Recognizing autoimmune hepatitis: Scores help, but no more
Authors: Ansgar W. Lohse
Journal: Journal of Hepatology (2010)

Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patientsJournal of HepatologyVol. 54Issue 2PreviewIn 1999, the International Autoimmune Hepatitis Group (IAIHG) revised the diagnostic criteria for autoimmune hepatitis (AIH). It subsequently developed the simplified criteria in 2008 to enhance clinical applicability and practicability. In this study, we validated the simplified diagnostic criteria in Chinese patients with AIH or other chronic liver diseases in comparison with the revised original criteria. Full-Text PDF Untreated autoimmune hepatitis (AIH) has a poor prognosis, while patients with adequate immunosuppressive therapy have an excellent prognosis [1Krawitt E.L. Autoimmune hepatitis.N Engl J Med. 2006; 354: 54-66Crossref PubMed Scopus (741) Google Scholar, 2Kanzler S. Lohr H. Galle P.R. Meyer zum Büschenfelde K.H. Lohse A.W. Long-term management and prognosis of autoimmune hepatitis (AIH): a single center experience.Z Gastroenterol. 2001; 39: 344-348Google Scholar]. Unrecognized AIH means untreated AIH, and the most important step in the medical history of affected patients with AIH is to have the disease recognized and diagnosed in a timely fashion. Several clues may hint at the diagnosis such as female sex, associated autoimmune conditions, arthralgias, and absence of obvious other liver diseases [1Krawitt E.L. Autoimmune hepatitis.N Engl J Med. 2006; 354: 54-66Crossref PubMed Scopus (741) Google Scholar, 3Mieli-Vergani G. Vergani D. Autoimmune paediatric liver disease.World J Gastroenterol. 2008; 14: 3360-3367Crossref PubMed Scopus (91) Google Scholar]. However, the heterogeneity of the clinical picture of autoimmune hepatitis ranging from very mild disease to fulminant hepatic failure, the wide age range at presentation from early childhood to the eighties, the affection of both sexes, and the varied serology as well as the relative rarity of the disease make the diagnosis often difficult, especially in general practise and non-specialist units. Algorithms and scoring systems may help to alert the clinician and can assist in teaching. In addition, they may help to define clinical entities. Furthermore, in scientific terms they can help to assist in assuring comparability of patient groups reported from different study centres. In AIH, in which timely recognition of the diagnosis has such important consequences, the most important function of a scoring system lies in assisting in early diagnosis. Since the original scoring system [[4]Johnson P.J. McFarlane I.G. Meeting report: International Autoimmune Hepatitis Group.Hepatology. 1993; 18: 998-1005Crossref PubMed Scopus (1096) Google Scholar] and its 1999 revision [[5]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.J Hepatol. 1999; 31: 929-938Abstract Full Text Full Text PDF PubMed Scopus (2596) Google Scholar] were not designed for this purpose, and were cumbersome to use in everyday practise, the International Autoimmune Hepatitis Group in 2008 has suggested and tested a new, simplified scoring system [[6]Hennes E.M. Zeniya M. Czaja A.J. Parés A. Dalekos G.N. Krawitt E.L. et al.International Autoimmune Hepatitis Group: simplified criteria for the diagnosis of autoimmune hepatitis.Hepatology. 2008; 48: 169-176Crossref PubMed Scopus (1425) Google Scholar], whose clinical usefulness and scientific validity is now being assessed by many groups [7Czaja A.J. Performance parameters of the diagnostic scoring systems for autoimmune hepatitis.Hepatology. 2008; 48: 1540-1548Crossref PubMed Scopus (178) Google Scholar, 8Muratori P. Granito A. Pappas G. Muratori L. Validation of simplified diagnostic criteria for autoimmune hepatitis in Italian patients.Hepatology. 2009; 49: 1782-1783Crossref PubMed Scopus (56) Google Scholar, 9Yeoman A.D. Westbrook R.H. Al-Chalabi T. Carey I. Heaton N.D. Portmann B.C. et al.Diagnostic value and utility of the simplified International Autoimmune Hepatitis Group (IAIHG) criteria in acute and chronic liver disease.Hepatology. 2009; 50: 538-545Crossref PubMed Scopus (139) Google Scholar, 10Gatselis N.K. Zachou K. Papamichalis P. Koukoulis G.K. Gabeta S. Dalekos G.N. et al.Comparison of simplified score with the revised original score for the diagnosis of autoimmune hepatitis: a new or a complementary diagnostic score?.Dig Liver Dis. 2010; 42: 807-812Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar], including a large study from China in this edition of the Journal of Hepatology [[11]Qiu D. Wang Q. Wang H. Xie Q. Zang G. Jiang H. et al.Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients.J Hepatol. 2011; 54: 340-347Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. What is the value, and what are the risks of scoring systems in making the diagnosis of AIH? A number of studies both of the previous revised original scoring system from 1999 and of the new simplified scoring system have now been published, and most of them have very similar results; by and large the scoring systems serve quite well but of course they do have limitations [[12]Wiegard C. Schramm C. Lohse A.W. Scoring systems for the diagnosis of autoimmune hepatitis: past, present, and future.Semin Liver Dis. 2009; 29: 254-261Crossref PubMed Scopus (34) Google Scholar]. Many recent studies have very much focussed on a comparison between the previous and the new system. Almost all these studies, and this also applies to today's paper, have a methodological problem, that is very difficult to avoid but deserves attention; what is the gold standard? In almost all studies, patients were included on the basis of the 1999 scoring system [[12]Wiegard C. Schramm C. Lohse A.W. Scoring systems for the diagnosis of autoimmune hepatitis: past, present, and future.Semin Liver Dis. 2009; 29: 254-261Crossref PubMed Scopus (34) Google Scholar]. This does of course introduce a bias into the study in favour of the 1999 scoring system. A new score is always likely to be, at least in some aspects, different from a previous score. Since patients in referral centres are usually classified on the basis of already existing diagnostic standards, the study population in retrospective analyses tends to comply with an established score, suggesting a certain advantage for the previous score. Keeping this in mind, the simplified score has been found to perform very reliably in highly heterogeneous populations in different regions of the world. This is further underlined by this issue's paper [[11]Qiu D. Wang Q. Wang H. Xie Q. Zang G. Jiang H. et al.Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients.J Hepatol. 2011; 54: 340-347Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. This first study in China underlines the value in a region of particular interest in view of the high prevalence rate of viral hepatitis in China. The new simplified score was specifically designed to help at the bedside and not primarily for scientific studies. In addition, it was meant to also be applicable in regions with a high viral hepatitis rate. It is likely that in a country with 10% of the population being HBsAg positive, 10% of all AIH patients will also be HBsAg positive, and these are likely to benefit from immunosuppression, if viral replication is suppressed in parallel. Unfortunately, the present study does not yet answer the validity of the new score in patients with both autoimmune hepatitis and viral infection, as these were not diagnosed previously using old diagnostic criteria. However, now that the simplified score has been shown to also be applicable to patients in China, it is to be hoped that its usefulness in these difficult-to-diagnose patients will be tested in the near future. In fact, a prospective validation of the score in all patients presenting to their physician with unexplained elevated transaminases would be extremely valuable. It is only by such a study that the true positive and negative predictive value in routine clinical practise can be assessed. However, what then will be the gold standard for such a study? It will be crucial to really perform a follow-up of the patients included for at least six months; only patients responding to immunosuppression (normalization of transaminases and immunoglobulin G levels) should be included into the final analysis as patients correctly classified as AIH, and better still, relapse after reduction of immunosuppression, or chronicity of inflammation, i.e. duration for more than six months, should be documented in order to distinguish drug-induced immune-mediated hepatitis reliably from genuine autoimmune hepatitis [[13]Björnsson E. Talwalkar J. Treeprasertsuk S. Kamath P.S. Takahashi N. Sanderson S. et al.Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.Hepatology. 2010; 51: 2040-2048Crossref PubMed Scopus (378) Google Scholar]. What are the other limitations that need to be considered? Some patients with primary biliary cirrhosis (PBC) may display features of autoimmune hepatitis [14Lohse A.W. Meyer zum Büschenfelde K.H. Franz B. Kanzler S. Gerken G. Dienes H.P. Characterisation of the 'overlap syndrome' of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) in genetically susceptible individuals.Hepatology. 1999; 29: 1078-1084Crossref PubMed Scopus (280) Google Scholar, 15Chazouilleres O. Wendum D. Serfaty L. Montembault S. Rosmorduc O. Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy.Hepatology. 1998; 28: 296-301Crossref PubMed Scopus (649) Google Scholar] and the same applies to patients with primary sclerosing cholangitis (PSC) [[16]Lüth S. Herkel J. Kanzler S. Frenzel C. Galle P.R. Dienes H.P. et al.Serologic markers compared with liver biopsy for monitoring disease activity in autoimmune hepatitis.J Clin Gastroenterol. 2008; 42: 926-930Crossref PubMed Scopus (122) Google Scholar]. These conditions, often termed overlap-syndromes, are subject to much debate [[17]Boberg K.M. Chapman R.W. Hirschfield G.M. Lohse A.W. Manns M.P. Schrumpf E. Overlap syndromes: The International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue J Hepatol. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar]. Similarly, the role of immunosuppressive therapy in these patients is a matter of debate, but most experts believe that the degree of inflammatory activity of the hepatitis component determines the need for immunosuppression. The new simplified score is designed to include and thus detect these patients, while the old revised score, for scientific reasons, tended to exclude these patients. A recent study from the Mayo clinic supports this concept [[18]Neuhauser M. Bjornsson E. Treeprasertsuk S. Enders F. Silveira M. Talwalkar J. et al.Autoimmune hepatitis-PBC overlap syndrome: a simplified scoring system may assist in the diagnosis.Am J Gastroenterol. 2010; 105: 345-353Crossref PubMed Scopus (93) Google Scholar]. Today's study confirms this distinction, as 5 out of 6 PBC-AIH patients were detected by the simplified score but only 1 out of 6 by the revised score [[11]Qiu D. Wang Q. Wang H. Xie Q. Zang G. Jiang H. et al.Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients.J Hepatol. 2011; 54: 340-347Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. Thus, the two scores seem to fulfil their purpose, and if a positive score results in a trial of immunosuppression, this suggests that the detection rate using the new score is valuable for these patients, with overlapping features of PBC or PSC and AIH. Recognizing AIH may be particularly challenging in regions with a high prevalence of other liver diseases, in particular viral hepatitis, as well as in resource poorer countries. While a number of large case series of patients with autoimmune hepatitis have been reported from Japan and both similarities and differences to AIH in Western patients have been described in detail, other reports from Asia are scarce, and it was long believed that AIH is an extremely rare condition in China. The paper by Qiu et al. in this issue is therefore a particularly welcome addition to the literature, because in addition to further evaluating the new simplified AIH score, it impressively demonstrates that autoimmune hepatitis is a prevalent and relevant disease entity in a country with an extremely high prevalence of viral hepatitis. While prevalence data are still missing, the present study as well as previous studies suggests that AIH exists in China with very much the same prevalence and severity as in most other regions of the world. In view of the enormous heterogeneity of autoimmune hepatitis, making a diagnosis of this disease remains an art and will remain so despite improved or simplified scoring systems. Scoring systems can help to focus attention to an often under-recognized and under-diagnosed disease. In autoimmune hepatitis, and in particular in severe and in advanced disease, it is essential that affected patients should receive adequate immunosuppression, and the diagnosis should neither be delayed nor missed. A therapeutic trial may often be required to really make the diagnosis, and in some patients, withdrawal of immunosuppression under close supervision may later help further. In patients with suggestive or unexplained features, a liver biopsy is crucial in guiding treatment. This experience is once again underlined by today's study, as histology proved to be particularly helpful. It should be performed in all patients with unexplained liver disease. It is not only essential for the diagnosis of AIH, it often may bring to light other unexpected findings. It is the combination of laboratory features and histological assessment that makes the diagnosis, it is only the response to immunosuppression that really confirms the diagnosis, and saves the patient. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.