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IgG4-related systemic disease presenting with pleural effusion, ascites and dilated cardiomyopathy

Abstract

Purpose

We report the case of a patient with IgG4-related disease with multiple organ involvement, especially myocardium, that was successfully treated with prednisone.

Methods

We performed several serological tests, electrocardiogram, echocardiography, computed tomography and inguinal lymph node biopsy.

Results

We diagnosed the patient with IgG4-related disease by the elevated serum IgG4 level and histological lymph node findings.

Conclusions

This is the first reported case of IgG4-related disease with dilated cardiomyopathy.

Tumori 2016; 102(Suppl. 2): e119 - e123

Article Type: CASE REPORT

DOI:10.5301/tj.5000502

Authors

Hee Jeong Lee, Hyoung Sul, Hyun Woo Kim, Young Sang Lyu, Chi Young Park, Ran Hong, Sang Gon Park

Article History

Disclosures

Financial support: None.
Conflict of interest: The authors have no conflicts of interest related to this paper.

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Introduction

IgG4-related disease (IgG4-RD) is a newly recognized concept presenting a potentially multiorgan disorder that was first described in 2001 (1). IgG4-RD is characterized histologically by dense infiltration of IgG4-positive cells and fibrosis (2). It can affect virtually any organ but most frequently involves the pancreas, bile ducts and gallbladder, liver, salivary glands or kidneys, and generally manifests as a mass at one or more sites mimicking neoplasia (3). There are a few reports on IgG4-RD cases complicated by constrictive pericarditis or aortitis (4, 5). However, no cases have been reported of IgG4-RD causing dilated cardiomyopathy (DCMP). Here we report on a case of IgG4-RD presenting with pleural effusion, enlargement of multiple abdominal lymph nodes, ascites, and especially DCMP, which improved after steroid therapy.

Case report

A 35-year-old man was admitted to our hospital for evaluation of exertional dyspnea that had started 3 weeks earlier. Despite previous treatment including mucolytics and bronchodilators, the patient’s condition was deteriorating. He had no history of irradiation or trauma, and he drank alcohol only once or twice a week.

Physical examination revealed his blood pressure was 110/80 mmHg, his pulse rate was 84 beats per minute, and his body temperature was 36.3°C. He had grade 2 pitting edema on both lower legs, neck vein engorgement, abdominal distension with a fluid wave, and rales over both lungs. Laboratory examinations revealed pancytopenia and mild hypoalbuminemia (supplementary Table I - Laboratory data at first and second admission. Available online at www.tumorijournal.com).

His electrocardiogram (ECG) revealed atrial fibrillation with a moderate ventricular response. Echocardiography revealed DCMP with no wall motion abnormality and mildly depressed systolic function (ejection fraction, 48%) with moderate pulmonary hypertension. Chest x-ray showed bilateral pleural effusion (Fig. 1A), and abdomen sonography demonstrated mild ascites. We performed cardiac computed tomography (CT), several viral tests for evaluation of DCMP, and a bone marrow biopsy for evaluation of pancytopenia. There was no significant stenosis of coronary arteries on cardiac CT and no evidence of bacterial or viral infection in several blood tests. A bone marrow biopsy showed normocellular marrow with a normal distribution of nucleated cells but iron deficiency anemia. The pancytopenia was considered secondary to some unidentified viral infection or drugs used to relieve cold symptoms.

Chest x-ray and CT scan at admission and follow-up. Chest x-ray showed pleural effusion changes in both lungs (A). CT scan showed abundant ascites and multiple enlarged lymph nodes including right inguinal, splenic hilum and periaortic lymph nodes as well as hypertrophic lesion of the retroperitoneum and mediastinum (arrow) (B). CT scan showed disappearance of ascites and decrease in size of the enlarged lymph nodes as well as retroperitoneal and mediastinal hypertrophy (C).

According to his clinical symptoms, signs, and echocardiography results, we presumptively diagnosed congestive heart failure, atrial fibrillation due to DCMP, or myocarditis of unknown viral infection.

We prescribed furosemide 40 mg, digoxin 0.125 mg, and aspirin 100 mg. His symptoms and chest radiography mildly improved, but the dyspnea, pitting edema and ascites persisted despite suitable medication for congestive heart failure.

After 8 months, he experienced worsening dyspnea, orthopnea, abdominal distension, and a new symptom in the form of a palpable inguinal lymph node. CT scan revealed pleural effusion in both lungs, a large amount of ascites, enlargement of the lymph nodes of the lesser omentum, splenic hilum, mesentery, and periaortic and right inguinal lymph nodes as well as hypertrophic lesion of the retroperitoneum and mediastinum (Fig. 1B). The patient’s cardiac function had deteriorated, and his ejection fraction had decreased by 21%. An excisional biopsy of the right inguinal area was performed, and the histopathological findings revealed dense lymphoplasmacytic infiltration, obliterative phlebitis, and dense fibrosis (Fig. 2). Immunohistochemical staining indicated that the majority (54%) of plasma cells were positive for IgG (Fig. 2). His serum IgG4 level was elevated to 196 mg/dL (normal, 3.9-86.4 mg/dL) (Tab. I).

Serum IgG4 levels, ejection fraction, and chamber size at admission and follow-up

IgG4 (mg/dL) EF (%) LVs/LVd dimension (mm) LVd mass/mass index (g/g/m2)
EF = ejection fraction; LVs = systolic left ventricle; LVd = diastolic left ventricle.
* We were able to assess only the result of echocardiography without further imaging.
First admission - 48.16 45.47/60.39
Second admission 196.0 20.54 55.88/61.78 185/97.4
After 1 month 130.0 -
After 2 months 82.1 -
After 6 months 83.6 36 Normal chamber size* -
After 1 year 83.1 52.19 38.52/52.75 164/82.3

Histopathological findings of the specimen obtained by excisional biopsy of right inguinal lymph node. Dense plasma cell infiltration and phlebitis (asterisk) (hematoxylin & eosin, ×400) (A). Dense fibrosis in lymph node stroma (hematoxylin & eosin, ×200) (B). Significant increase in IgG4-positive plasma cells (C) and IgG plasma cells (D). The ratio of IgG4 to IgG is 54% (immunohistochemical staining, ×400).

Based on the histopathological features and elevated serum IgG4 concentration, we diagnosed IgG4-related systemic disease. The patient was given prednisone at 125 mg/day for 7 days, 62.5 mg/day for 3 days, 30 mg/day for 3 weeks, and 20 mg/day for 2 weeks. The dose was then tapered by 5 mg every month to a maintenance dose of 5 mg/day. This dose of prednisone was maintained for about 2 months.

His symptoms improved dramatically, and follow-up chest radiography and CT scan showed markedly decreased pleural effusion, ascites, size of enlarged lymph nodes, and hypertrophy of the retroperitoneum and mediastinum (Fig. 1A and 1C).

In 2 months after starting treatment, his serum IgG4 level normalized to 82.1 mg/dL (Tab. I). His cardiac chamber size and heart function (ejection fraction) were also restored to normal 6 months and 1 year after starting steroid therapy, respectively (Tab. I). Also, the left ventricular (LV) mass and LV mass index decreased from 185 g/97.4 g/m2 to 164 g/82.3 g/m2 (Tab. I). These findings suggest that the fibrotic tissue of the myocardium decreased by steroid therapy. Corticosteroid therapy was discontinued at 6 months, and there was no recurrence of disease by 2 years of follow-up.

Discussion

IgG4-RD is a fibroinflammatory condition characterized by lymphoplasmacytic infiltration of affected tissues leading to fibrosis and obliterative phlebitis along with an elevated serum IgG4 concentration (2). IgG4-RD can involve any organ: pancreas, biliary tree, salivary glands, periorbital tissues, kidneys, lung, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium, and skin (3).

The disorder usually presents subacutely, often identified incidentally through radiological findings or unexpectedly in pathological specimens (2, 3). For the diagnosis of IgG4-RD, histopathological findings are essential. The histological appearance of IgG4-RD requires immunohistochemical confirmation with IgG4 immunostaining. More than 10 IgG4-positive plasma cells per high-power field or a ratio of IgG4-positive to IgG-positive plasma cells higher than 40% is highly suggestive of the diagnosis (3).

Elevated IgG4 concentrations in tissue and serum are helpful in diagnosing IgG4-RD, but neither is a specific diagnostic marker (6). The natural course of IgG4-RD is not well defined. Generally, systemic steroid therapy is effective in treating IgG4-RD. Although some reports have demonstrated that IgG4-RD spontaneously regressed without treatment, when a vital organ is involved, aggressive treatment is needed because IgG4-RD can lead to serious organ dysfunction (7).

The pathogenesis of IgG4-RD remains poorly understood, but multiple immune-mediated mechanisms contribute to the fibroinflammatory process. Autoimmunity and infectious agents are immunological triggers. Type 2 helper T cells and regulatory T cells overexpress cytokines such as interleukins 4, 5, 10, and 13 and transforming growth factor β, and these cytokines contribute to the eosinophilia, elevated serum IgG4 and IgE concentrations, and progression of fibrosis. Massive infiltration by inflammatory cells and fibrosis lead to organ damage (2).

DCMP is a myocardial disorder characterized by a dilated left ventricular chamber and systolic dysfunction (8). The underlying causes include genetics, arrhythmia, peripartum cardiomyopathy, inflammatory myocarditis, alcohol, chemotherapeutic agents, and endocrinopathies such as thyroid disease, pheochromocytoma and diabetes (8). In particular, peripartum DCMP and DCMP caused by excessive alcohol consumption, hyperthyroidism, hypocalcemia or prolonged periods of supraventricular or ventricular tachycardia are reversible (8).

Although the pathogenesis of DCMP is complicated, myocyte injury and myocardial fibrosis induced by abnormal immune responses after viral infections are considered to be the critical factors in the development of DCMP (9). Similarly, cardiac sarcoidosis may involve the development of fibrosis through infiltration of lymphocytes to the myocardium and lead to restrictive cardiomyopathy or DCMP (10). Moreover, early initiation of treatment for cardiac sarcoidosis can improve and possibly reverse cardiac disease. IgG4-RD can involve any organ and result in organ damage through lymphoplasmacytic infiltration and fibrosis. Therefore, immuno-inflammation such as IgG4-RD may underlie myocardial fibrosis, and DCMP might be caused by IgG4-RD.

Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) is systemic small-vessel vasculitis associated with asthma and eosinophilia. EGPA commonly involves the peripheral nerves, skin, upper airway tract, and lung. However, other organs such as the heart, kidney, and gastrointestinal tract may be affected (11). The clinical presentation of antineutrophil cytoplasmic antibodies (ANCA)-positive patients differs significantly from that of ANCA-negative patients, with more frequent mononeuritis multiplex and glomerular nephritis in the former, and more cardiomyopathy in the latter (11). EGPA may be associated with the development of fibrosis through infiltration of eosinophils within the endomyocardium and lead to restrictive cardiomyopathy (12). Indeed, eosinophils in EGPA secrete interleukin-25, which is a potent inducer of Th2 responses, with consequently elevated serum IgG4 and IgE concentrations (13). The response to glucocorticoid therapy in EGPA is excellent.

We diagnosed our patient with IgG4-related DCMP involving the spleen and abdominal lymph nodes. Although he drank alcohol, he drank only small amounts of 5 mg/day. He had experienced atrial fibrillation, which can cause reversible DCMP, but his heart rate was less than 100 beats per minute. Despite continued treatment for congestive heart failure due to DCMP and atrial fibrillation, the patient’s DCMP worsened after 8 months, and right inguinal lymph node enlargement was newly observed during his second hospitalization, for which a biopsy was performed. Eventually the patient was diagnosed with IgG4-RD and began steroid therapy. Within 3 weeks after treatment, his cardiac function was somewhat restored, and the pleural effusion and ascites disappeared (Fig. 1A and 1C). Atrial fibrillation had changed to a normal sinus rhythm on ECG only 3 months after treatment. Furthermore, normal cardiac function, normal chamber size of atria and ventricles, reduction of LV mass and LV mass index, which means disappearance of some fibrotic tissue after steroid therapy, were observed by echocardiography 1 year after termination of treatment. All of these normal findings were being maintained without recurrence at 2 years and 2 months. Although there was no pathology confirmation of heart involvement, the typical histopathological features, elevated serum IgG4 concentration, and response to steroid treatment (dramatic improvement of symptoms, cardiac function and LV mass) led us to conclude the patient suffered from DCMP caused by IgG4-RD. Although an elevated serum IgG4 concentration and excellent response to steroids is observed in EGPA, our patient had no history of asthma, recurrent sinusitis or nasal polyposis. Furthermore, ANCA was negative and there was no eosinophilia (supplementary Table 1 - Laboratory data at first and second admission. Available online at www.biological-markers.com). So we excluded a diagnosis of EGPA.

In summary, we reported a case of IgG4-RD with multiple organ involvement, especially myocardium. There are a few reports of IgG4-RD cases complicated by constrictive pericarditis (4, 5). However, there has been no case report of IgG4-RD causing DCMP. This case is notable as the first report of IgG4-RD with DCMP.

Disclosures

Financial support: None.
Conflict of interest: The authors have no conflicts of interest related to this paper.
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Authors

Affiliations

  • Department of Internal Medicine, Chosun University Hospital, Gwangju - Republic of Korea
  • Department of Pathology, Chosun University Hospital, Gwangju - Republic of Korea

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