It was 1949 when the term “primary biliary cirrhosis” first appeared in the literatures referring to the disease in which small intrahepatic bile ducts were destructed with massive infiltration of mononuclear cells [6]. The term “primary biliary cirrhosis” exactly reflected the disease at that time since most of PBC presenting with advanced liver disease. However, along with introduction of several biomarkers such as AMA which help physicians to diagnose the disease in much earlier stage, it is uncommon in these days that the patients are diagnosed as having PBC in advanced stage; rather, more than 70% of patients with PBC lack any symptom including variceal rupture, jaundice, and even pruritus [4].

With a global cooperative effort toward the correction of misuse, the Governing Board of European Association for the Study of the Liver (EASL), the American Association for the Study of Liver Diseases (AASLD), and the American Gastroenterological Association (AGA) approved the proposal for a name change of primary biliary cirrhosis to primary biliary “cholangitis” from 2014 to 2015, followed by publish of this statement in eight leading journals, including Hepatology, J Hepatology, and Gastroenterology [7–9]. At the moment of this article was written, the Japan Society of Hepatology (JSH) and Asia Pacific Association for the Study of the Liver (APASL) have not approved the name change yet, but are about to move on this direction as well. Hence, I choose the nomenclature “primary biliary “cholangitis,” instead of “cirrhosis” in this review. It may be true that the name “primary biliary cholangitis” is somewhat imperfect and is a tautology. But I believe it is time to go forward to the correction of misused term, leaving endless debates behind which term would be the best for describing the pathogenesis of this disease.

Although the precise pathophysiology of PBC remains unsolved, it is generally accepted that autoimmune reactions against bile duct epithelial cells play a critical role, mainly because of the followings. First, AMA, autoantibodies directed to mitochondrial autoantigens, are detected in more than 90% of patients with PBC. By contrast, AMA is scarcely seropositive in other autoimmune diseases, and therefore AMA is a hallmark of PBC. Major targeted autoantigens of AMA are E2 component of pyruvate dehydrogenase complex (PDC-E2), branched-chain 2-oxo acid dehydrogenase complex (BCOADC-E2), and 2-oxoglutarate dehydrogenase complex (OGDC-E2), all located in the inner membrane of the mitochondria [10]. It remains unsolved why these ubiquitous proteins are targeted by AMA which are highly disease-specific autoantibodies in PBC. Second, numerous mononuclear cells are accumulating around small damaged interlobular bile ductules, establishing PBC-specific histopathological features called chronic nonsuppurative destructive cholangitis (CNSDC) [11]. Among these inflammatory infiltrates, PDC-E2-specific T and B lymphocytes are detected, and obviously these autoantigen-specific lymphocytes are crucial for pathogenesis of PBC. In addition, recent studies revealed an important role of innate immunity for etiopathogenesis of PBC [12–14]. Indeed, NK cells as well as NKT cells increase in the periphery and liver of PBC [15], and innate immunity is supposed to operate as machinery attacking bile ducts before adaptive immunity [16]. Third, it is not uncommon that patients with PBC develop other autoimmune diseases as comorbidities, such as rheumatoid arthritis, Sjogren’s syndrome, and chronic thyroiditis (Hashimoto’s disease), suggesting for long that genetic backgrounds are identical in part among these autoimmune diseases and PBC [4]. Recent evidences with genome-wide association studies (GWAS) clearly support this hypothesis; a number of susceptible genes in PBC are shared with other autoimmune diseases including Crohn’s disease, multiple sclerosis, rheumatoid arthritis, and autoimmune thyroid disease [17], and it is also notable that most of these shared genes are related to immune pathways. The identification of shared susceptible genes between PBC and other autoimmune diseases is also confirmed in Japanese PBC patients [18].

In the past, cholangiocytes were believed to be “innocent victims” in PBC pathogenesis. Deteriorated immune reactions, both innate and adaptive, against intrahepatic small biliary ductules result in destruction of bile ducts, and biliary epithelial cells were supposed to be unilaterally damaged. Recent findings, however, have revealed that cholangiocytes are not “innocent victims” anymore but are “actively participating” in this process, and bile acids are important players in pathogenesis of PBC as well.

The cholangiocytes are physiologically exposed to hydrophobic bile acids, which are potentially toxic to cholangiocytes. Indeed, in acidic condition glycine conjugates of bile acids will be protonated and easily pass cell membranes by simple diffusion. It was also shown that bile acids at pH 4.0, but not pH 7.4, induce oxidative stress and DNA damage in human esophageal epithelial cells [19]. Additionally, acidification of bile at the apical membrane may damage cell membranes and mitochondria, leading to leakage of cytochrome c out of mitochondria and apoptosis [20].

To survive in this hazardous environment, the apical surface of cholangiocytes is covered and protected by dense layer of HCO₃ ⁻ secreted from cholangiocytes, which keeps luminal pH at alkaline level, resulting in deprotonation of apolar hydrophobic bile acids and preventing them from permeation into the cholangiocytes [20]. This biliary HCO₃ ⁻ “umbrella” is maintained by Cl⁻/HCO₃ ⁻ exchanger (anion exchanger 2 (AE2)) located at apical surface of cholangiocytes (Fig. 7.1).

Accumulating evidences have indicated that damaged biliary HCO₃ ⁻ “umbrella” through lack or reduction of AE2 activities is closely associated with cholangiopathies and PBC. Defects of the biliary HCO3⁻ umbrella due to inadequate AE2 expression may lead to the development of chronic cholangiopathies [21]. Mice lacking AE2 genes (Ae2a, b) related to the replacement of two anions including HCO3⁻ and Cl⁻ inside and outside the cells indicate the pathology similar to that of PBC [22]. In human, immunostaining demonstrated that expression of AE2 was decreased in PBC livers [23]. PBC cholangiocytes exhibit a widespread failure in the regulation of carriers involved in transepithelial HCO₃ ⁻ transport [24]. Genetic analysis revealed that allelic variations in AE2 were associated with disease susceptibility and progression of under UDCA therapy [25]. Finally, recent studies revealed that microRNA (miR-506) was upregulated in cholangiocytes from PBC patients and was directly associated with diminished AE2 expression through binding the 30UTR region of AE2 mRNA [26]. Taken together, destabilization of biliary HCO3⁻ umbrella over the apical membrane with the reduced expression and inadequate function of AE2 may expose cholangiocytes to apolar hydrophobic bile acids, thereby contributing to the development and progression on PBC [20].

For the moment, ursodeoxycholic acid (UDCA) is the only drug officially approved for the use in PBC. Besides, although not bile acids, bezafibrate (BF) is frequently used in patients with PBC refractory to UDCA, yet has not been officially approved in Japan. The third drug, obeticholic acid (OCA), is now under development and is expected to be another therapeutic option. All these three are able to diminish toxicity of hydrophobic bile acids with replacement to hydrophilic bile acids, stabilizing the biliary HCO₃ ⁻ umbrella and reducing de novo bile acid synthesis, and help to keep cholangiocytes intact.