Autoimmune hepatitis on the rise
Authors: Christoph Schramm, Ansgar W. Lohse
Journal: Journal of Hepatology (2013)

Autoimmune hepatitis in Denmark: Incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort studyJournal of HepatologyVol. 60Issue 3PreviewPopulation-based studies of the clinical course of autoimmune hepatitis are scarce. We conducted a nationwide study of incidence, prevalence, prognosis, and causes of death of autoimmune hepatitis in Denmark. Full-Text PDF Autoimmune hepatitis (AIH) is considered a rare disease. The incidence and prevalence of AIH has been assessed in only two studies on a population based level [1Boberg K.M. Aadland E. Jahnsen J. Raknerud N. Stiris M. Bell H. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population.Scand J Gastroenterol. 1998; 33: 99-103Crossref PubMed Scopus (456) Google Scholar, 2Ngu J.H. Bechly K. Chapman B.A. Burt M.J. Barclay M.L. Gearry R.B. et al.Population-based epidemiology study of autoimmune hepatitis: a disease of older women?.J Gastroenterol Hepatol. 2010; 25: 1681-1686Crossref PubMed Scopus (157) Google Scholar]. This is due to the fact that only few countries provide reliable information on their inhabitants diagnoses as well as their causes and date of death. In addition, diagnosing AIH is difficult, and the disease is often misinterpreted as toxic liver injury or non-specific elevation of liver enzymes. Even liver histology can be misleading, for example in variant syndromes or in patients with an acute presentation [3Boberg 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, 4Stravitz R.T. Lefkowitch J.H. Fontana R.J. Gershwin M.E. Leung P.S. Sterling R.K. et al.Autoimmune acute liver failure: proposed clinical and histological criteria.Hepatology. 2011; 53: 517-526Crossref PubMed Scopus (230) Google Scholar]. Taking this into account, the study presented by Grønbæk and colleagues in this issue of the journal [[5]Grønbæk L. Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A Nationwide Registry-based Cohort Study.J Hepatol. 2014; 60: 612-617Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar] provides some important novel information on the epidemiology of AIH as well as on the course of the disease. In their study, the incidence and prevalence of AIH in Denmark was assessed on a population level during a nearly 20 year time period ranging from 1994 to 2013. 1721 patients with AIH were identified. The diagnostic classification relied on the main diagnosis coded at hospital discharge as well as from outpatient services. For the interpretation of their data one has to consider the obvious drawbacks of such a registry based study design, including the lack of chart review for the validation of the diagnosis, the lack of data on treatment given as well as missing information on biochemical or histological response rates. Liver histology had been performed in the majority of cases, but in one quarter of cases no histology was apparently done or information available – even though liver biopsy is considered an essential part of making a diagnosis of AIH. The study confirms some of the previous findings on AIH epidemiology, including the peak incidence around the age of 60–70 years, the female predominance (72% female) and the high rate of liver cirrhosis at first presentation (28%). The most striking observation was the marked increase in incidence over time: Between the years 1994 to 2012 the incidence rate of AIH in Denmark has nearly doubled, reaching a point prevalence in the year 2012 of 24/100.000 (35/100.000 for females). This is one of the highest rates reported so far. The most obvious interpretation of such a finding in a rare disease is better case ascertainment in more recent years. However, coding practices, health care organisation and, most importantly, the stage of disease detected histologically remained similar over the complete time period. This strongly argues against a relative change in case ascertainment rates, and makes it very likely that these results represent a genuine rise in AIH incidence. Increasing rates of non-liver related autoimmune diseases such as rheumatoid arthritis [[6]Myasoedova E. Crowson C.S. Kremers H.M. Therneau T.M. Gabriel S.E. Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955–2007.Arthritis Rheum. 2010; 62: 1576-1582Crossref PubMed Scopus (592) Google Scholar] have been reported repeatedly during the past years. In addition, these novel data compare well with the marked rise in incidence rates reported for primary biliary cirrhosis [[7]Boonstra K. Beuers U. Ponsioen C.Y. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review.J Hepatol. 2012; 56: 1181-1188Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar] and recently also for primary sclerosing cholangitis [[8]Lindkvist B. Benito de Valle M. Gullberg B. Bjornsson E. Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden.Hepatology. 2010; 52: 571-577Crossref PubMed Scopus (163) Google Scholar], the two other autoimmune liver diseases. The hygiene hypothesis has been cited in order to explain the increasing incidence of autoimmune diseases in contrast to decreasing incidences of infectious diseases in general. In recent years we have learned that the interaction with our gut microbiota has a major influence on our health and especially on the shaping and functioning of our immune system [9Sommer F. Backhed F. The gut microbiota – masters of host development and physiology.Nat Rev Microbiol. 2013; 11: 227-238Crossref PubMed Scopus (2350) Google Scholar, 10Maslowski K.M. Mackay C.R. Diet, gut microbiota and immune responses.Nat Immunol. 2011; 12: 5-9Crossref PubMed Scopus (947) Google Scholar]. Therefore it could be speculated that changes in living conditions such as diet have led to changes in the intestinal microbiota, which in turn influences the regulation of the immune system including the gut-liver axis. The other worrying finding of this study is that 10 year mortality was significant. However, there is also good news from this study: Although the incidence of AIH was found to be on the rise, mortality from AIH seems to have decreased in Denmark. It is unlikely that this improved prognosis was due to earlier diagnosis of the disease, as the proportion of patients with cirrhosis at diagnosis remained stable throughout the study period. It is therefore more likely that this effect is a result of improved care and treatment of AIH in Denmark. Within the patient group, the risk to die from AIH was increased with male gender and the presence of liver cirrhosis at presentation. Liver cirrhosis was more prevalent in younger and older patients, with 43% of patients aged 10–19 years having cirrhosis at diagnosis of AIH. It has always been the experience that paediatric AIH is more severe than AIH in later adulthood, and the disease appears to be dichotomous with an aggressive and rapidly progressive disease manifesting in childhood or teenage years, and a usually, but not always, milder disease in late adulthood. Young age and male gender have recently also been identified as risk factors for severe disease in patients with primary biliary cirrhosis [[11]Carbone M. Mells G.F. Pells G. Dawwas M.F. Newton J.L. Heneghan M.A. et al.Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid.Gastroenterology. 2013; 144 ([e567; quiz e513–564]): 560-569Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar]. Male gender and cirrhosis were also the key risk factors for the development of hepatocellular carcinoma, which occurred at a very low rate with a 10 year cumulative incidence of only 0.7%. 6 of the 8 cases occurred in men with cirrhosis or fibrosis on histology. Surveillance recommendations for HCC in AIH presently include all patients with cirrhosis, and the present data are not sufficient to change these recommendations. Nonetheless, patients and their physicians will be reassured by the overall very low risk of HCC in AIH, especially in women. The study also suggests that we need to perform better in the treatment of our patients. The considerable mortality within the first year after presentation (6% with two thirds of deaths liver related) points to the fact that many patients had advanced or highly aggressive disease at diagnosis and died in spite of treatment initiation. Mortality in AIH patients remained doubled after surviving the first year and reached 26% after 10 years. Excellent survival rates have been reported for AIH patients depending on the study design and the length of observation [12Kanzler S. Lohr H. Gerken G. Galle P.R. Lohse A.W. Long-term management and prognosis of autoimmune hepatitis (AIH): a single center experience.Z Gastroenterol. 2001; 39: 344-348Crossref Scopus (117) Google Scholar, 13Yoshizawa K. Matsumoto A. Ichijo T. Umemura T. Joshita S. Komatsu M. et al.Long-term outcome of Japanese patients with type 1 autoimmune hepatitis.Hepatology. 2012; 56: 668-676Crossref PubMed Scopus (95) Google Scholar]. However, the standardized mortality ratio for AIH was doubled in another recent population based study from New Zealand [[14]Ngu J.H. Gearry R.B. Frampton C.M. Malcolm Stedman C.A. Mortality and the risk of malignancy in autoimmune liver diseases: a population-based study in Canterbury, New Zealand.Hepatology. 2012; 55: 522-529Crossref PubMed Scopus (88) Google Scholar]. Several factors such as multiple relapses, lack of remission after six months of treatment, young age and the presence of cirrhosis have been described as negative predictors of disease [13Yoshizawa K. Matsumoto A. Ichijo T. Umemura T. Joshita S. Komatsu M. et al.Long-term outcome of Japanese patients with type 1 autoimmune hepatitis.Hepatology. 2012; 56: 668-676Crossref PubMed Scopus (95) Google Scholar, 15Ngu J.H. Gearry R.B. Frampton C.M. Stedman C.A. Predictors of poor outcome in patients with autoimmune hepatitis: a population-based study.Hepatology. 2013; 57: 2399-2406Crossref PubMed Scopus (89) Google Scholar, 16Hoeroldt B. McFarlane E. Dube A. Basumani P. Karajeh M. Campbell M.J. et al.Long-term outcomes of patients with autoimmune hepatitis managed at a nontransplant center.Gastroenterology. 2011; 140: 1980-1989Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar]. Of particular importance in the current study is the fact that the increased mortality was not restricted to patients with cirrhosis. Mortality started to increase in patients initially presenting with liver fibrosis after around 9 years of treatment. Taking the potential of histological sampling error and the lack of follow-up data into account this suggests that the progression of disease was not sufficiently controlled in these patients. These data underline the requirement to suppress hepatic inflammation and the ensuing liver fibrosis in the long term. As a surrogate of this, complete biochemical remission as defined in the most recent guidelines (normalization of serum aminotransferase levels and IgG) [[17]Manns M.P. Czaja A.J. Gorham J.D. Krawitt E.L. Mieli-Vergani G. Vergani D. et al.Diagnosis and management of autoimmune hepatitis.Hepatology. 2010; 51: 2193-2213Crossref PubMed Scopus (1160) Google Scholar] should be aimed at and the maintenance of remission has to be verified on a regular basis. Although per definition rare diseases, autoimmune liver diseases including autoimmune hepatitis seem to be on the rise, and morbidity and mortality due to these diseases remain significant health care problems. Even though AIH almost always responds to initial immunosuppressive therapy, timely diagnosis, more specific and effective treatment options and better specialist care for all patients is required to prevent excess deaths due to this disease. With rising incidence and prevalence rates, the challenge is increasing for scientists and clinicians alike to elucidate the pathogenesis of autoimmune liver diseases in order to improve treatment options targeting disease progression as well as quality of life. This work was supported by the Deutsche Forschungsgemeinschaft (SFB841). The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.