PBC: No Longer a Western Disease?

Watch a video presentation of this article Watch an interview with the author Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic cholestatic liver disease for which a lack of appropriate treatment can lead to cirrhosis and liver failure. Global consensus states that PBC is diagnosed if two or three of the following criteria are met: chronic elevation of cholestatic liver enzymes (alkaline phosphatase and/or gamma-glutamyltransferase), detection of anti-mitochondrial antibody, and typical histopathological findings, such as chronic nonsuppurative destructive cholangitis.1 Although substantial evidence indicates that autoimmune responses against biliary epithelial cells are the first step leading to PBC, its etiology is not fully understood. Like other autoimmune diseases, environmental factors might trigger its onset in a genetically susceptible individual, and epidemiological studies definitely play a key role in elucidating environmental triggers. Until recently, PBC was considered mainly observed in Western countries and relatively rare in the East. Although this was probably true, no epidemiological data were available in Eastern countries. As concisely summarized in 2012 in the review by Boonstra et al.,2 the prevalence of PBC was exclusively reported in Europe and North America until 2010, with the exceptions of Australia and New Zealand. Because considerable proportions of these two Oceanian regions are of European ancestry (primarily the United Kingdom), researchers worldwide did not know the prevalence of patients with PBC in Asia. Furthermore, the reported prevalence in Victoria, Australia, was 1.91 per 100,000 individuals in 19953 and 5.1 in 2002,4 which was significantly lower than those in Europe. During the first decade of the 21st century, epidemiological studies in Europe and North America demonstrated a prevalence of 11.5 to 22.7 per 100,000 individuals5 (Fig. 1). Since 2010, epidemiological data of PBC from Oceanian and Asian countries have emerged. The prevalence of PBC was reportedly 9.9 per 100,000 individuals in Canterbury, New Zealand,6 followed by similar observations of 4.75 and 5.6 in South Korea7 and Hong Kong,8 respectively (Fig. 1). Surprisingly, a very high prevalence of 49.2 was reported in Southern China in 2006.9 This is the second highest worldwide prevalence to date, but it should be noted that the number of index cases in this study was only 5, decreasing the reliability of this report. In contrast, our group performed an epidemiological study in Japan and demonstrated that the prevalence of PBC in 2016 was 33.8 per 100,000 individuals, which was significantly higher than that of other Asian countries.5 As demonstrated in Fig. 1, the observed prevalence in Japan was comparable with those in Western countries, that is, Iceland, the United States, Greece, Italy, and Canada. Therefore, Japan is more likely not an exception in Asia. Recent studies consistently suggested an increasing trend in the worldwide prevalence of PBC. For instance, the number was increased from 22.7 (2002) to 31.8 (2015) in Canada, from 11.1 (2009) to 27.90 (2015) in Italy, and from 21.7 (2006) to 39.2 (2014) in the United States.10 Furthermore, in Japan, the prevalence was 11.6 in 2004; thus, it almost tripled in 12 years. It is likely that this increasing trend will also be observed in other countries in Asia in the near future, which share a number of genetic and environmental factors with Japan. An increasing trend may be partly explained by a better recognition of PBC among physicians, but it probably reflects a true increase in PBC cases as with other autoimmune diseases. Meanwhile, several studies indicated that incidence remained similar over time,10, 11 suggesting that an increasing prevalence might be because of improved outcome for patients with PBC. Another interesting epidemiological finding is the relative increase in male patients (Fig. 2). PBC was famous for significant female preponderance, and the male-to-female ratio of patients was about 1:8 to 1:10 in the 20th century. However, this is not the case anymore. The female/male ratio of patients with PBC was 7.06 in 2004 and 4.26 in 2016 in Japan.5 A similar trend was observed in Italy and Denmark, where the female/male ratio was 2.3 and 4.6, respectively, in 2009.11 A similar trend was observed worldwide, both in Western and Eastern countries (Fig. 2). Recent epidemiological studies accordingly demonstrate that the male/female ratio of patients with PBC was about 1:3 to 1:5. We should note, however, that methodological limitations might be present in these epidemiological studies. The statistics are largely derived from administrative data in which the diagnosis is not strictly confirmed, and the case-finding strategy varies as well. Nevertheless, because our studies in Japan in 2004 and 2016 applied an identical method to identify patients with PBC, a relative increase of male patients is likely to occur. Why has the proportion of male patients with PBC been relatively increased recently? The etiology of PBC is multifactorial and involves the interaction of both genetic background and environmental triggers in that environmental insult in genetically susceptible individuals can cause aberrant immunological reactions and lead to autoimmune-mediated bile duct injuries. Because the genetic background has not changed over just a few decades, this alteration in prevalence and female/male ratio should be explained by environmental changes over time. For instance, an etiological association of urinary tract infection (UTI) with PBC through molecular mimicry between Escherichia coli and E2 component of pyruvate dehydrogenase complex (PDC-E2), a dominant autoantigen of PBC, has been frequently reported, which accounted for the female predominance. However, the lower occurrence of UTI because of recent improvements in hygiene might reduce its etiological importance, and other environmental triggers that have increased in prevalence and are equally shared by the sexes and also by the East and West (e.g., xenobiotics or pollution) might play a more crucial role. Indeed, recent large-scale case-control studies illustrate that xenobiotic modification of PDC-E2 with environmental chemicals abundant in daily life generates immunogenic neoantigens and breaks immunological tolerance in PBC. A well-designed case-control study with international collaboration is warranted to elucidate the environmental factors that contribute to this global increase in the prevalence of PBC.

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