A Case of Multiple Giant Coronary Aneurysms and Abdominal Aortic Aneurysm Coexisting with IgG4-related Disease

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1 CASE REPORT A Case of Multiple Giant Coronary Aneurysms and Abdominal Aortic Aneurysm Coexisting with IgG4-related Disease Hirofumi Takei 1, Hayato Nagasawa 1, Ryota Sakai 1, Koji Nishimura 1, Takahiko Kurasawa 1, Ayumi Okuyama 1, Eiko Nishi 1, Yuichiro Shirai 1, Tsuneo Kondo 1,HiroeOgawa 1, Tatsuya Ito 2 and Koichi Amano 1 Abstract IgG4-related disease (IgG4RD) is a unique systemic lymphoproliferative disorder characterized by elevated serum IgG4 levels and IgG4-producing plasma cell expansion in the affected tissues, which are accompanied by fibrotic or sclerotic changes. Vascular lesions may also be a part of IgG4RD as a number of case reports have discussed inflammatory abdominal aortic aneurysms associated with IgG4RD, but coronary artery lesions seem to be rare complications of IgG4RD. A 71-year-old man suffered from multiple giant coronary aneurysms and an abdominal aortic aneurysm with concurrent pancreatic, gall bladder, bile duct, and salivary gland lesions resulting from IgG4RD. The present observations suggest that coronary aneurysms may also develop as a consequence of this disease. Key words: abdominal aortic aneurysm, bile duct, giant coronary aneurysm, IgG4, salivary gland (Intern Med 51: , 2012) () Introduction IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells (1). This disease can develop in various organs such as the pancreas (2), bile duct (3), salivary glands (4), lacrimal glands (5), retroperitoneum (6), aorta (7), lungs (8), and kidneys (9). Multiple lesions can develop simultaneously or metachronously in different organs of a patient. IgG4RD may cause vascular lesions most of which are abdominal aortic aneurysms. Tumorous lesions surrounding coronary arteries are also reported to be developed in patients with IgG4RD (10, 11). Here, we describe a patient suffering from multiple giant coronary aneurysms and an abdominal aortic aneurysm (AAA) with concurrent lesions of the pancreas, gallbladder, bile duct, and salivary glands, all of which were associated with IgG4RD. Further, we discuss that aneurysmal lesions may also develop in coronary arteries as shown in the abdominal aorta and may be a vascular lesion associated with IgG4RD. Case Report A 71-year-old man was admitted to a local hospital in July 2008 because of jaundice (total bilirubin, 3.9 mg/dl). Endoscopic retrograde cholangiopancreatography showed stenosis in the lower common duct (Fig. 1a). Abdominal computed tomography (CT) indicated a tumefaction localized to the head of pancreas (Fig. 1b) and a lower AAA with a maximum dimension of 3.9 cm (Fig. 1c, d). Because the patient was suspected to have cholangiocarcinoma, he was transferred to the surgical ward of our hospital, where a pancreaticoduodenectomy was performed. Macroscopic examination showed stenosis of the bile duct but no tumor. Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University, Japan and Department of Internal Medicine, Saitama Yorii Hospital, Japan Received for publication November 15, 2011; Accepted for publication January 6, 2012 Correspondence to Dr. Hayato Nagasawa, nagasawa@saitama-med.ac.jp 963

2 Figure 1. (a) Endoscopic retrograde cholangiopancreatography revealing stenosis in the lower common duct (arrow). (b) Enhanced abdominal CT showing a tumorous lesion in the head of the pancreas (arrow). Enhanced abdominal CT showing a lower abdominal aortic aneurysm (arrow) (c) axial view, (d) coronal view. Figure 2. Pathological examination showing infiltration of the pancreas. Hematoxylin and Eosin staining at low magnification (a) showing widespread fibrosis and inflammatory change and at high magnification (b) showing lymphocytes predominant over plasma cell infiltration. Immunohistochemical examination revealed IgG4-expressing plasma cells in the pancreas (c). Pathological examination showed infiltration of lymphocytes and plasma cells and fibrosis of the common bile duct, gallbladder wall, and pancreatic ducts (Fig. 2a, b). The patient was discharged in September 2008, and eight months later, he developed a dry cough and dry mouth. He visited our hospital again in November 2009, at which point we admit- 964

3 Table 1. Laboratory Data for the Patient well as fibrotic changes (Fig. 4a, b). Immunohistochemical examination demonstrated the presence of IgG4-expressing plasma cells in the salivary gland (Fig. 4c). Further, immunohistochemical re-examination of biopsies taken one year earlier of the common bile duct, gallbladder wall, and pancreatic duct revealed the presence of IgG4-expressing plasma cells and fibrotic changes (Fig. 2c). Given the present and previous findings, the patient was diagnosed with coronary and abdominal aortic aneurysms coexistant with IgG4RD, the latter according to the proposed guideline for the diagnosis of IgG4RD (elevated serum IgG4 levels and lymphocyte and IgG4+ plasma-cell infiltration with typical tissue fibrosis in the salivary gland, common bile duct, gallbladder wall, and pancreatic duct) (1). He did not agree to undergo coronary artery bypass grafting. The patient received immunosuppressive treatment (cyclophosphamide and corticosteroid) and has been under observation for approximately two years without significant changes in his vascular lesions. Discussion ted him because his laboratory tests revealed hypergammaglobulinemia and elevated serum IgG4 levels. The patient had a 53-year history of bronchial asthma. He had smoked an average of 7 cigarettes per day for 30 years between the ages of 20 and 50. Physical examination revealed swelling of the left submandibular and right parotid glands and fine crackles were auscultated along the left lower lung. His blood pressure was 112/50 mmhg. Laboratory test values upon admission were shown in Table 1. CT of the chest showed a linear shadow at the base of the left lung and a reticular shadow at the base of the right lung. Abdominal CT revealed an AAA with a maximum dimension of 4.7 cm. Echocardiography revealed moderate dilatation of right and left main trunks and a tumefaction (24 25 mm) at the side of the right atrium. The movement of the left ventricle was normal, and the ejection fraction was 66%. Coronary CT angiography showed multiple coronary aneurysms and dilatation and stenosis of both the right and left coronary arteries (Fig. 3a, b, c). Adenosine stress myocardial scintigraphy showed no evidence of myocardial ischemia and there was no complaint of chest pain. Pathological examination of the salivary gland following a lip biopsy showed significant infiltration of plasma cells as IgG4RD is characterized by elevated serum IgG4 levels, various fibrotic and/or sclerotic lesions with IgG4-positive plasma cell infiltration sclerosing sialadenitis, sclerosing cholangitis, sclerosing cholecystitis, and autoimmune pancreatitis. Recently there are quite a few reports suggesting that arterial lesions (mostly aortic aneurysms) may also be associated with IgG4RD. Here, we described a patient with multiple coronary aneurysms involving both right and left coronary arteries and an abdominal aortic aneurysm coexisting with IgG4RD. While the abdominal aorta is the most common site of arterial aneurysms, typically developing in adults over 60 years of age, the underlying cause of aneurysmal aortic dilatation is uncertain in most patients. Whether atherosclerosis causes aneurysmal disease or vice versa remains unclear (12-14), although most recent research suggests that atherosclerosis is not causal. Inflammation plays an important role in the pathophysiology of an AAA (15, 16), as evidenced in part by the association between aneurysm formation and markers of inflammation such as the acute phase protein CRP and interleukin (IL)-6. Further, physicians have identified the clinical entity inflammatory aortic aneurysm, which has distinct clinical and pathologic characteristics, although this may simply be an extreme manifestation of the process present in all aortic aneurysms (17). Kasashima et al. recently reported that some inflammatory AAA (IAAA) might be caused by IgG4RD. These authors noted high serum IgG4 concentrations and abundant IgG4-positive plasma cell infiltration in the aneurysmal wall in 4 of 10 IAAA cases (7). Sakata et al. also reported that IAAA might be an aortic manifestation of IgG4-related sclerosing disease (18). These authors further noted that IgG4-related retroperitoneal or mediastinal fibrosis is commonly observed around the aorta, suggesting that arterial vessels, particularly their ad- 965

4 Figure 3. Coronary CT angiography. (a) Three-dimensional (3D) image showing multiple coronary aneurysms, dilatation, and stenosis of both right and left coronary arteries (arrowheads). Contrast enhanced CT angiography showing multiple coronary aneurysms and thickening of the artery wall [(b) right coronary artery, (c) left coronary artery]. Figure 4. Pathological examination of the salivary glands. Hematoxylin and Eosin staining revealed significant infiltration of plasma cells and fibrotic changes. (a) Low magnification, (b) high magnification. (c) Immunohistochemical detection of IgG4-expressing plasma cells in the salivary glands. ventitia, may represent a non-glandular tissue target of IgG4RD. There are 2 case reports of an IgG4-related tumorous lesion in the coronary artery with aneurysmal changes (10, 11). Multiple giant coronary aneurysms are rare and may be typically seen in Kawasaki disease and the right coronary artery is said to be commonly affected (19). The present case had multiple giant coronary aneurysms affecting both right and left coronary arteries suggesting grave prognosis. Moreover he had no signs or symptoms suggestive of Kawasaki disease or other vasculitic syndromes such as polyarteritis nodosa, which can cause multiple coronary aneurysms. While we unfortunately could not get the patient s consent for histopathological examinations and surgical interventions of coronary and aortic lesions, we nevertheless surmised that vascular lesions of our case were also associated with IgG4RD similar to those described in previ- 966

5 ous cases (10, 11). The pathogenesis of IgG4RD remains unclear. Because regulation of IgG4 production is dependent on T-helper type 2 (Th2) cells, Th2-dependency associates the IgG4 and IgE responses. In the context of IgE-mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely due, at least in part, to an allergen-blocking effect at the mast cell level and at the level of the antigen-presenting cell (preventing IgEfacilitated activation of T cells), or either level (20). Greater than 30% of IgG4-related IAAA patients have bronchial asthma and other features more commonly seen in IgG4- related IAAA, including elevated IgE levels (21). The present patient also had a history of bronchial asthma, eosinophilia and elevated serum IgE levels. Regarding a mechanism involving the immunoglobulin isotype switching a previous report demonstrated the clonal relationship of IgE and IgG4 transcription (22). The participation of allergic reactions and the Th2 response, such as the contribution of IL-4 expression in IgG4RD requires further study. Although corticosteroids are generally effective in treating the extravascular lesions of IgG4RD (4, 23), the present case did not respond to immunosuppressive therapy including these drugs. Further, given that corticosteroids might increase the risk of aneurysmal rupture by making the vascular wall thinner and more fragile, corticosteroid dose was tapered off in this patient. Given the frequency of thrombosis in coronary artery aneurysms, antiplatelet therapy (with aspirin or clopidogrel) or anticoagulation (with warfarin) has predictably been reported useful in the medical management of these aneurysms (24, 25). Therefore, the patient also received antiplatelet therapy with aspirin. In conclusion, coronary aneurysms may also develop in association with IgG4RD. The authors state that they have no Conflict of Interest(COI). References 1. 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