close

Вход

Забыли?

вход по аккаунту

?

j.resinv.2017.08.010

код для вставкиСкачать
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
Contents lists available at ScienceDirect
Respiratory Investigation
journal homepage: www.elsevier.com/locate/resinv
Original article
Is hypothyroidism in idiopathic pleuroparenchymal
fibroelastosis a novel lung-thyroid syndrome?
Nobuyasu Awanoa,n, Takehiro Izumoa, Kensuke Fukudaa, Mari Tonea,
Daisuke Yamadab, Tamiko Takemurac, Soichiro Ikushimaa,
Toshio Kumasakac
a
Department of Respiratory Medicine, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo 150-8935,
Japan
b
Department of Radiology, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo 150-8935, Japan
c
Department of Pathology, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo 150-8935, Japan
ab st rac t
art i cle i nfo
Article history:
Background: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare type of interstitial
Received 1 March 2017
pneumonia characterized by fibroelastosis. Patients with IPPFE as well as idiopathic
Received in revised form
interstitial pneumonia often have autoimmune diseases, which sometimes coincide with
11 July 2017
hypothyroidism (HypoT). However, there have been no reports on the association between
Accepted 28 August 2017
IPPFE and HypoT. The purpose of this study was to evaluate the correlation between IPPFE
and HypoT. We also examined the pathological features of the thyroid glands from
autopsied cases.
Keywords:
Methods: Thirteen patients diagnosed with IPPFE from among 255 consecutive cases of
Idiopathic pleuroparenchymal
idiopathic interstitial pneumonia were included in this study; pertinent data were obtained
fibroelastosis
Idiopathic interstitial pneumonia
Hypothyroidism
from our hospital’s clinical library. We examined the prevalence of HypoT and compared
the clinical, radiological, and pathological features between the patients with and those
without HypoT. Histological analyses of the lungs and thyroid glands were performed in
Thyroid transcription factor-1
4 and 3 cases, respectively.
Surfactant protein-D
Results: HypoT was identified in 7 of 13 patients (53.8%). Sex, body mass index, survival
time, and laboratory test results were not significantly different between patients with and
those without HypoT. Radiological and pathological lung findings were similar between
both groups of patients. Thyroid gland histology demonstrated perifollicular or interlobular
fibrosis without inflammation in all three cases, including a euthyroid case.
Conclusions: Although we only analyzed a small number of IPPFE cases, HypoT was
Abbreviations:
HypoT,
den Lungen-6; NTI,
D,
BMI,
body
hypothyroidism; IPF,
mass
index;
nonthyroidal illness; PPFE,
surfactant protein-D; TPO,
FVC,
forced
vital
idiopathic pulmonary fibrosis; IPPFE,
capacity;
HRCT,
pleuroparenchymal fibroelastosis; RV/TLC,
thyroid peroxidase; TSH,
high-resolution
computed
tomography;
idiopathic pleuroparenchymal fibroelastosis; KL-6, Krebs von
residual volume to total lung capacity; SP-
thyroid-stimulating hormone; TTF,
Thyroid transcription factor;
UIP, usual interstitial pneumonia; VATS, video-assisted thoracic surgery
n
Corresponding author. Fax: þ81 3 3409 1604.
E-mail addresses: [email protected] (N. Awano), [email protected] (T. Izumo), [email protected] (K. Fukuda),
[email protected] (M. Tone), [email protected] (D. Yamada), [email protected] (T. Takemura),
[email protected] (S. Ikushima), [email protected] (T. Kumasaka).
http://dx.doi.org/10.1016/j.resinv.2017.08.010
2212-5345/& 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Awano N, et al. Is hypothyroidism in idiopathic pleuroparenchymal fibroelastosis a novel lungthyroid syndrome? Respiratory Investigation (2017), http://dx.doi.org/10.1016/j.resinv.2017.08.010
2
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
prevalent among all of them. Characteristic fibrosis in the thyroid gland was observed even
in a euthyroid case. Therefore, patients with IPPFE may potentially have thyroid gland
dysfunction through a common pathogenesis in both organs.
& 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
1.
Introduction
Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare
interstitial pneumonia that was first reported by Frankel et al.
in 2004 [1]. Recently, IPPFE was classified as rare idiopathic
interstitial pneumonia [2]. The clinical, radiological, and
pathological features of IPPFE have been studied recently.
Although the etiology of IPPFE is unknown, many patients
with pleuroparenchymal fibroelastosis (PPFE) have underlying conditions, such as connective tissue disease [3]; ankylosing spondylitis [4]; bone marrow or lung transplantation [5,6];
or drug-induced lung diseases, including cyclophosphamide
[7], hypersensitivity pneumonia [8], pulmonary mycobacterial
disease [9], Aspergillus infection [10], and asbestos-induced
lung diseases [11]. These diseases sometimes represent
characteristic features of PPFE.
Connective tissue diseases can also be associated with
other interstitial diseases. For example, patients with rheumatoid arthritis often develop usual interstitial pneumonia
(UIP) or non-specific interstitial pneumonia [12]. Chronic
autoimmune thyroiditis, or Hashimoto’s thyroiditis, is an
autoimmune disease in which the thyroid gland is gradually
destroyed, leading to hypothyroidism (HypoT). Recently, the
correlation between HypoT and idiopathic pulmonary fibrosis
(IPF) was reported [13]. The study revealed that patients with
IPF had a higher prevalence of HypoT than those with chronic
obstructive pulmonary disease and healthy controls. However, the association between IPPFE and HypoT has not yet
been reported. The exact cause of IPPFE remains unclear,
although one hypothesis is that it is an autoimmune disorder. In many previous studies, increased levels of autoantibodies in IPPFE patients have been reported [14].
However, there is no data on the association between thyroid
disease and IPPFE.
The aim of this study was to assess whether HypoT is
associated with IPPFE and to compare the clinical and radiological characteristics between IPPFE patients with and
those without HypoT. We also examined the pathological
features of thyroid glands from autopsied cases.
2.
Patients and methods
2.1.
Study population
We retrospectively reviewed medical records of patients who
attended the Japanese Red Cross Medical Center, Tokyo,
Japan, from January 1, 2006 to October 31, 2016. We searched
for the radiological and pathological records of patients with
idiopathic interstitial pneumonia using the terms “idiopathic
interstitial pneumonia,” “atelectatic fibrosis,” “intra-alveolar
fibrosis,” “pleuroparenchymal fibroelastosis,” and “idiopathic
pulmonary upper lobe fibrosis.” A total of 255 consecutive
patients with idiopathic interstitial pneumonia were selected
and then assessed for IPPFE using the criteria below.
2.2.
Assessment personnel
Three pulmonologists reviewed the clinical characteristics,
two pulmonologists and one radiologist evaluated the computed tomography scans, and two pathologists assessed the
pathological findings.
2.3.
Inclusion and exclusion criteria
The diagnosis of IPPFE was based on clinical and radiological
data with or without pathological data. Cases were included
when a definite or consistent diagnosis of IPPFE was made
according to radiological and/or pathological criteria [1,8,15].
Patients whose clinical data were unavailable were excluded.
If the pulmonologists, radiologists, or pathologists classified
findings as inconsistent with a diagnosis of PPFE, the case
was excluded. Patients with connective tissue disease, except
autoimmune thyroiditis, sarcoidosis, ankylosing spondylitis,
post-radiation pulmonary fibrosis, bone marrow or lung
transplantation, drug-induced lung disease, hypersensitivity
pneumonia, pulmonary mycobacterial disease, Aspergillus
infection, asbestos-induced lung diseases, or other forms of
secondary PPFE, were excluded.
2.4.
Clinical analyses
Body mass index (BMI), smoking history, past medical history, cause of death, laboratory data, and pulmonary function
tests were reviewed from medical records. In most patients,
pulmonary function tests were performed according to guidelines [16] at diagnosis and repeated at least once. At the first
visit, the levels of thyroid hormones and autoimmune antibodies, such as antinuclear, anti-thyroid peroxidase (antiTPO), and antithyroglobulin antibodies, were measured for
assessment of interstitial pneumonia. All laboratory data
were obtained at diagnosis, before IPPFE treatment. None of
the patients had congenital thyroid disease or took medications known to deteriorate thyroid function (i.e., amiodarone
or interferon-γ). HypoT was confirmed in patients with
elevated thyroid-stimulating hormone (TSH) and normal or
decreased free thyroid hormone levels. Hashimoto’s thyroiditis was diagnosed when elevated levels of anti-TPO and/or
antithyroglobulin antibodies were found and when hypoechogenicity of the thyroid gland was detected via ultrasound.
Subclinical HypoT was defined as a serum TSH level above
Please cite this article as: Awano N, et al. Is hypothyroidism in idiopathic pleuroparenchymal fibroelastosis a novel lungthyroid syndrome? Respiratory Investigation (2017), http://dx.doi.org/10.1016/j.resinv.2017.08.010
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
the upper limit despite normal levels of serum free thyroid
hormones [17].
2.5.
Radiological analyses
Observers were blinded to clinical data, and final highresolution computed tomography (HRCT) scan decisions were
reached by consensus. PPFE diagnosis was based on the
radiological criteria as previously reported [1,8,15]. Computed
tomography scans were performed using GE Healthcare
Advantage and Hispeed FX/I scanners (GE Healthcare Milwaukee, WI, USA) and Asteion 4–section and Aquilion 64–
section multidetector scanners (Toshiba Medical Systems
Corporation Tochigi, Japan). HRCT scanning was performed
with 1.5‘2-mm-thick samples at 10–20 mm slice intervals.
2.6.
Pathological analyses
The lungs and thyroid glands obtained from 3 autopsied
cases (Cases 1, 7, and 11) and lung tissue obtained using
video-assisted thoracic surgery (VATS) from 1 case (Case 3)
were examined. The lungs and thyroid glands obtained from
autopsy and lung tissue obtained from VATS were fixed in
10% buffered formalin for 7 days and 1 day, respectively. The
lungs obtained at autopsy were appropriately cut, and the
tissues were sampled from several lesions of macroscopic
PPFE; the thyroid glands were also sampled. All tissue
samples were embedded in paraffin and stained with hematoxylin and eosin and elastica-van Gieson using standard
procedures. We collected the date from 11 autopsy cases with
IPF from the clinical database in our hospital to examine the
histology of the thyroid gland.
2.7.
Statistical analysis
The Chi-squared test was used for categorical variables and
the Mann-Whitney U test was used for continuous variables.
All statistical analyses were performed using EZR (Saitama
Medical Centre, Jichi Medical University, Saitama, Japan), a
graphical user interface for R (The R Foundation for Statistical
Computing, Vienna, Austria). This is a modified version of R
commander designed to add statistical functions frequently
used in biostatistics. A two-tailed P-value of o0.05 was
considered statistically significant.
2.8.
Ethics statement
This study was approved by the Ethical Committee for
Clinical Studies, Japanese Red Cross Medical Center (No.
739, November 30, 2016), and informed consent was obtained
from the patients or their families.
3.
Results
3.1.
Clinical characteristics
Of the 255 consecutive cases, 13 were included. Of these,
9 were clinically and radiologically consistent with IPPFE, and
the remaining 4 fulfilled both radiological and pathological
3
criteria for IPPFE after multidisciplinary discussion among
pulmonologists, radiologists, and pathologists.
The clinical characteristics of the 13 patients with IPPFE
are described in Table 1. Seven were male and six were
female (median age, 67 years; range, 52–92 years at onset of
symptoms). All patients were slim, with a median BMI of
15.8 kg/m2 (range, 11.6–20). Nine patients were non-smokers.
Spontaneous pneumothorax developed in four patients during follow-up. None of the patients had a history of malignancy, occupational exposure, anticancer chemotherapy,
radiotherapy, and transplantation. HypoT was identified in
7 of 13 patients (53.8%) (group A); 4 patients had clinical
HypoT (1 met the criteria for Hashimoto’s thyroiditis) and
3 had subclinical HypoT. The remaining 6 patients were
diagnosed with euthyroidism (46.2%) (group B). Thyroid
hormone replacement therapy was administered in 3 patients
(Cases 1, 3, and 4) in group A. The remaining 4 patients with
HypoT received no treatment for HypoT. None of the patients
suffered from dysfunction of the hypothalamic-hypophyseal
system. Although antinuclear antibody was positive at 1:160
in 3 patients in group A and none in group B, no patients met
the criteria for connective tissue disease. The Krebs von den
Lungen-6 (KL-6) level was elevated in 6 of 13 cases, and the
surfactant protein-D (SP-D) level was elevated in all cases
available for analysis.
Six patients were treated with prednisolone. Of these,
4 patients received additional therapy (3 with cyclosporine
and 1 with pirfenidone). One patient was treated with
pirfenidone alone. However, no treatment was effective and
respiratory failure progressed in all patients. Eight patients
died of respiratory failure and one of pneumonia; the time
interval from onset of symptoms to death ranged from 10 to
81 months.
Sex, BMI, survival time, and the results of laboratory tests,
except the free T4 and TSH levels, were not significantly
different between groups. Although the patients tended to be
younger in group A, the difference was not significant (P ¼
0.053).
3.2.
Pulmonary function test
Serial pulmonary function tests were available in 10 of 13
patients (Fig. 1). All patients had a severe restrictive defect
and an increased ratio of residual volume to total lung
capacity (RV/TLC). The forced vital capacity (FVC) was
remarkably reduced in all patients of both groups (Fig. 1A
and B). During follow-up, RV/TLC increased in 2 of 4 patients
in group A and in all patients in group B (Fig. 1C and D).
3.3.
Radiological characteristics
Representative chest radiography and HRCT (Case 1) are
shown in Fig. 2. Chest radiography showed apical pleural
thickening associated with bilateral upper lobe volume loss,
but lower lobe involvement was less marked (Fig. 2A). HRCT
showed upper lobe volume loss, architectural distortion, and
pleural thickening (Fig. 2C). During follow-up, progression of
pleural thickening and fibrotic changes in the upper lobe
were observed (Fig. 2B and D). Radiological findings for other
patients were similar to those for Case 1. HRCT revealed
Please cite this article as: Awano N, et al. Is hypothyroidism in idiopathic pleuroparenchymal fibroelastosis a novel lungthyroid syndrome? Respiratory Investigation (2017), http://dx.doi.org/10.1016/j.resinv.2017.08.010
4
Group A (HypoT)
Group B (EUT)
Clinical
Age, years
Sex
BMI, kg/m2
Smoking history, pack/y
Pneumothorax
Diagnosis
KL-6, U/mL
SP-D, ng/mL
FT3, pg/mL
FT4, ng/dL
TSH, μIU/mL
anti-TPO Ab, IU/mL
anti-TG Ab, IU/mL
Treatment for IPPFE
Prognosis
Cause of death
Survival, months
P-value*
Subclinical
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Case 10
Case 11
Case 12
Case 13
52
F
16.6
Never
1
P
659
214
2.8
0.45
57.4 †
9
42.7
PSL, CyA
Dead
RF
44
61
M
18.6
Never
0
C
521
538
1.1
0.9
12.43
o5
o10
PSL, CyA
Dead
Infection
81
62
F
13.7
Never
0
P
1450
216
1.8
0.63
10.39 †
6
11
PSL. PFD
Dead
RF
77
62
F
18.3
Never
0
C
247
38.5
1.9
0.78
0.64 †
273
12
None
Survive
Alive
26
65
F
14.5
Never
0
C
395
209
3
0.81
4.49
5
11
None
Survive
Alive
20
70
M
20
140
2
C
578
162
3.2
0.66
4.86
N.A.
N.A.
PSL
Dead
RF
13
84
M
13.6
Never
0
P
449
146
2.6
1.24
7.22
6
11
PFD
Dead
RF
18
63
M
15.7
50
0
C
581
279
3
1.27
2.04
o5
o10
None
Survive
Alive
65
67
M
16.5
10
0
P
266
199
2.2
1.16
1.08
N.A.
N.A.
PSL
Dead
RF
22
70
M
16
Never
0
C
371
151
2.9
1.08
0.85
N.A.
N.A.
None
Survive
Alive
20
76
M
16.2
64
2
C
389
320
3
1.1
1.58
N.A.
N.A.
PSL, CyA
Dead
RF
24
89
F
13.7
Never
0
C
275
264
2
1.2
3
N.A.
N.A.
None
Dead
RF
38
92
F
11.6
Never
1
C
658
N.A.
2.5
1.27
1.72
N.A.
N.A.
None
Dead
RF
10
0.053
0.59
0.28
0.37
0.43
0.57
0.015
0.035
–
–
0.62
Reference range: FT3, 2.2–4.2 pg/mL; FT4, 0.7–1.8 ng/dL; TSH, 0.3–4.3 μIU/mL; anti TPO Ab, 0–15.9 IU/mL; anti TG Ab, 0–27.9 IU/mL.
Abbreviations: HypoT, hypothyroidism; EUT, euthyroidism; F, female; M, male; BMI, body mass index; P, pathological diagnosis; C, clinical diagnosis; KL-6, Krebs von den Lungen-6; SP-D, surfactant
protein-D; N.A., not available; FT3, free T3; FT4, free T4; TSH, thyroid–stimulating hormone; anti-TPO Ab, anti–thyroid peroxidase antibody; anti-TG Ab, antithyroglobulin antibody; PSL, prednisolone;
CyA, cyclosporine; PFD, pirfenidone; IPPFE, idiopathic pleuroparenchymal fibroelastosis; RF, respiratory failure.
*
: P-value is for comparison between group A and B, †: using hormone therapy.
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
Please cite this article as: Awano N, et al. Is hypothyroidism in idiopathic pleuroparenchymal fibroelastosis a novel lungthyroid syndrome? Respiratory Investigation (2017), http://dx.doi.org/10.1016/j.resinv.2017.08.010
Table 1 – Clinical characteristics of the patients.
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
5
Fig. 1 – Changes in forced vital capacity (FVC) and residual volume to total lung capacity (RV/TLC). The median follow-up was
18 months (range, 7.25–51.25 months) in group A and 8 months (range, 6.75–23 months) in group B (P ¼ 0.83). FVC was
significantly decreased in all patients in both groups (A, B). All patients had a high RV/TLC ratio. RV/TLC was increased in 2 of
4 patients in group A and in all patients in group B during the follow-up (C, D). FVC and RV/TLC changes per year were not
significant between groups with P ¼ 0.35 and 0.40, respectively. HypoT, hypothyroidism; EUT, euthyroidism.
Fig. 2 – A representative chest radiograph and high-resolution computed tomography (HRCT) (Case 1). Chest radiography
(A) and HRCT (C) revealed volume loss, architectural distortion, and pleural thickening in the upper lobes. After 4 years, these
imaging findings showed progression of pleural thickening and fibrotic changes in the marginal parenchyma in the upper
lobe (B, D).
Please cite this article as: Awano N, et al. Is hypothyroidism in idiopathic pleuroparenchymal fibroelastosis a novel lungthyroid syndrome? Respiratory Investigation (2017), http://dx.doi.org/10.1016/j.resinv.2017.08.010
6
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
lower lobe involvement and progression of abnormal findings. Lower lobe involvement developed in 5 patients in
group A and in 3 patients in group B during follow-up. Upper
lobes were more severely involved than lower lobes in all
cases.
3.4.
Lung and thyroid gland pathological characteristics
Lung macroscopic findings for autopsy cases were a white
thickening of the pleura and a broad band-like fibrosis in the
apical and/or laterobasal areas. Lung histology obtained on
autopsy or VATS demonstrated hyalinous thickening of the
pleura and marked subpleural elastosis. No inflammation in
the lung parenchyma was observed but peribronchiolar
lymphocyte infiltration was observed in the lung sample
obtained from VATS (Fig. 3). Thyroid gland histology in the
autopsy cases demonstrated diffuse perifollicular or interlobular fibrosis, with scattered elastosis and parenchymal
atrophy in the cases with clinical or subclinical hypothyroidism, and even focally perifollicular fibrosis in the euthyroid
case (Fig. 4). Neither extensive fibrosis nor inflammation
(indicated by infiltration of lymphocytes, plasma cells, histiocytes, or multinucleated giant cells), which are generally
observed in autoimmune thyroiditis, was observed in the
thyroid glands. For the cases with IPF, histological findings of
the thyroid gland were normal in 6, atrophy in 2, adenomatous goiter in 2, and chronic thyroiditis in 1 case. Among
them, perifollicular fibrosis was observed in the thyroid gland
of only 2 patients, both of whom had atrophy of the thyroid
gland.
4.
Discussion
This study evaluated the correlation between IPPFE and
HypoT. We found that 7 of 13 patients with IPPFE (53.8%)
also had HypoT, which is potentially higher than the prevalence in the general population [13]. Clinical, radiological,
and pathological features in all patients were identical to
those previously reported for IPPFE [1,8,18,19]. All patients
were slim with a tendency for elevated SP-D serum levels.
Decreases in FVC and increases in RV/TLC were observed;
these progressed during follow-up owing to fibrotic collapse
of the upper lobes, flattening of the chest cage, and reduction
in respiratory muscle strength [20,21]. These progressions
were associated with poor prognosis, and 9 of 13 patients
died. HRCT radiological findings showed apical pleural thickening with upper lobe volume loss in all patients. These
radiological changes significantly progressed in all patients,
with lower-lobe involvement in some. There was no statistically significant difference in the clinical presentation
between patients with and those without HypoT. Although
only three autopsy cases were histologically analyzed, the
thyroid glands in all 3 cases (including a euthyroid case)
showed perifollicular or interlobular fibrosis and follicular
atrophy. This indicated that patients with IPPFE and HypoT
and patients with euthyroidism are not different but should
be grouped together. Euthyroid IPPFE patients might develop
Fig. 3 – Macroscopic and microscopic findings of the lungs obtained from autopsy or video-assisted thoracic surgery (VATS).
On the cut surface in the mid-coronal section of the autopsied lungs, subpleural band-like fibrosis accompanying traction
bronchiectasis was seen in both apical and laterobasal areas. The border between fibrosis and lung parenchyma was sharply
demarcated. The bronchial trees, especially well demonstrated in the left lung, showed cylindrical bronchiectasis with a
bellows-like structure due to the longitudinal shortness of the lung (A). In a low-power view, the lung showed marked
hyalinous thickening of the visceral pleura and extensive collapse of the subpleural airspaces, similar to the finding for apical
fibrosis. Traction bronchiectasis developed because of the extensive collapse (B). The subpleural areas in lung parenchyma
showed marked alveolar collapse and traction bronchiectasis without inflammation (C) except for a few lymphocyte
accumulations around airways (Inset). (B: 0.5, elastica-van Gieson stain, C: 2, Inset: 10, hematoxylin and eosin stain).
Please cite this article as: Awano N, et al. Is hypothyroidism in idiopathic pleuroparenchymal fibroelastosis a novel lungthyroid syndrome? Respiratory Investigation (2017), http://dx.doi.org/10.1016/j.resinv.2017.08.010
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
7
Fig. 4 – Histological findings of the thyroid glands in the autopsy cases. The thyroid glands showed diffusely perifollicular
fibrosis with scattered elastosis in Case 1 with clinical hypothyroidism (A, B), and almost normal thyroid gland (C) but focally
perifollicular fibrosis (D) in Case 9 with normal thyroid function. There was no inflammatory cell infiltration in both cases.
(A, C: 10, hematoxylin and eosin stain. B, D: 10, elastica-van Gieson stain).
HypoT later in life because of fibrotic changes of the thyroid
gland. In fact, the prevalence of HypoT in patients with IPPFE
in this study is apparently higher than the prevalence in the
general population in Japan: 0.3% (clinical HypoT) or 4.2%
(subclinical HypoT) [22]. These results may confirm the
connection between HypoT and IPPFE.
Although some pulmonary disorders are known to be
associated with abnormal thyroid function, little has been
demonstrated on the basis of thyroid gland histology, except
for Hashimoto's thyroiditis, which is a major cause of HypoT
and is defined by enlargement and hypoechogenicity of the
thyroid gland on ultrasound and autoantibody detection.
Hashimoto’s thyroiditis is often complicated by other autoimmune diseases, such as Sjogren syndrome and rheumatoid
arthritis, both of which are often accompanied by interstitial
pneumonia [23,24]. In this study, we demonstrated that
thyroid gland histology showed perifollicular or interlobular
fibrosis without inflammatory cell infiltration in the thyroid
gland. Thyroid gland histology in IPPFE differs from that in
Hashimoto’s thyroiditis: diffuse lymphoplasmacytic infiltration, lymphoid follicle formation with germinal centers, and
varying degrees of geographic fibrosis [25]. Perifollicular
fibrosis of the thyroid gland may not be characteristic of the
histology of the thyroid gland in IPPFE patients. However,
perifollicular fibrosis was found in the normal thyroid gland
in the case of euthyroidism, possibly suggesting an early
stage of thyroid gland abnormality in the patients with IPPFE.
Recently, Oldham et al. demonstrated the correlation
between HypoT and IPF, although the mechanism by which
HypoT may contribute to IPF pathogenesis was unclear [13]. A
rare congenital disease, brain-lung-thyroid syndrome
(exhibiting a combination of HypoT, infant respiratory distress syndrome, and benign hereditary chorea) has recently
been reported [26]. The cause of the syndrome is elucidated
as haploinsufficiency for the NKX2-1 gene [27]. However,
thyroid gland histology has not been thoroughly evaluated
in these diseases. It is unclear if there is an association
between thyroid gland histology and thyroid dysfunction in
patients with IPPFE. Intralobular and/or perifollicular fibrosis
in the thyroid gland is an uncommon histology even in
chronic thyroiditis. Those fibrotic changes and follicular
atrophy without cellular inflammation are sometimes found
in irradiated thyroid tissue [28,29]. Interestingly, in our control subjects, perifollicular fibrosis without cellular inflammation was observed in the atrophy of thyroid gland of patients
with IPF. The histological analysis of the thyroid gland in
patients with IPPFE showed those histological changes, but
neither cellular inflammation nor atrophy indicate that thyroid follicular cells are susceptible to cell death. Additionally,
we have too little data to evaluate the thyroid gland histology
in IPPFE patients. Thus, further investigation is required to
understand the association between the histology and dysfunction of the thyroid.
The cause of lung fibroelastosis and thyroid dysfunction
in IPPFE is unclear. The present study revealed that a high
number of IPPFE cases were accompanied by HypoT, which
indicates that patients with IPPFE may be susceptible to
thyroid gland disorder and implies a common pathogenesis
for these diseases. We hypothesized three potential causes:
(1) autoimmune disease, (2) nonthyroidal illness (NTI), and
(3) dysfunction of thyroid transcription factor (TTF)-1. First,
autoimmune diseases may be associated with IPPFE;
Please cite this article as: Awano N, et al. Is hypothyroidism in idiopathic pleuroparenchymal fibroelastosis a novel lungthyroid syndrome? Respiratory Investigation (2017), http://dx.doi.org/10.1016/j.resinv.2017.08.010
8
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
increased levels of autoantibodies are often shown in IPPFE
patients. Although histological results of the thyroid gland
in IPPFE was atypical of autoimmune thyroiditis, chronic
inflammation in the thyroid gland sometimes becomes
fibrosis and/or fibroelastosis. The absence of cellular inflammation in the thyroid glands in IPPFE patients does not
necessarily contradict the autoimmune hypothesis. Second,
NTI may be one of the possible associated diseases. NTI is a
debilitating disease that presents as malnutrition or emaciation. Patients with NTI have low serum levels of T4, free
T4, and T3. Their serum TSH levels may also be low or
within the normal range [30]. It is theorized that the changes
in thyroid function during severe illness are protective in
that they prevent excessive tissue catabolism. Although this
pattern differs from that in patients with HypoT, the TSH
level can fluctuate during the course of the disease; the TSH
level can be high in NTI patients [31]. Because IPPFE is a
chronic wasting disease that can lead to emaciation, IPPFE
patients could experience NTI as a complication. Third,
dysfunction of TTF-1 may affect the association between
IPPFE and thyroid dysfunction. Lung fibroelastosis is a
characteristic histological feature of IPPFE and may be
implicated in alveolar collapse and dysfunction of surfactant
proteins. TTF-1 regulates the expression of surfactant proteins by binding to the promoter regions of genes encoding
surfactant proteins including SP-D. It is also an essential
regulator of thyroid gland and lung development [32]. NKX21 encodes TTF-1, which is expressed in the thyroid gland,
brain, and lungs [33,34]. In the lungs, NKX2-1 expression
occurs in type II pneumocytes [35]. These produce the
surfactant proteins essential for the reduction of alveolar
surface tension and local immune defense. In contrast, in
the thyroid gland, NKX2-1 is expressed in thyroid follicular
cells; it regulates thyroglobulin production and contributes
to maintenance of differentiated phenotype [36]. Therefore,
dysregulation of TTF-1 occurring through altered NKX2-1
gene expression may cause lung and thyroid gland abnormalities in IPPFE. Further studies are needed to determine
whether these factors contribute to the pathogenesis of
IPPFE and HypoT. Immunostaining and gene analysis or
evaluation of messenger RNA expression can be performed
in future studies.
This study has several limitations. It was a single-center
retrospective study with a small number of patients. The
sample size was too small to assess the precise prevalence
and characteristics of IPPFE patients with HypoT. However, a
prospective study would prove difficult because IPPFE is a rare
disease. Another limitation is the histopathological examination. Surgical lung biopsy is needed for definite IPPFE diagnosis according to the revised histopathological criteria [8]. In
this study, 4 of 13 patients underwent histopathological
analysis. However, in the remaining cases, generally poor
patient conditions rendered surgical lung biopsy impossible.
Because of the absence of histopathological findings, there is
the possibility that patients with IPF/UIP were included in the
study. Further, although we discussed genes such as NKX2-1,
we could not analyze them because of the lack of materials
and devices.
5.
Conclusions
In conclusion, we speculated that HypoT is prevalent among
patients with IPPFE. Although the pathogenesis of PPFE and
HypoT in IPPFE patients is unclear, autoimmune disease, NTI,
and dysregulation of TTF-1 may play an important role.
These findings help elucidate the mechanism of IPPFE and
HypoT, which will advance the development of a treatment
for IPPFE. However, larger studies are needed to determine
the characteristics of IPPFE patients with HypoT, the precise
prevalence of HypoT, and the mechanism of coincidence of
IPPFE and HypoT. Further studies are also needed to conclusively determine whether this condition is a novel lungthyroid syndrome.
Acknowledgments
The authors would like to thank Dr. Atsuko Moriya and Dr.
Tsunehiro Andoh from the Japanese Red Cross Medical
Center, Tokyo, Japan for their general support and provision
of lung materials.
Conflict of interest
There are no conflicts of interest.
r e f e r e n c e s
[1] Frankel SK, Cool CD, Lynch DA, Brown KK. Idiopathic pleuroparenchymal fibroelastosis: description of a novel clinicopathologic entity. Chest 2004;126:2007–13.
[2] Travis WD, Costabel U, Hansell DM, King Jr. TE, Lynch DA,
Nicholson AG, et al. An official American Thoracic Society/
European Respiratory Society statement: update of the
international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med
2013;188:733–48.
[3] Petrie GR, Bloomfield P, Grant IW, Crompton GK. Upper lobe
fibrosis and cavitation in rheumatoid disease. Br J Dis Chest
1980;74:263–7.
[4] Davies D. Lung fibrosis in ankylosing spondylitis. Thorax
1972;27:262.
[5] Hirota T, Fujita M, Matsumoto T, Higuchi T, Shiraishi T,
Minami M, et al. Pleuroparenchymal fibroelastosis as a
manifestation of chronic lung rejection? Eur Respir J
2013;41:243–5.
[6] Ofek E, Sato M, Saito T, Wagnetz U, Roberts HC, Chaparro C,
et al. Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis.
Mod Pathol 2013;26:350–6.
[7] Hamada K, Nagai S, Kitaichi M, Jin G, Shigematsu M, Nagao T,
et al. Cyclophosphamide-induced late-onset lung disease.
Intern Med 2003;42:82–7.
[8] Reddy TL, Tominaga M, Hansell DM, von der Thusen J, Rassl
D, Parfrey H, et al. Pleuroparenchymal fibroelastosis: a
spectrum of histopathological and imaging phenotypes. Eur
Respir J 2012;40:377–85.
[9] Watanabe K, Nagata N, Kitasato Y, Wakamatsu K, Nabeshima
K, Harada T, et al. Rapid decrease in forced vital capacity in
Please cite this article as: Awano N, et al. Is hypothyroidism in idiopathic pleuroparenchymal fibroelastosis a novel lungthyroid syndrome? Respiratory Investigation (2017), http://dx.doi.org/10.1016/j.resinv.2017.08.010
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
patients with idiopathic pulmonary upper lobe fibrosis.
Respir Investig 2012;50:88–97.
Piciucchi S, Tomassetti S, Casoni G, Sverzellati N, Carloni A,
Dubini A, et al. High resolution CT and histological findings
in idiopathic pleuroparenchymal fibroelastosis: features and
differential diagnosis. Respir Res 2011;12:111.
Wick MR, Kendall TJ, Ritter JH. Asbestosis: demonstration of
distinctive interstitial fibroelastosis: a pilot study. Ann Diagn
Pathol 2009;13:297–302.
Kim EJ, Collard HR, King Jr. TE. Rheumatoid arthritis-associated interstitial lung disease: the relevance of histopathologic and radiographic pattern. Chest 2009;136:1397–405.
Oldham JM, Kumar D, Lee C, Patel SB, Takahashi-Manns S,
Demchuk C, et al. Thyroid disease is prevalent and predicts
survival in patients with idiopathic pulmonary fibrosis.
Chest 2015;148:692–700.
Sato S, Hanibuchi M, Fukuya A, Yabuki Y, Bando H, Yoshijima
T, et al. Idiopathic pleuroparenchymal fibroelastosis is characterized by an elevated serum level of surfactant protein-D,
but Not Krebs von den Lungen-6. Lung 2014;192:711–7.
Oda T, Ogura T, Kitamura H, Hagiwara E, Baba T, Enomoto Y,
et al. Distinct characteristics of pleuroparenchymal fibroelastosis with usual interstitial pneumonia compared with
idiopathic pulmonary fibrosis. Chest 2014;146:1248–55.
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R,
Coates A, et al. Standardisation of spirometry. Eur Respir J
2005;26:319–38.
Cooper DS. Clinical practice. Subclinical hypothyroidism. N
Engl J Med 2001;345:260–5.
von der Thusen JH. Pleuroparenchymal Fibroelastosis: its
Pathological Characteristics. Curr Respir Med Rev
2013;9:238–47.
Watanabe K. Pleuroparenchymal Fibroelastosis: its Clinical
Characteristics. Curr Respir Med Rev 2013;9 [299–37].
Watanabe S, Waseda Y, Takato H, Matsunuma R, Johkoh T,
Egashira R, et al. Pleuroparenchymal fibroelastosis: distinct
pulmonary physiological features in nine patients. Respir
Investig 2015;53:149–55.
Yoshida Y, Nagata N, Tsuruta N, Kitasato Y, Wakamatsu K,
Yoshimi M, et al. Heterogeneous clinical features in patients
with pulmonary fibrosis showing histology of pleuroparenchymal fibroelastosis. Respir Investig 2016;54:162–9.
Okamura K, Nakashima T, Ueda K, Inoue K, Omae T,
Fujishima M. Thyroid disorders in the general population of
Hisayama Japan, with special reference to prevalence and
sex differences. Int J Epidemiol 1987;16:545–9.
Parambil JG, Myers JL, Lindell RM, Matteson EL, Ryu JH.
Interstitial lung disease in primary Sjogren syndrome. Chest
2006;130:1489–95.
9
[24] Solomon JJ, Fischer A. Rheumatoid arthritis interstitial lung
disease: time to take notice. Respirology 2014;19:463–4.
[25] Caturegli P, De Remigis A, Chuang K, Dembele M, Iwama A,
Iwama S. Hashimoto’s thyroiditis: celebrating the centennial
through the lens of the Johns Hopkins hospital surgical
pathology records. Thyroid 2013;23:142–50.
[26] Willemsen MA, Breedveld GJ, Wouda S, Otten BJ, Yntema JL,
Lammens M, et al. Brain-Thyroid-Lung syndrome: a patient
with a severe multi-system disorder due to a de novo
mutation in the thyroid transcription factor 1 gene. Eur J
Pediatr 2005;164:28–30.
[27] Kleinlein B, Griese M, Liebisch G, Krude H, Lohse P, Aslanidis
C, et al. Fatal neonatal respiratory failure in an infant with
congenital hypothyroidism due to haploinsufficiency of the
NKX2-1 gene: alteration of pulmonary surfactant homeostasis. Arch Dis Child Fetal Neonatal Ed 2011;96:F453–6.
[28] Nikiforov YE, Heffess CS, Korzenko AV, Fagin JA, Gnepp DR.
Characteristics of follicular tumors and nonneoplastic thyroid lesions in children and adolescents exposed to radiation
as a result of the Chernobyl disaster. Cancer 1995;76:900–9.
[29] Nikiforov Y, Gnepp DR. Pediatric thyroid cancer after the
Chernobyl disaster. Pathomorphologic study of 84 cases
(1991–1992) from the Republic of Belarus. Cancer
1994;74:748–66.
[30] Chopra IJ. Clinical review 86: euthyroid sick syndrome: is it a
misnomer? J Clin Endocrinol Metab 1997;82:329–34.
[31] Lee E, Chen P, Rao H, Lee J, Burmeister LA. Effect of acute
high dose dobutamine administration on serum thyrotrophin (TSH). Clin Endocrinol 1999;50:487–92.
[32] Lazzaro D, Price M, de Felice M, Di Lauro R. The transcription
factor TTF-1 is expressed at the onset of thyroid and lung
morphogenesis and in restricted regions of the foetal brain.
Development 1991;113:1093–104.
[33] Boggaram V. Thyroid transcription factor-1 (TTF-1/Nkx2.1/
TITF1) gene regulation in the lung. Clin Sci 2009;116:27–35.
[34] Pelizzoli R, Tacchetti C, Luzzi P, Strangio A, Bellese G, Zappia
E, et al. TTF-1/NKX2.1 up-regulates the in vivo transcription
of nestin. Int J Dev Biol 2008;52:55–62.
[35] Hamvas A, Deterding RR, Wert SE, White FV, Dishop MK,
Alfano DN, et al. Heterogeneous pulmonary phenotypes
associated with mutations in the thyroid transcription factor
gene NKX2-1. Chest 2013;144:794–804.
[36] Yamada H, Takano T, Matsuzuka F, Watanabe M, Miyauchi A,
Iwatani Y. Transcriptional activity of the 5’-flanking region of
the thyroid transcription factor-1 gene in human thyroid cell
lines. Genet Mol Biol 2011;34:6–10.
Please cite this article as: Awano N, et al. Is hypothyroidism in idiopathic pleuroparenchymal fibroelastosis a novel lungthyroid syndrome? Respiratory Investigation (2017), http://dx.doi.org/10.1016/j.resinv.2017.08.010
Документ
Категория
Без категории
Просмотров
2
Размер файла
1 289 Кб
Теги
2017, 010, resins
1/--страниц
Пожаловаться на содержимое документа