Risk factors for severe nonsteroidal anti-inflammatory drug-induced small intestinal damage

Watanabe, Toshio; Tanigawa, Tetsuya; Nadatani, Yuji; Nagami, Yasuaki; Sugimori, Satoshi; Okazaki, Hirotoshi; Yamagami, Hirokazu; Watanabe, Kenji; Tominaga, Kazunari; Fujiwara, Yasuhiro; Koike, Tatsuya

doi:10.1016/j.dld.2012.12.005

Cited by 86 publications

(66 citation statements)

References 26 publications

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“…This was confirmed by others, and was shown to occur also with histamine H 2 receptor antagonists [14][15][16]. Moreover, there is clinical evidence linking use of PPIs and H 2 receptor antagonists to severe intestinal damage observed in rheumatoid arthritis patients taking NSAIDs [8]. We also observed that lowdose aspirin significantly exacerbated NSAID-induced small intestinal ulceration and bleeding [13].…”

supporting

confidence: 73%

“…There are also no proven-effective treatments for NSAID enteropathy once it has occurred [1,2,4]. With improved means of detection, such as video capsule endoscopy, physicians are becoming more aware that the small intestinal damage caused by NSAIDs is much more common and much more serious than previously recognized [4,[6][7][8][9][10][11]. The prevalence of NSAIDinduced damage in the small intestine was highlighted by data showing that various features consistent with damage are common among long-term NSAID users: inflammation in 60-70 %, ulceration in 30-40 %, increased permeability in up to 70 %, bleeding/anemia in 30 %, and malabsorption in 40-70 % [4].…”

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confidence: 99%

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NSAID enteropathy and bacteria: a complicated relationship

et al. 2015

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The clinical significance of small intestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remains under-appreciated. It occurs with greater frequency than the damage caused by these drugs in the upper gastrointestinal tract, but is much more difficult to diagnose and treat. Although the pathogenesis of NSAID enteropathy remains incompletely understood, it is clear that bacteria, bile, and the enterohepatic circulation of NSAIDs are all important factors. However, they are also interrelated with one another. Bacterial enzymes can affect the cytotoxicity of bile and are essential for enterohepatic circulation of NSAIDs. Gram-negative bacteria appear to be particularly important in the pathogenesis of NSAID enteropathy, possibly through release of endotoxin. Inhibitors of gastric acid secretion significantly aggravate NSAID enteropathy, and this effect is due to significant changes in the intestinal microbiome. Treatment with antibiotics can, in some circumstances, reduce the severity of NSAID enteropathy, but published results are inconsistent. Specific antibiotic-induced changes in the microbiota have not been causally linked to prevention of intestinal damage. Treatment with probiotics, particularly Bifidobacterium, Lactobacillus, and Faecalibacteriaum prausnitzii, has shown promising effects in animal models. Our studies suggest that these beneficial effects are due to colonization by the bacteria, rather than to products released by the bacteria.

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supporting

confidence: 73%

mentioning

confidence: 99%

NSAID enteropathy and bacteria: a complicated relationship

et al. 2015

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“…Moreover, Watanabe et al (2013) recently reported that PPIs exacerbate small bowel injury in patients with rheumatoid arthritis taking NSAIDs on long term. Overall, it appears that PPIs can exert differential effects on NSAID-induced enteropathy, depending on the NSAID and PPI considered, and even the experimental model and PPI regimen adopted.…”

Section: Discussionmentioning

confidence: 99%

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

Fornai

Antonioli

Colucci

et al. 2013

J Pharmacol Exp Ther

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Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce intestinal mucosal damage, but the underlying mechanisms remain poorly understood. The present study investigated the effects of celecoxib, etoricoxib, indomethacin, and diclofenac on small bowel integrity in rats. Male rats were treated orally with test drugs for 14 days. Animals were processed for assessment of blood hemoglobin levels and hepatic mitochondrial functions, microscopic evaluation of small intestinal damage, Western blot analysis of cyclooxygenase-1 and -2 (COX-1, COX-2) expression, and assay of malondialdehyde (MDA), myeloperoxidase (MPO), and prostaglandin E 2 (PGE 2 ) levels in small intestine. Indomethacin and diclofenac decreased blood hemoglobin levels, whereas etoricoxib and celecoxib were without effects. Celecoxib caused a lower degree of intestinal damage in comparison with the other test drugs. Indomethacin and diclofenac, but not etoricoxib or celecoxib, reduced intestinal PGE 2 levels. Test drugs did not modify intestinal COX-1 expression, although they enhanced COX-2, with the exception of celecoxib, which downregulated COX-2. Indomethacin, diclofenac, and etoricoxib altered mitochondrial respiratory parameters, although celecoxib was without effects. Indomethacin or diclofenac increased MDA and MPO levels in both jejunum and ileum. In the jejunum, etoricoxib or celecoxib did not modify such parameters, whereas in the ileum, etoricoxib, but not celecoxib, increased both MDA and MPO levels. These findings suggest that nonselective NSAIDs and etoricoxib can induce enteropathy through a topic action, whereas celecoxib lacks relevant detrimental actions. The selectivity profile of COX-1/COX-2 inhibition by test drugs and the related effects on prostaglandin production do not appear to play a major role in the pathogenesis of enteropathy.

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“…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] .…”

Section: Discussionmentioning

confidence: 99%

“…Small bowel ulcerative lesions were 15% more frequent in our study than in Watanabe et al [12] report, a small study on 11 nonbleeding 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.…”

mentioning

confidence: 99%

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

Tsibouris

Kalantzis

Apostolopoulos

et al. 2014

WJGE

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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 antiinflammatory 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.© 2014 Baishideng Publishing Group Inc. All rights reserved. PROSPECTIVE STUDY

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Risk factors for severe nonsteroidal anti-inflammatory drug-induced small intestinal damage

Cited by 86 publications

References 26 publications

NSAID enteropathy and bacteria: a complicated relationship

NSAID enteropathy and bacteria: a complicated relationship

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

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

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