thirty patients were diagnosed with iac in the peking union medical college hospital ( pumch ) from january 2011 to september 2014 , during which 275 patients were diagnosed with cca .
all patients were retrospectively reviewed and information was collected including their sex , age , symptoms , weight loss ( decreased > 5% within 6 mo ) , and serological tests , including biochemical tests , tumor markers , and the sigg4 level .
imaging characteristics including endoscopic retrograde cholangiopancreatography ( ercp ) , magnetic resonance cholangiopancreatography ( mrcp ) , computed tomography ( ct ) , b - ultrasound , and endoscopic ultrasonography ( eus ) were also collected .
chicago , il ) . the primary outcome consisted of the clinical parameters that showed significant differences in iac and cca .
differences between the groups were evaluated using the independent samples t test , the  test , the mann - whitney u , or the fisher test according to their characteristic . in all tests , p values
receiver operating characteristic curves were used to estimate the diagnostic application of sigg4 levels ( youden index = sensitivity+specificity1 ) .
data were analyzed using spss version 13.0 ( spss inc . , chicago , il ) . the primary outcome consisted of the clinical parameters that showed significant differences in iac and cca .
differences between the groups were evaluated using the independent samples t test , the  test , the mann - whitney u , or the fisher test according to their characteristic . in all tests , p values
receiver operating characteristic curves were used to estimate the diagnostic application of sigg4 levels ( youden index = sensitivity+specificity1 ) .
thirty patients ( 21 male and 9 female ; median age 59.012.7 y ; ranging from 28 to 83 y ) were diagnosed with iac , with the criteria described in the introduction section , and 275 cca patients ( 170 male and 105 female ; median age 61.811.3 y ; ranging from 30 to 89 y ) were diagnosed with histopathology and/or cytology .
there was no significant difference in the gender and the age between the 2 groups ( table 1 ) .
demographic data and symptoms of iac and cca patients as shown in table 1 , a significantly higher number of iac patients experienced weight loss than cca patients ( 66.7% in iac vs. 45.1% in cca , p=0.025 ) . moreover , iac patients had a significantly higher level of weight loss than cca patients ( 7.58.1 vs. 3.24.0 kg , p=0.008 ) .
on comparing the prognosis of the 2 groups , iac patients had a significantly longer survival time than cca patients ( p<0.001 ) .
cca patients demonstrated significantly higher positive rates of tumor markers , including ca199 , ca242 , and cea , compared with iac patients .
positive rates of ca199 , ca242 , and cea in cca patients compared with iac patients were 81.5% versus 42.9% , 45.5% versus 4.5% , and 29.2% versus 7.1% , respectively .
in addition , average serological levels of these tumor markers in positive cca patients were significantly higher than those in positive iac patients ( p<0.05 in all cases ) ( table 2 ) .
there were no significant differences in the serum biochemistry tests including alt , ast , ggt , alp , tbil , and dbil between iac and cca patients ( table 3 ) .
tumor maker detection in the iac and the cca groups serological measurement for the liver function of iac and cca patients thirty - one cca patients were tested for their sigg4 level , among whom 16.1% ( 5/31 ) were found to have an elevated level with a range between 29 and 8230 mg / l and an average of 896.3 mg / l .
almost 100% of the iac patients showed elevated sigg4 ranging between 1650 and 78,590 mg / l , with an average of 16028.6 mg / l .
when a cutoff level was set at 6 times the upper normal limit , the area under the curve for sigg4 was 0.981 in receiver operating characteristic analysis and sigg4 had 100% specificity for iac .
on the basis of the youden index calculation , the best cutoff value for sigg4 in this cohort was 1575 mg /
bile duct  occupying lesions were detected with ercp , mrcp , ct , b - ultrasound , or eus .
an occupying lesion was defined as a thickening of the bile duct wall with a very clear margin . as
shown in table 4 , the thickening wall ( p=0.001 ) and the occupying lesion ( p<0.001 ) of the duct were found significantly different in iac and cca by eus .
imaging comparison of iac and cca patients by different radiologic methods an example of an image taken with endoscopic ultrasonography that exhibited an occupying lesion of the bile duct .
aip was the most frequent comorbidity of iac and the incidence reached as high as 83.3% in this study .
the imaging diagnosis for aip included diffused pancreatic enlargement , irregular narrowing of the main pancreatic duct , and bile duct strictures . among the 30 iac patients ,
however , only 10.2% of the cca patients were found to have pancreas involvement and presented as tumor invasion .
kidney ( 20% ) and parotid gland or lacrimal gland ( 53.3% ) involvement were also present in iac patients , whereas none was found in cca .
both groups had hepatic hilar lymph nodule hyperplasia , but the percentage of incidents in iac patients was significantly higher ( 56.7% vs. 30.5% , p=0.004 ) .
other organ involvement in iac and cca patients when diagnosed or highly suspected , iac patients were treated with steroid therapy ( initial prednisolone dose as 30 mg / d for 2 wk ) .
the average sigg4 and tbil levels of iac patients decreased to 6278.37 mg / l and 26.14 mol / l , respectively .
prednisolone application resulted in a decrease in the sigg4 level in all iac patients , and a decrease in the bilirubin level was noticed in 80.77% of the iac patients .
thirty patients ( 21 male and 9 female ; median age 59.012.7 y ; ranging from 28 to 83 y ) were diagnosed with iac , with the criteria described in the introduction section , and 275 cca patients ( 170 male and 105 female ; median age 61.811.3 y ; ranging from 30 to 89 y ) were diagnosed with histopathology and/or cytology .
there was no significant difference in the gender and the age between the 2 groups ( table 1 ) .
demographic data and symptoms of iac and cca patients as shown in table 1 , a significantly higher number of iac patients experienced weight loss than cca patients ( 66.7% in iac vs. 45.1% in cca , p=0.025 ) . moreover , iac patients had a significantly higher level of weight loss than cca patients ( 7.58.1 vs. 3.24.0 kg , p=0.008 ) .
on comparing the prognosis of the 2 groups , iac patients had a significantly longer survival time than cca patients ( p<0.001 ) .
cca patients demonstrated significantly higher positive rates of tumor markers , including ca199 , ca242 , and cea , compared with iac patients .
positive rates of ca199 , ca242 , and cea in cca patients compared with iac patients were 81.5% versus 42.9% , 45.5% versus 4.5% , and 29.2% versus 7.1% , respectively .
in addition , average serological levels of these tumor markers in positive cca patients were significantly higher than those in positive iac patients ( p<0.05 in all cases ) ( table 2 ) .
there were no significant differences in the serum biochemistry tests including alt , ast , ggt , alp , tbil , and dbil between iac and cca patients ( table 3 ) .
tumor maker detection in the iac and the cca groups serological measurement for the liver function of iac and cca patients thirty - one cca patients were tested for their sigg4 level , among whom 16.1% ( 5/31 ) were found to have an elevated level with a range between 29 and 8230 mg / l and an average of 896.3 mg / l .
almost 100% of the iac patients showed elevated sigg4 ranging between 1650 and 78,590 mg / l , with an average of 16028.6 mg / l .
when a cutoff level was set at 6 times the upper normal limit , the area under the curve for sigg4 was 0.981 in receiver operating characteristic analysis and sigg4 had 100% specificity for iac .
on the basis of the youden index calculation , the best cutoff value for sigg4 in this cohort was 1575 mg /
bile duct  occupying lesions were detected with ercp , mrcp , ct , b - ultrasound , or eus .
an occupying lesion was defined as a thickening of the bile duct wall with a very clear margin . as
shown in table 4 , the thickening wall ( p=0.001 ) and the occupying lesion ( p<0.001 ) of the duct were found significantly different in iac and cca by eus .
imaging comparison of iac and cca patients by different radiologic methods an example of an image taken with endoscopic ultrasonography that exhibited an occupying lesion of the bile duct .
aip was the most frequent comorbidity of iac and the incidence reached as high as 83.3% in this study .
the imaging diagnosis for aip included diffused pancreatic enlargement , irregular narrowing of the main pancreatic duct , and bile duct strictures . among the 30 iac patients ,
however , only 10.2% of the cca patients were found to have pancreas involvement and presented as tumor invasion .
kidney ( 20% ) and parotid gland or lacrimal gland ( 53.3% ) involvement were also present in iac patients , whereas none was found in cca .
both groups had hepatic hilar lymph nodule hyperplasia , but the percentage of incidents in iac patients was significantly higher ( 56.7% vs. 30.5% , p=0.004 ) .
when diagnosed or highly suspected , iac patients were treated with steroid therapy ( initial prednisolone dose as 30 mg / d for 2 wk ) .
the average sigg4 and tbil levels of iac patients decreased to 6278.37 mg / l and 26.14 mol / l , respectively .
prednisolone application resulted in a decrease in the sigg4 level in all iac patients , and a decrease in the bilirubin level was noticed in 80.77% of the iac patients .
iac was recently recognized as an independent disease from other igg4-related diseases , and there are no epidemiology data for iac based on a large population.6 differential diagnosis between iac and cca can be challenging as both diseases share several symptoms and signs.7 obstructive jaundice accompanied with skin pruritus , abdominal discomfort , and/or weight loss have been the most common symptoms in both iac and cca patients.810 iac patients may be positive for tumor markers , whereas cca patient can also exhibit elevated sigg4 .
imaging studies can also demonstrate many similarities including obstruction , dilatation , and a thickening wall of the bile duct . in this study
, we examined the clinical data collected from patients who were diagnosed with either iac or caa .
weight loss in iac patients was one of the symptoms that was significantly different from that of cca patients .
we observed similar incidences of iac in both male and female patients , which agrees with other studies reported earlier.11 no significant demographic differences were found between iac and cca patients .
the production of igg4 is related to the expression of several immune genetic factors , such as mhcii , polymorphism of nuclear factor-b , and fc - receptor - like ( fcrl ) 3.10 other scholars proposed the  induction and progression 
biphasic mechanism,12 in which decreased naive tregs may induce a th1 immune response with the release of proinflammatory cytokines to antigens such as self - antigen or microorganisms .
subsequently , th2-type immune responses may be involved in the disease progression , resulting in the production of igg4 . in the iac diagnosis criteria proposed by japanese scholars , the minimum level of igg4
was set as 1350 mg / l.2 however , the specificity at this cutoff is not sufficient to distinguish iac and cca .
oseini et al13 found that out of the 126 cca patients , 17 ( 13.5% ) had elevated sigg4 ( > 1400 mg / l ) and 4 ( 3.2% ) had a > 2-fold ( > 2800 mg / l ) increase . in our study ,
16.1% of the cca patients had an elevated sigg4 level ( range , 29 to 8230 mg / l ) , which could mislead to an iac diagnosis , although the level was significantly lower than that of the iac group . on the basis of this study , we concluded that the best cutoff value for sigg4 level was 1575
our study suggested a cutoff level that was 6-fold higher than the upper normal limit of igg4 , which was different from the 4-fold criteria proposed previously by oseini et al.13 ca199 presents in the fetal gastrointestinal and pancreatic epithelium , whereas its serum level in adults is very low .
its expression is elevated in adenocarcinoma cells , and is released into the blood through the thoracic duct .
therefore , it can be a useful marker for the diagnosis of pancreatic carcinoma , gastric carcinoma , cca , and intrahepatic cca.14 the serum level of ca199 can also be elevated in pancreatitis , obstructive jaundice , and sclerosing diseases , which may be produced by abnormal epithelial cells.1517 in our study , the serum ca199 level was found to be increased in most of the cca patients . in iac patients ,
the serum ca199 level also increased , but at a significantly lower incidence and a significantly lower level .
similarly , cea and ca242 were also found in the normal tissue.18 the incidence and elevated levels of cea and ca242 in cca patients were significantly higher than those in iac patients .
these findings were in line with the studies published earlier.14,19,20 space - occupying lesions of the biliary tract are often diagnosed by b - ultrasound , ct , mri , or ercp .
cca patients exhibit similar imaging characteristics , such as dilatation , thickening wall , or occupying lesion , which makes it difficult to distinguish one from the other . on reviewing the cases in our study
, we found that these 3 manifestations exhibited significantly differently under eus between iac and cca , which could make eus a valuable tool to distinguish these 2 diseases .
this finding was consistent with a previous study.21 multiple organ involvement , including most commonly the pancreas,19 the kidney , and the salivary and the lacrimal glands , is characteristic of iac.22,23 in this study , we had similar observations : 83.3% of the iac patients had obvious involvements of the pancreas , 20% had involvement of the kidney , and 53.3% had involvement of the salivary or the lacrimal glands .
in contrast , in cca patients , the biliary tract was always the only involved organ at an early stage and few had other organs involved even though neighboring tissue / organ invasion and distant metastasis could occur at middle and advanced stages .
. however , obtaining pathologic samples by puncture or ercp brush before surgery is invasive and may not be suitable for all patients , such as patients who are old , patients with coagulopathy , or those with high bilirubin.24 in addition , the positive rate of brush check is low.25 therefore , clinical examination and experimental treatment are very important for a differential diagnosis .
we observed complete response of iac patients to the steroid treatment , although in some cases the stent placement also played a role in the symptom alleviation .
the retrospective nature of this study made it difficult to obtain data of a single variable from all patients .
the case number of the iac was low , which may affect the significance of the study .
the use of a stent in some patients could be another factor in alleviating symptoms in iac patient , which was not taken into account for the response to steroid treatment because of the limited numbers .
our study suggested that 6-fold higher levels of sigg4 , tumor markers ( ca199 , cea , and ca242 ) , and other organ involvement could be used as reference criteria for the differential diagnosis of iac and cca .
for difficult cases , experimental steroid treatment can be used for further diagnosis under appropriate conditions .
 background and aim : immunoglobulin g4-associated cholangitis ( iac ) shares many similar symptoms with cholangiocarcinoma ( cca ) . however , the treatment and the prognosis are substantially different . this study aimed to identify the important markers for the differential diagnosis of these 2 diseases.methods:thirty iac patients and 275 cca patients 
 were reviewed retrospectively for their clinical symptoms , serological tests , and imaging characteristics . 
 posttreatment responses were also studied.results:igg4 had 100% specificity for iac at a cutoff of 6 times the upper normal limit . 
 iac patients had a significantly higher incidence of weight loss ( p=0.025 ) and a higher level of weight loss ( p=0.008 ) than cca patients . 
 the positive rates of biological markers ca199 , ca242 , and cea in cca and iac were 81.5% versus 42.9% , 45.5% versus 4.5% , and 29.2% versus 7.1% , respectively . 
 levels of these tumor markers in cca were significantly higher than in iac ( p<0.05 ) . 
 the thickened wall [ 17/18 ( 94.4% ) vs. 3/10 ( 30% ) , p=0.001 ] and the occupying lesion on the bile duct [ 1/18 ( 5.6% ) vs. 8/10 ( 80% ) , p<0.001 ] were found to be significantly different in iac and cca , respectively , by endoscopic ultrasonography . 
 autoimmune pancreatitis was the most frequently observed comorbidity of iac ( 25/30 ) . 
 all iac patients respond positively to steroid treatment.conclusions:increased tumor markers , 6-fold higher levels of serum igg4 , and other organs involvement could be the reference factors for a differential diagnosis of iac and cca . 
 endoscopic ultrasonography might be an effective imaging tool for diagnosis , although clinical signs and symptoms of iac and cca are similar . 
 experimental steroid treatment can be useful in the diagnosis for certain difficult cases . 
MATERIALS AND METHODS
Statistical Analysis
RESULTS
Demographical Data and Symptoms
Serological Tests
Imaging
Other Organ Involvements
Response to Treatment
DISCUSSION
CONCLUSIONS