pulmonary arterial hypertension associated with igg4
TRANSCRIPT
493
□ CASE REPORT □
Pulmonary Arterial Hypertension Associatedwith IgG4-related Disease
Motoko Ishida 1, Tomoya Miyamura 1, Shinji Sato 2, Daisaku Kimura 1 and Eiichi Suematsu 1
Abstract
A 22-year-old woman with generalized lymphadenopathy and symmetrical swelling of the lacrimal and
submandibular glands was diagnosed with IgG4-related disease. Biopsy specimens of the lips, lymph nodes,
gastrointestinal tract and bronchus showed IgG4-positive plasma cell infiltration. Echocardiography and right
heart catheterization revealed a high mean pulmonary arterial pressure. The patient was treated with 50 mg of
prednisolone daily and rapidly improved. This is the first reported case of pulmonary arterial hypertension as-
sociated with IgG4-related disease.
Key words: IgG4-related disease, pulmonary arterial hypertension
(Intern Med 53: 493-497, 2014)(DOI: 10.2169/internalmedicine.53.0154)
Introduction
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is
a recently described entity characterized by multiorgan
IgG4-positive plasma cell infiltration and high serum IgG4
concentrations (1). Umehara et al. described a consensus re-
garding the diagnostic criteria for IgG4-RD in 2011 (2).
IgG4-RD includes Mikulicz’s disease, orbital pseudotumors,
autoimmune pancreatitis, sclerosing cholangitis, prostatitis,
pulmonary disease, interstitial nephritis, hypophysitis and in-
flammatory aneurysms. We herein report a patient with
IgG4-RD with pulmonary arterial hypertension (PAH) and
multiple organ involvement who was successfully treated
with oral glucocorticoids.
Case Report
A 22-year-old woman was admitted to our hospital in
April 2011 due to generalized lymphadenopathy and hyper-
γ-globulinemia. She complained of shortness of breath on
effort. She had a history of bronchial asthma starting at 5
years of age; however, she had not experienced a clear epi-
sode of a severe asthma attack for several years. On a physi-
cal examination, there was symmetrical swelling of the lac-
rimal and submandibular glands and parotid glands that had
been present for several years. Chest auscultation revealed
coarse inspiratory crackles over the patient’s right upper
chest and abnormal increased splitting of the second heart
sound (IIA<IIP) on the second left sternal border with no
heart murmurs. The patient had generalized lymphadenopa-
thy, with lymph nodes measuring 5-20 mm in diameter in
the neck, bilateral axillae and bilateral inguinal regions.
There was no skin edema, eruptions, Raynaud’s phenome-
non or sclerodactyly. A urinalysis was normal. Blood testing
showed the following results: leukocytes, 9,000/μL; neutro-
phils, 3,501/μL; lymphocytes, 2,340/μL; eosinophils, 2,520/
μL; hemoglobin, 10.2 g/dL; platelets, 29.5×104/μL; total pro-
tein, 10.7 g/dL (normal range, 6.7-8.3 g/dL); albumin, 2.4 g/
dL (4.0-5.0 g/dL); CK, 161 IU/L (45-165 U/mL); KL-6,
283 U/mL (<500 U/mL); surfactant protein-D, 101 ng/mL
(<110 ng/mL); brain natriuretic peptide, 43.8 pg/dL; C-
reactive protein, 0.09 mg/dL (<0.30 mg/dL); CH50, <15 IU/
mL (30-45 IU/mL); C3, 30 mg/dL (63-134 mg/dL); C4, 2
mg/dL (13-36 mg/dL); IgE, 1,388 IU/mL (<300 IU/mL);
IgG, 7,183 mg/dL (870-1,700 mg/dL); IgG4, 3,230 mg/dL
(<108 mg/dL); and soluble interleukin 2 receptor, 1,490 U/
mL (124-466 U/mL). Serological data were negative for an-
tinuclear antibodies (ANA), anti-U1RNP antibodies, anti-SS-
A antibodies, anti-ds DNA antibodies, myeloperoxidase anti-
1Department of Internal Medicine and Rheumatology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Japan
and 2Department of Cardiology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Japan
Received for publication January 15, 2013; Accepted for publication September 17, 2013
Correspondence to Dr. Motoko Ishida, [email protected]
Intern Med 53: 493-497, 2014 DOI: 10.2169/internalmedicine.53.0154
494
Figure 1. Chest computed tomography image showing consolidation, solid nodules and irregular thickening of bronchovascular bundles and interlobular septa (a, b) . A remarkable improvement was observed two months after the initiation of corticosteroid therapy (c, d) .
(a)
(c)
(b)
(d)
neutrophil cytoplasmic antibodies and proteinase 3 anti-
neutrophil cytoplasmic antibodies. However, the levels of
rheumatoid factor (RF) and complement-binding immune
complexes were elevated to 101 IU/mL (<15 IU/mL) and
3.9 μg/mL (<1.5 μg/mL), respectively. The results of a
blood gas analysis were almost within the normal ranges. A
chest X-ray showed bilateral infiltration, cardiac enlargement
and an enlarged left main pulmonary artery. Computed to-
mography (CT) revealed solid nodules with irregular thick-
ening of bronchovascular bundles and interlobular septa in
both lung fields (Fig. 1a, b). CT also disclosed enlargement
of the superficial, mediastinal, parabronchial and para-aortic
lymph nodes and thickening of the gastric wall. There was
no evidence of pancreatitis, biliary tract disease or interstitial
nephritis. Ga-67 scintigraphy disclosed a positive image of
the bilateral submandibular glands. We did not perform
fluorodeoxyglucose positron emission tomography.
A lymph node biopsy showed fibrosis; however, there
was no characteristic storiform fibrosis (Fig. 2a, b). Immu-
nohistochemical staining showed dense lymphoplasmacytic
infiltration with IgG4-positive plasma cells (Fig. 2c, d). The
ratio of IgG4-positive to IgG-positive plasma cells (IgG4+/
IgG+) was approximately 50%. A histopathological examina-
tion of subsequent lip biopsy, transbronchial lung biopsy
and esophageal and gastroduodenal biopsy specimens also
showed lymphoplasmacytic infiltration with IgG4-positive
plasma cells. The IgG4+/IgG+ plasma cell ratio was approxi-
mately 20% in the lip biopsy specimen (Fig. 2e, f) and 40%
in the biopsy specimens obtained from the esophagus, stom-
ach and duodenum (Fig. 2g); the ratio could not be deter-
mined in the lung biopsy specimen (Fig. 2h). The lip biopsy
specimen showed fibrosis; however, there was no oblitera-
tive phlebitis or eosinophil infiltration (Fig. 2i). Based on
these findings, we diagnosed the patient with IgG4-RD with
Mikulicz’s disease, gastrointestinal tract disease and lympha-
denopathy. We concluded that the findings of the lung bi-
opsy specimen were highly suspicious for IgG4-related pul-
monary disease (IgG4-PD).
The patient’s shortness of breath on effort was catego-
rized as World Health Organization class II. Her 6-minute
walking distance was 400 m. Respiratory function test re-
sults were almost normal, including the diffusing capacity
for carbon monoxide/alveolar volume (5.71 mL/min/mmHg/
L). Electrocardiography showed pulmonary P waves, a nor-
mal axis and normal T waves. Echocardiography disclosed
tricuspid regurgitation with an increased tricuspid pressure
gradient (52 mmHg); however, there were no signs of re-
traction of the ventricular septum. The chamber size, ejec-
tion fraction and valvular movements were normal (Fig. 3a).
Right heart catheterization showed a mean pulmonary arte-
rial pressure of 40 mmHg and a mean pulmonary capillary
wedge pressure of 17 mmHg. The pulmonary vascular resis-
tance index was 399 dyne/sec/cm-5/M2 (normal, 123±54
dyne/sec/cm-5/M2) and did not improve with supplemental
oxygen. These findings satisfied the criteria for PAH.
The patient was treated with 50 mg of prednisolone daily
Intern Med 53: 493-497, 2014 DOI: 10.2169/internalmedicine.53.0154
495
Figure 2. Hematoxylin and Eosin (HE) staining and immunohistochemical staining of the biopsy specimens. HE staining of an inguinal lymph node biopsy specimen showing massive infiltration of plasma cells without malignant cells (a, original magnification, ×40; inset, ×400) . Masson trichrome staining of a lymph node biopsy specimen showing fibrosis (b, ×40) . IgG immunostaining (c, ×200) and IgG4 immunostaining (d, ×200) of the lymph node biopsy specimen showing infiltration of IgG- and IgG4-positive plasma cells (the IgG4+/IgG+ plasma cell ratio was approximately 50%) . IgG im-munostaining (e, ×400) and IgG4 immunostaining (f, ×400) of a lip biopsy specimen showing infiltra-tion of IgG- and IgG4-positive plasma cells (the IgG4+/IgG+ plasma cell ratio was approximately 20%) . IgG4 immunostaining of the stomach biopsy (g, ×200) and transbronchial lung biopsy (h, ×200) specimens showing IgG4-positive plasma cell infiltration. The lip biopsy specimen also exhibits fibrosis (i, Masson trichrome stain, ×100) .
(a)
(i)(h)
(g)(f)(e)
(d)
(b)
(c)
Intern Med 53: 493-497, 2014 DOI: 10.2169/internalmedicine.53.0154
496
Figure 3. Echocardiography showing tricuspid regurgitation with a tricuspid pressure gradient of 52 mmHg (a) . One month after the initiation of treatment, the tricuspid pressure gradient had de-creased to <17 mmHg (b) .
(a) (b)
for pulmonary disease and PAH. The swelling of the lacri-
mal glands, submandibular glands and lymph nodes rapidly
decreased over the first week. After one month, the serum
IgG4 concentration decreased to 504 mg/dL. The serum
IgG, IgE and soluble interleukin 2 receptor concentrations
also decreased and the complement concentrations (CH50,
C3 and C4) increased after one month. Follow-up chest CT
showed a remarkable reduction in the abnormal areas in the
lung fields (Fig. 1c, d). Echocardiography demonstrated that
the tricuspid pressure gradient was normal (<17 mmHg)
(Fig. 3b).
Discussion
IgG4-RD was first described in 2001 as autoimmune pan-
creatitis with an elevated serum IgG4 concentration (1).
IgG4-RD has subsequently been found in various target or-
gans. Considering the histological and physiological findings
of our patient, we diagnosed her with IgG4-RD with
Mikulicz’s disease, pulmonary disease, lymphadenopathy,
gastrointestinal tract disease and PAH. The latest clinical
classification of pulmonary hypertension was published in
2009 (3). We concluded that the patient had PAH because
the laboratory data and results of the blood gas analysis, res-
piratory function tests and right heart catheterization did not
suggest pulmonary hypertension due to lung disease and/or
hypoxia and chronic thromboembolic pulmonary hyperten-
sion. In the present case, the mean pulmonary capillary
wedge pressure was 17 mmHg. We considered the possibil-
ity of cardiac dysfunction due to myocardial infiltration by
IgG4-positive plasma cells; however, we were unfortunately
unable to biopsy the myocardium. However, there was no
evidence of myocardial damage or left heart disease. We
concluded that the increased mean pulmonary capillary
wedge pressure was within the margin of error of the test
and excluded a diagnosis of pulmonary hypertension due to
left heart disease.
Galiè et al. reported that most patients with IgG4-PD are
positive for RF and ANA and many exhibit hypocomple-
mentemia with a high serum IgE concentration (4). The
presence of ANA, RF, IgG and complement fraction depos-
its in the walls of the pulmonary vessels suggests an immu-
nological mechanism. Some reports have indicated that pa-
tients with IgG4-PD demonstrate diffuse lymphoplasmacytic
infiltration with irregular fibrosis and obliterative vascular
changes, such as obliterating phlebitis and arteritis, with
eosinophil infiltration (5, 6). Abundant infiltration of IgG4-
positive plasma cells and the presence of obliterative phlebi-
tis have also been reported in patients with IgG4-related aor-
titis (7). Interestingly, our patient exhibited an increased
transpulmonary pressure gradient (>12 mmHg). A previous
report showed that such increases in pressure result from
structural changes in the pulmonary arteries and capillar-
ies (8). We speculate that this finding indicates damage to
the pulmonary arteries. The pathophysiological mechanisms
underlying the development of PAH remain unknown, even
in patients with connective tissue disease. Although it is dif-
ficult to prove the occurrence of PAH, we consider that
obliterative vasculitis of the pulmonary arteries due to an
immunological mechanism may have played a role in the
pathogenesis of PAH in our patient.
The primary aim of treatment was to improve the pa-
tient’s PAH and pulmonary disease associated with IgG4-
RD. Glucocorticoids are considered to be effective in treat-
ing IgG4-RD. Case reports and literature reviews have sug-
gested that glucocorticoid therapy combined with vasodila-
tors may be effective for the treatment of connective tissue
disease PAH, at least in the short term (9). Our patient re-
sponded well, and her abnormal test results normalized fol-
lowing glucocorticoid treatment. Furthermore, the PAH also
improved. Our findings suggest that the PAH was associated
with IgG4-RD.
Intern Med 53: 493-497, 2014 DOI: 10.2169/internalmedicine.53.0154
497
In summary, we herein described a patient with IgG4-RD
with multiorgan involvement, including PAH, who was suc-
cessfully treated with oral prednisolone. This is the first re-
ported case of PAH associated with IgG4-RD and is inter-
esting due to the presence of multiorgan plasma cell infiltra-
tion. Although we were unable to prove our speculation
with histological findings, a PAH mechanism is hypothe-
sized to involve obliterative arteritis of the pulmonary arter-
ies in the present patient. Her response to treatment supports
this possibility.
The authors state that they have no Conflict of Interest (COI).
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