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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 4  |  Page : 1275-1283

Serum immunoglobulin G4 in patients with nonmalignant common bile duct stricture


1 Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Menoufia, Egypt
3 Department of Clinical Pathology, National Liver Institute, Menoufia University, Menoufia, Egypt
4 Department of Gastroenterology and Hepatology, Shebin El-Kom Hospital of Fever, GI Diseases and Hepatic Diseases, Menoufia, Egypt

Date of Submission25-Dec-2020
Date of Decision26-Jan-2021
Date of Acceptance01-Feb-2021
Date of Web Publication24-Dec-2021

Correspondence Address:
Omar R Abdelmaksoud
MBBCh, Department of Gastroenterology and Hepatology, Shebin El-Kom Hospital of Fever, GI Diseases and Hepatic Diseases, Shebin El-Kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_464_20

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  Abstract 


Objectives
The aim of the present study was to assess the levels of serum immunoglobulin G4 (IgG4) in patients with distal common bile duct strictures in patients with benign biliary stricture (BBS).
Background
Biliary strictures frequently present a challenge in terms of diagnosis, which requires a multidisciplinary approach. Although up to 30% of biliary strictures can be benign, the vast majority are malignant, the two major malignancies being pancreatic adenocarcinoma and cholangiocarcinoma. One of the underdiagnosed causes of BBS is IgG4-associated cholangiopathy. Increased serum IgG4 levels can be observed in most patients with IgG4-related disease.
Patients and methods
Sixty-two patients with obstructive jaundice attending the endoscopy unit of National Liver Institute, Menoufia University, for endoscopic retrograde cholangiopancreatography in the duration from April 2019 to February 2020, were included in the present study. Twenty seven of them with BBSs, and the other 35 have malignant biliary strictures (MBSs). Another 35 healthy individuals of matched age and sex were included as a control group. Serum IgG4 was determined by ELISA.
Results
There was a high statistically significant difference regarding serum IgG4 between benign and control group and benign and malignant group. Serum IgG4 level above 134.95 mg/dl has specificity 82.86% and sensitivity 96.3% in distinguishing BBS from MBS. Serum IgG4 level above 129.8 mg/dl has specificity 94.29% and sensitivity 96.3% in distinguishing BBS from control. There was a statistically significant correlation between serum IgG4 level and alkaline phosphatase level (correlation coefficient 0.419).
Conclusion
A significant proportion of non-MBS could be IgG4-related cholangitis.

Keywords: autoimmune biliary stricture, common bile duct stricture, serum immunoglobulin G4


How to cite this article:
Seleem HM, Nada AS, Naguib MA, Abdelmaksoud OR, El-Gazzarah AR. Serum immunoglobulin G4 in patients with nonmalignant common bile duct stricture. Menoufia Med J 2021;34:1275-83

How to cite this URL:
Seleem HM, Nada AS, Naguib MA, Abdelmaksoud OR, El-Gazzarah AR. Serum immunoglobulin G4 in patients with nonmalignant common bile duct stricture. Menoufia Med J [serial online] 2021 [cited 2024 Mar 28];34:1275-83. Available from: http://www.mmj.eg.net/text.asp?2021/34/4/1275/333263




  Introduction Top


Biliary strictures represent a major diagnostic challenge in clinical practice, that usually necessitates a multidisciplinary approach [1]. The term 'indeterminate biliary strictures' has been proposed when an etiological diagnosis cannot be established after basic workup of abdominal imaging and endoscopic retrograde cholangiopancreatography (ERCP) has been made [2]. Although pancreatic adenocarcinoma and cholangiocarcinoma represent the most frequent causes, up to 30% of biliary strictures are benign [3]. Iatrogenic stricture represents the most frequent cause for benign biliary stricture (BBS) in western countries (up to 80%) [4].

Immunoglobulin G4-related disease (IgG4-RD) is a systemic chronic fibroinflammatory disorder that affects multiple organs [5]. The established diagnostic criteria for IgG4-RD include elevated serum IgG4 concentration (cut-off value of IgG4 levels >135 ng/dl). However, reference material selection is critical for accurate measurement of IgG subclasses [6].

In the last 2 years, we met a nonsmall number of cases with indeterminate biliary stricture in the ERCP unit of National Liver Institute. After reviewing the literature, we decided to study the prevalence of IgG4-RD as a cause of BBS and to achieve this goal, the present study aimed at assessing the level of serum IgG4 in patients with distal common bile duct (CBD) strictures.


  Patients and methods Top


An observational, analytical, case–control study in which 62 patients with obstructive jaundice attending the endoscopy unit of National Liver Institute, Menoufia University for ERCP in the duration from April 2019 to February 2020, were included. Twenty seven of them with BBSs were designated group I (benign group), and the other 35 patients with malignant biliary strictures (MBS) were designated group II (malignant group). Another 35 healthy individuals of matched age and sex were designated group III (control group). Inclusion criteria: patient age more than 18 years, patients with malignant or idiopathic CBD strictures. Exclusion criteria: patient age less than 18 years, posttraumatic or postsurgical CBD strictures, and patients with choledocholithiasis, patients with concomitant extrahepatic malignancies, or collagen diseases.

The approval of the ethical committee and informed written consent were taken from both the patients and control-group participants before being included in the present study.

All participants were subjected to detailed medical history and complete clinical examination. The following laboratory investigations were done: liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total and direct bilirubin, serum albumin, international normalized ratio (INR), tumor markers (carcinoembryonic antigen (CEA), cancer antigen (CA19-9)] (Roch Cobas 6000, Rotkreuz, Switzerland) for all patients with CBD strictures. Serum immunoglobulin G4 (IgG4) was measured for all patients in addition to the control group by ELISA using SinoGeneClon Hangzhou, China Biotech Company Chemicals. The following imaging investigations were done: abdominal ultrasonography (US) for all participants, magnetic resonance cholangiopancreatography (MRCP), or ERCP or both for cases only.

Statistical analysis

Statistical analysis of this study was conducted using SPSS, version 20.0 (SPSS Inc., Chicago, Illinois, USA). Data were expressed into two phases: descriptive and analytical study. χ2 test, t test, Mann–Whitney test, Kruskal–Wallis test, F test, post-hoc test, and Fisher's exact test were used. P value more than 0.05 was considered statistically nonsignificant. P value less than or equal to 0.05 was considered statistically significant. P value less than 0.001 was considered statistically highly significant.


  Results Top


There was a statistically insignificant difference between the studied groups in terms of age and sex (P > 0.05) [Table 1].
Table 1: Comparison between the three studied groups according to serum immunoglobulin G4 and patients characteristics

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There was a high statistically significant difference between groups I and II regarding the prevalence of biliary pain (P < 0.001), while there was a statistically insignificant difference regarding the prevalence of jaundice and fever (P > 0.05) [Table 1].

Statistical analysis of laboratory results of the studied groups revealed a high statistically significant difference as regards serum levels of AST, ALT, ALP, total and direct bilirubin, serum albumin, and INR (P < 0.001). On further analysis of the laboratory data of groups I and II, there was a statistically significant difference regarding ALP, serum albumin, INR, and tumor markers (CEA, CA19-9) (P ≤ 0.05) [Table 2].
Table 2: Comparison between the three studied groups according to laboratory results

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Regarding abdominal US results of the studied groups, there was a high statistically significant difference between the studied groups regarding the presence of pancreatic mass, presence of CBD stricture, intrahepatic biliary radicle dilatation (IHBRDs), and CBD diameter (P < 0.001) [Table 3].
Table 3: Comparison between the three studied groups according to abdominal ultrasound and between magnetic resonance cholangiopancreatography in benign and malignant groups

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Statistical analysis of MRCP findings of groups I and II revealed a high statistically significant difference regarding pancreatic duct diameter (P < 0.001), while there was a statistically significant difference regarding the presence of hepatic focal lesions, pancreatic mass, and CBD diameter (P ≤ 0.05), while there was a statistically insignificant difference regarding CBD-stricture site, IHBRDs, and the existence of endoluminal masses (P > 0.05) [Table 3].

Regarding ERCP data of groups I and II, there was a high statistically significant difference regarding papilla shape (P < 0.001), while there was a statistically significant difference regarding CBD diameter and number of biopsies taken (P ≤ 0.05), while there was a statistically insignificant difference as regards CBD-stricture site, papillotomy, papilloplasty, and plastic stent insertion [Table 4].
Table 4: Comparison between the two studied groups according to endoscopic retrograde cholangiopancreatography

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There was a high statistically significant difference regarding serum IgG4 of the three studied groups (P < 0.001). Further intergroup analysis revealed a high statistically significant difference between group I and each of the other two groups (P ≤ 0.001), while there was a statistically insignificant difference between groups II and III regarding serum IgG4 [Table 1].

Receiver-operating characteristic curve analysis revealed that serum IgG4 level at a cut-off level of 134.95 mg/dl has specificity 82.86% and sensitivity 96.3% in distinguishing BBS from MBS [Table 5].
Table 5: Receiver-operating characteristic curve identifying the appropriate serum immunoglobulin G4 cut offs for the two groups (benign and malignant) (benign and control)

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Univariate analysis within group I showed that there was a significant positive correlation between serum IgG4 level and ALP level (correlation coefficient 0.419, P < 0.05), while there was an insignificant correlation between serum IgG4 with any of the other parameters [AST, ALT, total and direct bilirubin, CBD diameter, biliary pain, jaundice, MRCP findings (pancreatic duct), and last ERCP CBD-stricture site] [Table 6].
Table 6: Relation and correlation between serum immunoglobulin G4 and different parameters in benign group (N=27)

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  Discussion Top


Indeterminate biliary strictures are strictures of the intrahepatic or extrahepatic bile ducts with no mass or lesion detectable on abdominal imaging, and without a clear explanation from the clinical context (e.g., traumatic or iatrogenic causes of biliary strictures, such as recent surgery), in which conventional workup is nondiagnostic [7].

In the present study, there was a statistically insignificant difference between the studied groups regarding age and the sex distributions (P > 0.05); similar results have been reported in a retrospective study by Kim et al. [8], in which the patients of both groups were of matched age and sex. In contrast, in the study of Al-Mofleh et al. [9], there was a statistically significant difference regarding age between benign and malignant groups.

Regarding the clinical manifestations of groups I and II, there was a high statistically significant difference regarding biliary pain (P < 0.001), while there was a statistically insignificant difference regarding the prevalence of jaundice and fever (P > 0.05).

These results are in agreement with Al-Mofleh et al.[9] who reported that jaundice was evident in more than 80% of patients with BBS and MBS, and right upper-quadrant pain in 50% of patients. Fever was less common and no significant differences were observed when both groups were compared. This statistically significant difference regarding biliary pain could be due to the early stage of BBS at the time of presentation in our patients.

Concerning lab results of the included patients in the present study, there was a high statistically significant difference between the studied groups regarding AST, ALT, ALP, total and direct bilirubin, serum albumin, and INR (P < 0.001). Further intergroup analysis revealed a statistically insignificant difference between groups I and II regarding AST, ALT, ALP, total bilirubin, and direct bilirubin.

In contrast with these results, Al-Mofleh et al.[9] reported that the mean serum values of bilirubin, ALP, ALT, and AST were significantly higher in patients with MBS. ALP resides in hepatic sinusoidal and biliary canalicular membranes and is overexpressed in cholestatic diseases. Several studies have shown that patients with malignant strictures or cholangiocarcinoma have higher levels of ALP than those with benign biliary diseases such as gallstones [10]. This may be due to the fact that biliary duct obstructions of malignant origins have higher tendency to cause complete obstruction and usually have prolonged durations than those of benign origins. The discrepancy between our results and Al-Mofleh and colleagues may be rationalized by the fact that the included patients with MBS in that study were at a more advanced stage with more aggressive stricture.

In the present study, further intergroup analysis revealed a statistically significant difference regarding serum albumin, INR, and tumor markers (CEA, CA19-9) (P < 0.05) and this was in agreement with Thomasset et al.[11] who stated that hypoalbuminemia was significantly associated with malignancy, despite normal bilirubin levels and normal liver-function tests. This was explained by the fact that hypoalbuminemia secondary to nutritional deficiency and cachexia typify terminal hepato–pancreatico–biliary cancers, while in the earlier stages, it arises from systemic inflammatory-response syndrome initiated by the presence of malignant cells [12].

Prolonged prothrombin time, although nonspecific, may reflect hepatic synthetic dysfunction and/or prolonged severe cholestasis in the absence of other nonhaptic etiologies [13].

CA19-9 is a well-known, very helpful biomarker for pancreaticobiliary cancer and its prognosis [14]. CEA is a well-established serum marker for gastrointestinal tract and pulmonary cancer, as well as a prognostic factor for cholangiocarcinoma [15].

In this study, there was a statistically significant difference among groups I and II regarding tumor markers CEA and CA 19-9 (P < 0.05) shown in [Table 2]. Mean serum values of CEA (ng/ml) and CA19-9 (U/ml) were significantly elevated in the MBS group (mean ± SD: 10.95 ± 26.35, 4467.6 ± 13086.7) than the BBS group (mean ± SD: 2.88 ± 1.28, 411.8 ± 972.9), respectively.

Elevated levels of CA19-9 and CEA were independently associated with malignant strictures in multivariate analysis. Park and Jeon[10] reported that mean serum values of CEA nanograms per milliliter and CA19-9 units per milliliter (U/ml) were significantly higher in the MBS group (mean ± SD: 3.96 ± 5.34, 1682 ± 3155.64) than the BBS group (mean ± SD: 1.49 ± 1.78, 91.02 ± 272.22), respectively. However, Navaneethan et al.[16] identified an association between elevated CA19-9 level and the diagnosis of cancer in indeterminate biliary strictures on follow-up. But there was no significant difference between BBS and MBS as regards serum levels of CEA (P > 0.05).

In the present study, in comparing the three studied groups, there was a high statistically significant difference regarding the presence of pancreatic mass, presence of CBD stricture, IHBRDs, and CBD diameter (P < 0.001).

US showed biliary dilatation and correctly identified the level of obstruction in all patients when compared with MRCP and ERCP. There was a high statistically significant difference between the studied groups regarding CBD dilatation and CBD diameter with mean diameters of 12.9, 14.99, and 4.7 mm, respectively. Pancreatic mass was found in 17/35 cases in group II, while no pancreatic masses were found in BBS and control.

These findings agreed with Saluja et al.[17] who concluded that US correctly determined the level of obstruction in all cases, but the patency of the confluence was assessed correctly in 96% of cases. The accuracy of US to determine the level of obstruction varies between 80 and 100% according to the literature [18].

In the present study, 37% of group I (10/27 patients) and 70% of group II (27/35 patients) were investigated by MRCP. There was a high statistically significant difference between groups I and II regarding pancreatic duct diameter (P < 0.001), while there was a statistically significant difference regarding the presence of focal liver lesion, presence of pancreatic mass, and CBD diameter (P < 0.05), while there was a statistically insignificant difference regarding the site of CBD stricture, IHBRDs, and endoluminal mass (P > 0.05).

On analyzing the MRCP results, 30% of group I (3/10 patients) had pancreatic duct dilatations versus 59.26% of group II (16/27 patients). Sixteen out of 27 patients in group II had pancreatic mass and a similar number showed focal hepatic lesions. Although all cases had distal CBD stricture, 3/10 patients in group I demonstrated the associated proximal stricture and two of them had intrahepatic strictures, while 2/27 patients in group II had associated proximal stricture and a similar number had intrahepatic stricture. Six patients in group II had endoluminal mass and three patients had increased CBD wall thickness. The mean values of CBD diameter in groups I and II were 12 and 15.7 mm, respectively.

MRCP can determine the level of obstruction in 85–100% of cases [19], while the sensitivity of differentiation of benign from malignant strictures varied widely from 30 to 98% in the literature [20]. Malignant strictures are usually long as they have an infiltrative growth pattern, which spreads intramurally beneath the epithelial lining. It was concluded that the presence of a mass, stricture with long length (3 vs. 1.2 cm), and an irregular margin and asymmetric dilatation of the bile ducts helped in making a diagnosis of a malignant stricture [21].

ERCP remains the most important procedure in the management of obstructive jaundice [22]. The yield of ERCP in differentiating MBS from BBS can be further improved with tissue sampling [23].

All the included patients in groups I and II underwent ERCP. Failed canulation occurred in four cases in group II. There was a high statistically significant difference regarding papilla shape (usually was enlarged in the malignant group) (P < 0.001), but there was a statistically significant difference regarding CBD diameter and number of biopsies taken from each group (P = 0.015, 0.001, respectively), there was a statistically insignificant difference between both groups regarding CBD-stricture site, papillotomy, and plastic stent insertion.

Biopsies were taken from 87.09% of group II (27/31 patients) versus only 33.33% of group I (9/27 patients). All cases had distal CBD strictures. In addition, 11.11% of group I (3/27 patients) had also proximal CBD stricture and 7.41% (2/27 patients) had intrahepatic stricture versus 6.45% (2/31 cases) with proximal CBD stricture and 3.23% (1/31 cases) with intrahepatic stricture in group II. All the cannulated cases within both groups were managed endoscopically.

These results disagreed with Al-Mofleh et al.[9] who reported that distal bile duct strictures were mainly associated with a malignant process, 48.6 versus 9% in BBS. This can be rationalized by the fact that we included benign cases with distal CBD strictures in our study.

In the present study, there was a high statistically significant difference between the studied groups regarding serum IgG4 (P < 0.001). Further intergroup analysis revealed that this highly significant difference is due to abnormally high serum IgG4 levels among group-I patients. Again, there was a statistically insignificant difference regarding serum IgG4 on comparing the results of groups II and III.

These results disagreed with Raina et al.[24] who concluded a statistically significant difference between pancreatic cancer group and the control group regarding serum IgG4 levels. Although the gap between both means looks too narrow (44.8 and 42.6 mg/dl, respectively), Fisher exact test demonstrated that the elevation was significant in pancreatic cancer cases when compared with controls (two-sided) (P = 0.04).

Receiver-operating characteristic curve analysis revealed that serum IgG4 above a cut-off level of 129.8 mg/dl had a specificity and sensitivity of 94.29 and 96.3%, respectively, in distinguishing BBS from control, while serum IgG4 levels above 134.95 mg/dl had a specificity and sensitivity of 82.86 and 96.3% in distinguishing BBS from MBS [Figure 1].
Figure 1: a) Multiple-comparison graph between the three studied groups as regards serum IgG4 level Box and Whisker with mean error bars (95% confidence interval of means). (b) Receiver-operating characteristic (ROC) curve identifying the appropriate serum IgG4 cutoffs for the two groups (benign and malignant). (c) ROC curve identifying the appropriate serum IgG4 cutoffs for the two groups (benign and control). IgG4, immunoglobulin G4.

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A serum cut-off value of IgG4 levels more than 135 mg/dl has been widely accepted for the diagnosis of the IgG4-RD and serum IgG4 concentrations were reported to be associated with disease activity [25]. Increased levels of serum IgG4 have been reported in cholangiocarcinoma, sclerosing cholangitis, and pancreatic carcinoma [26]. In a few patients who suffered from asthma, allergic dermatitis, rheumatoid arthritis, connective disease, and Castleman's disease, elevated serum IgG4 levels have also been observed [27],[28].

Yu et al.[29] indicated that the serum IgG4 concentration has a moderate-to-good positive predictive value in the diagnosis of IgG4-related sclerosing disease when it is more than two or three times the upper limit of the manufacturer's reference range of the IgG4 level.

In the present study, 26/27 (96.3%) cases within group I had serum IgG4 values above 135 mg/dl. These cases need further investigations to fulfill the criteria of diagnosis of IgG4-RD. This is obviously higher than that reported by Su et al.[27] who stated that 44/957 (4.6%) cases exhibited elevated serum IgG4 above 135 mg/dl, and 12/44 patients had definite IgG4-RD. This discrepancy might be rationalized by the difference of ethnicity, race, and patient characteristics, as well as the larger number of patients included in that study.

In group II, 17.1% of patients (only six patients) had serum values above 135 mg/dl. The etiological diagnoses of biliary obstruction in these cases were there are eight patients (four cases with pancreatic cancer, three cases with cholangiocarcinoma, and one case with hepatocellular carcinoma). Determining whether any relationship exists between malignant tumors and IgG4-RD will require further studies. Histopathological findings remain the gold standard for making differential diagnoses between IgG4-RD and cancer.

This rate was obviously higher than that reported by Su et al.[27] (3.39% in non-IgG4-RD patients had significant rates of serum IgG4 levels). They reported that 2.06% of carcinoma entities were associated with a positive serum IgG4 titer, including cases of hepatocellular carcinoma, gallbladder carcinoma, lung neoplasms, colorectal cancer, and hematologic malignancies. This discrepancy might be due to variable types of tumors included in that study, as well as difference of ethnicity and race of patients and our relatively limited number of samples.

In the present study, univariate analysis in the benign group revealed a significant positive correlation between serum IgG4 and ALP levels (correlation coefficient 0.419, P < 0.05), while there was an insignificant correlation between serum IgG4 and other parameters [AST, ALT, total bilirubin, direct bilirubin, US CBD diameter (by U/S and ERCP), IHBRDs, MRCP pancreatic duct diameter, and CBD-stricture site by ERCP].


  Conclusion Top


Our study presents primary but highly suggestive evidence that IgG4-RD can account for a nonsmall number of cases of benign (idiopathic) biliary strictures.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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