IgG4-SC was recently recognized as an independent disease from other IgG4-related diseases, and there are no epidemiology data for IgG4-SC based on a large population. Currently, it is a challenge to distinguish between IgG4-SC and CCA, as both may cause similar signs and symptoms. These patients presented with obstructive jaundice, pruritus, abdominal discomfort, and weight loss, vomiting, pancreatitis either as a single symptom or in combination.
In this study, we examined the clinical data collected from patients who were diagnosed with either IgG4-SC or CAA. We also observed similar incidences of IgG4-SC in both males and females, which agrees with other studies reported earlier. No significant demographic differences were observed between IgG4-SC and CCA patients. However, weight loss in IgG4-SC patients was one of the symptoms that was significantly different from that of CCA patients. This result was in line with the formal research, and may provide a clue for differentiated the two diseases.
Other diagnostic methods such as ultrasound, CT, and MRI could be applied for detecting the organ involvement. Multiple organ involvement such as the kidney, and the salivary and lacrimal glands is specific in IgG4-SC patients, while the biliary tract was always the only involved organ in CCA.  Approximately 90% IAC patients have symptoms of AIP, which can be obviously observed in imageological examinations. These typical manifestation helps differentiate IAC patients from CCA. However, organ involvement may be occult in several IAC patients. Therefore, IAC and CCA patients may exhibit similar imaging characteristics, such as dilatation, thickening wall, or occupying lesion, which makes it difficult to distinguish one from the other. [10, 11]
Histopathologic examination has been the gold standard and definitive method for IgG4-SC and CCA diagnosis. However, obtaining pathologic samples by puncture or ERCP brush before surgery is invasive and may not be suitable for all patients, such as elderly patients, patients with coagulopathy, or those with high bilirubin. In addition, the low positive rate of brush check may cause more problems. [12, 13] Therefore, clinical examination and experimental treatment are of great importance a differential diagnosis. We observed complete response of IgG4-SC patients to the steroid treatment, although in some cases the stent placement also played a part in the symptom alleviation.
Therefore, classification of benign-malignant biliary strictures has traditionally been regarded as a serious challenge. In many suspected IgG4-SC patients, the accuracy of the existing diagnostic methods is still deemed to be unsatisfactory, which may lead to misdiagnosis of CCA. These reporting of results should be interpreted carefully since cholangiocarcinoma is a high malignant cancer.
IgG4-SC patients may be positive for tumor markers, whereas CCA patient can also exhibit elevated sIgG4. The serum CA19-9 is an essential tumor marker which is extensively used to the differentiate the IgG4-SC and CCA cases. Previous studies have revealed that 70%-90% pancreatic or biliary adenocarcinoma demonstrated with elevation of serum CA19-9. In our study, the serum CA199 level was found to be increased in most of the CCA patients(81.1%). In IgG4-SC patients, the serum CA199 level also increased, but at a significantly lower incidence and a significantly lower level. These findings were consistent with the studies published earlier. However, the differentiation proficiency of CA19-9 may be interfered by obstructive jaundice and the subsequent inflammatory responses. Many strategies have been investigated to raise the discrimination proficiency of CA19-9 for IgG4-SC and CCA diagnosis, such as choosing a higher cutoff value and combining it with other inflammatory markers. 
The sIgG4 level is a major characteristic of IgG4-related diseases. In the IgG4-SC diagnosis criteria proposed by Japanese scholars, the minimum level of IgG4 was set as 1350 mg/L. However, the specificity at this cutoff is not sufficient to distinguish IgG4-SC and CCA. In our study, 11.1% of the CCA patients had an elevated sIgG4 level (range 46 to 2960 mg/L), which could mislead to an IgG4-SC diagnosis, although the level was significantly lower than that of the IgG4-SC group.
In clinical work, it was usually found that several patients with a high level of CA19-9 or sIgG4 gradually return to normal when their TBIL fall back into the normal range after PTBD, ERBD or ENBD used to decrease obstructive jaundice. Even if IAC patients have not received hormone therapy, their sIgG4 may immediately decrease in after relief of obstructive jaundice, so we considered that the serum level of Tbil may affect the serum level of IgG4. According to our results of linear regression, the elevation of IgG4 was positively correlated with the elevation of TBIL in the exponential model, which supported our hypothesis. In a study investigating the ratio of the increase-folds of CA19-9 to increase-folds of TBIL, Liu W and his colleague found the CA19-9/ TBIL ratio has higher differentiating power for IgG4-SC and CCA than CA19-9 or TBIL alone.  However, there are almost no historical studies in the area of the efficiency of the serum IgG4/TBIL ratio for differentiation between IgG4-SC and CCA.
On the basis of this study, we concluded that the best cutoff value for sIgG4 level was 1780 mg/L, with 95.3% sensitivity and 94.9% specificity. Unfortunately, IgG4 seems to be sufficiently effective for differential diagnosis in overall patients, and the ratio of IgG4 to TBIL can not further improve the diagnostic effectiveness. Therefore, a stratified analysis is necessary. As we observed, for those patients with elevation of serum IgG4 ranging from 650 to 3000 mg/L, who are difficult to be diagnosed before resection, the discrimination capacity of the IgG4/TBIL ratio was higher than the serum value of IgG4 or TBIL, which suggested that the ratio IgG4/TBIL had higher differentiation potentials for IgG4-SC and CCA, respectively. The combination of the serum IgG4 and the IgG4/TBIL ratio was confirmed to have increased the specificity and accuracy for differentiating IgG4-SC from CCA.
The production of IgG4 is related to the expression of several immune genetic factors, such as MHCII, nuclear factor-kB, and Fc-receptor-like molecules. For instance, reduced naive Tregs can activate a Th1 immune response with secretion of proinflammatory cytokines to antigens such as self-antigen or microorganisms. Th2 immunoreaction may be involved in the subsequent progression of the disease, resulting in the release of IgG4. But there is no literature about the Th2-type immune responses caused by bilirubin stimulation, which needs further research. Likewise, bilirubin may have an effect on laboratory serum detection of IgG4, though there is no related study.
The generalisability of these results is subject to certain limitations. For instance, the retrospective nature of this study made it difficult to obtain data of a single variable from all patients. The case number of the IGG4-SC and CCA was low, which may affect the significance of the study. In addition, there is no exact literature on the relationship between serum IgG4 and bilirubin levels, which needs more experimental investigations.