ANA pattern on HEp-2 cells and specific Sp100 and gp210 ELISA results in AMA-negative subjects were 92% for nuclear dots and Sp100 and 99% for nuclear rim and gp210. Our data confirm the hypothesis that a substantial part of IIF AMA-negative (formerly coined “probable”) PBC cases manifest disease-specific autoantibodies when tested using newly available tools and thus overcome the previously suggested diagnostic classification. As suggested by the recent literature, we are convinced that the proportion of AMA-negative PBC cases will be significantly minimized by the use of new laboratory methods and recombinant antigens.

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Authors and Affiliations

  1. Laboratorio di Patologia Clinica, Ospedale Civile, Tolmezzo, Italy

    Nicola Bizzaro & Fiorenza Pesente

  2. Dipartimento di Gastroenterologia, IRCCS Istituto Clinico Humanitas, Rozzano, Italy

    Giovanni Covini & Elena Bredi

  3. Gastroenterologia ed Epatologia, Presidio Sanitario Gradenigo, Torino, Italy

    Floriano Rosina

  4. Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, Policlinico Universitario Sant’Orsola-Malpighi, Bologna, Italy

    Paolo Muratori

  5. Allergologia e Immunopatologia, Azienda Ospedale-Università, Udine, Italy

    Elio Tonutti

  6. Immunologia e Virologia, Azienda Ospedaliera, Pordenone, Italy

    Danilo Villalta

  7. Laboratorio Analisi, Ospedali Riuniti, Bergamo, Italy

    Maria Grazia Alessio

  8. Patologia Clinica, Policlinico Universitario, Bari, Italy

    Marilina Tampoia

  9. Laboratorio Analisi, Ospedale Civile, Cittadella, Italy

    Antonio Antico

  10. Laboratorio Centrale, Ospedale Civile, Merano, Italy

    Stefan Platzgummer

  11. Dipartimento di Medicina Interna, Scienze Endocrino-Metaboliche e Biochimica, Università degli Studi, Siena, Italy

    Brunetta Porcelli & Lucia Terzuoli

  12. Laboratorio Analisi, Azienda Ospedaliera G. Brotzu, Cagliari, Italy

    Marco Liguori

  13. Laboratorio di Patologia Clinica, Ospedale S. Chiara, Trento, Italy

    Danila Bassetti

  14. Laboratorio Analisi, Ospedale Buccheri La Ferla, Palermo, Italy

    Ignazio Brusca

  15. Unità di Gastroenterologia ed Epatologia, Università degli Studi, Palermo, Italy

    Piero L. Almasio & Giuseppe Tarantino

  16. Laboratorio di Analisi Ematochimiche, Azienda Ospedaliera, Parma, Italy

    Chiara Bonaguri

  17. Divisione di Medicina Interna, Ospedale Civile, Tolmezzo, Italy

    Paolo Agostinis

  18. Laboratorio di Patologia Clinica, Ospedale Civile, Latisana, Italy

    Renato Tozzoli

  19. Departimento di Medicina, IRCCS Istituto Clinico Humanitas, Rozzano, Italy

    Pietro Invernizzi & Carlo Selmi

  20. Dipartimento di Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy

    Carlo Selmi

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  1. Nicola Bizzaro
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  2. Giovanni Covini
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  3. Floriano Rosina
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  4. Paolo Muratori
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  6. Danilo Villalta
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  7. Fiorenza Pesente
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  8. Maria Grazia Alessio
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  9. Marilina Tampoia
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  10. Antonio Antico
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  11. Stefan Platzgummer
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  12. Brunetta Porcelli
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  13. Lucia Terzuoli
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  14. Marco Liguori
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  15. Danila Bassetti
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  17. Piero L. Almasio
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  19. Chiara Bonaguri
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  21. Elena Bredi
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  22. Renato Tozzoli
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  23. Pietro Invernizzi
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  24. Carlo Selmi
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Corresponding author

Correspondence to Nicola Bizzaro.

Additional information

Nicola Bizzaro, Elio Tonutti, Danilo Villalta, Maria Grazia Alessio, Marilina Tampoia, Antonio Antico, Stefan Platzgummer, Brunetta Porcelli, Lucia Terzuoli, Marco Liguori, Danila Bassetti, Ignazio Brusca, Chiara Bonaguri, and Renato Tozzoli: study group on autoimmune diseases of the Italian Society of Laboratory Medicine

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Bizzaro, N., Covini, G., Rosina, F. et al. Overcoming a “Probable” Diagnosis in Antimitochondrial Antibody Negative Primary Biliary Cirrhosis: Study of 100 Sera and Review of the Literature. Clinic Rev Allerg Immunol 42, 288–297 (2012). https://doi.org/10.1007/s12016-010-8234-y

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