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doi:10.1111/jgh.12894
B I L I A R Y A N D PA N C R E AT I C
Comparison of intraductal ultrasonography findings between primary sclerosing cholangitis and IgG4-related sclerosing cholangitis Itaru Naitoh,* Takahiro Nakazawa,* Kazuki Hayashi,* Katsuyuki Miyabe,* Shuya Shimizu,* Hiromu Kondo,* Yuji Nishi,* Michihiro Yoshida,* Shuichiro Umemura,* Yasuki Hori,* Akihisa Kato,* Fumihiro Okumura,† Hitoshi Sano,† Hirotaka Ohara‡ and Takashi Joh* *Department of Gastroenterology and Metabolism, ‡Department of Community-Based Medical Education, Nagoya City University Graduate School of Medical Sciences, Nagoya, and †Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan
Key words cholangiogram, diverticulum-like outpouching, IgG4-related sclerosing cholangitis, intraductal ultrasonography, primary sclerosing cholangitis. Accepted for publication 4 January 2015. Correspondence Dr Takahiro Nakazawa, Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Email: [email protected] Disclosure: The authors declare that they have no conflict of interest.
Abstract Background and Aim: Comparisons of intraductal ultrasonography (IDUS) findings between primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis (IgG4-SC) have not been elucidated. We aimed to clarify the differences in transpapillary IDUS findings between PSC and IgG4-SC. Methods: We retrospectively compared transpapillary IDUS findings between 15 patients with PSC and 35 patients with IgG4-SC between 2004 and 2014. Results: IDUS findings of circular-asymmetric wall thickness, irregular inner margin, diverticulum-like outpouching, unclear outer margin, heterogeneous internal echo, and disappearance of three layers were significantly higher in PSC than in IgG4-SC (P < 0.001). Irregular inner margin, diverticulum-like outpouching, and disappearance of three layers were specific IDUS findings for PSC compared to IgG4-SC. Diverticulum-like outpouching on IDUS and endoscopic retrograde cholangiogram (ERC) was observed in 10 (67%) and five (33%) of 15 patients with PSC, respectively. However, based on IDUS and ERC, diverticulum-like outpouching was not observed in any patient with IgG4-SC. All five patients with diverticulum-like outpouching on ERC had diverticulum-like outpouching on IDUS, and five (50%) of 10 patients without diverticulum-like outpouching on ERC had diverticulum-like outpouching on IDUS. Conclusions: The IDUS findings differed between PSC and IgG4-SC. Irregular inner margin, diverticulum-like outpouching, and disappearance of three layers are specific IDUS findings for PSC compared to IgG4-SC. IDUS is a more useful procedure than ERC for the early detection of diverticulum-like outpouching.
Introduction Primary sclerosing cholangitis (PSC) is a chronic inflammatory cholestatic disease of unknown etiology, characterized by chronic inflammation and obliterative fibrosis of the intrahepatic and extrahepatic bile ducts. The diagnostic criteria of PSC proposed by the Mayo Clinic are in widespread use.1 Conversely, IgG4-related sclerosing cholangitis (IgG4-SC) is characterized by increased levels of serum IgG4, dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, frequent association with type 1 autoimmune pancreatitis (AIP), and a good response to steroid therapy. The concept of IgG4-SC has been recognized worldwide, and the clinical diagnostic criteria of IgG4-SC were first proposed recently in Japan.2 The cholangiographic features of IgG4-SC are similar to those of PSC or cholangiocarcinoma. Differentiating IgG4-SC from PSC or 1104
cholangiocarcinoma is critical because the therapeutic approaches for each disease are completely different. IgG4-SC is treated effectively with corticosteroids, whereas only liver transplantation is an effective therapy for PSC, and cholangiocarcinoma requires surgical intervention. Association with type 1 AIP is a useful finding in the diagnosis of IgG4-SC. However, cases of isolated IgG4-SC without type 1 AIP or other organ involvement exist.3,4 In previous reports, the serum IgG4 level was not high in cases of isolated IgG4-SC.4 Therefore, distinguishing isolated IgG4-SC from PSC or cholangiocarcinoma preoperatively is difficult, and so modalities that facilitate differentiation of IgG4-SC from the two diseases are necessary. We previously reported that the intraductal ultrasonography (IDUS) findings of IgG4-SC and cholangiocarcinoma were different and enabled distinction of the two conditions.5 Various procedures to differentiate between IgG4-SC and PSC have been reported.6–8 We reported that characteristic
Journal of Gastroenterology and Hepatology 30 (2015) 1104–1109 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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cholangiographic features using endoscopic retrograde cholangiogram (ERC) were useful for discriminating between IgG4-SC and PSC. Band-like stricture, beaded or pruned-tree appearance, and diverticulum-like outpouching were cholangiographic findings specific for PSC.7 However, the sensitivity of diverticulum-like outpouching was the lowest of the above-mentioned three ERC findings. We previously showed that circular-symmetrical wall thickening, smooth outer and inner margin, and homogeneous internal echo at the biliary strictures observed on IDUS were useful for the diagnosis of IgG4-SC.5 Currently, however, only one report focuses on the IDUS findings of PSC,9 which have thus not been elucidated. Consequently, we retrospectively compared the IDUS findings of PSC and IgG4-SC to clarify the features of PSC.
Patients and methods Fifteen patients (seven males and eight females; median age: 37 years) with PSC and 35 patients with IgG4-SC (29 males and six females; median age: 69 years) who underwent endoscopic transpapillary IDUS at the Nagoya City University Graduate School of Medical Sciences between 2004 and 2014 were enrolled in this study. All 15 patients were diagnosed with PSC on the basis of the diagnostic criteria reported by Lindor et al.,1 and all 35 patients were diagnosed with IgG4-SC on the basis of clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012.2 Inclusion criteria for IDUS were (i) biliary stricture by suspected PSC or IgG4-SC, and (ii) first ERCP. Exclusion criteria were (i) inability to obtain informed consent, and (ii) age ≤ 18 years. There were 20 patients with PSC and 37 patients with IgG4-SC who fulfilled inclusion criteria for IDUS between 2004 and 2014. Five (25%) of 20 patients were excluded because of (i) inability to obtain informed consent (one patient), (ii) age ≤ 18 years (three patients), and (iii) Billroth-II reconstruction (one patient). Two (5%) of 37 patients with IgG4-SC were excluded because of the failure of biliary cannulation. IDUS was performed after ERC. Endoscopic sphincterotomy was not performed prior to IDUS insertion in all patients. The IDUS probe was inserted into the bile duct along the guidewire. The IDUS probe was routinely inserted into right and/or left hepatic bile duct. The IDUS probe was 2.4 mm in diameter with a monorail-type tip and a scanning frequency of 20 MHz (UM-G20-29R, Olympus Optical Co, Tokyo, Japan). The study was approved by the Review Board of Nagoya City University Graduate School of Medical Sciences (approval no. 1053), and informed consent was obtained from all patients. IDUS findings. The IDUS findings were evaluated at the biliary strictures between hepatic bile duct and duodenal papilla. In the case of diffuse biliary stricture, the priority order of biliary location in which IDUS findings was evaluated was as follows: (i) proximal-middle common bile duct; (ii) hilar hepatic bile duct; and (iii) intrapancreatic bile duct. Modified criteria were used to evaluate the IDUS findings,9,10 as follows: (i) origin (wall thickness, extrinsic compression); (ii) symmetry (circular-symmetric, circular-asymmetric, semicircular); (iii) outer margin (clear, unclear); (iv) inner margin (smooth, irregular); (v) internal echo (homogeneous, heterogeneous); (vi) internal foci (present, absent); and (vii) bile duct wall thickness. In this study, we incor-
IDUS findings between PSC and IgG4-SC
porated (viii) diverticulum-like outpouching (present, absent) and (ix) three layers (preservation, disappear) as new IDUS findings. Diverticulum-like outpouching was defined as outpouching into the bile duct wall resembling diverticula. The bile duct wall usually consists of three layers on IDUS. We defined preservation of three layers when their construction was preserved and disappearance when absent. We compared the nine IDUS findings of PSC and IgG4-SC. We also compared the association of diverticulum-like outpouching with IDUS and ERC results in all patients. The IDUS images were reviewed by two experts (IN, TN) who were blinded to ERC findings and the other clinical data. Statistical analysis. The chi-squared test and Fisher’s exact test were used for comparison of categorical data. Comparisons between continuous variables and categorical variables were performed using the Mann–Whitney U-test and Fisher’s exact test, respectively. Statistical tests were two sided, and significance was defined as P < 0.05. All statistical analyses were performed using the IBM SPSS statistics software, version 21 (IBM, Armonk, New York, USA).
Results Patient characteristics. A total of 50 patients (15 patients with PSC and 35 patients with IgG4-SC) were included in this study (Table 1). The age and male/female ratio were significantly higher in patients with IgG4-SC. The serum IgG4 level was significantly higher in patients with IgG4-SC than those with PSC (320 versus 38 mg/dL; P < 0.001). An increased serum IgG4 level (> 135 mg/dL) was observed significantly more frequently in patients with IgG4-SC than PSC (71% vs 7%; P < 0.001). The serum aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, and total-bilirubin levels were significantly higher in patients with IgG4-SC than those with PSC. Cholangiograms showed intra- and extrahepatic types in all 15 patients with PSC. Cholangiograms of the 35 patients with IgG4-SC were classified into 21cases of type 1, eight of type 2, two of type 3, and four of type 4 according to our classification.11 IDUS findings of PSC. The IDUS probe could be inserted into right and/or left hepatic bile duct, and IDUS findings from hepatic bile duct to duodenal papilla were analyzed in all 15 (100%) patients with PSC (Table 2, Figs 1 and 2). The origin of the strictures was wall thickening in all 15 (100%) patients. The symmetry was circular-asymmetric in 14 (93%) patients. The inner margin was irregular in all 15 patients and diverticulum-like outpouching was observed in 10 (67%) patients. The outer margin was unclear in 13 (82%) patients, the internal echo was heterogeneous in eight (53%) patients and the internal foci were observed in all (100%) patients. Disappearance of three layers was observed in all (100%) patients. The median wall thickness in which the bile duct wall was thickest was 2.4 mm (interquartile range 1.8–3.0 mm). IDUS findings of IgG4-SC. The IDUS probe could be inserted into right and/or left hepatic bile duct, and IDUS findings from hepatic bile duct to duodenal papilla were analyzed in all 35 (100%) patients with IgG4-SC (Table 2, Fig. 3). The origin of the
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IDUS findings between PSC and IgG4-SC
Table 1
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Patient characteristics
Parameter
PSC (n = 15)
Clinical features Age (years), median (range) Gender (male : female) Association of Type1 AIP, n (%) Association of IBD, n (%) Serology and Biochemistry IgG4 > 135 mg/dL, n (%) IgG4 (mg/dL), median (range) IgG (mg/dL), median (range) AST (IU/L), median (range) ALT (IU/L), median (range) ALP (IU/L), median (range) γ-GTP (IU/L), median (range) T-Bil (mg/dL), median (range) Endoscopic retrograde choangiogram PSC type (Intra: Intra and extra hepatic) IgG4-SC type (1:2:3:4)
IgG4-SC (n = 35)
P-value
69 (45–83) 29:6 35 (100) 0
< 0.001** 0.009** < 0.001** < 0.001**
1 (7.7) 38 (3–200) 1499 (962–3150) 49 (12–117) 65 (6–183) 834 (182–1722) 253 (17–679) 0.8 (0.4–1.7)
25 (71) 320 (28–2932) 1689 (1021–5041) 103 (16–708) 159 (13–608) 1016 (246–2350) 495 (13–1930) 3.2 (0.2–16.4)
< 0.001** < 0.001** 0.166 0.016* 0.029* 0.276 0.013* 0.038*
0:15 —
— 21:8:2:4
— —
37 (22–72) 7:8 0 7 (46.7)
**P < 0.01; *P < 0.05. AIP, autoimmune pancreatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; γ-GTP, γ-glutamyl transpeptidase; IBD, inflammatory bowel disease; IgG4-SC, IgG4-related sclerosing cholangitis; PSC, primary sclerosing cholangitis; T-Bil, totalbilirubin.
Table 2
IDUS findings between PSC and IgG4-SC
IDUS findings
PSC (n = 15)
IgG4-SC (n = 35)
15:0
33:2
P-value
Origin Wall thickness : extrinsic compression
1
Symmetry Symmetric : asymmetric**
1:14
27:6
< 0.001**
0:15 10:5
33:0 0:33
< 0.001** < 0.001**
2:13
33:0
< 0.001**
7:8 15:0
33:0 33:0
< 0.001** 1
0:15 2.4 (1.8–3.0)
33:0 2.5 (2.2–2.9)
< 0.001** 0.469
Inner margin Smooth : irregular** Diverticulum-like outpouching (+ : −)** Outer margin Clear : unclear** Internal echo Homogeneous : heterogeneous** Internal foci (+ : −) Three layers structure Preservation : disappearance** Wall Thickness (mm), median (IQR)
**P < 0.01. IgG4-SC, IgG4-related sclerosing cholangitis; IQR, interquartile range; PSC, primary sclerosing cholangitis.
strictures was wall thickening in 33 (94%) of 35 patients and extrinsic compression from the pancreas in the remaining two (7%) patients. Among the 33 patients with wall thickening, the symmetry was circular-symmetric in 27 patients (82%) and circular-asymmetric in six (18%). The inner margin, outer margin, and internal echo were smooth, clear, and homogeneous, respectively, in all patients. The internal foci were observed in all (100%) patients. Diverticulum-like outpouching was not observed in any of the patients. Preservation of three layers was observed in all (100%) patients. The median wall thickness in which the bile duct wall was thickest was 2.5 mm (interquartile range 2.2–2.9 mm). 1106
Comparison of IDUS findings between PSC and IgG4-SC. Circular-asymmetric wall thickness, irregular inner margin, diverticulum-like outpouching, unclear outer margin, a heterogeneous internal echo, and disappearance of three layers in the stricture observed on IDUS were significantly more frequent in PSC than in IgG4-SC (P < 0.001). Irregular inner margin, diverticulum-like outpouching, and disappearance of three layers were IDUS findings specific for PSC (Table 2). Diverticulum-like outpouching between IDUS and ERC. Diverticulum-like outpouching was not observed in any IgG4-SC patient on IDUS and ERC. Diverticulum-like
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IDUS findings between PSC and IgG4-SC
Figure 1 Endoscopic retrograde cholangiography showed diverticulum-like outpouching (white arrows) in a patient with primary sclerosing cholangitis. (a) Intraductal ultrasonography showed diverticulum-like outpouching (white arrow). Symmetry was circularasymmetric. Inner margin was irregular, and outer margin was notched. Three layers were disappeared. Internal echo was heterogeneous, and internal foci were observed.
Figure 2 Endoscopic retrograde cholangiography showed no diverticulum-like outpouching in a patient with PSC. (a) Intraductal ultrasonography showed diverticulum-like outpouching (a white arrow). Symmetry was circular-asymmetric. Inner margin was irregular, and outer margin was notched. Three layers were disappeared. Internal echo was homogeneous, and internal foci were observed.
outpouching on IDUS and ERC was observed in 10 (67%) and five (33%) of 15 patients with PSC, respectively. Diverticulum-like outpouching on IDUS was slightly higher than on ERC (67% vs 33%; P = 0.068). All five patients with diverticulum-like outpouching on ERC showed diverticulum-like outpouching on IDUS, and five (50%) of 10 patients without diverticulum-like outpouching on ERC showed diverticulum-like outpouching on IDUS. Conversely, none of the five patients without diverticulumlike outpouching on IDUS showed diverticulum-like outpouching on ERC.
Discussion The present study revealed that the typical IDUS findings of PSC were circular-asymmetric wall thickness, irregular inner margin, unclear outer margin, diverticulum-like outpouching, heterogeneous internal echo, and disappearance of three layers. Irregular inner margin, diverticulum-like outpouching, and disappearance of three layers were IDUS findings specific for PSC compared to IgG4-SC. The differences in the IDUS findings of PSC and IgG4-SC are summarized in Figure 4. We previously compared the IDUS findings of IgG4-SC with cholangiocarcinoma to clarify the typical IgG4-SC IDUS
findings.5 The most characteristic IgG4-SC IDUS finding was thickening of the bile duct wall that appeared normal on ERC. However, the IDUS findings of PSC have not yet been elucidated. Currently, only one study of the IDUS findings of PSC has been reported by Kubota et al.9 Our results of wall thickness, wall symmetry, and outer margin findings of PSC were similar to those of Kubota et al.; however, our incidence of internal foci of PSC was higher (100% vs 10%). Kubota et al. presumed that internal foci in the bile duct indicated the same type of inflammation that could be detected in the pancreas of type 1 AIP patients. We also considered internal foci to be a typical IDUS finding of IgG4-SC. However, we observed internal foci on IDUS in patients with PSC. Therefore, the specificity of internal foci for IgG4-SC was not considered high. The histological features of PSC are the “onionskin” type periductal fibrosis and collagen bands that are usually lamellated, better organized, and less cellular.12,13 Therefore, internal foci can hypothetically be observed in PSC based on pathological PSC features. Furthermore, the diagnostic standard for foci observed on IDUS may differ among observers due to the subjectivity of this finding. In the present study, irregular inner margin and disappearance of three layers observed on IDUS showed high sensitivity (100%) and specificity (100%) in the differential diagnosis of PSC from
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a1
a b
b2 Figure 3 Endoscopic retrograde cholangiography showed hilar stricture in a patient with IgG4-sclerosing cholangitis. (a), (b) Intraductal ultrasonography showed wall thickness in hilar stricture. Symmetry was circularsymmetric. Inner margin and outer margin were smooth and clear. Three layers were preserved. Internal echo was homogeneous, and internal foci were observed.
Figure 4 Summary of intraductal ultrasonography (IDUS) findings between primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis (IgG4-SC).
IgG4-SC. Pathological findings of PSC included the luminal side of the bile ducts (including the biliary epithelial cell lining) being preferentially affected compared with in IgG4-SC,12,13 whereas fibroinflammatory involvement was observed mainly in the submucosa of the bile duct wall, and the epithelium of the bile duct was intact in IgG4-SC.14 We suggest that irregular inner margin and disappearance of three layers observed on IDUS represent inflammation of the luminal side of the bile duct in PSC. In the present study, we first evaluated diverticulum-like outpouching observed on IDUS. We previously reported that ERC is a useful method for distinguishing IgG4-SC from PSC.7 In the previous study, diverticulum-like outpouching was an ERC finding specific for PSC, similar to band-like stricture and a beaded or pruned-tree appearance. We suggest that the diverticulum-like outpouching observed on ERC is the most objective finding that can be judged adequately by investigators, but has the lowest sensitivity for PSC among the specific findings. The sensitivities of 1108
diverticulum-like outpouching on ERC for PSC were 34% (10/29) and 33% (5/15) in the previous7 and present study, respectively. In the present study, diverticulum-like outpouching on IDUS was observed in 10 (67%) of 15 patients with PSC, which was slightly higher than on ERC (67% vs 33%; P = 0.068). Conversely, diverticulum-like outpouching on IDUS and ERC was not observed in any patient with IgG4-SC. All five patients with diverticulum-like outpouching on ERC had diverticulum-like outpouching on IDUS, and five (50%) of 10 patients without diverticulum-like outpouching on ERC had diverticulum-like outpouching on IDUS. Conversely, none of the five patients without diverticulum-like outpouching on IDUS had diverticulum-like outpouching on ERC. We suggest that diverticulum-like outpouching is a useful finding for differentiation of PSC from IgG4-SC on IDUS in addition to ERC. These results suggest that IDUS is a more useful procedure than ERC for early detection of diverticulum-like outpouching. It is difficult to differentiate PSC and IgG4-SC especially in PSC cases with high serum IgG4 levels or IgG4-SC cases with little or without pancreatic involvement (type 1 AIP).3,4,15,16 A small proportion of PSC cases demonstrated high-serum IgG4 level,17 and showed periductal infiltration of IgG4-positive plasma cells.18,19 Clinical differences between PSC cases with and without increased IgG4-positive plasma cells have also been reported. In the present study, there were no differences of IDUS findings between PSC cases with normal serum IgG4 level and high-serum IgG4 level, and there were also no differences between IgG4-SC cases with typical and little pancreatic involvement. The present study has several limitations. These include the retrospective and uncontrolled study design, the relatively low number of available patients, and the fact that there was a selection bias to perform IDUS among patients with PSC or IgG4-SC. Therefore, a prospective, randomized controlled trial and a larger number of patients must be conducted. In conclusion, the characteristic features of PSC on IDUS were useful for distinguishing PSC from IgG4-SC. Irregular inner
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margin, diverticulum-like outpouching, and disappearance of three layers were IDUS findings specific for PSC compared to IgG4-SC. IDUS is a more useful procedure than ERC for the early detection of diverticulum-like outpouching.
Acknowledgment
IDUS findings between PSC and IgG4-SC
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This work was supported by “Research on Measures for Intractable Diseases” Project: matching fund subsidy from Ministry of Health Labor and Welfare, Japan.
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References
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1 Lindor KD, LaRusso NF. Primary sclerosing cholangitis. In: Schiff L, Schiff ER, eds. Schiff’s Disease of the Liver, 9th edn. Philadelphia: JB Lippincott, 2003; 673–84. 2 Ohara H, Okazaki K, Tsubouchi H et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J. Hepatobiliary Pancreat. Sci. 2012; 19: 536–42. 3 Hamano H, Kawa S, Uehara T et al. Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of a spectrum of autoimmune pancreatitis? Gastrointest. Endosc. 2005; 62: 152–7. 4 Graham RP, Smyrk TC, Chari ST, Takahashi N, Zhang L. Isolated IgG4-related sclerosing cholangitis: a report of 9 cases. Hum. Pathol. 2014; 45: 1722–9. 5 Naitoh I, Nakazawa T, Ohara H et al. Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing cholangitis. J. Gastroenterol. 2009; 44: 1147–55. 6 Nakazawa T, Ohara H, Sano H et al. Clinical differences between primary sclerosing cholangitis and sclerosing cholangitis with autoimmune pancreatitis. Pancreas 2005; 30: 20–5. 7 Nakazawa T, Ohara H, Sano H et al. Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis. Gastrointest. Endosc. 2004; 60: 937–44. 8 Naitoh I, Zen Y, Nakazawa T et al. Small bile duct involvement in IgG4-related sclerosing cholangitis: liver biopsy and
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cholangiography correlation. J. Gastroenterol. 2011; 46: 269–76. Kubota K, Kato S, Uchiyama T et al. Discrimination between sclerosing cholangitis-associated autoimmune pancreatitis and primary sclerosing cholangitis, cancer using intraductal ultrasonography. Dig. Endosc. 2011; 23: 10–6. Tamada K, Kanai N, Wada S et al. Utility and limitations of intraductal ultrasonography in distinguishing longitudinal cancer extension along the bile duct from inflammatory wall thickening. Abdom. Imaging 2001; 26: 623–31. Nakazawa T, Ohara H, Sano H, Ando T, Joh T. Schematic classification of sclerosing cholangitis with autoimmune pancreatitis by cholangiography. Pancreas 2006; 32: 229. Ludwig J. Surgical pathology of the syndrome of primary sclerosing cholangitis. Am. J. Surg. Pathol. 1989; 13 (Suppl. 1): 43–9. Scheuer PJ. Ludwig Symposium on biliary disorders – part II. Pathologic features and evolution of primary biliary cirrhosis and primary sclerosing cholangitis. Mayo Clin. Proc. 1998; 73: 179–83. Zen Y, Harada K, Sasaki M et al. IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am. J. Surg. Pathol. 2004; 28: 1193–203. Hayashi K, Nakazawa T, Ohara H et al. Autoimmune sclerosing cholangiopancreatitis with little pancreatic involvements by imaging findings. Hepatogastroenterology 2007; 54: 2146–51. Matsubayashi H, Uesaka K, Sugiura T, Ohgi K, Sasaki K, Ono H. IgG4-related sclerosing cholangitis without obvious pancreatic lesion: difficulty in differential diagnosis. J Dig Dis. 2014; 15: 394–403. Ohara H, Nakazawa T, Kawa S et al. Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related sclerosing cholangitis: a Japanese cohort. J. Gastroenterol. Hepatol. 2013; 28: 68–72. Zhang L, Lewis JT, Abraham SC et al. IgG4+ plasma cell infiltrates in liver explants with primary sclerosing cholangitis. Am. J. Surg. Pathol. 2010; 34: 88–94. Matsubayashi H, Igarashi K, Kishida Y, Yoshida Y, Sasaki K, Ono H. Sclerosing cholangitis with thumbprint appearance and incomplete steroid response. J Dig Dis. 2014; 15: 578–82.
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doi:10.1111/jgh.12894
B I L I A R Y A N D PA N C R E AT I C
Comparison of intraductal ultrasonography findings between primary sclerosing cholangitis and IgG4-related sclerosing cholangitis Itaru Naitoh,* Takahiro Nakazawa,* Kazuki Hayashi,* Katsuyuki Miyabe,* Shuya Shimizu,* Hiromu Kondo,* Yuji Nishi,* Michihiro Yoshida,* Shuichiro Umemura,* Yasuki Hori,* Akihisa Kato,* Fumihiro Okumura,† Hitoshi Sano,† Hirotaka Ohara‡ and Takashi Joh* *Department of Gastroenterology and Metabolism, ‡Department of Community-Based Medical Education, Nagoya City University Graduate School of Medical Sciences, Nagoya, and †Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan
Key words cholangiogram, diverticulum-like outpouching, IgG4-related sclerosing cholangitis, intraductal ultrasonography, primary sclerosing cholangitis. Accepted for publication 4 January 2015. Correspondence Dr Takahiro Nakazawa, Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Email: [email protected] Disclosure: The authors declare that they have no conflict of interest.
Abstract Background and Aim: Comparisons of intraductal ultrasonography (IDUS) findings between primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis (IgG4-SC) have not been elucidated. We aimed to clarify the differences in transpapillary IDUS findings between PSC and IgG4-SC. Methods: We retrospectively compared transpapillary IDUS findings between 15 patients with PSC and 35 patients with IgG4-SC between 2004 and 2014. Results: IDUS findings of circular-asymmetric wall thickness, irregular inner margin, diverticulum-like outpouching, unclear outer margin, heterogeneous internal echo, and disappearance of three layers were significantly higher in PSC than in IgG4-SC (P < 0.001). Irregular inner margin, diverticulum-like outpouching, and disappearance of three layers were specific IDUS findings for PSC compared to IgG4-SC. Diverticulum-like outpouching on IDUS and endoscopic retrograde cholangiogram (ERC) was observed in 10 (67%) and five (33%) of 15 patients with PSC, respectively. However, based on IDUS and ERC, diverticulum-like outpouching was not observed in any patient with IgG4-SC. All five patients with diverticulum-like outpouching on ERC had diverticulum-like outpouching on IDUS, and five (50%) of 10 patients without diverticulum-like outpouching on ERC had diverticulum-like outpouching on IDUS. Conclusions: The IDUS findings differed between PSC and IgG4-SC. Irregular inner margin, diverticulum-like outpouching, and disappearance of three layers are specific IDUS findings for PSC compared to IgG4-SC. IDUS is a more useful procedure than ERC for the early detection of diverticulum-like outpouching.
Introduction Primary sclerosing cholangitis (PSC) is a chronic inflammatory cholestatic disease of unknown etiology, characterized by chronic inflammation and obliterative fibrosis of the intrahepatic and extrahepatic bile ducts. The diagnostic criteria of PSC proposed by the Mayo Clinic are in widespread use.1 Conversely, IgG4-related sclerosing cholangitis (IgG4-SC) is characterized by increased levels of serum IgG4, dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, frequent association with type 1 autoimmune pancreatitis (AIP), and a good response to steroid therapy. The concept of IgG4-SC has been recognized worldwide, and the clinical diagnostic criteria of IgG4-SC were first proposed recently in Japan.2 The cholangiographic features of IgG4-SC are similar to those of PSC or cholangiocarcinoma. Differentiating IgG4-SC from PSC or 1104
cholangiocarcinoma is critical because the therapeutic approaches for each disease are completely different. IgG4-SC is treated effectively with corticosteroids, whereas only liver transplantation is an effective therapy for PSC, and cholangiocarcinoma requires surgical intervention. Association with type 1 AIP is a useful finding in the diagnosis of IgG4-SC. However, cases of isolated IgG4-SC without type 1 AIP or other organ involvement exist.3,4 In previous reports, the serum IgG4 level was not high in cases of isolated IgG4-SC.4 Therefore, distinguishing isolated IgG4-SC from PSC or cholangiocarcinoma preoperatively is difficult, and so modalities that facilitate differentiation of IgG4-SC from the two diseases are necessary. We previously reported that the intraductal ultrasonography (IDUS) findings of IgG4-SC and cholangiocarcinoma were different and enabled distinction of the two conditions.5 Various procedures to differentiate between IgG4-SC and PSC have been reported.6–8 We reported that characteristic
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cholangiographic features using endoscopic retrograde cholangiogram (ERC) were useful for discriminating between IgG4-SC and PSC. Band-like stricture, beaded or pruned-tree appearance, and diverticulum-like outpouching were cholangiographic findings specific for PSC.7 However, the sensitivity of diverticulum-like outpouching was the lowest of the above-mentioned three ERC findings. We previously showed that circular-symmetrical wall thickening, smooth outer and inner margin, and homogeneous internal echo at the biliary strictures observed on IDUS were useful for the diagnosis of IgG4-SC.5 Currently, however, only one report focuses on the IDUS findings of PSC,9 which have thus not been elucidated. Consequently, we retrospectively compared the IDUS findings of PSC and IgG4-SC to clarify the features of PSC.
Patients and methods Fifteen patients (seven males and eight females; median age: 37 years) with PSC and 35 patients with IgG4-SC (29 males and six females; median age: 69 years) who underwent endoscopic transpapillary IDUS at the Nagoya City University Graduate School of Medical Sciences between 2004 and 2014 were enrolled in this study. All 15 patients were diagnosed with PSC on the basis of the diagnostic criteria reported by Lindor et al.,1 and all 35 patients were diagnosed with IgG4-SC on the basis of clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012.2 Inclusion criteria for IDUS were (i) biliary stricture by suspected PSC or IgG4-SC, and (ii) first ERCP. Exclusion criteria were (i) inability to obtain informed consent, and (ii) age ≤ 18 years. There were 20 patients with PSC and 37 patients with IgG4-SC who fulfilled inclusion criteria for IDUS between 2004 and 2014. Five (25%) of 20 patients were excluded because of (i) inability to obtain informed consent (one patient), (ii) age ≤ 18 years (three patients), and (iii) Billroth-II reconstruction (one patient). Two (5%) of 37 patients with IgG4-SC were excluded because of the failure of biliary cannulation. IDUS was performed after ERC. Endoscopic sphincterotomy was not performed prior to IDUS insertion in all patients. The IDUS probe was inserted into the bile duct along the guidewire. The IDUS probe was routinely inserted into right and/or left hepatic bile duct. The IDUS probe was 2.4 mm in diameter with a monorail-type tip and a scanning frequency of 20 MHz (UM-G20-29R, Olympus Optical Co, Tokyo, Japan). The study was approved by the Review Board of Nagoya City University Graduate School of Medical Sciences (approval no. 1053), and informed consent was obtained from all patients. IDUS findings. The IDUS findings were evaluated at the biliary strictures between hepatic bile duct and duodenal papilla. In the case of diffuse biliary stricture, the priority order of biliary location in which IDUS findings was evaluated was as follows: (i) proximal-middle common bile duct; (ii) hilar hepatic bile duct; and (iii) intrapancreatic bile duct. Modified criteria were used to evaluate the IDUS findings,9,10 as follows: (i) origin (wall thickness, extrinsic compression); (ii) symmetry (circular-symmetric, circular-asymmetric, semicircular); (iii) outer margin (clear, unclear); (iv) inner margin (smooth, irregular); (v) internal echo (homogeneous, heterogeneous); (vi) internal foci (present, absent); and (vii) bile duct wall thickness. In this study, we incor-
IDUS findings between PSC and IgG4-SC
porated (viii) diverticulum-like outpouching (present, absent) and (ix) three layers (preservation, disappear) as new IDUS findings. Diverticulum-like outpouching was defined as outpouching into the bile duct wall resembling diverticula. The bile duct wall usually consists of three layers on IDUS. We defined preservation of three layers when their construction was preserved and disappearance when absent. We compared the nine IDUS findings of PSC and IgG4-SC. We also compared the association of diverticulum-like outpouching with IDUS and ERC results in all patients. The IDUS images were reviewed by two experts (IN, TN) who were blinded to ERC findings and the other clinical data. Statistical analysis. The chi-squared test and Fisher’s exact test were used for comparison of categorical data. Comparisons between continuous variables and categorical variables were performed using the Mann–Whitney U-test and Fisher’s exact test, respectively. Statistical tests were two sided, and significance was defined as P < 0.05. All statistical analyses were performed using the IBM SPSS statistics software, version 21 (IBM, Armonk, New York, USA).
Results Patient characteristics. A total of 50 patients (15 patients with PSC and 35 patients with IgG4-SC) were included in this study (Table 1). The age and male/female ratio were significantly higher in patients with IgG4-SC. The serum IgG4 level was significantly higher in patients with IgG4-SC than those with PSC (320 versus 38 mg/dL; P < 0.001). An increased serum IgG4 level (> 135 mg/dL) was observed significantly more frequently in patients with IgG4-SC than PSC (71% vs 7%; P < 0.001). The serum aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, and total-bilirubin levels were significantly higher in patients with IgG4-SC than those with PSC. Cholangiograms showed intra- and extrahepatic types in all 15 patients with PSC. Cholangiograms of the 35 patients with IgG4-SC were classified into 21cases of type 1, eight of type 2, two of type 3, and four of type 4 according to our classification.11 IDUS findings of PSC. The IDUS probe could be inserted into right and/or left hepatic bile duct, and IDUS findings from hepatic bile duct to duodenal papilla were analyzed in all 15 (100%) patients with PSC (Table 2, Figs 1 and 2). The origin of the strictures was wall thickening in all 15 (100%) patients. The symmetry was circular-asymmetric in 14 (93%) patients. The inner margin was irregular in all 15 patients and diverticulum-like outpouching was observed in 10 (67%) patients. The outer margin was unclear in 13 (82%) patients, the internal echo was heterogeneous in eight (53%) patients and the internal foci were observed in all (100%) patients. Disappearance of three layers was observed in all (100%) patients. The median wall thickness in which the bile duct wall was thickest was 2.4 mm (interquartile range 1.8–3.0 mm). IDUS findings of IgG4-SC. The IDUS probe could be inserted into right and/or left hepatic bile duct, and IDUS findings from hepatic bile duct to duodenal papilla were analyzed in all 35 (100%) patients with IgG4-SC (Table 2, Fig. 3). The origin of the
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IDUS findings between PSC and IgG4-SC
Table 1
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Patient characteristics
Parameter
PSC (n = 15)
Clinical features Age (years), median (range) Gender (male : female) Association of Type1 AIP, n (%) Association of IBD, n (%) Serology and Biochemistry IgG4 > 135 mg/dL, n (%) IgG4 (mg/dL), median (range) IgG (mg/dL), median (range) AST (IU/L), median (range) ALT (IU/L), median (range) ALP (IU/L), median (range) γ-GTP (IU/L), median (range) T-Bil (mg/dL), median (range) Endoscopic retrograde choangiogram PSC type (Intra: Intra and extra hepatic) IgG4-SC type (1:2:3:4)
IgG4-SC (n = 35)
P-value
69 (45–83) 29:6 35 (100) 0
< 0.001** 0.009** < 0.001** < 0.001**
1 (7.7) 38 (3–200) 1499 (962–3150) 49 (12–117) 65 (6–183) 834 (182–1722) 253 (17–679) 0.8 (0.4–1.7)
25 (71) 320 (28–2932) 1689 (1021–5041) 103 (16–708) 159 (13–608) 1016 (246–2350) 495 (13–1930) 3.2 (0.2–16.4)
< 0.001** < 0.001** 0.166 0.016* 0.029* 0.276 0.013* 0.038*
0:15 —
— 21:8:2:4
— —
37 (22–72) 7:8 0 7 (46.7)
**P < 0.01; *P < 0.05. AIP, autoimmune pancreatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; γ-GTP, γ-glutamyl transpeptidase; IBD, inflammatory bowel disease; IgG4-SC, IgG4-related sclerosing cholangitis; PSC, primary sclerosing cholangitis; T-Bil, totalbilirubin.
Table 2
IDUS findings between PSC and IgG4-SC
IDUS findings
PSC (n = 15)
IgG4-SC (n = 35)
15:0
33:2
P-value
Origin Wall thickness : extrinsic compression
1
Symmetry Symmetric : asymmetric**
1:14
27:6
< 0.001**
0:15 10:5
33:0 0:33
< 0.001** < 0.001**
2:13
33:0
< 0.001**
7:8 15:0
33:0 33:0
< 0.001** 1
0:15 2.4 (1.8–3.0)
33:0 2.5 (2.2–2.9)
< 0.001** 0.469
Inner margin Smooth : irregular** Diverticulum-like outpouching (+ : −)** Outer margin Clear : unclear** Internal echo Homogeneous : heterogeneous** Internal foci (+ : −) Three layers structure Preservation : disappearance** Wall Thickness (mm), median (IQR)
**P < 0.01. IgG4-SC, IgG4-related sclerosing cholangitis; IQR, interquartile range; PSC, primary sclerosing cholangitis.
strictures was wall thickening in 33 (94%) of 35 patients and extrinsic compression from the pancreas in the remaining two (7%) patients. Among the 33 patients with wall thickening, the symmetry was circular-symmetric in 27 patients (82%) and circular-asymmetric in six (18%). The inner margin, outer margin, and internal echo were smooth, clear, and homogeneous, respectively, in all patients. The internal foci were observed in all (100%) patients. Diverticulum-like outpouching was not observed in any of the patients. Preservation of three layers was observed in all (100%) patients. The median wall thickness in which the bile duct wall was thickest was 2.5 mm (interquartile range 2.2–2.9 mm). 1106
Comparison of IDUS findings between PSC and IgG4-SC. Circular-asymmetric wall thickness, irregular inner margin, diverticulum-like outpouching, unclear outer margin, a heterogeneous internal echo, and disappearance of three layers in the stricture observed on IDUS were significantly more frequent in PSC than in IgG4-SC (P < 0.001). Irregular inner margin, diverticulum-like outpouching, and disappearance of three layers were IDUS findings specific for PSC (Table 2). Diverticulum-like outpouching between IDUS and ERC. Diverticulum-like outpouching was not observed in any IgG4-SC patient on IDUS and ERC. Diverticulum-like
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IDUS findings between PSC and IgG4-SC
Figure 1 Endoscopic retrograde cholangiography showed diverticulum-like outpouching (white arrows) in a patient with primary sclerosing cholangitis. (a) Intraductal ultrasonography showed diverticulum-like outpouching (white arrow). Symmetry was circularasymmetric. Inner margin was irregular, and outer margin was notched. Three layers were disappeared. Internal echo was heterogeneous, and internal foci were observed.
Figure 2 Endoscopic retrograde cholangiography showed no diverticulum-like outpouching in a patient with PSC. (a) Intraductal ultrasonography showed diverticulum-like outpouching (a white arrow). Symmetry was circular-asymmetric. Inner margin was irregular, and outer margin was notched. Three layers were disappeared. Internal echo was homogeneous, and internal foci were observed.
outpouching on IDUS and ERC was observed in 10 (67%) and five (33%) of 15 patients with PSC, respectively. Diverticulum-like outpouching on IDUS was slightly higher than on ERC (67% vs 33%; P = 0.068). All five patients with diverticulum-like outpouching on ERC showed diverticulum-like outpouching on IDUS, and five (50%) of 10 patients without diverticulum-like outpouching on ERC showed diverticulum-like outpouching on IDUS. Conversely, none of the five patients without diverticulumlike outpouching on IDUS showed diverticulum-like outpouching on ERC.
Discussion The present study revealed that the typical IDUS findings of PSC were circular-asymmetric wall thickness, irregular inner margin, unclear outer margin, diverticulum-like outpouching, heterogeneous internal echo, and disappearance of three layers. Irregular inner margin, diverticulum-like outpouching, and disappearance of three layers were IDUS findings specific for PSC compared to IgG4-SC. The differences in the IDUS findings of PSC and IgG4-SC are summarized in Figure 4. We previously compared the IDUS findings of IgG4-SC with cholangiocarcinoma to clarify the typical IgG4-SC IDUS
findings.5 The most characteristic IgG4-SC IDUS finding was thickening of the bile duct wall that appeared normal on ERC. However, the IDUS findings of PSC have not yet been elucidated. Currently, only one study of the IDUS findings of PSC has been reported by Kubota et al.9 Our results of wall thickness, wall symmetry, and outer margin findings of PSC were similar to those of Kubota et al.; however, our incidence of internal foci of PSC was higher (100% vs 10%). Kubota et al. presumed that internal foci in the bile duct indicated the same type of inflammation that could be detected in the pancreas of type 1 AIP patients. We also considered internal foci to be a typical IDUS finding of IgG4-SC. However, we observed internal foci on IDUS in patients with PSC. Therefore, the specificity of internal foci for IgG4-SC was not considered high. The histological features of PSC are the “onionskin” type periductal fibrosis and collagen bands that are usually lamellated, better organized, and less cellular.12,13 Therefore, internal foci can hypothetically be observed in PSC based on pathological PSC features. Furthermore, the diagnostic standard for foci observed on IDUS may differ among observers due to the subjectivity of this finding. In the present study, irregular inner margin and disappearance of three layers observed on IDUS showed high sensitivity (100%) and specificity (100%) in the differential diagnosis of PSC from
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a1
a b
b2 Figure 3 Endoscopic retrograde cholangiography showed hilar stricture in a patient with IgG4-sclerosing cholangitis. (a), (b) Intraductal ultrasonography showed wall thickness in hilar stricture. Symmetry was circularsymmetric. Inner margin and outer margin were smooth and clear. Three layers were preserved. Internal echo was homogeneous, and internal foci were observed.
Figure 4 Summary of intraductal ultrasonography (IDUS) findings between primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis (IgG4-SC).
IgG4-SC. Pathological findings of PSC included the luminal side of the bile ducts (including the biliary epithelial cell lining) being preferentially affected compared with in IgG4-SC,12,13 whereas fibroinflammatory involvement was observed mainly in the submucosa of the bile duct wall, and the epithelium of the bile duct was intact in IgG4-SC.14 We suggest that irregular inner margin and disappearance of three layers observed on IDUS represent inflammation of the luminal side of the bile duct in PSC. In the present study, we first evaluated diverticulum-like outpouching observed on IDUS. We previously reported that ERC is a useful method for distinguishing IgG4-SC from PSC.7 In the previous study, diverticulum-like outpouching was an ERC finding specific for PSC, similar to band-like stricture and a beaded or pruned-tree appearance. We suggest that the diverticulum-like outpouching observed on ERC is the most objective finding that can be judged adequately by investigators, but has the lowest sensitivity for PSC among the specific findings. The sensitivities of 1108
diverticulum-like outpouching on ERC for PSC were 34% (10/29) and 33% (5/15) in the previous7 and present study, respectively. In the present study, diverticulum-like outpouching on IDUS was observed in 10 (67%) of 15 patients with PSC, which was slightly higher than on ERC (67% vs 33%; P = 0.068). Conversely, diverticulum-like outpouching on IDUS and ERC was not observed in any patient with IgG4-SC. All five patients with diverticulum-like outpouching on ERC had diverticulum-like outpouching on IDUS, and five (50%) of 10 patients without diverticulum-like outpouching on ERC had diverticulum-like outpouching on IDUS. Conversely, none of the five patients without diverticulum-like outpouching on IDUS had diverticulum-like outpouching on ERC. We suggest that diverticulum-like outpouching is a useful finding for differentiation of PSC from IgG4-SC on IDUS in addition to ERC. These results suggest that IDUS is a more useful procedure than ERC for early detection of diverticulum-like outpouching. It is difficult to differentiate PSC and IgG4-SC especially in PSC cases with high serum IgG4 levels or IgG4-SC cases with little or without pancreatic involvement (type 1 AIP).3,4,15,16 A small proportion of PSC cases demonstrated high-serum IgG4 level,17 and showed periductal infiltration of IgG4-positive plasma cells.18,19 Clinical differences between PSC cases with and without increased IgG4-positive plasma cells have also been reported. In the present study, there were no differences of IDUS findings between PSC cases with normal serum IgG4 level and high-serum IgG4 level, and there were also no differences between IgG4-SC cases with typical and little pancreatic involvement. The present study has several limitations. These include the retrospective and uncontrolled study design, the relatively low number of available patients, and the fact that there was a selection bias to perform IDUS among patients with PSC or IgG4-SC. Therefore, a prospective, randomized controlled trial and a larger number of patients must be conducted. In conclusion, the characteristic features of PSC on IDUS were useful for distinguishing PSC from IgG4-SC. Irregular inner
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margin, diverticulum-like outpouching, and disappearance of three layers were IDUS findings specific for PSC compared to IgG4-SC. IDUS is a more useful procedure than ERC for the early detection of diverticulum-like outpouching.
Acknowledgment
IDUS findings between PSC and IgG4-SC
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This work was supported by “Research on Measures for Intractable Diseases” Project: matching fund subsidy from Ministry of Health Labor and Welfare, Japan.
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References
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