PBC is an intrahepatic cholestasis disease that damages < 100 μm interlobular bile ducts of the biliary tree. The bile ducts are composed of cuboidal cells with a basement membrane and are easily identified by CK7 immunohistochemical staining. There are some histological staging systems for PBC, such as Scheuer’s and Ludwig’s systems, thatdescribe the histology by inflammation and fibrosis. However, it is not reasonable to ignore bile duct injury according to the pattern of the system, which is not parallel to inflammation or fibrosis. Therefore, Nakanuma  established a scoring system to evaluate the histological features of PBC, including fibrosis, bile duct loss and chronic cholestasis (deposition of orcein-positive granules). Because the pathological changes in PBC are extremely uneven, some patients possess only one typical portal tract characteristic, such as a florid bile duct and lymphocyte follicles. Other researchers have found that the CK7 score in liver tissues can discriminate the stage of PBC better than the CK19 score.Additionally some hepatocytes are stained by CK7 rather than CK19 , although both kinds of CK have the ability to mark the bile ducts.
In this study, we explored the clinical and pathological differences associated with different degrees of CK7+Hs in 89 liver specimens from patients diagnosed with PBC, 49 of whom had overlapping AIH. It is difficult to diagnose overlap syndrome, because the IAIHG cumulative score used to identify AIH has not been validated in this particular setting . However, in this study, overlap syndrome patients were diagnosed by Paris criteria [16, 17]. This study demonstrated that anti-gp210, interface activity, and ductopenia grade are risk factors for CK7+Hs in PBC. Interface activity and ductopenia grade were positively correlated with CK7+Hs. Moreover, we found that TB, DB, ALP, and TA were different between CK7−Hs and CK7+Hs (2 +), showing that the cluster or diffuse distributions of CK7+Hs indicate cholestasis of the liver. Previous studies have shown that ductopenia is related to CK7+Hs, but in this study, we showed that anti-gp210 and interface activity are risk factors for CK7+Hs.
There were differences in AMA, AMA-M2, and anti-gp210 between the CK7+Hs and CK7−Hs groups in this article. However, some patients may not exhibit typical staining patterns for AMA or AMA-M2, and they need liver biopsy to diagnose PBC.Thus, the difference may be related to this reason. Anti-gp210 is an index that can be used to help diagnose AMA-negative PBC  and evaluate the severity or prognosis of PBC . It is also a risk factor for CK7+Hs. There were significant differences in patients with CK7+Hs (2 +) and CK7+Hs (1 +) according to sex; however, the number of men with CK7+Hs (2 +) was zero. Therefore, the sample size needs to be increased to confirm this finding in the future. In addition, fibrosis was significantly different between the CK7−Hs and CK7+Hs groups (P = 0.018) but not between the CK7+Hs (2 +), CK7+Hs (1 +), and CK7−Hs groups (P = 0.056) (close to 0.05). Differences among the three groups may also be observed if we expand the subject. As the disease progresses, the bile duct is gradually damaged, and fibres extend from one portal tract to another portal tract or central lobule.Eventually bridging fibres and cirrhotic nodules are formed. Furthermore, there were differences in interface activity, in which the amount of CK7+Hs increased with increasing interface activity. Interface activity may tend to be a feature of overlap syndrome (OS) because PBC possesses only mild lymphocyte interface activity. During this process, inflammatory cells can spill over from the portal tracts into the adjacent parenchyma or biliary interface changes at the plate between portal tracts and parenchyma take place. Therefore, damage to the interface plate is limited to PBC, and OS is considered when there is a prominent lymphocytic interface or lobular inflammation.
CK7+Hs are hepatocyte-shaped cells., Not only is the nuclear/cytoplasm ratio lower than that of BECs, but staining for CK7+Hs and ductular reactions are also weaker. The main feature of CK7+Hs, especially in ductopenia patients, is considered to be cholestasis. Matsukuma  found that GGT was associated with CK7+Hs; however, we discovered that TB, DB, ALP, and TA were different between CK7−Hs and CK7+Hs (2 +). In addition, IgM, another typical index of PBC, also showed differences between CK7−Hs and CK7+Hs (2 +). The increase in ALP should be connected with AMA or typical liver lesions when diagnosing PBC, and the degree of ALP elevation may be associated with different outcomes that are closely related to the severity of ductopenia and inflammation in cirrhosis. IgM is an antibody secreted by plasma cells; however, we did not discover differences in plasma cells that were stained with CD38 in liver tissues in our experiments. This finding may be because the subjects included AIH patients, in whom plasma cells may also secrete IgG in tissues.Thus, the results would be inconsistent. The differences between CK7−Hs and CK7+Hs (2 +) indicate that the cluster or diffuse distributions of CK7+Hs may be related to the cholestasis index. In addition, the cholestasis index may be associated with ductopenia and reduce the connections between the biliary tree and hepatocytes. In normal tissues, hepatocytes possess three specialized membrane domains.Tthe basolateral or sinusoidal domainis the vascular pole that faces the sinusoids.The lateral membrane of the cell is made up of two domains: the canalicular domain and the lateral domain. The canalicular domain, along with the canicular domain of the adjoining hepatocyte, makes up the bile canaliculus and is also called the biliary or apical pole of the hepatocyte. The bile secreted by hepatocytes flows from the bile ductile to bile canaliculi; finally, it gathers to in the IBID. When the bile duct is lost, the link between hepatocytes and IBID is interrupted. This may be related to cholestasis. The body will change to alleviate the lesions, and CK7+Hs may be observed.
Currently, the mechanisms of CK7+Hs are not clear. Some studies have illustrated that aberrant CK7 expression by hepatocytes originates from the canals of Hering, where HPCs differentiate into hepatocytes and cholangiocytes when the periportal areas between portal tracts and parenchyma are damaged . HPCs are similar to oval cells in rodents, and the ductular reaction (DR) is also believed to originate from HPCs. DR is usually the earliest change to occur when the bile duct without cavity structures is injured. It provides a bypass and promotes the movement of bile fluid from the small-diameter bile duct to the predominate bile duct during damage to or loss of BECs. CK7+Hs may be another product of DR and possess a similar morphology to hepatocytes during regeneration of the liver. However, CK7 staining is weaker than that of BECs. Although HPCs are usually located around periportal areas, CK7+Hs in centrilobular hepatocytes can sometimes be found.This may be another niche for migrating HPCs .
Other studies have suggested that CK7+Hs is related to metaplasia, which is transdifferentiated by mature hepatocytes  by signalling pathways, such as the Notch and TGF-β pathways. Some researchers  have found transdifferentiation from hepatocytes to cholangiocytes during severe biliary damage and established a chimeric liver model. In this model, dipeptidyl peptidase (DPP)IV- rats were transplanted with hepatocytes from DPP IV + rats and underwent bile duct ligation (BDL) following pretreatment with 4,4’-methylenedianiline (DAPM). Approximately 47.5% DPP IV + cholangiocytes were observed in the chimeric rat liver. Other researchers also found negative correlations between changes in hepatocytes and BECs.The expression of CK7( +) was increased in BDL rats [24, 25] which showed that the positive expression of Hepar in hepatocytes was decreased. In addition, some researchers consider the process of CK7+Hs to occur inthe middle process during of the transdifferentiation from mature hepatocytes to cholangiocytes. Sato et al.  introduced the mechanism of DR. They elucidated that mature hepatocytes could change to hepatocytes and that DR was also derived from the transdifferentiation of hepatocytes.
There are some limitations to this study. The total number of PBC patients who had to undergo liver biopsy for diagnosis and treatment was too small to use ordinal regression to investigate the relationships among the degree of CK7+Hs in PBC. Some patients can be diagnosed without liver biopsy for classic PBC. However, some of them need a biopsy to assist in diagnosis and treatment. For example, patients with staging and grading of PBC, such as antibody-negative PBC, and patients with poor Ursodeoxycholic Acid (UDCA) treatment, overlapping autoimmune hepatitis, and differentiation from other liver diseases. Moreover, the mechanism of CK7+Hs needs further study. The sample size needs to be increased to confirm the data and explore the mechanisms of CK7+Hs in the future.