GastroenterologiaJaponica Copyright 9 1976 by The Japanese Society of Gastroenterology
Vol. 11, No. 3 Printed in Japan
--Original Article--
T H Y M U S A B N O R M A L I T I E S IN U L C E R A T I V E COLITIS --COMPARATIVE STUDY WITH OTHER A U T O I M M U N E DISEASES Yoshio M I Z U N O , K a s h u S H I M A B U K U R O , Masaharu TSUCHIYA
K e n K U R I T A and
Department of Internal Medicine, School of Med. Keio University, 35 Shinano-Machi, Shinjuku-ku, Tokyo
Summary Since the thymus is thought to play an important role in the pathogenesis of ulcerative colitis, thymic abnormalities were studied on 18 cases of ulcerative colitis by using pneumomediastinography and histopathological examination. We have compared the thymic abnormality of ulcerative colitis with that of 104 cases of variety of autoimmune diseases. The denser and larger thymic shadow was seen in ulcerative colitis and this finding was same as in other autoimmune diseases. But the thymic size in ulcerative colitis was the largest in all examined autoimmune diseases. The incidence of thymic lymphoid follicle formations in ulcerative colitis was significantly higher than that of accidental death and this high incidence of lymphoid follicle formation is similar to other autoimmune diseases. We suggested that ulcerative colitis might be caused by the abnormal thymus dependent system.
Key Words:
ulcerative colitis, thymus, pneumomediastinography, autoimmune disease.
Introduction Ulcerative colitis is a chronic disease mainly affecting the large bowel. A u t o i m m u n e pathogenesis in this disease has been postulated by some investigators. Since the thymus is thought to be a central organ in the i m m u n e system of m e n and animals, a n u m b e r of investigators have focused their efforts on the elucidation of thymic role in the pathogenesis of a u t o i m m u n o p a t h y . I n 1936, Condorelli 1) first introduced the technique of p n e u m o mediastinography showing its usefulness in visualization of persistent or hyperplastic thymus and otherwise undetectable tumor. I n the present study, thymic abnormalities were studied on ulcerative colitis by using
pneumomediastinography. T h e purpose of the study is to evaluate the usefulness of p n e u m o m e d i a s t i n o g r a p h y in the detection of thymic abnormalities including occult thymom a and to correlate the pneumomediastinographic findings with histopathological changes of the thymus in ulcerative colitis in contrast with other a u t o i m m u n e diseases.
Materials and M e t h o d s Patients: Nineteen patients colitis were studied. Eleven female and eight were male. of the patients was 31 years
with ulcerative patients were T h e m e a n age old. Thirteen
patients were performed thymectomy. Ulcerative patients were c o m p a r e d with 104 patients
September 1976
with
other
209
Thymus Abnormalities in Ulcerative Colitis
Patients
so that the a d m i n i s t e r e d gas could be dis-
consist of 51 cases of m y a s t h e n i a gravis, 31 cases of Behget's diseases, 12 cases of systemic
autoimmune
diseases.
t r i b u t e d diffusely a r o u n d the area. I n addition to anteroposterior, lateral, a n d oblique
lupus erythematodes, 7 cases of Hashimoto's
X - r a y pictures, five lateral tomograms are o b t a i n e d at a distance of 1 cm to the right
diseases a n d 3 cases of Sj6gren's syndrome. P n e u m o m e d i a s t i n o g r a p h y2): T h e a p p r o c h
a n d left of the m i d l i n e respectively.
t h r o u g h the supra-sternal fossa was used for pneumomediastinography.
No special a p p a r -
atus was necessary for this procedure except for a three-way stop-cock, a p u n c t u r e needle, a 100 ml syringe, a small oxygen c o n t a i n e r a n d pieces of r u b b e r t u b i n g .
Local anesthesia
was applied to the supra-sternal region with the neck extended in a supine position. T h e p u n c t u r e needle held at a n angle of a b o u t 120 degrees was then inserted in the suprasternal fossa toward the posterior surface of the m a n u b r i u m of the s t e r n u m to a depth of 3-4 cm.
Oxygen gas was then administered
to the fossa through the syringe very slowly, at a rate of a b o u t 10 ml per m i n u t e up to
Diagnosis
by
pneumomediastinography3):
T h e thymic shadow was classified by the following criteria. 1)
Shape a n d location
T h e thymic shadows were classified into ten types according to the shape a n d location (Fig. 1).
T y p e I to I I I
is located at the
posterior part of the anterior m e d i a s t i n u m , type I V to V I I is located at the middle part of the anterior m e d i a s t i n u m a n d type V I I I to IX
is located at the a n t e r i o r part
of the
a n t e r i o r m e d i a s t i n u m . T y p e X means the occult t h y m o m a which is not shown by p l a i n
At 10-15 m i n u t e intervals, the
X - r a y film a n d tomography. 2) Size T h e size of the t h y m u s on p n e u m o m e d i a s -
p a t i e n t was asked to lie on his right a n d left
t i n o g r a p h was estimated by m e a s u r i n g the
sides alternatively before taking X - r a y pictures,
largest part on the lateral t o m o g r a m as follows.
150-300 ml.
Loeation
L S
(eases) \ Ulcerative eotitis (18)
Posterior
Middle
Anterior
Occult Thymoma (X)
I
II
lIl
IV
V
VI
Vli
18
11
5
0
45
5
11
5
0
0Cases
Myasthenia gravis (46) Behcet's disease (31)
9
9
9
2
61
4
0
4
2
5
25
16
7
0
45
0
0
7
0
0
S L E(12)
8
17
8
0
25
0
8
34
0
0
0
29
0
57
0
0
0
0
0
0
0
0
0
67
0
33
0
0
0
15
1i
8
1
50
3
4
7
1
5Cases
Hashimoto's disease (7) Sji;gren syndrome(3) Total
(117)
14
Fig. 1. Types of shape of the thymus and their incidence in various autoimmune
diseases. (122 cases) (%).
210
Y. M I Z U N O E T A L .
The thymic outline was traced onto paper of standard thickness and the weight of this template was correlated with the weight of 1 sq crn of the same paper to obtain the area. And we also measured the widest part of the thymic shadow on the lateral tomogram. 3) Density Density of the thymic shadows were divided into three grades: a; implies same density of that of the heart. b; implies same density of that of the vertebra. c; implies intermediate density of a and b. Histopatological study a~: The thymuses were extirpated through the supra-sternal notch as previously described 4). The extirpated thymuses were fixed in 10% formalin and paraffin sections were stained with hematoxylin and eosin. Results Fig. 2 shows a pneumomediastinogram of 42 years old male patient. Right side is a simple lateral projection and left side is a tomogram in lateral projection of pneumomediastinography. We can see the denser
Vol. 11, No. 3
thymic shadow (type V, density " a " ) even in the patient aged over 40. Fig. 3 shows lymphoid follicle formation found in the thymus extirpated from same patient. 1) Shape and location (Fig. 1) In ulcerative colitis the most frequently encountered type (45%) was of tongue-like shape localized in the middle of the anterior mediastinum (type V) and this was followed by type I (18~o). Type V was found in 61~o of myasthenia gravis and 45% of Behget's disease, T y p e I plus type V (type I and type V were of same shape but different in location and width.) was found in 63~o of ulcerative colitis, 70~o of myasthenia gravis and 70~o of Beh~et's disease. T y p e I was found more frequently in ulcerative colitis and Behget's disease. Type V I I was found in two cases of ulcerative colitis, a case of Sj6gren's syndrome and a case of SLE. Type X (occult thymoma) was found in 5 cases of myasthenia gravis, but we could not find the occult thymoma in ulcerative colitis. 2) Size (Fig. 4) In ulcerative colitis, thymic size on pneumomediastinograph was the largest in autoimmune
Fig. 2. Case H.K. 42 Y.O. Male. Ulcerative colitis.
Thymus Abnormalities in Ulcerative Colitis
S e p t e m b e r 1976
211
0 T
5O
Ulcerative Cdiris I L blyasthenia Gravis t Beh?et's Disease f
100 ] ] ]
/
SLE
I
Hashimot0's Diseases/ Fig. 5. Incidence of the density " a " a u t o i m m u n e diseases.
Fig. 3. L y m p h o i d follicle f o r m a t i o n in the thymic medulla.
1
5
10 cm 2
Flcerative Colitis (13)
~--
Myasthenia Gravis (23)
I
l~eh(/et's Disease (18) i S I. E
{4) t
]
1 ,
]
f
flashim<~)'s Disease (2~) / Sjiigren's Syndrome (2)
' I
PI
Fig. 4. Size of the thymus in various automimune diseases. diseases and its size was 6.30 4- 1.77 sq cm (Mean 4- SEM). In other autoimmune diseases the thymic size was 5.7 4- 2.19 sq cm in myasthenia gravis, 6.26 4- 3.24 sq cm in Beh~et's disease, 3.15 • 0.73 sq cm in Hashimoto's disease, 4.25 4- 1.13 sq cm in SLE, and 5.76 and 4.36 sq cm in Sj6gren's syndrome. 3) Density of the thymic shadows (Fig. 5) Density of the thymic shadows was divided into three grades by previously described criteria. Density " a " occupied 78% of 18 cases of ulcerative colitis. But in other autoimmune diseases density " a " occupied from 93 to 100% except Hashimoto's disease. 4) Relationship between normal and abnormal thymus on age involution
I j in various
Fig. 6 is a diagram to illustrate the relationship between age and age involution of normal thymus modified from H a m m a r and Boyd 5). The solid triangle means the extirpated thymus of ulcerative colitis. The solid circle means the extirpated thymus of myasthenia gravis. The open square and circle mean the extirpated thymus of Beh~et's disease and the open square indicates the cases under treatment with prednisolone (PSL) and the open circle indicates the cases under treatment without PSL. The solid line indicates normal age involution curve. As shown in this diagram, 64% of ulcerative colitis, 93% of myasthenia gravis and 63% of Beh~et's disease were below the solid line. This finding suggests that the thymic involution is delayed in ulcerative colitis, myasthenia gravis and Behget's disease. 5) Histopathological examination of extirpated thymus (Fig. 7) In ulcerative colitis, thymic lymphoid follicle formation was found in 8 cases out of 13 patients (61%). This incidence is significantly higher than that of accidental death ( p < 0.001). And this high incidence of lymphoid follicle formation is similar to other autoimmune diseases such as myasthenia gravis (71 out of the 92 cases, 77%), Behget's disease (20 out of the 43 cases, 46%), SLE (5 out of the 9 cases, 56%) and autoimmune hemolytic anemia (3 out of the 3 cases, 100%). There was no significant relationship between the thymic shadows and histopathological findings in ulcerative colitis.
212
Vol. 11, No. 3
Y. M I Z U N O E T A L .
Grade of Involution
Connective
Tissue
and
9 Ulcerative
colitis
9
gravis
Myasthenia
n ~. PSL [
Fat
o ~ PSL
IV
Behget Disease
~s Hammar-Boyd 1932)
I11
9
eot:xx)o o o ~ o ~ o . o o
,
o
9
i:] b~
II
o
6
o~
o9 o
9
9
I
0
9 it
9 9
9
O
1'0 Fig. 6.
20
10
4'0
5'0
6'0
7'0 Age in Year
Relationship between age and age involution of the thymus in ulcerative colitis myasthenia gravis and Behget's syndrome.
Fig. 7. Number of subjects and incidence of thymic lymphoid follicles in thymectomized cases. No. cases studied
No. cases with lymphoid follicles
~o positive
13 43 92 15 9 3 2
8 20 71 6 5 3 2
61.5" 46.5 77.5 40.0 55.6 100.0 100.0
177
115
64.9
71
12
16.9
Ulcerative colitis Behqet's disease Myastenia gravis Hashimoto's thyroiditis SLE AIHA Sj6gren's syndrome Total Accidental death *P<0.001, X- = 12.1.
Discussion
P n e u m o m e d i a s t i n o g r a p h y was first d e s c r i b e d in 1936 b y C o n d o r e l l i z) a n d soon b e c a m e a n i m p o r t a n t diagnostic tool a m o n g the E u r o p i a n countries. A l t h o u g h it is v e r y useful for the d e m o n s t r a t i o n of the thymus, this t e c h n i q u e has not g a i n e d wide a c c e p t a n c e in J a p a n untill w h e n T s u c h i y a 2) first i n t r o d u c e d this technique in 1958. A l t h o u g h there a r e several ways of insufflation of gas into the m e d i a s t i n u m as described b y Simecek 6), the r e t r o s t e r n a l
m e t h o d a p p e a r s most useful to d e m o n s t r a t e the thymus, b e c a u s e we can see not only the a n t e r i o r m e d i a s t i n u m b u t also the posterior m e d i a s t i n u m b y c h a n g i n g the position of the patient. N o special a p p a r a t u s is necessary for this technique. W e r e c o m m e n d to use the oxygen for visualization, b e c a u s e the oxygen was a b s o r b e d quickly w i t h i n 4 - 6 hours. T h e p a t i e n t m i g h t c o m p l a i n of slight sensation of compression in the epigastric a n d d i a p h r a g m a t i c regions at short time a n d
September 1976
Thymus Abnormalities in Ulcerative Colitis
usually no dangerous side effect occurs. However some authors described other complications such as air embolism, pneumothorax, mild fever and myasthenic crisis6, 7>. H a r e et al. s) and Benendo-Kapugcifiska et al. 7) described about location of the thymic shadows. According to Benendo-Kapu~cifiska et al., the thymic shadows were divided into six types and most frequent type (61%) was a "tongue-like" one, long and flat in myasthenia gravis. This thymic shadow corresponds to type V of our classification. They also described that the second most frequent shape was "band-like" form which corresponds to our classification type V I I . We observed that type in 4 cases of ulcerative colitis, SLE and Sj6gren's syndrome. These 4 patients are over 40 years old and were not treated with PSL. So we suggest that these thymus contained large amount of fatty tissue comparable to age involution, but remaining several narrow bands were abnormal findings according to histopathological examination. It is suggested from the present study that type V is a characteristic shadow in autoimmune diseases including ulcerative colitis, however type I was relatively frequently found in ulcerative colitis and Behqet's disease. Since these two diseases were very similar in clinical findings, we suggest that these two diseases have similar thymic abnormalities. There were several reports concerning the thymic size on pneumomediastinography 9"12>. Nakata et al. Z2~ reported that the largest size was seen in Hashimoto's disease and the second in ulcerative colitis and the third in myasthenia gravis. However, the present study showed that ulcerative colitis had the largest thymic shadow. We have thought that the thymic size of SLE would be small because the patients with SLE are almost invariable placed on PSL which is known to have thymolytic action and produce thymic
213
involution. H a r e et al. ll~ reported that the thymus of SLE was small and its size did not depend on the treatment with PSL. Then the question arises whether PSL affects the thymic size. The present study suggests that PSL does not affect the thymic size when judged by pneumomediastinography. Thus it appears that the various diseases have their own thymic size irrespective of the treatment. This is further supported by the fact that the thymic size of hypoplastic anemia 13~ or Beh~et's disease m which is often placed on PSL was larger than that of myasthenia gravis which is usually not treated with PSL. In contrast to the pneumomediastinographic findings, the PSL seems to affect involution of the thymus when examined histopathologically because the patients of Beh~et's disease with PSL have more involuted thymus than the patients without PSL (Fig. 6). A formation of lymphoid follicles in thymus of ulcerative colitis was observed in 61%. This high incidence of lymphoid follicle formation is similar to other autoimmune diseases. The presence or absence of lymphoid follicle formation is an important factor for establishing diagnosis of thymic abnormality in autoimmunopathy, because in non-autoimmunopathy, lymphoid follicle formation was noted in 12 out of the 71 cases (17%) of accidental death. An extremely frequent detection of the lymphoid follicle formation in autoimmunopathy m a y be the evidence to indicate positive intrathymic proliferation of auto-antibody producting cells. As for relationship between thymus and ulcerative colitis, Schmid 15) described that 8 severe chronic ulcerative colitis patients were performed thymectomy and he found thymic lymphoid follicle formations in 3 cases out of 3 ulcerative colitis patients. So he considered that this finding is a sign of increased activity of the thymus as well as supporting sign for
Y. MIZUNO ETAL.
214
the assumption of a n a u t o i m m u n o l o g i c a l process w i t h i n the ulcerative colitis. N o k i t a et al. ~6) also performed t h y m e c t o m y for three ulcerative colitis patients who have no effects for medical t r e a t m e n t a n d described that they have a good clinical course a n d t h y m e c t o m y should be considered as a choice of t r e a t m e n t for ulcerative colitis. C o n c e r n i n g the occult t h y m o m a we f o u n d 5 cases of occult t h y m o m a by using p n e u m o m e d i a s t i n o g r a p h y a n d 3 out of 5 patients were found less t h a n one year d u r a t i o n of disease. But we could n o t find the occult t h y m o m a in ulcerative colitis. Therefore this m e t h o d is a very useful tool to find the occult t h y m o m a even when t h y m o m a is not shown by X - r a y film a n d tomographyl7,18~. W e strongly r e c o m m e n d to a p p l y the p n e u m o m e d i a s t i n o g r a p h y in ulcerative colitis a n d also i n other a u t o i m m u n e diseases so that we are able to find the occult t h y m o m a associated with the a u t o i m m u n e diseases. References
1) Condorelli, L.: II Pneumo-mediastino artificiale. Minerva Med., 27: 81, 1936. 2) Tsuchiya, M.: Pneumomediastinography. NichiFutsu Igaku, 5: 91-97, 1958 (in Japanese) 3) Tsuchiya, M.: Thymus--its special biopsy. Medicina, 11:1041 1043, 1974 (in Japanese). 4) Yoshimatsu, H. et al.: Mediastinoscopy and its application; thymectomy via the suprasternal notch. Keio J. Med., 20: 29-43, 1971. 5) Boyd, E.: The weight of the thymus gland in health and disease. Amer. J. Dis. Child., 43:11621214, 1932.
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6) Simecek, C.: Diagnostic pneumomediastinography. Dis. Chest, 53: 24-29, 1968. 7) Benendn-Kapugcirlska, B. and Malanowska, S.: Diagnostic pneumomediastinography in 100 cases of myasthenia gravis. Polish Medical J., ii: 1292-1298, 1972. 8) Hare, W.S.C. and Mackay, I.R.: Radiological assessment of thymic size in myasthenia gravis and systemic lupus erythematosus. Lancet, i: 746-748, 1963. 9) Irvine, W.J. and Sumerling, M.D.: Radiological assessment of the thymus in thyroid and other diseases. Lancet, i: 998-999, 1965. 10) Michie, W. et al.: Quantitative radiological and histological studies of the thymus in thyroid diseases. Lancet, i: 691-695, 1967. 11) Hare, W.S.C. and Mackay, I.R.: Thymic size in systemic lupus erythematosus. Arch. Intern. Med., 124: 60-63, 1969. 12) Nakata, Y. et al.: Pneumomediastinography in autoimmune diseases. Jap. J. Clin. Immunol., 5: 865-869, 1973 (in Japanese). 13) Nakata, Y. et al.: Pneumomediastinography in patients with hypoplastic anemia. Jap. J. Clin. Hematology, 14: 757-761, 1973 (.Japanese with English abstracts). 14) Tsuchiya, M. et ah: Thymic hyperplasia and therapeutic approach of thymectomy in Behset's syndrome. Biochemistry and Experimental Biology, 11 : 47-52, 1974. 15) Schmid, K.O.: Thymus and ulcerative colitis. Verhand. Deutsch. Gesell. Pathol., 54: 313-319, 1970. 16) Nokita, H. et al.: Thymectomy on ulcerative colitis. Jap. J. Gastroentero. Surg., 6: 169-170, 1973 (in Japanese). 17) Kreel, L. et al.: Pneumomediastinography by the trans-sternal method. Clin. Radiol., 15:219-223 1964. 18) Latos, D.L. and Burns, W.M.: Diagnostic pneumomediastinography. South. Med. J., 66: 1073-1074, 1973.
Received June 11, 1976 Accepted June 14, 1976 Address requestsfor reprints to: Dr. M. Tsuchiya M.D., Department of Medicine, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160 Japan.
