Prednisolone was started from 40 mg daily, tapered gradually, and totally withdrawn in October 2013. Liver biochemical tests and IgG4 level returned to normal, and the MRCP scan showed a significant improvement (Fig. 3) in follow-up examinations.
Two months later in December 2013, MRCP showed abnormal perfusion foci of liver S5, together with atrophic pancreas (Fig. 4). Liver function tests and serum IgG4 level were within normal range. Combining with laboratory examinations and MRCP signs, the patient could be diagnosed as new-onset cholangitis. Prednisolone 10 mg daily was administered again and maintained three years without recurrence and new lesions by regularly checking liver function tests, serum IgG4 level (every 0.5 year) and MRCP (every 1 year). The patient reduced prednisolone to 5 mg every other day without consultation with his doctor in May 2017.
Four years after his initial admission, he presented to our hospital again with recurrent abdominal pain and jaundice in March 27, 2018. The patient was diagnosed with esophageal and gastric cancer 5 months ago, and received the first chemotherapy treatment in March 8, 2018. The laboratory studies revealed unbalanced liver function test (gamma glutamyl transpeptidase [GGT] = 506 IU/L, alanine aminotransferase [ALT] = 101 IU/L, aspartate transaminase [AST] = 55 IU/L, and total bilirubin in serum [TBil] = 21.5 umol/L) (Table 1). The serum levels of IgG, IgG1, and IgG4 were 12.7 g/L, 7.17 g/L, and 2.19 g/L, respectively. The ratio of IgG4 to IgG was 0.17 and IgG4 to IgG1 was 0.31. Contrast-enhanced MRCP showed irregular dilation and wall thickening of the intrahepatic bile ducts, enhancement of partial bile duct, and atrophic pancreas without pancreatic duct dilation. Given that the patient was in an immunosuppressive state, prednisolone was added to 25 mg daily.
A 4-day treatment with prednisolone helped improve his liver function (GGT = 353 IU/L, ALT = 55 IU/L, AST = 29 IU/L and TBIL = 13.0 umol/L) (Table 1). The drug dosage will be reduced gradually after 2 weeks and maintained at 10 mg daily at last.
IgG4-SC is most common in elderly men, being observed with obstructive jaundice. Japanese Biliary Association established the clinical diagnostic criteria in 2012, which included 4 criteria to diagnosis IgG4-SC: typical biliary imaging findings, elevated level of serum IgG4 (1.35 g/L or higher), the coexistence of other IgG4-related diseases, and characteristic histopathological features.
IgG4-SC is frequently associated with autoimmune pancreatitis, with 80% to 90% of cases accompanied by AIP. It is especially difficult to diagnose IgG4-SC accurately without AIP.[2,5] IgG4-related dacryoadenitis/sialadenitis and IgG4-related retroperitoneal fibrosis are also occasionally observed in IgG4-SC. Our patient was associated with pancreas involvement. However, some IgG4-SC cases do not involve other organs.
Elevated level of serum IgG4 (1.35 g/L or higher) is one of the diagnostic criteria for IgG4-SC, which is elevated in about 84% of cases. Furthermore, the serum IgG4 cut-off value of 5.4 g/L have been reported to be useful for ruling out almost all PSC, pancreatic cancer, and cholangiocarcinoma (>99%). When setting the cut-off value at 2.7 g/L, it can distinguish IgG4-SC from all cholangiocarcinoma, 98.4% pancreatic cancer, and 96.5% PSC. The patient in our report is over 1.35 g/L in both hospitalizations.
Regarding pathological features, infiltration of massive IgG4-positive plasma cells (>10 /HPF) is another diagnostic criteria for IgG4-SC, but this criteria is not the necessary one. In the present study, our patient implicated extrahepatic bile duct with stent implantation, which might explain the negative result of infiltration with IgG4-positive plasma cells.
There are typical biliary imaging findings in our patient, but discerning IgG4-SC from PSC is challenging on the basis of cholangiographic findings and IgG4 level because various clinical features of IgG4-SC are similar to PSC. Boonstra et al pointed out that in patients with serum IgG4 >1.4 and <2.8 g/L, incorporating the serum IgG4/IgG1 ratio with a cutoff at 0.24 in the diagnostic algorithm significantly improved sensitivity and positive predictive value (PPV), by measuring total IgG and IgG subclasses in serum samples of patients with IgG4-SC (n = 73) and PSC (n = 310), as well as in serum samples of disease controls (primary biliary cirrhosis; n = 22). In this subgroup, the serum IgG4/IgG1 ratio cutoff of 0.24 yielded a sensitivity of 80%, a specificity of 74%, a PPV of 55%, and a negative predictive value of 90%. The serum IgG4/IgG1 ratio of our patient was respectively 0.5 and 0.31 in both hospitalizations, supporting the diagnosis of IgG4-SC.
Glucocorticoid treatment as the first-line therapy with an initial dosage of prednisolone 0.6−1.0 mg/kg daily has been shown to exert a marked effect on the inflammatory activity of IgG4-SC. However, practice varies as to the duration and initial dosage of steroid therapy. Relapse occurs in 53% of cases after steroid withdrawal. The presence of proximal extrahepatic and intrahepatic bile duct strictures is predictive of relapse. Our patient presented with obstructive jaundice at first, relapsed 2 months after steroid withdrawal, and suffered a horrible flare when maintenance dose of glucocorticoid was not enough. Hence, we hold the opinion that IgG4-SC patients with obstructive jaundice, tending to recrudesce, require an enough initial and maintenance doses, and a long therapeutic course.
In addition, the indicators used to assess the immune state, including the IgG4 level, showed low sensitivity and accuracy. A maintenance therapy with glucocorticoid 2.5 to 5 mg/day for at least 3 years is recommended by the Research Committee for Intractable Pancreatic Disease and Japan Pancreas Society. Here, long-term maintenance therapy with a low-dose steroid (10 mg/d) is recommended because of the lack of accurate indicators reflecting the immune state of patients. At the same time, a longer duration of follow-up is needed to avoid relapse.
In conclusion, the present study reported that our patient did not match all the criteria of IgG4-SC, but steroid therapy were effective. Long-term maintenance therapy with a low and adequate dose steroid should be administered.
Data curation: Xiaoqin Dong, Na Huo, Zhao Wu, He Wang.
Methodology: He Wang, Hong Zhao.
Formal analysis: Hong Zhao.
Resources: Hong Zhao.
Writing – original draft: Xiaoqin Dong, Zhao Wu.
Writing – review & editing: Xiaoqin Dong, Na Huo, Zhao Wu, Guiqiang Wang, He Wang, Hong Zhao.
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
immunoglobulin G4-related sclerosing cholangitis; immunoglobulin G4-related disease; primary sclerosing cholangitis; relapse