We retrospectively reviewed the medical records of 402 patients who were diagnosed with PPU (either gastric or duodenal ulcer) from January 2010 through December 2015 at Hallym university-affiliated hospitals, including the Chuncheon, Kangdong, Dongtan, Hangang, Kangnam and Hallym University Sacred Heart Hospital. Except 6 patients with unknown histology of PPU, remaining 396 ulcers were verified as benign ulcers by histology after surgical resection or endoscopic biopsy. This study was approved by the institutional review board of Chuncheon Sacred Heart Hospital (2016-86).

We retrospectively collected the clinical data including age, sex, body mass index (BMI), smoking status and alcohol consumption for the last 3 mo, presence of any comorbidities, and current medications, such as NSAIDs or ASA, steroid, H₂-blockers, or PPIs. BMI was calculated as weight in kilograms divided by the square of height in meters. Positive alcohol consumption was defined as those who drink more than 20 g of alcohol amount in a week.

Chief complaints and laboratory data including white blood count (WBC), hemoglobin (Hb), serum creatinine (_SCr), C-reactive protein (CRP) at admission period were obtained. Also, sites of perforation, treatment methods, the development of postoperative complication if surgical management was done, the length of hospital stay, and mortality rate were identified. The sites of perforation were divided into 3 areas in stomach (from cardiac to body area, proximal antrum, and from prepyloric to pyloric area) and 2 areas in duodenum (bulb, and 2^nd portion). The size of perforated peptic ulcer was categorized on the basis of centimeter. The methods of operation were classified into 3 groups: (1) simple closure with or without omentopexy; (2) pyloroplasty with or without vagotomy; and (3) any other form of gastrectomy (total, subtotal, or antrectomy). If patients were assessed H. pylori infection status, diagnostic methods such as rapid urease test, ¹³C-urea breath test, or the serological test and the infection status were identified. All patients who were examined for H. pylori were discontinued PPIs or H₂-blockers at least 4 wk before H. pylori test. Treatment regimen and whether the treatment was successful or not were also identified.

Continuous variables were expressed as mean ± SD. Categorical variables were expressed as number and percentage. We compared the differences in the clinical characteristics and therapeutic outcomes of the study population using the Student’s t-test for the continuous variables and the Fisher’s exact test for the categorical variables. To identify the risk of non-H. pylori, non-NSAIDs associate PPU, we performed univariate and subsequent multivariate logistic regression analysis. In this study, a P value < 0.05 (2-tailed) was adopted as the threshold of statistical significance for all tests. All of the analyses were performed using SPSS version 20.0. (SPSS Inc., Chicago, IL, United States).

The baseline characteristics of the study population and site specific characteristics classified according to the site of perforation are shown in Table 1. We identified a total of 396 benign PPU patients, consisting of 173 (43.7%) in gastric ulcer group and 223 (56.3%) in duodenal ulcer group. Men predominance was observed (85.1%). The mean age and BMI of the subjects were 50.6 ± 18.3 years and 21.7 ± 2.9 kg/m², respectively. And about half of patients had alcohol consumption (47.2%) and smoking habit (55.8%). Of all, 54 (13.6%) patients had been diagnosed with peptic ulcer at median 12 mo before the time of perforation (interquartile range: 2-36 mo). In terms of the comorbidities, 123 (31.1%) patients had at least one comorbidities, which were cardiovascular disease (67.5%), diabetes mellitus (33.3%), chronic liver disease (10.6%) and cerebrovascular disease (8.9%) in the order. The proportion of taking medication was as follows; 44 (11.2%) patients on NSAIDs including ASA (n = 23), 8 (2%) patients on steroid, and 31 (7.8%) patents on anti-ulcer medication such as PPIs (n = 19) or H₂-blocker (n = 12).

At admission, the majority of patients (92.2%) complained abdominal pain and 16 (4.0%) patients experienced melena or hematemesis. The mean levels of WBC (13.4 ± 7.8 × 10³/uL) and CRP (93.7 ± 89.0 mg/L) were above normal range. However, the mean levels of Hb (13.7 ± 6.0 g/dL) and _SCr (1.02 ± 0.7 mg/dL) were within normal value. Among 174 (43.9%) patients who were tested for H. pylori infection, 78 (44.8%) patients were positive for H. pylori tests, which were rapid urease test (n = 60), urea breath test (n = 5), and serologic test (n = 13). Comparing with the 222 patients who did not perform H. pylori test, patients who tested for H. pylori infection were significantly younger (47.6 ± 16.8 vs 53.0 ± 19.1 years, P = 0.003) and none of them had malignant disease. The other baseline characteristics were comparable between the patients who were tested for H. pylori infection or not (Table 2). Except 9 patients who were lost to follow-up, 69 (88.5%) patients were prescribed with 7 or 14 d of standard triple therapy (n = 66), or 14 d of bismuth-based quadruple therapy (n = 3) as the first-line regimen. Among them, 33 patients achieved successful eradication after the first-line treatment (eradication rate of 47.8%) and 4 patients who failed to eradication after first line regimen achieved successful eradication after 2^nd line treatment (overall eradication rate of 53.6%). We could not evaluate eradication status in the remaining 32 patients due to lost to follow up during or after eradication treatment.

In terms of the site of perforation, bulb of duodenum (55.1%) was the most common site, followed by pylorus (25.3%), and antrum (15.7%). The proportion of duodenal ulcer perforation was 56.3% and the gastric ulcer perforation was 43.7%, respectively. Except 8 (2.0%) patients who were treated by medical management, remaining 388 patients (98.0%) underwent surgical management. The operative methods were primary closure with or without omentopexy (n = 307), pyloroplasty with or without vagotomy (n = 43), and any other form of gastrectomy (total, subtotal or antrectomy, n = 36). The mean duration of hospital stay was 13.1 ± 9.4 d. Though 36 (9.1%) patients experienced postoperative complication, only 3 (0.8%) patients died during hospitalization because of acute respiratory distress syndrome or uncontrolled sepsis. All of the baseline characteristics and clinical manifestations were comparable between perforated gastric ulcer and duodenal ulcer group. The detailed characteristics of all of the enrolled population are described in Tables 1 and 2.

The annual incidences of PPU showed decreasing trend for study periods, especially in gastric ulcer (Figure 1). The incidence of gastric ulcer perforation was 49.8% in the first 3 years and 36.9% in the last 3 years, which was statistically significant (P = 0.01). The decreasing incidence of perforated gastric ulcer was mainly observed in male under the age of 60. In these patients, the proportions of H. pylori infection, NSAIDs use, alcohol consumption, and any comorbidities were increased during study period, whereas the proportion of smoking habit was decreased from 65.9% in the first 3 years to 57.9% in the last 3 years, although the statistical significance was not reached.

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Figure 1 Annual incidence of perforated peptic ulcer according to anatomic location.

Among 396 patients, 121 (30.6%) patients were older than 60 years and the proportion of women was significantly higher in patients older than 60 years (old age group) compared with patients younger than 60 years (young age group) (5.5% vs 36.4%, P < 0.001). The proportion of alcohol consumption (56.0% vs 27.3%) and smoking habit (62.5% vs 40.5%) was higher in young age group than those of patients in old age group (P < 0.001). The proportions of patients with comorbidities (14.9% vs 67.8%) and taking NSAIDs (2.9% vs 30.0%) were significantly higher in old age group (P < 0.001), whereas the proportion of patients with H. pylori infection was significantly higher in young age group (50.4% vs 26.8%, P = 0.008). Although the site of perforation was comparable between two groups, the higher proportion of patients in old age group had PPU over 1 cm (31.1% vs 53.0%, P < 0.001). Moreover, the length of hospitalization (11.3 ± 7.7 vs 17.0 ± 11.7 d) and postoperative complication rate (4.0% vs 20.7%) were significantly higher in old age group (P < 0.001). All of the in-hospital mortality cases were also occurred in old age group (Table 3).

A total of 174 patients who were tested for H. pylori infection status were categorized into 4 groups in terms of the etiology of peptic ulcer (both H. pylori positive and NSAIDs use, either H. pylori positive or NSAID use, and Non-H. pylori, non-NSAIDs group). The patients with solely H. pylori positive were 73 and the patients taking NSAIDs without H. pylori infection were 16. Five patients were infected H. pylori and also taking NSAIDs (Both H. pylori positive and NAIDs user group). The remaining 80 patients who were negative for H. pylori test and not taking any kinds of NSAIDs or ASA were categorized into Non-H. pylori, non-NSAIDs group. Men predominance was observed consistently in all of the 4 groups. The mean age (69.5 ± 12.2 years) and the proportion of patients with any comorbidities (75.0%) were significantly higher in NSAIDs user group (P < 0.001). The mean BMI level and the proportion of patients with alcohol consumption, current smoking, and peptic ulcer history were similar among the 4 groups. More than half of patients in each group experienced duodenal ulcer perforation, which were most commonly in bulb area. Also, the proportion of patients with perforation more than 1 cm in diameter was significantly higher in NSAIDs group (66.7%) than the other groups (P = 0.002). The lengths of hospital stay and postoperative complication rates were comparable among 4 group. There was no mortality during hospitalization in 4 groups. The detailed clinical characteristics of PPU according to the etiology are described in Table 4.

To identify the associated risk factors according to the etiology, we performed univariate and subsequent multivariate regression analysis. Older age [odds ratio (OR) = 1.09, 95% confidence interval (CI): 1.04-1.16] and comorbidity (OR = 4.11, 95%CI: 1.03-16.48) were associated with NSAID-associated PPU compared with non-H. pylori, non-NSAID associated PPU (Table 5). Older age (OR = 1.04, 95%CI: 1.02-1.07) and alcohol consumption (OR = 2.08, 95%CI: 1.05-4.13) were associated with non-H. pylori, non-NSAID associated PPU compared with solely H. pylori positive PPU (Table 6).

The incidence of complications of peptic ulcer has not decreased, and limited data are available regarding the epidemiological characteristics and associated risk factors of perforated peptic ulcers.

In a retrospective review of medical records from multicenter in Korea revealed that elderly patients with comorbidities are associated with non-steroidal anti-inflammatory drugs (NSAIDs)-associated peptic ulcer perforation and non- Helicobacter pylori (H. pylori), non-NSAID peptic ulcer is important etiology in the development of peptic ulcer perforation.

Thorsen et al, Epidemiology of perforated peptic ulcer: age- and gender-adjusted analysis of incidence and mortality. World J gastroenterol 2013; 19(3): 347-354.

In the analysis for the risk factors of non-H. pylori, non-NSAID peptic ulcer perforation, alcohol consumption is suspected to be associated risk factor.

Risky patients for the development of peptic ulcer perforation should be educated and managed separately according to the different etiology to prevent the serious complications of peptic ulcer.

Non-H. pylori, non-NSAID peptic ulcer refers to etiologic terminology diagnosed by exclusion of common causes of peptic ulcer such as H. pylori, ulcerogenic drugs, and malignancy. Although clinical course of this disease entity is more serious compared with solely H. pylori or NSAID associated peptic ulcer, there has been no clinical recommendation in the management according to the etiology of peptic ulcer.

The authors elucidated the epidemiological characteristics and associated risk factors of perforated peptic ulcer in Korea. The present study was well organized and well investigated.