Volume 4 • Number 2 • 1999HELICOBACTER

© Blackwell Science, Inc. 1083-4389/99/$10.50/94 94–99

94

Gastric Ulcer Formation after the Hanshin-Awaji Earthquake: A Case Study of

Helicobacter pylori

Infection and Stress-Induced Gastric Ulcers

Yumi Matsushima,

†§

Nobuo Aoyama,* Haruhiko Fukuda,

†¶

Yoshikazu Kinoshita,

†#

Akio Todo,

‡

Seiichi Himeno,

‡

Sotaro Fujimoto,

‡

Masato Kasuga,* Hiroshi Nakase,

§

and Tsutomu Chiba

†§

*Second and

†

Fourth Department of Internal Medicine, and

‡

Hyogo Gastroenterology Study Group, Kobe University School of Medicine, Kobe 650;

§

Division of Gastroenterology and Hepatology, Department of Medicine, Postgraduate School of Medicine, Kyoto University, Kyoto 606;

¶

Department of Internal Medicine, National Cancer Center Hospital, Tokyo 104;

A B S T R A C T

and

#

Second Department of Internal Medicine, Shimane University School of Medicine, Shimane 693, Japan

Background.

Both

Helicobacter pylori

(

H. pylori

) infec-tion and various stresses are known to induce peptic ulcerdisease of the upper gastrointestinal tract. However, thepathogenetic relationship between the two factors has notyet been clarified. We conducted a case

-

control study toexamine whether

H. pylori

infection played a role in thedevelopment of gastric ulcer (GU) induced by life-eventstresses that were experienced after the Hanshin-Awajiearthquake.

Materials and Methods.

Serum samples from patients inthe devastated area who developed GUs during the 2months following the Hanshin-Awaji earthquake andthose from GU patients in the same area during the corre-sponding period of the previous year, and from gender-,age- and institute-matched ulcer-free controls were tested

for the presence of the

H. pylori

IgG antibody.

Results.

A significant association between

H. pylori

in-fection and the development of GU in uninjured patientswas observed in all sets [matched odds ratio (OR)

5

3.23, 95% confidence interval: 1.95–5.35]. Moreover,the prevalence of

H. pylori

infection in patients who de-veloped GUs after the earthquake was not different fromthat for GU patients in the previous year. In contrast,there was no association between

H. pylori

infection andthe development of GU in the physically injured patientsafter the earthquake.

Conclusions.

H. pylori

infection may play an importantrole in the development of GUs that are induced byemotional life-event stresses.

G

astric ulcers (GUs) are induced by various fac-tors including

Helicobacter pylori

(

H. pylori

)infection [1–3], nonsteroidal anti-inflammatory drug(NSAID) administration [4,5], and physical or emo-tional stress [6–11].

H. pylori

infection induceschronic inflammation in the gastric mucosa and in-creases the vulnerability of the mucosal epithelialcells, with resulting peptic ulcer formation [1–3].NSAIDs inhibit mucosal prostaglandin synthesis byblocking cyclooxygenase activity which reduces theability of the gastric mucosa to protect itself againstdamaging agents [4,5]. Various stresses have beenshown to induce gastric mucosal lesions by severalmechanisms both in humans [6–11] and animals

[12–13]. Among these

, H. pylori

infection plays amajor role in the development of peptic ulcer dis-ease, and NSAID administration is also consideredto be an independent risk factor for the disease[14,15]. However, it is still unclear whether thestress, either physical or mental, can be consideredto be an independent risk factor for peptic ulcers ofthe upper gastrointestinal tract.

After the Hanshin-Awaji earthquake that oc-curred on January 17, 1995 in Japan, people in thedevastated area have experienced serious life-eventstresses. During this period, we observed an in-creased incidence of GU as compared to the previousyear. Indeed, in spite of a dramatic decrease in thetotal number of endoscopies performed (50.0%),patients with GU were increased from 297 to 335in the most devastated area. In particular, the num-ber of bleeding GU was markedly increased (100vs. 35). We also found that seroprevalence of

H.pylori

infection in patients with GUs in the most

Reprint requests to:

Tsutomu Chiba, MD, PhD, Divisionof Gastroenterology and Hepatology, Department of Med-icine, Postgraduate School of Medicine, Kyoto University,Sakyo-ku, Kyoto 606, Japan.

H. pylori

and Stress-Induced Gastric Ulcers

95

devastated area was 81.8%, which was not differ-ent from that in the less devastated surroundingarea [16], and was similar to or higher than that inthe reported GU cases in Japan that were unrelatedto the earthquake [17,18]. Since it is well knownthat the prevalence of

H. pylori

infection in olderpeople is very high in Japan [19], these facts raisethe possibility that

H. pylori

may be a factor in theincreased incidence of GUs after the earthquake[16]. The study described here was therefore de-signed to examine whether a pre-existing

H. pylori

infection could be a risk factor for the developmentof the GUs induced by life-event stresses that wereexperienced after the Hanshin-Awaji earthquake.

Patients and Methods

Twenty-five hospitals located near the epicenter ofthe Hanshin-Awaji earthquake, covering as manyas 50% of all upper gastrointestinal endoscopycases seen in this region, participated in this study.This region corresponds to Area I (the most badlyaffected area) and Area II (the area surroundingArea I) in our previous study (henceforth to be re-ferred to as “our surveillance study”) [16]. A totalof 456 cases of GU, who were free from majorphysical injury, were diagnosed endoscopically inthese hospitals during the 8 weeks immediately af-ter the earthquake [16]. These patients correspondto a part of the GU patients in Area I and II of oursurveillance study [16].

From this case pool, we selected the patients forwhom stored serum sampled at or just after the di-agnosis of ulcers was available. This selection pro-vided us with 166 cases. A control group was

taken from outpatients who visited the hospitalswhich participated in this study during the 10months after the earthquake with the following re-strictions: no abdominal symptoms or gastrointesti-nal disease, stored serum available that was takenduring the 10 months following the earthquake. Thisgave us a control pool of 4210 patients. We per-formed sequentially individual case-control match-ing under the following matching conditions: samegender, age difference less than 3 years, visited thesame or the nearest hospitals, until at least 3 con-trols were matched to each case. At that point, wediscarded 36 patients to whom 3 controls were notavailable. In the end, we obtained 130 matchedcase-control sets with three controls for each case(130 cases and 390 controls). We selected randomlythree control subjects when more than three con-trols could be matched to each case. The mean ageand the sex ratio of the case patients were not sig-nificantly different from those of all of the 456 GUpatients. Moreover, the proportion of the case pa-tients with a history of peptic ulcer disease was notsignificantly different from that of all of the GUpatients.

In the subgroup analyses, categorizations ofmatched sets were performed using the informationfrom each case. To compare younger and olderpopulations, we divided both the case and the con-trol groups into two at the age of 62, since this wasthe median age for both the case and the controlgroups (Tables 1 and 2).

We also obtained sera from the 288 GU pa-tients who had visited the participating hospitalsduring the corresponding period of the previousyear (1994). We compared their seroprevalence of

Table 1

Seropositive subjects in GU cases and controls

Cases Control

Total 108/130 (83.1) 237/390 (60.8)

Gender female 39/51 (76.4) 101/153 (66.0)male 69/79 (87.3) 136/237 (57.4)

Age (years)

,

62 51/62 (82.3) 97/186 (52.2)

$

62 57/68 (83.8) 140/204 (68/6)

History of peptic ulcer yes 42/48 (87.5) 93/144 (64.6)no 66/82 (80.5) 144/246 (58.5)

Active bleeding yes 36/43 (83.7) 77/129 (59.7)no 72/87 (82.8) 160/261 (61.3)

Residential damage unknown 21/28 (75.0) 49/84 (58.3)no damage 24/27 (88.9) 47/81 (58.0)moderate damage 35/42 (83.3) 78/126 (61.9)destroyed 28/33 (84.8) 63/99 (63.6)

Case data are for uninjured patients who developed GUs after the earthquake. Data given represent number of seropositive cases or controls/total number ofcases or controls. Values in parentheses are percentages of seropositive cases.

96

Matsushima et al.

H. pylori

infection with that of the GU patients af-ter the earthquake (166 patients).

In a separate study, we collected sera from 62 pa-tients who developed GU during the hospitalizationdue to severe physical injury by the earthquake. Weperformed individual case-control matching as de-scribed previously, and obtained 62 matched case-control sets (62 cases and 186 controls).

Measurement of Anti-

H. pylori

Antibody

An EPI test kit (Enteric Products INC, NY) withpurified high molecular weight cell-associated pro-tein (HM-CAP) specific to

H. pylori

was used formeasurement of anti-

H. pylori

antibody in the se-rum [20]. The serum was taken as positive whenthe titer was above a 2.2 ELISA value.

Statistical Analysis

Matched analyses were performed. The seropreva-lence of

H. pylori

infection in cases and controlswere compared, and odds ratios, which approxi-mate the relative risk, and their 95% confidence in-tervals were determined according to the Mantel-Haenszel method [21]. Proportions were comparedby a simple chi-square test or the Mantel-Haenszelchi-square test for trend. Means of continuous vari-ables were compared using the Student’s

t

-test. Forcomparison between the GU cases occurring afterthe earthquake and those that developed during thecorresponding period in the previous year (1994),we used chi-square test with Yates correction. Allcalculations were performed using SAS software(SAS 6, 10 for Macintosh, SAS Institute Inc., Tokyo,Japan) run on a Power Macintosh model 7500.

Results

Both the mean age (61.3

6

15.2) and the sex ratio(M/F

5

1.60) of the uninjured GU patients ob-served in this study were not significantly differentfrom those of all of the patients with GUs in ourprevious surveillance study [16]. The proportionsof the case patients with both a history of peptic ul-cer disease (36.9%) and active bleeding (33.1%)were not significantly different from those of thepatients with GUs in our surveillance study (Tables1 and 2) [16]. Moreover, the percentage of the casepatients with a history of NSAIDs intake (4.6%)was not different from those of the GU patients inArea I in both 1994 and 1995 in our surveillancestudy [16]. The seroprevalence of

H. pylori

infec-tion was 83.1% in the cases, and was higher thanthat of the controls (60.8%) (Tables 1 and 2). Thematched odds ratio in all sets was 3.23, with a 95%confidence interval of 1.95–5.35 (the

p

-value ob-tained using the Mantel-Haenszel test was 0.001),showing a strong association between the develop-ment of GU after the earthquake and seropositivityfor

H. pylori

infection in uninjured patients. The se-roprevalence of

H. pylori

infection and the odds ra-tio of the cases were similar to those of patientswhose GUs were unrelated to the earthquake, as re-ported previously [22–24]. Indeed, we observedthat the seroprevalence of

H. pylori

infection in theGU cases that developed during the correspondingperiod of the previous year (1994) in the same hos-pitals was 82.3% (237/288), which was not signifi-cantly different from that of the GUs that occurredafter the earthquake (134/166, 80.7%).

Table 2

Case-control comparisons of the seroprevalence of

H. pylori

infection

VariableNo. of cases

(% of all cases)% Seropositive(cases/controls)

p

-valueOdds ratio

(OR)95% Confidenceintervals of ORs

Total 130 83.1/60.8 0.001 3.23 1.95–5.35

Gender female 51 (39.2) 76.4/66.0 0.176 1.67 0.80–3.50male 79 (60.8) 87.3/57.4 0.001 5.73 2.78–11.82

Age (years)

,

62 62 (47.7) 82.3/52.2 0.001 5.31 2.41–11.67

$

62 68 (52.3) 83.8/68.6 0.022 2.19 1.12–4.29

History of peptic ulcer yes 48 (36.9) 87.5/64.6 0.005 3.54 1.47–8.57no 82 (63.1) 80.5/58.5 0.001 3.08 1.67–5.68

Active bleeding yes 43 (33.1) 83.7/59.7 0.007 3.21 1.37–7.53no 87 (66.9) 82.8/61.3 0.001 3.24 1.73–6.06

Residential damage unknown 28 (21.5) 75.0/58.3 0.059 3.00 0.96–9.40no damage 27 (20.8) 88.9/58.0 0.006 6.00 1.67–21.58moderate damage 42 (32.3) 83.3/61.9 0.007 3.14 1.38–7.18destroyed 33 (25.4) 84.8/63.6 0.088 2.33 0.88–6.18

Case data are for uninjured patients who developed GUs after the earthquake. The

p

-values and odds ratios were calculated according to the Mantel-Haenszelmethod. Information concerning damage to the patients’ residence was not available for 28 cases.

H. pylori

and Stress-Induced Gastric Ulcers

97

The results of subgroup analysis on gender, age,history of peptic ulcer disease, absence or presenceof active bleeding and the degree of damage to thepatients’ residence are shown in Tables 1 and 2. Inthe subgroup analysis, the odds ratios were differ-ent only for age and in gender. Although the oddsratio in the male group was high (5.73), and wasstatistically significant (

p

5

.001), that in the fe-male group was relatively low (1.67) and was notstatistically significant (

p

5

.176). This differencein odds ratios between the genders appears to bedue to the higher and lower seroprevalence of thecontrols and the cases, respectively, in the femalegroup. The high seroprevalence of the female con-trols could be due to the fact that the mean age offemale cases in this study was 8 years older thanthat of male cases (66.1

6

13.1 vs. 58.2

6

15.7),and the same tendency was observed in our previ-ous surveillance study (16). Indeed, when logisticregression analysis was performed by adjusting forage distribution using SAS, difference of the oddsratios between the genders became smaller (2.88for female vs. 4.16 for male). As for the age, theodds ratio in the younger population (5.31) washigher than that for the older population (2.19).These data reflect the low seroprevalence of thecontrols in the younger population (Table 2).

In contrast, the matched odds ratios in the setswith and without a history of peptic ulcers weresimilar (3.54 vs. 3.08). Likewise, the matched oddsratios for the sets with and without active bleedingwere also similar (3.21 vs. 3.24). We used the ex-tent of damage to the patients’ residence as a mea-sure to assess the intensity of life-event stress. Noobvious difference in odds ratios was observedamong the groups with or without various degreesof damage (Table 2).

In contrast to the data for uninjured patients,the seroprevalence of

H. pylori

infection in the GUpatients with severe physical injury was 64.5%(40/62), which was not significantly different fromthat of the control (114/186, 61.3%). The matchedodds ratio for all sets was 1.08 (

p

5

0.231), show-ing no association between the development of GUand seropositivity for

H. pylori

infection in physi-cally injured patients after the earthquake.

Discussion

Three major causative factors,

H. pylori

infection,NSAIDs administration and various stresses, areconsidered to be involved in the development ofGU. Among them, the most important factor is the

H. pylori

infection. Indeed, approximately 70–90%

of patients with GU are infected with

H. pylori

[22–24]. The second most important etiologicalfactor in the development of GU is the chronic ad-ministration of NSAIDs, which is known to induceGU independently from

H. pylori.

Indeed, preva-lence of

H. pylori

infection in NSAID-induced ulcerhas been reported to be relatively low [14,15]. Incontrast, although physical or emotional stress isalso believed to be a risk factor for GU [6–11],whether it is capable of inducing GU independentlyfrom

H. pylori

infection is still unclear.Because the Hanshin-Awaji earthquake caused

serious life-event stresses for the residents of thedevastated area, the patients who developed GUsjust after the earthquake are considered to be typi-cal of patients with stress-induced GUs. Indeed, inour previous surveillance study, we observed thatthe number of patients with GU increased immedi-ately after the earthquake and, in particular, thenumber of bleeding ulcers increased dramatically[16]. Because stress, either physical or mental, hadbeen believed to be an independent risk factor forthe development of GUs until the discovery of

H.pylori

[7–13], it is interesting to examine the prev-alence of

H. pylori

infection in patients with GUsthat developed after the Hanshin-Awaji earth-quake. For this purpose we utilized measurementof the anti-

H. pylori

IgG antibody, because it wasthe only way to diagnose

H. pylori

infection afterthe earthquake.

Surprisingly, it was found that as many as83.1% of the uninjured patients with GUs that de-veloped after the earthquake were infected with

H. pylori.

This seroprevalence of the infection wassimilar to that in the GUs that developed duringthe corresponding period of the previous year inthe same hospitals. Moreover, it was similar to orhigher than that reported previously in patientswith GUs that were unrelated to the earthquake[22–24]. These results suggest that the infection of

H. pylori

exerts some additive effects on the devel-opment of GUs that occurred under the emotionalstresses caused by the Hanshin-Awaji earthquake.Confirming this possibility, an association was ob-served in this study between

H. pylori

infectionand GUs developed after the Hanshin-Awaji earth-quake in uninjured subjects.

This study also showed that

H. pylori

infectionwas more strongly associated with the developmentof the stress-induced GU in the younger populationthan in the older population. The data might suggestthat emotional stress plays a more important role inthe development of GU in the older population thanin the younger population. However, it appears

98

Matsushima et al.

more reasonable to consider that the difference inodds ratio between the younger and the older popu-lation is explained simply by the epidemiology of

H.pylori

infection. Indeed, the rate of seropositivityfor

H. pylori

were similarly high in the younger andthe older GU patients, whereas the seroprevalenceof the infection was lower in younger populationthan in older population in this study.

In this study, we found that prior history of pep-tic ulcers did not influence the association betweenthe seroprevalence of

H. pylori

and the developmentof GUs after the earthquake. Considering that afterthe earthquake we had many older patients withGU, the data were rather unexpected. However,these results raise the caution that any

H. pylori

-positive older subjects, even without a history ofpeptic ulcer disease, may be at a higher risk of devel-oping GUs under such serious stressful conditions.

The most serious complications of gastric ulcersare perforation and bleeding, and it is important toclarify whether the

H. pylori

infection can be an ag-gravating factor that causes these complications.However, this is unlikely, because matched odds ra-tios in the sets with and without active bleeding weresimilar. Because we found a dramatic increase inbleeding ulcers after the earthquake, emotional stressitself might be more responsible for the bleeding.

An interesting observation in this study is thatthere was no association between

H. pylori

infec-tion and the development of GU in physically in-jured patients. Thus, in contrast to the GUs devel-oped in uninjured subjects,

H. pylori

infection doesnot appear to be involved in the development ofGU induced by physical stress. Although the rea-son for the discrepancy concerning involvement of

H. pylori

infection in the development of GU be-tween physically injured and uninjured patients isunknown, these data clearly demonstrate distinctpathophysiology of the GUs induced by physicaland emotional stresses.

In conclusion, our study of the development ofGUs after the Hanshin-Awaji earthquake clarifiedfor the first time that

H. pylori

is an important co-stimulatory factor in the development of GUs un-der emotional life-event stresses. Considering thefact that the prevalence of

H. pylori

infection isvery high in older people in Japan [19], and thatmany patients with no prior history of peptic ul-cers developed GUs after the earthquake, eradica-tion of

H. pylori might be recommended for allolder people, regardless of peptic ulcer history

The members of the Hyogo Gastroenterology StudyGroup that participated in this study are Akasi City Hos-

pital, Ino Hospital, Higuchi GI Hospital, Tabata GI Hos-pital, Ono City Hospital, Kobe Central Hospital, KobeUniversity Hospital, Kobe Rosai Hospital, Hyogo Saisei-kai Hospital, Itami City Hospital, Shinsuma Hospital,Nishinomiya City Hospital, Amagasaki Prefectural Hos-pital, Awaji Prefectural Hospital, Hyogo Adult DiseaseCenter, Maikodai Hospital, Miki City Hospital, Mitsub-ishi Kobe Hospital, Hanshin Hospital of Self-DefenseForces, Rokko Island Hospital, and Rokko Hospital. Thisstudy was supported in part by a grant from the Ministryof Health and Welfare and the Ministry of Education, Sci-ence and Culture, Japan.

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