Small bowel ulcerative lesions are common in elderly NSAIDs users with peptic ulcer bleeding

Abstract

AIM: To determine the frequency of small bowel ulcerative lesions in patients with peptic ulcer and define the significance of those lesions.

METHODS: In our prospective study, 60 consecutive elderly patients with upper gastrointestinal bleeding from a peptic ulceration (cases) and 60 matched patients with a non-bleeding peptic ulcer (controls) underwent small bowel capsule endoscopy, after a negative colonoscopy (compulsory in our institution). Controls were evaluated for non-bleeding indications. Known or suspected chronic inflammatory conditions and medication that could harm the gut were excluded. During capsule endoscopy, small bowel ulcerative lesions were counted thoroughly and classified according to Graham classification. Other small bowel lesions were also recorded. Peptic ulcer bleeding was controlled endoscopically, when adequate, proton pump inhibitors were started in both cases and controls, and Helicobacter pylori eradicated whenever present. Both cases and controls were followed up for a year. In case of bleeding recurrence upper gastrointestinal endoscopy was repeated and whenever it remained unexplained it was followed by repeat colonoscopy and capsule endoscopy.

RESULTS: Forty (67%) cases and 18 (30%) controls presented small bowel erosions (P = 0.0001), while 22 (37%) cases and 4 (8%) controls presented small bowel ulcers (P < 0.0001). Among non-steroidal anti-inflammatory drug (NSAID) consumers, 39 (95%) cases and 17 (33%) controls presented small bowel erosions (P < 0.0001), while 22 (55%) cases and 4 (10%) controls presented small bowel ulcers (P < 0.0001). Small bowel ulcerative lesions were infrequent among patients not consuming NSAIDs. Mean entry hemoglobin was 9.3 (SD = 1.4) g/dL in cases with small bowel ulcerative lesions and 10.5 (SD = 1.3) g/dL in those without (P = 0.002). Cases with small bowel ulcers necessitate more units of packed red blood cells. During their hospitalization, 6 (27%) cases with small bowel ulcers presented bleeding recurrence most possibly attributed to small bowel ulcers, nevertheless 30-d mortality was zero. Presence of chronic obstructive lung disease and diabetes was related with unexplained recurrence of hemorrhage in logistic regression analysis, while absence of small bowel ulcers was protective (relative risk 0.13, P = 0.05).

CONCLUSION: Among NSAID consumers, more bleeders than non-bleeders with peptic ulcers present small bowel ulcers; lesions related to more severe bleeding and unexplained episodes of bleeding recurrence.

Key Words: Non-steroidal anti-inflammatory drugs, Aspirin, Wireless capsule endoscopy, Small bowel ulcerative lesions, Peptic ulcer bleeding

Core tip: Non-steroidal anti-inflammatory drugs (NSAIDs) can frequently cause small bowel ulcerative lesions. In our prospective case control study we found that 95% of elderly patients with peptic ulcer bleeding consuming NSAIDs also presented small bowel erosions and 55% small bowel ulcers. Small bowel ulcerative lesions were 3 times less frequent in patients with a non-bleeding peptic ulcer consuming NSAIDs, and infrequent among patients with a peptic ulcer not receiving NSAIDs. Small bowel ulcers in peptic ulcer bleeders were related with lower entry hemoglobin and increased need for blood transfusion. Moreover, they could be incriminated for unexplained bleeding recurrence despite successful peptic ulcer hemostasis.

INTRODUCTION

Non-steroidal anti-inflammatory drug (NSAID) therapy reduces inflammation and pain very effectively[1], whilst low-dose aspirin is a common antithrombotic drug[2]. Benefits from NSAID use are offset by potentially life-threatening gastrointestinal complications[3-5]. NSAIDs can cause functional and structural small intestinal abnormalities[4,5]. The later could be accessed by either double-balloon[6] or capsule endoscopy (WCE)[1].

WCE identified small bowel mucosal damage (mucosal breaks, reddened folds, petechiae and denuded mucosa) in 50%-70% of healthy volunteers after a short course of NSAIDs and even more lesions in chronic NSAID consumers[1,7,8]. On the contrary mucosal damage was present only in 10% of subjects not exposed to NSAIDs[1]. Although small bowel mucosal lesions are frequent, they rarely produce small and large bowel complications[9]. Less than 1% of overt or obscure gastrointestinal bleeding cases can be attributed to small bowel ulcerative lesions[10]. Type of NSAID treatment (aspirin, non-aspirin NSAIDs) and patient age can increase the risk for a bleeding episode[11]. The role of a concurrent peptic ulcer is rather unknown.

In a small study, 90% of patients with a non-bleeding gastric ulcer receiving low dose aspirin also presented small bowel mucosal lesions[12]. A small pilot study in our department provided an indication that small bowel ulcerative lesions are even more frequent in peptic ulcer bleeders[13].

Our primary end-point was to determine the frequency of small bowel ulcerative lesions in patients with peptic ulcer bleeding compared to those with non-bleeding ulcers. While our secondary end-points were to determine: (1) whether NSAID use affects the frequency of small bowel lesions and (2) whether presence of small bowel lesions affects the severity of the bleeding episode and its’ outcome.

MATERIALS AND METHODS

Patients-data

Our study was a prospective one. 60 consecutive patients older than 18 years, admitted in NIMTS Hospital (Military Insurance Fund Hospital) between the 1/1/2008 and 31/12/2009 with upper gastrointestinal bleeding due to a peptic ulcer entered the study (cases). None had a previous history of iron deficiency anemia. Each case was matched for age, gender, smoking, and alcohol consumption, to a non-bleeding ulcer patient (control) evaluated with WCE, between 1/1/2008 and 31/12/2012 in our department. Controls had WCE performed for chronic diarrhea or unexplained diffuse abdominal pain.

Upper gastrointestinal endoscopy was performed for each case within 24 h from admission and comprised hemostasis for Forrest Ia, Ib or IIa ulcers[14]. For controls upper gastrointestinal endoscopy was performed before WCE study. During entry gastroscopy, Helicobacter pylori (H. pylori) infection was determined using rapid urease test and histology (haematoxylin-eosin and modified Giemsa). A negative colonoscopy was an inclusion prerequisite for both cases and controls. Colonoscopy was obligatory in our hospital for every case of gastrointestinal bleeding, regarded as alarm symptomatology not with-held by upper-endoscopy findings, because a significant percentage of patients with peptic ulcer might have a colonic pathology as well[15]. No case or control was on proton pump inhibitor or H-2 receptor blocker before the study period. Continuous iv infusion of pantoprazole 8 mg/h after a bolus of 40 mg was started after hemostasis for 48 h; switched thereafter to pantoprazole 40 mg po o.d. Cases not necessitating hemostasis and controls received pantoprazole 40 mg po o.d.

Hemoglobin levels were measured in every case on admission and daily thereafter until discharge. Hemoglobin drop on admission was calculated from a reference level of 14 g/dL.

Exclusion criteria were pregnancy, known or suspected complete or partial stenosis of the small intestine, gastric or intestinal surgery, established delayed gastric emptying or diabetic gastroparesis, history of, or active, malignancy, history of hypersensitivity to proton pump inhibitors and presence of any serious central nervous system, psychiatric, cardiovascular, respiratory, musculoskeletal, or intestinal disease preventing the performance of WCE. We also excluded patients with known or suspected small bowel inflammation, including Crohn’s disease, spondyloarthropathy, and seronegative athritides; patients with celiac disease and patients on medication that influence NSAID enteropathy[16] (biologicals, sulphasalazine, misoprostol, metronidazole and biphosphonates). No case or control had a systemic rheumatic disease or received anticoagulants. Alcohol intake was withheld during the study period.

Actual NSAIDs consumption (including self medication and defaults from prescribed drugs) was accessed before WCE using a life style and medication questionnaire[17]. We validated the questionnaire, applying it to 20 patients before study initiation (k-value = 0.81). Although we intended to record any NSAID consumption, we have considered NSAIDs consumers only those patients who had received even a single dose of NSAIDs the week preceded WCE study. Continuous NSAIDs consumption (both aspirin and non-aspirin) for up to 2 wk was recorded as short term, while longer-term use was considered long-term[1,7,8].

The study protocol has the approval of the Scientific Council of NIMTS Hospital, standing for Ethics Committee of NIMTS Hospital. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki (6^th revision, 2008). All patients gave and signed written informed consent, before entering the study.

Capsule endoscopy

Both cases and controls underwent WCE within 4 d after upper gastrointestinal endoscopy and colonoscopy. WCE study (Given SB2 video capsule system; Given Imaging Ltd) was performed according to conventional procedures described elsewhere[10] and it was part of the investigation protocol.

Monitoring period was 9 h. A.Z. has initially gone through all videos and defined the second part of the duodenum. Two independent endoscopists (P. T. and C. K) with vast endoscopic experience separately reviewed all videos, starting video reading from the second part of the duodenum. Both had no information on patient clinical characteristics or presence of any gastric or duodenal bulb lesions. In case of investigator disagreement, a third blinded expert (P. A.) reviewed the findings with the purpose of reaching a consensus. Small bowel mucosal lesions were classified according to Graham et al[1]: category 0, normal; category 1, petechiae/red spots; category 2, 1-4 ulcerative lesions up to 5 mm (erosions); category 3, > 4 erosions; and category 4, larger ulcerative lesions. Because agreement between the two investigators was almost perfect (k-value = 0.84) for grade-3 and 4 lesions and fair (k-value = 0.28) for scarce red spots and petechiae and because grade-2 lesions could be found in normal subjects[1], we confined the analysis in grade-3 (erosions) and 4 (larger ulcers) lesions. Other pathologic findings, mainly lymphangiectasia, angiodysplasias and polypoid lesions/tumors were also reported.

Patients with any small bowel pathology undergone repeat capsule endoscopy study a year later. In the meanwhile, NSAID use was prevented; H. pylori infection eradicated and polypoid/submucosal lesions received relevant treatment.

To overcome relevant biases, both Head of the Department (G. A.), responsible for treatment decision and ward trainee doctors were unaware of WCE report, unless it was decisive to refer for surgical or endoscopic treatment.

Statistical analysis

Student’s t-test was used to calculate the difference between the means. The chi-square test or Fisher’s exact test was used for nonparametric data as appropriate. A P < 0.05 was considered to be statistically significant. We performed logistic regression analysis to access risk factors for unexplained bleeding recurrence. We included known risk factors for ulcer bleeding recurrence (old age, male gender, diabetes mellitus, body mass index and presence of chronic obstructive lung disease) as well as a possible risk factor, presence of small bowel ulcers. The magnitude of each association was expressed in terms of odds ratio and the corresponding 95% confidence interval.

Assuming that: (1) two thirds of patients with peptic ulcer consumed NSAIDs; (2) 30% of patients with no bleeding peptic ulcer consuming NSAIDs and 10% of those not consuming NSAIDs had > 4 erosions[9]; and (3) 90% of peptic ulcer bleeders, consuming NSAIDs and 10% of those not consuming NSAIDs had > 4 erosions[13]: we estimated that a sample size of 30 patients in each patient group was adequate to reach a study power of 90%. We doubled sample size to secure adequate subgroup analysis (aspirin, non-aspirin NSAIDs).

RESULTS

Patients

A duodenal ulcer was found in 38 (63%) cases and as many controls and a gastric ulcer in 32 (53%) cases and an equal number of controls. Both gastric and duodenal ulcers were present in 10 (17%) cases and 10 (17%) controls. 6 (10%) cases had bled from the gastric and 4 (7%) from the duodenal ulcer. Hemostasis was performed in 12 (20%) cases; 8 (13%) with a duodenal and 4 (7%) with a gastric ulcer. Thirty-two (53%) cases and as many controls were receiving NSAIDs short-term (P = 1.00), while 8 (13%) cases and as many controls were on NSAIDs long-term (P = 1.00). There was no difference between cases and controls in any demographic or disease related characteristic, apart from diffuse abdominal pain that was more frequent among controls (Table 1). No case or control had chronic renal failure, liver failure or cirrhosis and none was receiving anticoagulants.

Table 1 Demographic and disease related characteristics of bleeders and controls.

Characteristic	Patients (n = 60)	Controls (n = 60)	P
Mean age (yr)	75 (SD = 8)	74 (SD = 9)	0.26
Male gender	44 (73%)	44 (73%)	1.00
Active smoking	18 (30%)	18 (30%)	1.00
Alcohol abuse	12 (20%)	12 (20%)	1.00
BMI > 25	36 (60%)	36 (60%)	1.00
NSAIDs consumption	40 (67%)	40 (67%)	1.00
Ischaemic heart disease	20 (33%)	20 (33%)	1.00
Chronic pain	6 (10%)	22 (37%)	0.006
Diabetes melitus	11 (18%)	12 (20%)	0.82
COPD	4 (7%)	4 (7%)	1.00
Low dose aspirin use1	22 (37%)	22 (37%)	1.00
Non aspirin NSAIDs use1	24 (40%)	24 (40%)	1.00
COX-2 selective use	6 (10%)	6 (10%)	1.00
Non selective NSAIDs use	18 (30%)	18 (30%)	1.00
Clopidogrel co-administration	12 (20%)	12 (20%)	1.00
Gastric passing time (min)	41 (SD = 49)	42 (SD = 57)	0.46
Small bowel passing time (min)	221 (SD = 117)	271 (SD = 117)	0.01
H. pylori positive	37 (60%)	37 (62%)	1.00

¹Three bleeders and 6 controls received both low-dose aspirin and non-aspirin NSAIDs. SD: Standard deviation; NSAIDs: Non-steroidal anti-inflammatory drugs; BMI: Body mass index; COPD: Chronic obstructive lung disease; COX-2 selective use: Cyclooxygenase-2 selective inhibitors.

Findings in capsule endoscopy

Small bowel ulcerative lesions were found in 40 (67%) cases and 18 (30%) controls (P = 0.0001). All of them had erosions (grade-3 lesions), while small bowel ulcers (grade-4 lesions) were found 22 cases (37%) and 4 (8%) controls (P = 0.0001). Small bowel erosions were found in 27 (71%) cases with a duodenal and 20 (62%) with a gastric ulcer (P = 0.45), while small bowel ulcers were found in 16 (42%) cases with a duodenal and 10 (31%) with a gastric ulcer (P = 0.35). Moreover erosions were found in 14 (37%) controls with a duodenal and 9 (28%) with a gastric ulcer (P = 0.44), while small bowel ulcers were found in 3 (8%) controls with a duodenal and 2 (6%) with a gastric ulcer (P = 0.79).

Among NSAID consumers, 39 (98%) cases and 17 (43%) controls presented small bowel ulcerative lesions (P < 0.0001). All of them had small bowel erosions, while small bowel ulcers were present in 22 (55%) cases and 4 (10%) controls (P < 0.0001). Small bowel erosions were found in 26 (96%) cases with a duodenal and 20 (100%) with a gastric ulcer (P = 0.38), while larger ulcerative lesions were found in 16 (100%) cases with a duodenal and 10 (100%) with a gastric ulcer (P = 1.00). Moreover erosions were found in 13 (48%) controls with a duodenal and 9 (45%) with a gastric ulcer (P = 0.83), while larger ulcerative lesions were found in 3 (11%) controls with a duodenal and 2 (10%) with a gastric ulcer (P = 0.90).

There was no difference in small bowel mucosal lesions between cases and controls consuming no NSAIDs (Table 2). All cases and controls with small bowel erosions reporting no NSAID consumption admitted that they had received at least a single NSAID dose more than a week before WCE.

Table 2 Small bowel mucosal lesions found during video capsule endoscopy in both bleeders and controls.

Patient group	Cases	Controls	P
All patients	n = 60	n = 60
Grade 4 lesions	22 (37%)	4 (8%)	0.0001
Grade 3 lesions	40 (67%)	18 (30%)	0.0001
Grade 2 lesions	41 (68%)	21 (35%)	0.0003
Grade 1 lesions	42 (70%)	28 (47%)	0.0100
NSAID consumers	n = 40	n = 40
Grade 4 lesions	22 (55%)	4 (10%)	< 0.0001
Grade 3 lesions	39 (95%)	17 (33%)	< 0.0001
Grade 2 lesions	40 (100%)	20 (50%)	< 0.0001
Grade 1 lesions	40 (100%)	26 (65%)	< 0.0001
No-NSAID consumers	n = 20	n = 20
Grade 4 lesions	0	0
Grade 3 lesions	1 (5%)	1 (5%)	1.00
Grade 2 lesions	1 (5%)	1 (5%)	1.00
Grade 1 lesions	2 (10%)	2 (10%)	1.00

NSAIDs: Non-steroidal anti-inflammatory drugs.

Among NSAID consumers, cases presented more small bowel erosions than controls both in the jejunum and the in the ileum (Table 3).

Table 3 Number of mucosal lesions found during video capsule endoscopy in both bleeders and controls consuming non-steroidal anti-inflammatory drugs, after stratification according to the type of non-steroidal anti-inflammatory drug consumed.

Patient group	Patients	Controls	P
All patients	n = 40	n = 40
Jejunum
Grade 4 lesions	1 (SD = 2)	0.3 (SD = 0.7)	0.02
Grade 3 lesions	10.8 (SD = 4.3)	1 (SD = 0.6)	< 0.0001
Ileum
Grade 4 lesions	1.1 (SD = 1.9)	0.2 (SD = 0.3)	0.002
Grade 3 lesions	8.1 (SD = 4.8)	1.2 (SD = 2.2)	< 0.0001
Low dose aspirin users	n = 22	n = 22
Jejunum
Grade 4 lesions	0.8 (SD = 1.3)	0.2 (SD = 0.4)	0.02
Grade 3 lesions	9.9 (SD = 4.7)	0.8 (SD = 0.5)	< 0.0001
Ileum
Grade 4 lesions	0.9 (SD = 1.4)	0.1 (SD = 0.3)	0.006
Grade 3 lesions	10.3 (SD = 4.6)	1 (SD = 1.6)	< 0.0001
Non-aspirin NSAID consumers	n = 24	n = 24
Jejunum
Grade 4 lesions	1.4 (SD = 2.6)	0.4 (SD = 0.9)	0.04
Grade 3 lesions	11.9 (SD = 3.8)	1.2 (SD = 0.7)	< 0.0001
Ileum
Grade 4 lesions	1.6 (SD = 2.4)	0.3 (SD = 0.3)	0.02
Grade 3 lesions	7.7 (SD = 4.8)	1.4 (SD = 2.3)	< 0.0001
COX-2 NSAID consumers	n = 6	n = 6
Jejunum
Grade 4 lesions	0.3 (SD = 0.6)	0	0.27
Grade 3 lesions	5.7 (SD = 6.7)	0.4 (SD = 1.4)	0.04
Ileum
Grade 4 lesions	0.7 (SD = 1.2)	0	0.15
Grade 3 lesions	6.7 (SD = 5.7)	0.5 (SD = 0.7)	0.01

NSAIDs: Non-steroidal anti-inflammatory drugs; SD: Standard deviation; COX-2: Cyclooxygenase-2 selective inhibitors.

Small bowel erosions were present in 31 (97%) cases receiving NSAIDs long-term and 8 (100%) short-term (P = 0.61), while larger ulcerative lesions were found in 19 (59%) cases consuming NSAIDs long-term and 3 (38%) consuming them short-term (P = 0.27). On the other hand, small bowel erosions were found in 15 (47%) controls consuming NSAIDs long-term and 3 short-term (38%, P = 0.63); while small bowel ulcers were found in 3 (9%) controls consuming NSAIDs long-term and 1 long-term (13%, P = 0.79).

Twenty-four (67%) H. pylori positive and 15 (63%) negative cases (P = 0.74), as well as 11 (31%) H. pylori positive and 7 (29%) negative controls (P = 0.91) presented small bowel ulcerative lesions.

Small bowel ulcerative lesions were present in all cases (n = 16) and 1 (5%) control consuming low-dose aspirin only (P < 0.0001); 14 (78%) cases and 2 (9%) controls receiving non-aspirin NSAIDs only (P = 0.0001); 5 cases (83%) and 2 (33%) controls receiving both types of NSAIDs (P = 0.08). 4 (67%) cases receiving cyclooxygenase-2 selective inhibitors and one (16%) control presented small bowel erosions (P = 0.08), while larger lesions presented only in 2 (33%) cases (P = 0.12).

There was no difference between the two groups concerning presence of angiodysplasias [24 (40%) cases vs 25 (42%) controls, P = 0.85] and polypoid/submucosal lesions [2 (3%) cases vs 2 (3%) controls, P = 1.00].

Clinical course of peptic ulcer hemorrhage

Mean entry hemoglobin was 9.3 (SD = 1.4) g/dL in cases with grade-3 or 4 lesions and 10.5 (SD = 1.3) g/dL in those without (P = 0.002). It was 9.9 (SD = 1.5) g/dL in cases with small bowel erosions and 8.6 g/dL (SD = 1.2) in those with larger ulcerative lesions (P = 0.002). Thus calculated hemoglobin drop due to the bleeding episode was 4.7 g/dL in cases with grade 3 or 4 lesions and 3.5 g/dL in cases without ulcerative lesions (P = 0.001).

Cases with small bowel ulcerative lesions necessitated transfusion of 2.8 (SD = 1.2) units of packed red blood cells units while those without 1.1 (SD = 0.6, P < 0.0001). In addition, cases with small bowel ulcers necessitated transfusion of 3.9 (SD = 1.3) packed red blood cells units, while those with small bowel erosions 1.7 (SD = 0.9, P < 0.0001).

After admission and despite successful hemostasis, 7 (32%) cases with small bowel ulcers and none without presented a drop of hemoglobin > 2 g/dL (P = 0.05). Repeat upper gastrointestinal endoscopy revealed peptic ulcer rebleeding in one of them followed by repeat hemostasis, while repeat colonoscopy was negative. In repeat WCE study (because balloon enteroscopy was not available in the country), the remaining patients had at least one small bowel ulcer with a visible vessel on ulcer base with (n = 2) or without active bleeding (n = 4). Five (83%) bleeding recurrences that could possibly attributed to small bowel lesions were mild and self-limited. Nevertheless, one case necessitated operative small bowel endoscopy and hemostasis.

Logistic regression analysis, revealed that presence of diabetes mellitus and chronic obstructive lung disease were independent risk factors for bleeding recurrence possibly attributed to the small bowel, while absence of small bowel ulcers were protective (Table 4).

Table 4 Logistic regression analysis of demographic characteristics and co-morbidities related to a hemorrhage recurrence possibly related to the small bowel.

Characteristic	Relative risk	Confidence intervals	P
Age	1.03	0.96-1.10	0.40
Male gender	3.63	0.61-21.46	0.15
Body mass index	1.22	0.90-1.63	0.19
Diabetes	2.14	1.35-3.40	0.001
Chronic obstructive lung disease	6.67	1.01-46.3	0.05
Absence of small bowel ulcers	0.13	0.01-0.99	0.05

Thirty-day mortality was zero for both cases and controls and none reported any adverse event related to medical treatment or WCE.

Repeat capsule endoscopy a year later, revealed no ulcerative lesion in patients with small bowel ulcerative lesions in the entry endoscopy, providing that they had stopped NSAIDs during follow-up.

DISCUSSION

In our prospective case control study we found that 95% of elderly patients with peptic ulcer bleeding consuming NSAIDs presented small bowel erosions and 55% small bowel ulcers. Moreover, 30% of patients with a non-bleeding peptic ulcer consuming NSAIDs had small bowel erosions and 10% small bowel ulcers. Absence of small bowel ulcerative lesions was recorded in patients with peptic ulcer not receiving any NSAIDs. Small bowel ulcerative lesions in peptic ulcer bleeders were related with lower entry hemoglobin and increased need for blood transfusion. Finally, one out of four small bowel ulcers could bleed during the convalescence period of peptic ulcer bleeding leading to unexplained hemoglobin drop or even melena.

Our study has a number of limitations. It was conducted in a relatively limited number of rather old subjects; the vast majority of whom consumed NSAIDs chronically, while rheumatic disease was excluded. Thus although we included one of the main target groups of NSAID treatment, the elderly, we excluded the other, patients with rheumatic diseases[1]. Our study population old age was a result of reference bias, because our hospital is mainly a Veterans Hospital and referrals from secondary Hospitals usually exclude very young patients. More bowel ulcerative lesions are expected in the elderly because their large[18] and small bowel[19] is more vulnerable to NSAIDs. Patients with rheumatic diseases were excluded because rheumatoid artritis can cause small bowel ulcerative lesions in the absence of NSAID consumption[20]. Rheumatoid arthritis has been related to an increased frequency of iron deficiency anemia[21] and small bowel ulcerative lesions[20], among NSAIDs consumers, but no overt bleeding episodes[21]. Sample size although marginally adequate to explore the role of aspirin and non-selective NSAIDs, it was insufficient to study the effect of cyclooxygenase-2 selective inhibitors. Proton pump inhibitors were given to all study subjects, a common practice when the study was conducted. Nevertheless recent reports suggest that proton pump inhibitors could exacerbate small bowel ulcerative lesions[22].

Small bowel ulcerative lesions are more frequent in reports including chronic NSAID consumers[1,23] than those including healthy volunteers who received NSAIDs short-term[8,23-26]. A head to head comparison in our study revealed no difference between short and long-term NSAID consumers with concurrent peptic ulcer. Thus, some kind of mucosal adaptation, such as heme oxygenase-1 up regulation[27], could have balanced NSAIDs deleterious effect over time[1].

Small bowel injury and clinically relevant complications associated with the use of NSAIDs, even small dose aspirin, are well recognized[23,25-27]. Nevertheless data on peptic ulcer patients are limited[12]. In our study, prevalence of small bowel ulcerative lesions in NSAID users with non-bleeding peptic ulcer equals the mean of medical literature for non-ulcer NSAIDs consumers[1,23,25-27], even that reported by our group for NSAID consumers with iron deficiency anemia[13]. On the contrary, prevalence of small bowel ulcerative lesions was much higher among NSAID consumers with peptic ulcer bleeding. High prevalence of small bowel mucosal lesions in peptic ulcer bleeders receiving NSAIDs could attributed either to a genetically determined susceptibility for mucosal damage[12] or to an alternated NSAID metabolism due to different CYP2C9 polymorphism[28]. Small bowel ulcerative lesions were 15% more frequent in our study than in Watanabe et al[12] report, a small study on 11 non-bleeding gastric ulcer patients receiving low-dose aspirin and proton pump inhibitors. The difference could be attributed to the younger age of Watanabe et al[19] patients and the use of low dose aspirin, a less toxic NSAID[11,27]. Inclusion of patients with duodenal ulcer, in our study, could not influence the final outcome, as we found no difference between gastric and duodenal ulcer patients.

Although small bowel mucosal lesions are frequent, small and large bowel complications are infrequent[29], but increase with the exposure to NSAIDs use[9]. Presence of small bowel ulcerative lesions in our non-bleeding ulcer patients was rather indolent, while small bowel ulcers could possibly related to obscure bleeding recurrence in peptic ulcer bleeders. Small bowel ulcers were rather infrequent found in 5%-25% of NSAID consumers[1,23,25-27], but 55% of peptic ulcer bleeders. The probability of small bowel lesions responsible for gastrointestinal bleeding beyond gastric/duodenal ulcers states that we should consider WCE in patients with persistent hemorrhage or bleeding recurrence and negative or inconclusive gastroscopy.

Balloon enteroscopy would have been a preferable option for unexplained bleeding recurrence episodes since it also holds therapeutic capabilities[30]. Nevertheless it was not available in our country during most of the study period.

Gastrointestinal bleeding episodes in NSAID consumers characterized by more severe blood loss and need for more transfusions[31,32], due to co-existence of various co-morbidities and bleeding time prolongation as a result of the antiplatelet effect of NSAIDs[32]. Our study pointed out that small bowel ulcerative lesions could be also important. Old age[33,34], obesity[33,35], presence of diabetes mellitus[35] and chronic obstructive lung disease[33,36] are risk factors for peptic ulcer rebleeding after successful hemostasis because they favor microcirculatory disturbances. Although numbers are too small to draw safe conclusions, our study speculated that presence of diabetes mellitus and chronic obstructive lung disease are important for bleeding recurrence due to small bowel lesions.

In conclusion, more than half patients with peptic ulcer bleeding who consume NSAIDs presented small bowel ulcers. Those lesions were related to lower entry hemoglobin, increased need for blood transfusion and possibly unexplained episodes of bleeding recurrence. Despite study limitations, the results provide a compelling argument for the design of further large-scale studies to define the extent of this potential problem, unravel the mechanisms determining a worse prognosis of patients with peptic ulcer bleeding due to NSAID use and develop strategies to treat small bowel lesions in addition to peptic ulceration.

COMMENTS

Background

Non-steroidal anti-inflammatory drugs are very effectively painkillers, while low-dose aspirin is a common antithrombotic drug. Nevertheless they have been incriminated for causing gastric and duodenal ulcers and their complications, the most common of which is bleeding. Non-steroidal anti-inflammatory drugs can also harm the small bowel. Although small bowel lesions are very common their significance is poorly defined.

Research frontiers

There are very few data pointing out that small bowel ulcers might be very common in patients with gastric ulcers receiving non-steroidal anti-inflammatory drugs. Also it seems that patients receiving non-steroidal anti-inflammatory drugs lose more blood and do worse when they bleed. The explanation given today is that their blood is thinner or that they suffer more co-morbidities, such as heart disease, stroke, lung or kidney diseases.

Innovations and breakthroughs

The authors have found that small bowel ulcers are more common in patients with a gastric or a duodenal ulcer receiving non-steroidal anti-inflammatory drugs and presenting with bleeding than those without bleeding. The authors have also found no small bowel ulcers in patients not receiving non-steroidal anti-inflammatory drugs. The ulcer bug does not affect the possibility to develop small bowel lesions. The authors have shown that small bowel ulcers in patients with bleeding that receive non-steroidal anti-inflammatory drugs mean greater blood loss and need for more transfusions. Final the authors found that in patients with a bleeding from a gastric or a duodenal ulcer that receive non-steroidal anti-inflammatory drugs can relapse not only from their gastric or duodenal ulcer but also from a small bowel ulcer.

Applications

The probability of small bowel lesions responsible for bleeding beyond gastric/duodenal ulcers states that the authors should consider pill camera gut investigation in patients with persistent bleeding or bleeding recurrence and negative or inconclusive gastroscopy.

Terminology

A gastric or a duodenal ulcer represents a wound in the lining of the stomach or the beginning of the small bowel. The most common causes are the ulcer bug and non-steroidal anti-inflammatory drugs.

Peer review

It is an interesting work.