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Journal of advances in internal medicine vol01_issue0

Journal of Advances in Internal Medicine Editorial
Underestimation of clinical importance of non-steroidal anti-inflammatory drug induced enteropathy and its exacerbation by proton pump inhibitors Umid Kumar Shrestha* Manipal College of Medical Sciences & Manipal Teaching Hospital, Pokhara, Nepal Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used over-the-counter to relieve pain and symptoms of arthritis and soft tissue inflammation. Proton pump inhibitors (PPIs) are often used simultaneously with NSAID to protect against its gastroduodenal side effects. However, the suppression of gastric acid secretion by PPIs does not seem to protect against the damage caused by NSAIDs in the more distal small intestine, often called as NSAID induced enteropathy. In fact, the small intestine seems to be more susceptible to the damaging effects of NSAIDs than the stomach1 and PPI may even exacerbate the NSAID induced enteropathy.2 The main reason of the unawareness and the underestimation of NSAID enteropathy is the difficulty in making a diagnosis. Its diagnosis is often based on the following tests, as evidenced by the previ-ous studies: 1. The use of 51Cr-EDTA or the differential urinary excretion of 51Cr-EDTA or lactulose/mannitol or rhamnose given with or without osmotic fillers detected the increased intestinal permeability caused by NSAID in 50%–70% of patients, but the test is non-specific.3 2. Four day fecal excretion of 111Indium labeled white cells showed the presence of NSAID enter- opathy in 50%–70% of patients, but the test is expensive.3 3. Fecal calprotectin (a non-degraded neutrophil cytosolic protein) showed the presence of NSAID enteropathy in 44% of patients receiving NSAID.4 However, this test is again non-specific as the raised levels of fecal calprotectin are also seen in inflammatory bowel disease and colo-rectal cancer.5 4. Enterescopy showed NSAID enteropathy in 47% of patients with rheumatoid arthritis on 5. Wireless Capsule endoscopy (WCE) detected NSAID enteropathy in 68% of patients.7 Although WCE visualizes the entire small bowel, fecal reflux into the terminal ileum often prevents optimal visualization of this area, Because of the predilection of NSAID for damage in the distal il-eum,8 terminal ileoscopy should be performed at all colonoscopies. In fact, terminal ileoscopy might be complementary in the diagnosis of NSAID enteropathy. Accepted on
May 24th, 2012
Whereas inhibition of mucosal cyclooxygenase -1 and -2 leads to the gastroduodenal damage, the mechanism of NSAID on mid or distal small intestine is different. The NSAID induced enteropathy seems to be mediated by intestinal permeability, enterohepatic circulation and bile. The injury of small intestinal is contributed by neutrophil infiltration, release of tumor necrosis factor-alpha and the increase in gram-negative bacteria in the small intestine.2 The clinical features of NSAID enter- opathy may be unremarkable, but some complications can be subtle or potentially life threatening. enteropathy, non steroidal anti inflammatory drugs, It can lead to chronic iron deficiency anemia due to the continuous and mild bleeding from the small protein pump inhibitors bowel ulcerations, the amount of blood loss in most cases being 2–10 ml/day.9 The other complica-tion can be protein losing enteropathy, which can result in hypoalbuminaemia.9 Citation
Shrestha UK. Underestimation of clinical impor- The injury of small intestine was demonstrated in healthy volunteers consuming NSAID and PPI for
tance of non-steroidal anti-inflammatory
14-16 days.10 Microscopic colitis was found to be more common among both NSAID and PPI users.11 drug induced enteropathy and its exacerbation by Recent animal studies demonstrated that PPI may exacerbate NSAID enteropathy by changing the proton pump inhibitors. Journal of Advances in In- small intestinal bacteria.2 In this study, omeprazole was given to the rats, and this was associated ternal Medicine 2012;01(02):50-1. with a significant increase in the aerobic bacteria (both gram-negative and gram-positive) in the jejunum, but a significant reduction (80%) in Actinobacteria and Bifidobacteria spp.2 The intestinal ulceration or bleeding in response to omeprazole or naproxen was prevented by *Corresponding author Department of MedicineManipal College of Medical Sciences & Manipal Teaching Hospital, Pokhara, NepalEmail address - JAIM volume 01 issue 02 July-December 2012
Use of PPIs has also been associated with a significant increase in the 4. Metronidazole with indomethacin resulted in a significant reduction incidence of various infections, most notably Clostridium difficile.12 Ab- in NSAID induced intestinal permeability in volunteers.18 However, sorption of calcium, iron, magnesium and vitamin B12 can be impaired, long term use of metronidazole is not justified in the clinical setting.
and increased rates of osteoporosis-associated bone fractures in patients 5. The NSAID enteropathy and inflammatory bowel disease have got chronically treated with PPIs were also found in the study.13 the similar pathological findings which led to the suggestion that sulphasalazine may be a possible therapeutic drug in NSAID enter- Therefore, a careful assessment of the use of PPIs together with NSAIDs opathy.19 In one study, Sulphasalazine significantly reduced the in- is warranted. The benefits of the protection from gastroduodenal damage testinal inflammation and blood loss in patients taking NSAIDs.
with PPI therapy could be offset by more distal damage, which is more 6. There may be a possible role of prebiotic and probiotic in NSAID difficult to detect.The suggested prevention and treatment strategies for enteropathy. Animal studies showed that a lactate-producing spe- NSAID induced enteropathy are given below: cies of Bifidobacteria significantly reduced the severity of NSAID enteropathy in rats, while a species of Bifidobacteria not producing 1. The offending drugs should be withdrawn as far as possible.
lactate had no effect.20 Lactate-producing Bifidobacteria may be a 2. Misoprostol, which has an established role in preventing NSAID in- viable prophylactic therapy for NSAID enteropathy. However, further duced gastroduodenal adverse effects, has also been found to de- study is required to establish the role of probiotic in alleviating the crease the incidence of more distal intestinal damage due to NSAID, NSAID enteropathy in human being.
as assessed by video capsule endoscopy.14 3. Novel NSAID with fewer gastrointestinal adverse effects are under In conclusion, since NSAIDs and PPIs are widely used concomitantly and development. Nitric Oxide-releasing NSAIDs were found to be bet- also available without prescription, additional studies are needed to ex- ter tolerated in the small intestine in animal studies15 and in a clini- plore their associations with enteropathy on humans, and if patients, cal trial, to cause less increase in small intestinal permeability than receiving both classes of medications, present with diarrhea, abdominal the parent drug (naproxen).16 Hydrogen sulphide-releasing NSAIDs distention, flatulence, or abdominal pain, they should be reassessed for have been shown to cause negligible damage in the small intestine the enteropathy and treated accordingly of rats,17 but have not yet been evaluated in humans.
11. Pardi DS, Kelly CP. Microscopic colitis. Gastroenterology 1. Whittle BJ. Mechanisms underlying intestinal injury in- 2011;140:1155–65. duced by anti-inflammatory COX inhibitors. Eur J Pharmacol 12. McCarthy DM. Adverse effects of proton pump inhibitor drugs: clues and conclusions. Curr Opin Gastroenterol 2010;26:624-31.
2. Wallace JL, Syer S, Denou E, et al. Proton pump inhibitors 13. Ito T, Jensen RT. Association of long-term proton pump inhibi- exacerbate NSAID-induced small intestinal injury by inducing tor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol 3. Sigthorsson G, Tibble J, Hayllar J, et al. Intestinal permeability and inflammation in patients on NSAIDs. Gut 1998;43:506–11.
14. Fujimori S, Seo T, Gudis K, et al. Prevention of nonsteroidal anti- 4. Tibble JA, Sigthorsson G, Foster R, et al. High prevalence of inflammatory drug-induced small-intestinal injury by prosta- NSAID enteropathy as shown by a simple faecal test. Gut glandin: a pilot randomized controlled trial evaluated by capsule endoscopy. Gastrointest Endosc 2009;69:1339-46. 5. Tibble JA, Bjarnason I. Faecal calprotectin as an index of intesti- 15. Davies NM, Røseth AG, Appleyard CB, et al. NO-naproxen vs. nal inflammation. Drugs Today (Barc) 2001;37:85–96.
naproxen: ulcerogenic, analgesic and anti-inflammatory effects. 6. Morris AJ, Madhok R, Sturrock RD, et al. Enteroscopic diagnosis Aliment Pharmacol Ther 1997;11: 69–79.
of small bowel ulceration in patients receiving non-steroidal 16. Hawkey CJ, Jones JI, Atherton CT, et al. Gastrointestinal safety anti-inflammatory drugs. Lancet 1991;337:520.
of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: 7. Maiden L, Thjodleifsson B, Theodors A, et al. A quantitative proof of concept study in humans. Gut 2003;52:1537- 42.
analysis of NSAID-induced small bowel pathology by capsule 17. Wallace JL, Caliendo G, Santagada V, et al. Markedly reduced toxicity of a hydrogen sulfide-releasing derivative of naproxen 8. Kameda N, Higuchi K, Shiba M, et al. A prospective, single-blind (ATB-346). Br J Pharmacol 2010;159:1236–46.
trial comparing wireless capsule endoscopy and double-balloon 18. Davies GR, Wilkie ME, Rampton DS. Effects of metronidazole enteroscopy in patients with obscure gastrointestinal bleeding. J and misoprostol on indomethacin-induced changes in intestinal Gastroenterol 2008;43:434–40. permeability. Dig Dis Sci1993;38:417–25.
9. Adebayo D, Bjarnason I. Is non-steroidal anti-inflammaory drug 19. Hayllar J, Smith T, Macpherson A, et al. Nonsteroidal antiinflam- (NSAID) enteropathy clinically more important than NSAID matory drug-induced small intestinal inflammation and blood gastropathy? Postgrad Med J 2006;82:186–191.
loss. Effects of sulfasalazine and other disease-modifying anti- 10. Hawkey CJ, Ell C, Simon B, et al. Less small-bowel injury with rheumatic drugs. Arthritis Rheum 1994;37:1146-50.
lumiracoxib compared with naproxen plus omeprazole. Clin 20. Syer S, McKnight G, Langella P, et al. High lactate-producing Bifi- dobacteria as a potential prophylactic therapy for NSAID-enter-opathy. Can J Gastroenterol 2012;26 (suppl A):A284 [Abstract] JAIM volume 01 issue 02 July-December 2012



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