GASTROENTEROLOGY 2000;119:502–506
CASE REPORTS
A Patient With Improvement of Ulcerative Colitis
After Appendectomy
KAZUICHI OKAZAKI,* HISASHI ONODERA,‡ NORIHIKO WATANABE,* HIROSHI NAKASE,*
SUGURU UOSE,* MITSUNOBU MATSUSHITA,§ CHIHARU KAWANAMI,*
MASAYUKI IMAMURA,‡ and TSUTOMU CHIBA*
Departments of *Gastroenterology and Endoscopic Medicine and ‡Surgery and Surgical Basic Science, Kyoto University Hospital, Kyoto;
and §Department of Gastroenterology, Tenri Hospital, Nara, Japan
Recently, several retrospective studies have shown an
inverse association between appendectomy and devel-
opment of ulcerative colitis. We describe a 21-year-old
man with distal ulcerative colitis and appendiceal in-
volvement. The patient passed bloody stools continually
during the 3 years before admission. Macroscopic and
microscopic findings showed chronic moderate inflam-
mation of the appendix and rectum. The ratio of CD4 to
CD8 lymphocytes isolated from rectal and appendiceal
mucosa was increased (4.3 and 3.8, respectively) com-
pared with controls (n ⴝ 11; 1.0 in the rectum and 1.4
in the appendix). Clinical symptoms and colonoscopic
and microscopic findings improved significantly after
appendectomy. In addition, the amount of interferon
gamma secreted from rectal lymphocytes was reduced
to 89 pg/mL after surgery (before appendectomy, 254
pg/mL). However, interleukin 4 production was below
detectable levels both before and after appendectomy.
These findings suggest that appendectomy resulted in
altered T-helper (Th)1/Th2 balance in this patient. In the
3 years since surgery, the patient has been in good
condition without recurrence of symptoms. This is the
first report demonstrating therapeutic benefit of appen-
dectomy in a patient with ulcerative colitis and potential
mechanistic relationship.
lthough the triggering factor for ulcerative colitis
A (UC) is still unknown, UC should be regarded as a
multifactorial disease involving an interaction between
genetic and environmental factors that give rise to an
inappropriate immunologic response.1 There is much
evidence for abnormal mucosal immune responses asso-
ciated with the activation of lymphocytes and macro-
phages.1,2 The gut-associated lymphoid tissue system
(GALT), including Peyer’s patches, is involved in sam-
pling antigens from the lumen and induction of the
mucosal immune response in the intestine.3 However,
the appendix, as a part of GALT, has long been consid-
ered as a redundant organ.4 Recent retrospective studies
have shown an association between appendectomy and
UC.5–14 Although this correlation does not in itself im-
ply a causative role of the appendix in the development
of UC, it has led to a hypothesis that appendectomy may
afford protection against UC. In an animal model of
young T-cell receptor (TCR)-␣ deficient mice, removal
of the appendix either protected against or improved
experimental colitis.15 However, no report has described
improvement in UC after appendectomy alone in hu-
mans. We now describe a young man with distal UC and
appendiceal involvement. He passed bloody stools con-
tinually during the 3 years before appendectomy, and his
condition has improved during the 3 years after appen-
dectomy. This is the first study supporting a close rela-
tionship between the appendix and development of UC
by the ability to modulate the chronic course of UC.
Case Report
A 21-year-old man was admitted to our unit in Sep-
tember l996 with symptoms of bloody stools. For 3 years
before this time, he had passed bloody stools daily but had
never received medication for the symptom. On admission, he
had no other complaints. Hematologic and biochemical blood
tests including serum electrolytes, liver enzymes, and amylase
showed no abnormalities. Erythrocyte sedimentation rate was
normal at 5 mm/h, but C-reactive protein level was slightly
increased at 2.0 mg/dL (normal, ⬍0.1 mg/dL). Specific sero-
logic studies as well as stool cultures for bacteria and viruses
showed negative findings. Autoantibodies, including rheuma-
toid factor, antinuclear, anti–smooth muscle, anti-ribonucleo-
protein, and antineutrophil cytoplasmic antibodies, were all
Abbreviations in this paper: GALT, gut-associated lymphoid tissue
system; IFN, interferon; IL, interleukin; TCR, T-cell receptor; Th, T-helper
cell; UC, ulcerative colitis.
© 2000 by the American Gastroenterological Association
0016-5085/00/$10.00
doi:10.1053/gast.2000.9368
Figure 1. Colonoscopic findings. Colonoscopic examination showed (A) diffusely edematous, inflammatory mucosa with ulcers in the rectum and
(B) skipped erosions in the orifice of the appendix. One month after appendectomy, colonoscopic findings had improved remarkably, with no
erosions or redness in the (C) rectum and (D) cecum. Three years after appendectomy, colonoscopic findings showed an inactive state in the
(E ) rectum and (F ) cecum.

Figure 2. Microscopic findings. (A) Before the appendectomy, there was remarkable infiltration of mononuclear cells in the rectal mucosa, which
was diagnosed as a grade IV in Matt’s classification. (B) Microscopic findings of the appendix showed moderate appendicitis, with mucosal
erosions and moderate infiltration of lymphocytes. (C) One month after appendectomy, inflammation in the rectal mucosa had improved
remarkably and was diagnosed as grade III in Matt’s classification. (D) Three years after appendectomy, biopsy specimens from the rectal
mucosa showed grade II in Matt’s classification. (H&E staining; original magnifications: A, C, and D, 125⫻; B, 50⫻.)
504 OKAZAKI ET AL.
Table 1. Ratio of CD4/CD8-Positive Lymphocytes in the
Colonic Mucosa
Normal subjects
Site (n ⫽ 11) UC (n ⫽ 10) Present case
Appendix 1.41 ⫾ 0.43 3.89 ⫾ 2.13a,b 3.8
Rectum 1.00 ⫾ 0.70 4.27 ⫾ 1.16a 4.3
a Significantly different vs. normal subjects (P ⬍ 0.05).
b No cecal lesions in the appendix.
negative. Colonoscopic examination showed diffusely edema-
tous, inflammatory mucosa with erosions in the rectum (Figure
1A) and skipped erosions in the orifice of the appendix (Figure
1B), but no other lesions from the ascending to sigmoid colon.
Histologic examination of rectal and appendiceal biopsy spec-
imens revealed depletion of goblet cells, crypt abscesses, and
severe lymphoplasmacytic infiltration in the mucosa, which is
consistent with UC of grade IV in Matt’s classification (Figure
2A). On this basis, the patient’s condition was diagnosed as
distal UC with mild activity.
The patient and his family rejected systemic administration
of specific drugs such sulfasalazopyridine, 5-azosulfapyridine,
or steroids. He strongly desired to receive local therapy such as
suppositories or enemas of such drugs, which seem to have
fewer side effects than systemic administration. Then, appen-
dectomy was proposed as an alternative treatment to remove 1
of 2 lesions, which would enable him to have subsequent
topical treatment via the anus. After the patient’s fully in-
formed consent had been obtained, an appendectomy was
performed by open surgery under spinal anesthesia. The ap-
pendix was 13 cm long and appeared swollen and red macro-
scopically. Microscopic findings showed mucosal erosions and
moderate infiltrations of lymphocytes, especially around the
small vessels (Figure 2B). The occurrence of bloody stools
gradually decreased and eventually ceased 2 weeks after the
appendectomy. One month later, the colonoscopic and micro-
scopic findings of the rectum had clearly improved (Figures
1C, 1D, and 2C). Because he had no recurrence of bloody
stools, he never received any local therapy.
Flow-cytometric analysis showed that the ratios of CD4/
CD8 lymphocytes isolated from the rectal and appendiceal
mucosa before appendectomy had subsequently increased (4.3
and 3.8, respectively) compared with controls (n ⫽ 11; 1.0 in
the rectum and 1.4 in the appendix without cecal lesions)
(Table 1). Solid-phase enzyme-linked immunosorbent assay16
showed medium levels of interferon (IFN)-␥ and interleukin
(IL)-4 cytokines, which were secreted from the rectal mucosal
lymphocytes after stimulation with l0 ng/mL phorbol myris-
tate acetate and 1 ␮g/mL ionomycin for 24 hours. The IFN-␥
level before appendectomy (254 pg/mL) was higher than that
measured 2 weeks after appendectomy (89 pg/mL) and that of
the controls (n ⫽ 5; 38 ⫾ 12 pg/mL). However, IL-4 levels
both before and after appendectomy were below detectable
levels (⬍10 pg/mL). Thus, in this patient, the rectal lympho-
cytes produced predominantly more IFN-␥ than IL-4, and the
ratio of IFN-␥ and IL-4 decreased after appendectomy. The
GASTROENTEROLOGY Vol. 119, No. 2
patient was discharged 1 month after surgery and followed up
as an outpatient without medication. He has been in good
condition, with no occult blood in stools, for the 3 years since
the appendectomy. A follow-up colonoscopic examination 3
years after appendectomy showed an inactive state (Figures 1E
and F and 2D).
The study was performed according to the Helsinki Decla-
ration and was approved by the hospital’s human subject
protection committee.
Discussion
This young patient’s diagnosis was mildly active
UC because he had proctitis and skipped appendiceal
lesions. To avoid adverse effects, the patient and his
family wanted local therapy such as suppositories or
enemas of specific drugs such as sulfasalazopyridine,
5-azosulfapyridine, or steroids rather than systemic ad-
ministration. However, we predicted that a topical drug
in the rectum would not directly reach the skipped
appendiceal lesions. Therefore, appendectomy was per-
formed. His clinical course during the past 6 years
suggested that the appendectomy played an important
role in the regression of his colitis, although a variation
in the natural course of UC cannot be completely ex-
cluded.
The human appendix has been considered to play little
role in the mucosal immune system.4 However, some
recent studies have shown significant associations be-
tween the appendix and UC5–15,17–26 despite other con-
troversial reports.27 First, the prevalence of appendec-
tomy is low in patients with UC.5–14 Second, appendiceal
inflammation with cecal sparing occurs commonly as a
skip lesion in UC, which is more characteristic of the
underlying UC than in acute appendicitis.17–26 These
findings led us to the concept that the appendix (1) may
be a protective or causative factor, (2) may play a central
immunologic role in the pathogenesis of UC, and (3)
may be an indication of the heterogeneity of UC. Most
important is whether the appendix plays a protective or
causative role in UC. However, this correlation does not
in itself imply a causative role of the appendix in the
development of UC.
This hypothesis has been supported recently in studies
using TCR-␣– deficient mice that spontaneously develop
colitis. In these mice, removal of the appendix at a young
age suppresses the development of colitis,15 suggesting a
significant role of the appendix in mucosal immunologic
signaling and the pathophysiology of UC.
In general, UC is considered to occur in the distal
colon, and extends to the proximal colon.19 However,
appendiceal inflammation and patchy cecal inflamma-
August 2000
tion, as in our patient, have been observed in some
patients with left-sided UC as a skip lesion.17–26
Although the function of the appendix is still un-
known, it is most likely involved in sampling antigens
from the lumen and in inducing mucosal immunologic
responses as a part of GALT, together with Peyer’s
patches and the tonsils.28 –31 The appendiceal lymphoid
tissue is predominantly composed of B cells and CD4-
positive T-helper (Th) cells.4,29 The balance of T cells in
UC is shifted toward a helper type rather than a sup-
pressor type.28 In the appendiceal mucosa of our patient,
CD4-positive cells were predominant over CD8-positive
cells compared with those of normal subjects. CD4⫹ T
cells are further subdivided into Th1 and Th1 cells based
on profiles of cytokine production, and these 2 T-cell
populations counterregulate each other.32 Thl cells,
which produce IL-2, tumor necrosis factor ␣, and IFN-␥,
mediate cellular immunity, macrophage activation, and
cytotoxicity and help B-cell production of opsonizing
and complement-fixing antibodies.32 In contrast, Th2
cells, which produce IL-4, IL-5, IL-6, and IL-10, pro-
mote humoral and allergic responses.32 By using the
cloned mucosal CD4 T cells, Parronchi et al.33 found that
patients with Crohn’s disease produced high levels of
IFN-␥ but low or undetectable amounts of IL-4. UC
patients, on the other hand, produced IL-4 in addition to
IFN-␥. However, it is still unclear which population of
T-helper cells is predominantly involved in UC. In our
patient, the level of IFN-␥ produced by the rectal lym-
phocytes was greater than that of IL-4, but decreased
after appendectomy. A possible explanation for a protec-
tive role of appendectomy against the development of
UC is that removal of the appendix, a T-helper cell
organ, may change the Th1/Th2 balance and thus pre-
vent the induction of inappropriate immune responses.5,34
It is reasonable to consider that in our patient the ap-
pendectomy was effective in protecting the development
of colitis.
On the basis of these findings, we propose that appen-
dectomy may have a place as a therapeutic strategy in
young patients with mildly active UC. Further investi-
gations into the exact role of the appendix in the patho-
physiology and indications of appendectomy in UC are
needed.
References
1. Shanahan F. Pathogenesis of ulcerative colitis. Lancet 1993;
342:407– 411.
2. Okazaki K, Nishimori I, Morita M, Sano S, Toyonaga M, Nakazawa
Y, Yamamoto Y, Yamamoto Y. Major histocompatibility antigen–
restricted cytotoxicity in chronic inflammatory bowel disease.
Gastroenterology 1993;104:384 –391.
IMPROVEMENT OF UC AFTER APPENDECTOMY 505
3. Kraehenbuhl JP, Neutra MR. In: Ogra PL, et al., eds. Handbook of
mucosal immunology. New York: Academic, 1994:403– 410.
4. Kawanishi H. Immunocompetence of normal human appendiceal
lymphoid cells: in vitro studies. Immunology 1987;60:19 –28.
5. Rutgeerts P, D’Haens G, Hiele M, Geboes K, Vantrappen G.
Appendectomy protects against ulcerative colitis. Gastroenterol-
ogy 1994;106:1251–1253.
6. Duggan AE, Usmani I, Neal KR, Logan RFA. Appendectomy, child-
hood hygiene, Helicobacter pylori status, and risk of inflammatory
bowel disease: a case control study. Gut 1998;43:494 – 498.
7. Smithson JE, Radford-Smith G, Jewell GP. Appendectomy and
tonsillectomy in patients with inflammatory bowel disease. J Clin
Gastroenterol 1995;21:283–286.
8. Russel MG, Dorant E, Brummer RJM, Van De Kruus M, Muris JW,
Bergers JM, Goedhard J, Stockbrügger RW. Appendectomy and
the risk of developing ulcerative colitis or Crohn’s disease: re-
sults of a large case-control study. Gastroenterology 1997;113:
377–382.
9. O’Gorman P, Bennett D, Kavanagh E, Twohig LB, O’Sullivan GC,
O’Regan P, Shanahan F. MALTectomy (appendectomy/tonsillec-
tomy) does not influence the occurrence or mode of presentation
of adult celiac disease. Am J Gastroenterol 1996;91:723–725.
10. Breslin NP, McDonnell C, O’Morain C. Surgical and smoking
history in inflammatory bowel disease. Inflamm Bowel Dis 1997;
3:1–5.
11. Gent AE, Heller MD, Grace RH, Swarbrick ET, Coggon D. Inflam-
matory bowel disease and domestic hygiene in infancy. Lancet
1994;343:766 –767.
12. Gilat T, Hacohen D, Lilos P, Langman MJS. Childhood factors in
ulcerative colitis and Crohn’s disease: an international coopera-
tive study. Scand J Gastroenterol 1987;22:1009 –1024.
13. Minocha A, Raczkowski CA. Role of appendectomy and tonsillec-
tomy in pathogenesis of ulcerative colitis. Dig Dis Sci 1997;42:
1567–1569.
14. Wurzelmann JI, Lyle CM, Sandler RS. Childhood infections and
the risk of inflammatory bowel disease. Dig Dis Sci 1994;39:
555–560.
15. Mizoguchi A, Mizoguchi E, Chiba C, Bhan AK. Role of appendix in
the development of inflammatory bowel disease in TCR-␣ mutant
mice. J Exp Med 1996;184:707–715.
16. Katamura K, Shintaku N, Yamauchi Y, Fukui T, Oshima Y, Mayumi
M, Furusho K. Prostaglandin E2 at priming of naive CD4⫹ T cells
inhibits acquisition of ability to produce IFN-␥ and IL-12, but not
IL-4 and IL-5. J Immunol 1995;155:4604 – 4612.
17. Scott IS, Sheaff M, Coumbe A, Peakins RM, Rampton DS. Ap-
pendiceal inflammation in ulcerative colitis. Histopathology
1998;33:168 –173.
18. Kahn E, Markowitz J, Daum F. The appendix in inflammatory
bowel disease in children. Mod Pathol 1992;5:380 –383.
19. Jahadi MR, Shaw ML. The pathology of the appendix. Dis Colon
Rectum 1976;345–349.
20. Okawa K, Aoki T, Sano K, Harihara S, Kitano A, Kuroki T. Ulcer-
ative colitis with skip lesions at the mouth of the appendix: a
clinical study. Am J Gastroenterol 1998;93:2405–2410.
21. Goldblum JR, Appleman HD. Appendiceal involvement in ulcer-
ative colitis. Mod Pathol 1992;5:607– 610.
22. Davison AM, Dixon MF. The appendix as a ’skip lesion’ in ulcer-
ative colitis. Histopathology 1990;16:93–95.
23. D’Haens G, Geboes K, Peeters M, Baert F, Ectors N, Rutgeerts P.
Patchy cecal inflammation associated with distal ulcerative coli-
tis: a prospective endoscopic study. Am J Gastroenterol 1997;
92:1275–1279.
24. Kroft SH, Stryker SJ, Rao MS. Appendiceal involvement as a skip
lesion in ulcerative colitis. Mod Pathol 1994;7:912–914.
25. Groisman GM, George J, Harpaz N. Ulcerative appendicitis in
universal and non universal ulcerative colitis. Mod Pathol 1994;
7:322–325.
506 OKAZAKI ET AL.
26. Cohen T, Pfeffer RB, Valensi Q. “Ulcerative appendicitis” occur-
ring as a skip lesion in chronic ulcerative colitis: report of a case.
Am J Gastroenterol 1974;62:151–155.
27. Marison JF, Bodian CA, Janowitz HD. The appendix and IBD:
appendectomy does not protect against ulcerative colitis. In-
flamm Bowel Dis 1996;2:217–221.
28. Mayer L, Eisenhardt D. Lack of induction of suppressor T cells by
intestinal epithelial cells from patients with inflammatory bowel
disease. J Clin Invest 1990;86:1255–1260.
29. Bjerke K, Brandtzaeg P, Rognum TO. Distribution of immunoglob-
ulin producing cells is different in normal human appendix and
colon mucosa. Gut 1986;27:667– 674.
30. Dasso JF, Howell MD. Neonatal appendectomy impairs mucosal
immunity in rabbits. Cell Immunol 1997;182:29 –37.
31. Yamagiwa S, Sugahara S, Shimizu T, Iwanaga T, Yoshida Y,
Honda S, Watanabe H, Suzuki K, Asakura H, Abo T. The primary
site of CD4⫺8⫺B220⫹ ␣␤T cells in lpr mice: the appendix in
normal mice. J Immunol 1998;160:2665–2674.
32. De Carli M, D’Elios MM, Zancuoghi G, Romagnani S, Del Prete G.
Human Th1 and Th2 cells: functional properties, regulation of
development and role in autoimmunity. Autoimmunity 1994;18:
301–308.
GASTROENTEROLOGY Vol. 119, No. 2
33. Parronchi P, Romagnani P, Annunziato F, Sampognaro S, Becchio
A, Giannarini L, Maggi E, Pupilli C, Tonelli F, Romagnani S. Type
1 T-helper cell predominance and interleukin-12 expression in the
gut of patients with Crohn’s disease. Am J Pathol 1997;150:
823– 832.
34. Scott IS, Sheaff M, Coumbe A, Feakins RM, Rampton DS. The
appendix in ulcerative colitis: a not so innocent bystander. Gas-
troenterology 1999;117:272–273.
Received November 15, 1999. Accepted March 30, 2000.
Address requests for reprints to: Kazuichi Okazaki, M.D., Ph.D.,
Department of Gastroenterology and Endoscopic Medicine, Kyoto Uni-
versity Hospital, Kyoto, Japan. e-mail: okak@kuhp.kyoto-u.ac.jp; fax:
(81) 75-751-3414.
Supported by a Grant-in-Aid for Scientific Research from the Ministry
of Culture and Science of Japan (11670495); Grant-in-Aid for a “Re-
search for the Future” Program from The Japan Society for Promotion
of Science (JSPS-RFTF97I00201); and Supporting Research Funds
from The Japanese Foundation for Research and Promotion of Endos-
copy (JFE-1997).