IgG4-related disease complicated with diffuse and chronic gastrointestinal inflammation leading to small intestinal perforation (2024)

Article history

ABSTRACT

Introduction

Immunoglobulin (Ig) G4–related disease (IgG4-RD) is a systemic inflammatory disease involving multiple organs characterised by serum IgG4 elevation and histopathological IgG4⁺ cell infiltration, storiform fibrosis, and obliterative phlebitis. It is well known to be mainly involved with lachrymal and salivary glands, pituitary, lymph nodes, kidney, pancreas, bile duct, retroperitoneum, and artery, although gastrointestinal tract is less common [1, 2]. Previously, various types of gastrointestinal lesions have been reported, such as wall thickening, ulcer, tumour, polyp, and appendicitis [3–7]. However, there have been few case reports of small intestinal lesions [8–16], and furthermore, there has been no case report of diffuse gastrointestinal inflammation leading to perforation. We herein report the first case of IgG4-RD complicated with diffuse and chronic gastrointestinal inflammation leading to small intestinal perforation.

Case presentation

A 70-year-old female, who had past histories of cholecystectomy, appendectomy, and tonsillectomy and had no histories of taking nonsteroidal anti-inflammatory drugs, Helicobacter Pylori infection, inflammatory bowel diseases, and allergic diseases, was presented with anorexia, abdominal pain, vomiting, and diarrhoea. She was admitted due to ileus, relieved by conservative therapy. However, her symptoms were recurrent, requiring several hospitalisations. Two months later, she subsequently developed gastrointestinal perforation and was transferred to our emergency department.

On arrival, the body temperature was 37.6˚C with abdominal rebound tenderness. The laboratory test revealed leucocytosis, hypoproteinaemia, hypoalbuminaemia, an elevated C-reactive protein (CRP) and a soluble interleukin-2 receptor (sIL-2R), and coagulopathy (Table1). Contrast-enhanced computed tomography (CT) scan showed oedematous and dilated duodenum, small intestine, and colon, as well as free air in the abdominal cavity and multiple mesenteric and para-aortic lymphadenopathies [Figure1(a–c)]. Urgent surgery was performed for suspected gastrointestinal perforation due to malignant lymphoma. The small intestine was found to be partially black, and entirely dilated, erythematous and oedematous with strong interloop adhesions, indicating ischaemic changes and chronic inflammation, respectively [Figure1(d)]. As a result, the purulent ascites was drained and three perforated sites in the small intestine and regional lymph nodes were resected. The postoperative course was uneventful, and the patient was discharged 13 days after surgery, although she continued to experience abdominal pain, vomiting, and diarrhoea.

Pathological examination of resected small intestine revealed massive transmural inflammation [Figure2(a)]. In addition, most of the mesenteric small arteries were occluded both in the area of ischemic changes and at the perforated sites [Figure2(b)]. Elastica van Gieson staining revealed intimal thickening of the arteries without necrotizing vasculitis and tearing of the internal elastic lamina [Figure2(c)], which was surrounded by the plasmacytes. There was no evidence of malignancy, monoclonal cell proliferation, and light chain restriction. Thus, occlusion of mesenteric small arteries was considered to be the cause of small intestine perforation. The regional lymph node showed follicles with plasmacytic proliferation, increased hypervascularisation slightly penetrating the atrophic germinal centre without hyalinisation, and enlarged sinuses [Figure2(d)]. These features included the absence of mature plasma cell sheet-like proliferation, marked hemosiderin deposition, or marked neutrophilic infiltration. The observed features were not conclusive enough to diagnose Castleman’s disease. Interestingly, immunohistochemistry showed massive IgG4⁺ and cluster of differentiation (CD) 138⁺ plasmacyte infiltration in the mucosa of the perforated site [Figure2(e)] and regional lymph node with IgG4⁺ plasmacytes >10 per high power field (HPF) and IgG4/IgG ratios >95% without storiform fibrosis and obliterative phlebitis [Figure2(f,g)]. Plasmacytes surrounding small arteries with occlusion and intima thickening were also positive for IgG4⁺ [Figure2(h)]. In addition, serum IgG and IgG4 levels were found to be elevated at 2278 mg/dl and 969 mg/dl, respectively. Furthermore, serum C₃ levels were decreased to 52 mg/dl. Thus, the patient was suspected of IgG4-RD and referred to our department.

Random biopsies of the gastric, duodenum, ileal, and colonic mucosa were performed to evaluate the extensive lesions. Pathology revealed diffuse and massive infiltration of IgG4⁺ and CD138⁺ plasmacytes (all specimens demonstrated IgG4⁺ plasmacytes >10 per HPF, and the IgG4/IgG ratio was >50%, >95%, >95%, and >95%, respectively), yet endoscopically, the mucosa was intact [Figure3(a–h)]. Storiform fibrosis and obliterative phlebitis were not observed. Subsequent clinical evaluation revealed no other causes that could explain the patient’s condition. In particular, the patient denied a history of fever, skin rash, arthralgia, or other constitutional symptoms. Autoantibody examination, including antinuclear antibody and antineutrophil cytoplasmic antibody (ANCA), was negative (Table2), as were serologies for hepatitis B virus, hepatitis C virus, and H. pylori. Whole-body examination revealed no other organ involvement. Despite not fully satisfying the 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-RD [17], according to the 2020 revised comprehensive diagnostic criteria for IgG4-RD [18], the diagnosis of IgG4-RD was made based on an elevated serum IgG4 and diffuse infiltration of IgG4⁺ plasmacytes into gastrointestinal tract after excluding other causes. 18F-fluorodeoxyglucose positron emission tomography CT was not performed at this time. Treatment with 30 mg/day prednisolone (PSL) rapidly ameliorated symptoms and was gradually reduced to 10 mg maintaining remission (Figure4). The CT abnormalities disappeared 4 months after initiation of treatment (Figure5), and she has been in remission with 10 mg/day PSL.

Discussion

Nine cases of IgG4-RD with small intestinal lesions have been reported [8–16] (Table3). All these cases were diagnosed based on pathological findings: six cases through surgical resection [8, 9, 12, 14–16], one case via double balloon small intestinal endoscopy [10], and two cases through endoscopic biopsy [11, 13].

It is worth noting that in six out of nine cases, there was no involvement of other organs, suggesting that small intestinal lesions may develop independently without other typical organ involvement. Moreover, histopathological storiform fibrosis and obliterative phlebitis were less frequent. In a multicentre survey of IgG4-RD patients with gastrointestinal manifestations, only two out of eight cases demonstrated storiform fibrosis and obliterative phlebitis [19]. In addition, similar to our case, IgG4⁺ lymphoplasmacytic infiltration was found in the endoscopically normal mucosa in two cases [10, 13]. Regarding treatment, some cases had a favourable response to glucocorticoids [8, 10, 11, 13], which is consistent with the clinical features of IgG4-RD. On the other hand, as many cases archived a remission with surgical intervention [9, 12, 14–16], if the lesions are resected completely, a careful follow-up may be a good option. In our case, the patient experienced gastrointestinal manifestations and was repeatedly hospitalised due to ileus, resulting in small intestinal perforation requiring surgical intervention. IgG4-RD is a condition that is often misdiagnosed as other diseases. When presented with gastrointestinal manifestation with serum IgG4 elevation, it is important to consider differential diagnoses including inflammatory bowel diseases, systemic vasculitis, malignant lymphoma, and infectious diseases such as parasitosis.

Pathology revealed chronic inflammation due to diffuse and numerous IgG4⁺ plasmacyte infiltration in the gastrointestinal tract. Although neither typical organ involvements nor pathological findings such as storiform fibrosis and obliterative phlebitis were observed, we diagnosed IgG4-RD based on the following reasons: (1) chronic inflammation accompanied by abundant IgG4⁺ plasmacyte infiltration was detected not only in the small intestine but also in the stomach, duodenum, and colon; (2) other causes were completely ruled out; and (3) symptoms and CT abnormalities showed improvement following glucocorticoid therapy. In terms of pathophysiology, we found that the persistent inflammation due to the infiltration of IgG4⁺ plasmacytes may be responsible for chronic gastrointestinal manifestations. Moreover, this inflammatory process may contribute to the fragility of the gastrointestinal wall and arterial occlusion as a reactive change. It is important to mention that there were no pathological findings of polyarteritis or ANCA-RD, such as fibrinoid necrosis. Furthermore, there were no specific clinical features related to other systemic vasculitis. Therefore, it is suggested that chronic inflammation may have caused oedematous wall thickening, which could have led to a reduction in intestinal peristatic movement. Furthermore, surgical findings revealed the presence of strong interloop adhesions in the small intestine, which may have caused small intestinal ileus. In addition, persistent inflammation caused arterial occlusion, which resulted in subsequent ischaemic perforation of the small intestine.

In summary, we present the first case of IgG4-RD complicated by small intestinal perforation due to diffuse and chronic gastrointestinal inflammation. Because gastrointestinal lesions in IgG4-RD may manifest nonspecifically, IgG4-RD should be considered in the differential diagnosis for chronic gastrointestinal symptoms of unknown aetiology. Histopathological assessment, particularly not only of radiographic and endoscopic abnormalities but also normal mucosa, should be conducted to establish an accurate diagnosis of IgG4-RD with gastrointestinal lesion and to avoid fatal complications. In the future, further investigations are needed to clarify the characteristics of IgG4-RD complicated with gastrointestinal lesion.

Acknowledgements

The authors would like to express thanks to the kindness of the patient and her family and also gratefully acknowledge Drs Itaru Sanoyama and Hiroyuki Takahashi of the Department of Pathology, Kitasato University School of Medicine, for advice on pathological findings.

Conflict of interest

None declared.

Funding

None declared.

Patient consent

Written informed consent was obtained from the patient for publication.

Ethical approval

Not applicable.

References

© Japan College of Rheumatology 2024. Published by Oxford University Press.

Issue Section:

Case Report

Email alerts

Citing articles via

More from Oxford Academic