Pictorial review of computed tomography and magnetic resonance imaging findings of cardiovascular manifestations of IgG4-related disease

Introduction

IgG4 is a multisystem disease with vascular manifestations including aortitis and periaortitis. In a previous study [1] it was reported that 41% of patients who had IgG4-related disease exhibited signs and symptoms of IgG4-related aortitis and/or peri-aortitis, and 80% of these patients had multiple vascular region involvement. The iliac arteries (35% of cases) and infrarenal abdominal aorta (33% of cases) were the most common sites of IgG4-related cardiovascular disease [1]. Radiologically, periaortitis might be distinguished from other large vessel vasculitides because the latter lacks the typical periaortic or perivascular inflammatory cuff that often characterizes periaortitis lesions [2]. IgG4-related disease also causes mediastinal involvement in the form of fibrosing mediastinitis.

Aim

We performed a retrospective review of cases of IgG4-related diseases with cardiovascular involvement with an intent to characterize the extent of disease and involvement of segments of aorta (Table 1).

Methodology

All 5 cases underwent a contrast-enhanced computed tomography study and contrast-enhanced magnetic resonance imaging study. We retrieved the data from departmental PACS and RIS systems. All scans underwent ECG-triggered computed tomography using a third-generation, dual-source, 384-slice machine (CT scanner (DSCT) (SOMATOM Definition Force, Siemens, Erlangen, Germany) and MRI using a 1.5-tesla MRI scanner (MAGNETOM AERA, Siemens).

Case history

Case 1

A 47-year-old male, a shopkeeper by profession, presented with hoarseness of voice for 2 years and atypical chest pain for 6 months. He had a history of treatment for pulmonary tuberculosis in childhood (10 years of age). He had left-sided vocal cord palsy on a laryngoscopic examination. There were raised inflammatory markers (erythrocyte sedimentation rate [ESR] 50 mm/h [normal range 0-22 mm/h], C-reactive protein [CRP] 20 mg/l [normal range 1-5 mg/l]). Computed angiography revealed circumferential peri-aortic hypodense soft tissue mass encasing the aortic arch, ostio-proximal aortic arch branches, and left pulmonary artery (Figure 1A-B). MRI revealed a lobulated uniformly T1 and T2 hypointense lobulated peri-aortic soft tissue lesion (Figure 2A-B and Figure 3A-C) measuring ~4.3 × 4.7 × 5.2 cm (AP × trans × CC dimensions), encasing arch of aorta, proximal descending aorta, ostio-proximal left common carotid artery, and left subclavian artery. It was indenting the proximal left pulmonary artery (Figure 4A, C) without causing any significant stenosis. No infiltration of adjacent organs, i.e. pulmonary arteries, trachea, oesophagus, was seen. Thin peripheral rim enhancement of the mass was seen in post-contrast images (Figure 5A-C). No mediastinal adenopathy or pleural/pericardial effusion was seen. Endobronchial ultrasound revealed possible organized haematoma. On echocardiography, biventricular functions were normal. There was increased globulin – 5 g/dl (normal range – 3-3.7 g/dl) with albumin; the globulin ratio was low (0.8). The IgG4 level was 2961 mg/dl (700-1600), lymphocytic Abs– 4.05 × 103 [1-3]. Differentials to be considered in this case were IgG4-related peri-aortitis tubercular peri-aortitis, organized haematoma, thrombosed pseudoaneurysm, lymphoma, and histiocytosis (Erdheim-Chester) disease. However, given the raised serum IgG4 levels, a diagnosis of IgG4-related peri-aortitis was considered. The patient was started on steroids. A follow-up examination revealed significant clinical improvement.

Case 2

A 49-year-old male presented with pain in the abdomen for 3 months. Contrast-enhanced computed tomography of the abdomen revealed enhancing soft tissue thickening along the infra-renal abdominal aorta (Figure 6A and Figure 7A-B).
MRI and MR angiography revealed circumferential lobulated periaortic soft tissue thickening (maximum thickness ~22 mm) involving juxta-renal and infra-renal abdominal aorta up to bilateral ostio-proximal common iliac artery. The soft tissue thickening was T1 hypointense (Figure 6D), heterogeneously T2 hypointense (Figure 8A-D and Figure 7C), and showed enhancement on delayed (10 and 15 min) post-contrast images (Figure 6B-C and Figure 9). It partially encased the inferior vena cava (Figure 8A) and encased the bilateral ostio-proximal renal arteries (Figure 8B) and veins (Figure 6B and Figure 8A). No significant retroperitoneal and mesenteric adenopathy was present. There were raised inflammatory markers, i.e ESR (45), CRP (43.5), and ferritin (177.9). The A/G ratio was 1.6 (normal rage 0.8-2.0). Normal biventricular functions were demonstrated on echocardiography. IgG4 levels were elevated at 256 mg/dl. Given th4 raised IgG4 level and typical location of periaortic soft tissue thickening, a diagnosis of IgG4-related peri-aortitis was made. The patient was started on steroids. On follow-up examination after 3 months, there was resolution of abdominal pain and follow-up MRI revealed a significant decrease in thickening and enhancement of the periaortic soft tissue lesion, the maximum thickness now measuring ~1 cm.

Case 3

A 20-year-old man presented with heaviness in his chest for 5 months. There was no history of tuberculosis or travel history to a histoplasmosis endemic area. Computed tomography in the arterial and venous phase revealed a large multilobulated, heavily calcified mass in the left hemi-thorax (Figure 12A-C). Contrast enhanced cardiac MRI revealed heterogeneous peripheral enhancement with central non-enhancing areas. The mass involved the parietal pericardium along the left cardiac border and posterior atrioventricular groove with moderate pericardial effusion (Figure 13A, D). The LV free wall appeared uninvolved. The mass was encasing the left atrium and left side pulmonary veins. The left pulmonary artery and its branches were encased and narrowed. The mass had a broad area of contact with the anterior and lateral left chest wall with no definite chest wall invasion seen. No mediastinal lymphadenopathy was seen. A/G ratio was 0.77. CT-guided biopsy from the mass was consistent with diagnosis of fibrosing mediastinitis. The serum IgG4 level was 1040.2 mg/dl. Diagnosis of IgG4 related fibrosing mediastinitis was made and the patient improved clinically with steroid therapy followed by surgical resection.

Case 4

A 49-year-old female complained of neck swelling for one year. Anteroposterior chest radiograph revealed significant pericardial effusion (Figure 15). Ultrasound neck revealed diffuse heterogeneous echotexture and enlarged thyroid gland with mildly increased vascularity (Figure 17C, D and Figure 20B). A biopsy from the thyroid nodule revealed Riedel’s thyroiditis with infiltration by immunoglobulin 4 (IgG4)-positive plasma cells. Computed tomography of the thorax, abdomen, and pelvis and contrast-enhanced MRI and neck ultrasound revealed a diffusely enlarged thyroid gland (Figure 18A). The circumferential soft tissue lesion in the superior mediastinum was encasing the arch of the aorta (Figure 16A) and main pulmonary artery, extending to the bilateral hilum AP window region and along the right atrial wall, interatrial septum, and the wall of the superior and inferior vena cava (Figure 18B, D-F) causing luminal narrowing of the right atrium and SVC-right atrial junction (Figure 18 E, F) and IVC (Figure 19A). The lesion encased the right coronary artery (Figure 16D, E). CT-guided biopsy from the anterior mediastinal lesion revealed fibro-collagenous tissue with mild chronic inflammation. The albumin : globulin ratio was 1.35, and the serum IgG4 level was 3.31 g/l (normal range 0.03-2.01 g/l). T4 was 7.93 µg/dl, and TSH was decreased, at 0.2258 uIU/ml. The patient was started on steroids, with significant clinical improvement, as well as echocardiography.

Case 5

A 36-year-old woman presented with pain in the abdomen and vomiting for 4 months. History of surgery for a left adnexal mass with adhesions in the posterior wall of the uterus 7 years previously and hysterectomy 5 years ago. Computed tomography of the abdomen and contrast-enhanced MRI and MR angiography revealed circumferential homogeneously enhancing peri-aortic soft tissue thickening (maximum thickness: 5 mm) encasing infra-renal abdominal aorta, and bilateral ostio-proximal common iliac artery (Figure 19 A-C, E). The ostio-proximal inferior mesenteric artery was also encased. This caused minimal luminal narrowing of the infrarenal aorta (Figure 19D) and bilateral ostio-proximal CIA and mild luminal narrowing of the ostio-proximal IMA (~50%) (Figure 20B). This thickening was iso- to hypointense on T1 and T2 and showed post-contrast enhancement. There was no significant retroperitoneal and mesenteric lymphadenopathy. The albumin : globulin ratio was 1.5. Serum IgG was elevated, at 1.932 mg/dl (normal: 0.1-1.2).

Discussion

In this case series, the mean age was 40.2 (range 20-49) years, with 4 male subjects and only one female subject – consistent with the fact that IgG4-related disease is more common among elderly males compared to Takayasu arteritis, which is more common among young females.
In this above series, cases 1, 3, and 4 presented with intrathoracic masses, whereas cases 2 and 5 presented with wall thickening along the abdominal aorta. For case 1, 3 possible differential diagnoses including lymphoma and thymoma should be considered. Case 3 was diagnosed as IgG4-related fibrosing mediastinitis – a subset of non-granulomatous fibrosing mediastinitis. None of the cases had an aneurysm or significant stenosis of the vessel. Case 4 had right coronary artery involvement in the form of pseudotumor formation.
Two cases, i.e. case 3 and case 4, had pulmonary artery involvement; in case 1, there was indentation of the left pulmonary artery. Both case 2 and case 5 had ostio-proximal common iliac artery involvement and encasement of the inferior mesenteric artery, with case 2 having bilateral ostio-proximal renal artery involvement. There was no hydroureteronephrosis in these cases, as sometimes found in IgG4-related idiopathic retroperitoneal fibrosis cases. Both case 1 and case 4 had involvement of the bilateral ostio-proximal left common carotid artery and left subclavian artery.
Two patients in whom ESR and CRP levels were available, i.e cases 1 and 2, had raised ESR and CRP, which are considered useful markers for the inflammatory activity of IgG4-related disease.
Previous literature revealed that IgG4-related disease generally presents with normal CRP levels [3]. Some forms of IgG4-related disease, such as IgG4-related retro­peritoneal fibrosis, periaortitis, inflammatory aortic aneurysms, and fibrosing mediastinitis, can present with high serum CRP [4].
IgG4-related disease is accompanied by a decreased albumin : globulin (A/G) ratio, which reflects the overproduction of immunoglobulin; therefore, it is useful for simplified screening and follow-up of IgG4-related disease patients. In this case series the mean albumin : globulin ratio was 1.2 (0.8, 1.6, 0.77, 1.35, 1.5).
Other cardiovascular involvement of IgG4-related disease ranges from abdominal aortic aneurysm, thoracic aortic aneurysm, coronary aneurysm, aneurysm of other arteries (constrictive pericarditis), and pseudo-tumours around coronary arteries [6]. IgG4-posi­tive plasma cell infiltration into pericardium can cause IgG4-related constrictive pericarditis. Most cases of IgG4-related aneurysm and aortitis show IgG4-positive cell and eosinophil infiltration in adventitia, but some cases also show them in intima in addition to the adventitia. Therefore, aneurysm formation might follow aortitis or arteritis. The thickened inflammatory aneurysmal wall protects itself from rupture risk and corticosteroid therapy may increase rupture risk by weakening the aneurysmal wall.

Diagnosis

Characteristic diffuse/localized swelling in one or more organs at clinical examination, increased serum IgG4 level (≥ 135 mg/dl [≥ 1.35 g/l]) at the haematological examination, marked lymphoplasmacytic infiltration, and storiform fibrosis with organ infiltration by IgG4-positive plasma cells at the histopathologic examination were present in IgG4-related disease. The diagnosis of IgG4-related disease is considered to be definite when all these 3 criteria are fulfilled, probable when the first and third criteria are satisfied, and possible when only the first and second criteria are met [5].
In the case of periaortitis/periarteritis, other differential diagnoses, i.e giant cell arteritis, Takayasu arteritis, rheumatoid arthritis, systemic lupus erythematosus (SLE), HLA-B27-associated spondyloarthropathies, ANCA-associated vasculitides, and Behçet disease should also be considered [6].
Histopathological analysis in IgG4-related peri-aortitis/periarteritis reveals inflammatory infiltrates in the adventitia, while they were seen in the medial layer in giant cell arteritis and the medial layer to adventitia in Takayasu arteritis and SLE-associated arteritis.

Conclusions

These cases demonstrate that cardiovascular manifestations of IgG4-related disease were diverse, ranging from typical peri-aortitis of the abdominal aorta to fibrosing mediastinitis with adjacent pericardial involvement, intra-cardiac involvement in the form of atrial wall thickening, and pseudotumour around the coronary artery. The albumin:globulin ratio can be normal in such cases. Because IgG4-related cardiovascular disorder affects prognosis, early detection and treatment are important. Corticosteroids suppress the development of active inflammatory diseases such as aortitis, pericarditis, and pseudotumours, but lesions with predominant fibrosis may need surgical resection in view of less response to corticosteroids.

Disclosure

The authors report no conflict of interest.

References