A good response to steroid therapy in IgG4-related sclerosing cholangitis: a case report

Introduction

IgG4-related sclerosing cholangitis is a rare autoimmune liver disease, in which other organs, such as the pancreas and salivary glands, are often involved [1]. The major clinical presentations of IgG4-related sclerosing cholangitis include abdominal pain, jaundice, pruritus, and weight loss [2, 3]. The current diagnostic criteria for IgG4-related sclerosing cholangitis include serum IgG4 level, biliary tract imaging, and steroid trial as well as histopathological examination [4]. Prednisolone 40 mg/day orally can improve the liver function in IgG4-related sclerosing cholangitis [5, 6]. However, relapse after steroid withdrawal is common [7]. Other treatments include rituximab and immunomodulators [8, 9].
Herein, we report an elderly male patient with yellowish skin and sclera who was diagnosed with IgG4-related sclerosing cholangitis and achieved a complete response after oral methylprednisolone.

Case description

On July 14, 2017, a 66-year-old man was admitted to his local hospital due to jaundice and abdominal discomfort. At his local hospital, laboratory tests demonstrated that total bilirubin (TBIL) was 177.4 mol/l (reference range: 5.1-22.2 mol/l), direct bilirubin (DBIL) was 104.8 mol/l (reference range: 0-8.6 mol/l), aspartate aminotransaminase (AST) was 111 U/l (reference range: 15-40 U/l), alanine aminotransaminase (ALT) was 179 U/l (reference range: 9-50 U/l), alkaline phosphatase (ALP) was 164 U/l (reference range: 45-125 U/l), and γ-glutamyl transpeptidase (γ-GGT) was 554 U/l (reference range: 10-60 U/l). He was treated with urso­deoxycholic acid, magnesium isoglycyrrhizinate and S-adenosylmethionine. Contrast-enhanced abdominal computed tomography revealed a distal bile duct stricture. Magnetic resonance imaging showed dilatation of the upper middle segment of the common bile duct and stenosis of the lower part of the common bile duct. Colonoscopy showed colonic polyps and then he underwent endoscopic resection of colonic polyps.
On July 20, 2017, liver dysfunction was worsened. Laboratory tests were as follows: TBIL was 388.1 mol/l, DBIL 231.9 mol/l, AST was 104 U/l, ALT was 104 U/l, ALP was 242 U/l, and γ-GGT was 377 U/l. On July 24, 2017, he was transferred to our department. He denied any history of alcohol abuse. He had a prior suspected diagnosis of autoimmune submandibular gland inflammation by ultrasound and IgG4 test (IgG4: 7.750 g/l [reference range: 0.03-2.01 g/l]) on May 2, 2017. Laboratory tests demonstrated that TBIL was 251.5 mol/l, DBIL was 203 mol/l, AST was 91.64 U/l, ALT was 88.48 U/l, ALP was 314.21 U/l, γ-GGT was 178.49 U/l, IgG was 23.29 g/l (reference range: 7-16 g/l), IgM was 0.46 g/l (reference range: 0.4-2.3 g/l), CA199 was 13.67 U/ml (reference range: 0-30 U/ml), and CEA was 1.75 ng/ml (reference range: 0-6 ng/ml).
Serum lipase and amylase were within the reference range. Hepatitis B virus, hepatitis C virus, hepatitis A virus, hepatitis E virus, Epstein-Barr virus, antinuclear antibody, antimitochondrial antibody, and rheumatoid factors were negative. Magnetic resonance cholangiopancreatography revealed stenosis of the lower part of the common bile duct and dilatation of the left and right intrahepatic duct and the top part of the common bile duct (Figure 1). Endoscopic ultrasound suggested stenosis of the lower part of the common bile duct and swelling of the pancreas (Figure 2). The patient refused to undergo liver biopsy and histopathological examination. The patient had a probable diagnosis of IgG4-related sclerosing cholangitis according to the Japanese clinical diagnostic criteria 2012 for IgG4-related sclerosing cholangitis. From July 26, 2017, methylprednisolone 24 mg/day orally was given for 2 weeks and then was tapered by 4 mg/week for a total of 7 weeks. On August 13, 2017, laboratory tests were as follows: TBIL was 58.5 mol/l, DBIL was 46.5 mol/l, AST was 45 U/l, ALT was 79.79 U/l, ALP was 138.85 U/l, and γ-GGT was 185.19 U/l. Then he was discharged.
On August 30, 2017, laboratory tests demonstrated that TBIL was 27.6 mol/l, DBIL was 41.7 mol/l, AST was 23.9 U/l, ALT was 63.53 U/l, ALP was 107 U/l, and γ-GGT was 160.26 U/l. On September 15, 2017, laboratory tests demonstrated that TBIL was 20.4 mol/l, DBIL was 12.0 mol/l, AST was 29.28 U/l, ALT was 39.72 U/l, ALP was 105.93 U/l, and γ-GGT was 103.5 U/l. On September 20, 2017, methylprednisolone was stopped.
On October 16, 2017, he was admitted to our department for endoscopic resection of gastric polyps. Pathological findings revealed gastric polyps without any malignant lesion. Laboratory tests showed that TBIL was 13.0 mol/l, DBIL was 6.0 mol/l, AST was 26.97 U/l, ALT was 27.56 U/l, ALP was 78.39 U/l, and γ-GGT was 61.23 U/l (Figure 3).

Discussion

IgG4-related sclerosing cholangitis is often misdiagnosed as other biliary disorders, such as hilar cholangiocarcinoma, primary sclerosing cholangitis, and pancreatic cancer [10-13]. All of them often have jaundice and similar imaging features, such as a stenosis at the bile duct. However, there was some difference among them. Primary sclerosing cholangitis is characterized by fibrosis and multifocal stenosis of the bile ducts [14-16]. Furthermore, primary sclerosing cholangitis is always associated with inflammatory bowel disease [17, 18]. The characteristics of hilar cholangiocarcinoma are hilar mass and malignant stenosis of the bile ducts [19, 20]. Elevated tumor markers, such as serum cancer antigen 19-9, may be helpful to distinguish hilar cholangiocarcinoma from IgG4-related sclerosing cholangitis [21, 22]. The imaging findings of pancreatic head cancer include a focal mass at the pancreatic head and dilatation of the main pancreatic duct [23]. Serum pancreatic enzymes and tumor markers are also useful for a diagnosis of pancreatic cancer [24]. Certainly, the histology is the golden test for a differential diagnosis.
Patients with IgG4-related sclerosing cholangitis have good responses to steroid treatment [1]. The treatment strategy of IgG4-related sclerosing cholangitis is similar to that of autoimmune pancreatitis [5]. The treatment strategy is mildly different among regions. In Japan, prednisolone 0.6 mg/kg/day orally is prescribed for 2-4 weeks and then is gradually tapered to be maintained within 2.5-5 mg/day for at least 3 years [25]. At the Mayo Clinic, the treatment strategy is that prednisone 40 mg/day orally is initially prescribed for 4 weeks and then the dose of prednisone is tapered by 5 mg/week for a total of 11 weeks [26]. In the UK, the steroid treatment is that prednisolone 30 mg daily is prescribed for 2 weeks and then is tapered by 5 mg every 2 weeks for 3-4 months [27]. In China, prednisone 40 mg/day orally is prescribed for 4-6 weeks and then is tapered by 5 mg/week for 13 weeks [28]. In our case, the therapeutic strategy is that methylprednisolone 24 mg/day orally is prescribed for 2 weeks and then is tapered by 4 mg/week for 7 weeks.
We also summarized the findings of 4 clinical trials on the treatment of IgG4-related sclerosing cholangitis. The response rate with steroid was 72.3-97% [26, 28, 29], while the disease relapse rate was 19%-66.1% after steroid withdrawal [2, 26, 28, 29] (Table 1). Our patient achieved a complete response to the steroid treatment.
In conclusion, it is crucial for patients with IgG4- related sclerosing cholangitis to receive an accurate diagnosis and to initiate steroid treatment as soon as possible. Response to steroids is common. However, considering the relatively high relapse rate after steroid withdrawal, we should perform a watchful follow-up of patients with IgG4-related sclerosing cholangitis.

Disclosure

The authors report no conflict of interest.

References

1. Okazaki K, Uchida K, Koyabu M, et al. IgG4 cholangiopathy: current concept, diagnosis, and pathogenesis. J Hepatol 2014; 61: 690-695.
2. Tanaka A, Tazuma S, Okazaki K, et al. Clinical Features, Response to Treatment, and Outcomes of IgG4-Related Sclerosing Cholangitis. Clin Gastroenterol Hepatol 2017; 15: 920-926.e3.
3. Rastogi A, Bihari C, Grover S, et al. Hepatobiliary IgG4 Cholangiopathy: Case Series and Literature Review. Int J Surg Pathol 2015; 23: 531-536.
4. Ohara H, Okazaki K, Tsubouchi H, et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J Hepato­biliary Pancreat Sci 2012; 19: 536-542.
5. Khosroshahi A, Stone JH. Treatment approaches to IgG4-related systemic disease. Curr Opin Rheumatol 2011; 23: 67-71.
6. Maillette de Buy Wenniger LJ, Beuers U. Immunoglobulin G4-related cholangiopathy: clinical and experimental insights. Curr Opin Gastroenterol 2015; 31: 252-257.
7. Culver EL, Sadler R, Simpson D, et al. Elevated Serum IgG4 Levels in Diagnosis, Treatment Response, Organ Involvement, and Relapse in a Prospective IgG4-Related Disease UK Cohort. Am J Gastroenterol 2016; 111: 733-743.
8. Grados A, Ebbo M, Jean E, et al. IgG4-related disease treatment in 2014: Update and literature review. Rev Med Interne 2015; 36: 395-404 [Article in French].
9. Topazian M, Witzig TE, Smyrk TC, et al. Rituximab therapy for refractory biliary strictures in immunoglobulin G4-associated cholangitis. Clin Gastroenterol Hepatol 2008; 6: 364-366.
10. Zen Y, Kawakami H, Kim JH. IgG4-related sclerosing cholangitis: all we need to know. J Gastroenterol 2016; 51: 295-312.
11. Zaydfudim VM, Wang AY, de Lange EE, et al. IgG4-Associated Cholangitis Can Mimic Hilar Cholangiocarcinoma. Gut Liver 2015; 9: 556-560.
12. Geary K, Yazici C, Seibold A, Guzman G. IgG4-Related Cholangiopathy and Its Mimickers: A Case Report and Review Highlighting the Importance of Early Diagnosis. Int J Surg Pathol 2018; 26: 165-173.
13. Chen CT, Chiang CL, Huang HH. IgG4-related double duct sign mimicking pancreatic head cancer. QJM 2016; 109: 207-208.
14. Lian M, Li B, Xiao X, et al. Comparative clinical characteristics and natural history of three variants of sclerosing cholangitis: IgG4-related SC, PSC/AIH and PSC alone. Autoimmun Rev 2017; 16: 875-882.
15. Moon SH, Kim MH, Lee JK, et al. Development of a scoring system for differentiating IgG4-related sclerosing cholangitis from primary sclerosing cholangitis. J Gastroenterol 2016; 52: 483-493.
16. Smolka V, Karaskova E, Tkachyk O, et al. Long-term follow-up of children and adolescents with primary sclerosing cholangitis and autoimmune sclerosing cholangitis. Hepatobiliary Pancreatic Dis Int 2016; 15: 412-418.
17. Gidwaney NG, Pawa S, Das KM. Pathogenesis and clinical spectrum of primary sclerosing cholangitis. World J Gastroenterol 2017; 23: 2459-2469.
18. Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis – a comprehensive review. J Hepatol 2017; 67: 1298-1323.
19. Du S, Liu G, Cheng X, et al. Differential Diagnosis of Immunoglobulin G4-associated Cholangitis From Cholangiocarcinoma. J Clin Gastroenterol 2016; 50: 501-505.
20. Nguyen Canh H, Harada K. Adult bile duct strictures: differentiating benign biliary stenosis from cholangiocarcinoma. Med Mol Morphol 2016; 49: 189-202.
21. Yadav KS, Sali PA, Mansukhani VM, et al. IgG4-associated sclerosing cholangitis masquerading as hilar cholangiocarcinoma. Indian J Gastroenterol 2016; 35: 315-318.
22. Lee JJ, Schindera ST, Jang HJ, et al. Cholangiocarcinoma and its mimickers in primary sclerosing cholangitis. Abdom Radiol 2017; 42: 2898-2908.
23. Witkowski ER, Smith JK, Ragulin-Coyne E, et al. Is it worth looking? Abdominal imaging after pancreatic cancer resection: a national study. J Gastrointest Surg 2012; 16: 121-128.
24. Grossjohann HS, Rappeport ED, Jensen C, et al. Usefulness of contrast-enhanced transabdominal ultrasound for tumor classification and tumor staging in the pancreatic head. Scand J Gastroenterol 2010; 45: 917-924.
25. Kamisawa T, Okazaki K, Kawa S, et al. Japanese consensus guidelines for management of autoimmune pancreatitis: III. Treatment and prognosis of AIP. J Gastroenterol 2010; 45: 471-477.
26. Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology 2008; 134: 706-715.
27. Sandanayake NS, Church NI, Chapman MH, et al. Presentation and management of post-treatment relapse in autoimmune pancreatitis/immunoglobulin G4-associated cholangitis. Clin Gastroenterol Hepatol 2009; 7: 1089-1096.
28. Liu W, Chen W, He X, et al. Poor response of initial steroid therapy for IgG4-related sclerosing cholangitis with multiple organs affected. Medicine 2017; 96: e6400.
29. You MW, Kim JH, Byun JH, et al. Relapse of IgG4-related sclerosing cholangitis after steroid therapy: image findings and risk factors. Eur Radiol 2014; 24: 1039-1048.