Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to have adverse effects on the upper gastrointestinal tract, however, its effect on the small intestine are not well described [1]. It is proven that NSAIDs can be harmful to the small intestine and can be associated with multiple complications, such as, small intestinal strictures, ulcerations, perforations, diarrhea, and villous atrophy. The NSAIDs can have adverse effects in any part of the gastrointestinal tract including, oesophagus, stomach, duodenum, small intestine, or colon [2] [3]. Risk is increased with age, in first three months of treatment, smoking, associated cardiovascular or respiratory disease, high dose and multiple NSAIDs, and concomitant use of anticoagulant or steroids [1] [3].

Herein, we report a case of NSAID-induced multiple small bowel erosions and perforations that involved the proximal as well as distal ileum. Furthermore, similar cases of NSAID-induced enteropathy described in literature are also reviewed, in which other causes were ruled out by obtaining biopsy specimens for histologic analysis.

A 31-years-old male, with no known co-morbidity, presented in emergency department with a history of severe right lower quadrant pain of more than 12 hours that was not responding to analgesics. There is associated intermittent high grade fever (up to 39.5°C), severe sore throat, and weight loss of 6 kg over 2 weeks, for which he received augmentin for a week and cefuroxime for another week with no improvement.

On physical examination in the emergency room the patient was tachycardiac, tachypneic, febrile and showed presence of severe follicular tonsillitis with oral ulcers. On further interrogation , the patient revealed that 16–20 tablets of diclofenac potassium per day for his pain for two weeks prior to the onset of his abdominal symptoms.

Systemic examination showed bilaterally equal air entry in the chest with regular heart sounds and no audible murmur. There was diffuse abdominal distention along with tenderness more in the lower abdomen. Although white cell count was high, however, all other laboratory tests including the Widal test were normal.

Urgent ultrasound of abdomen done which revealed free fluid in the abdomen. A chest X-ray showed free air under the diaphragm on the right side and an emergency laparotomy was performed for suspected peritonitis associated with intestinal perforation. Peroperatively, there were multiple small bowel perforation in the terminal ileum each approximately 5 mm in size along with a few impending perforations (Figure 1).

Approximately 15 cm of the ileum was resected due to very close and tinny perforations in which suturing was impossible, ileostomy was done with planned scheduled relook laparotomy through the laparostomy (mesh and VAC used).

Three relook laparotomies were performed and showed new perforations with impending peforations which were fixed by either primary repair or burying it inside

Workup was done for the etiology including stool analysis for Compylobacter jejuni , Yersinia enterocolitica, Salmonella, Shigella and Clostridium difficile and found to be negative. Serum markers for vasculitis were also negative.

Histopatholgy report showed nonspecific inflammation and excluded inflammatory bowel disease, vasculitis, and vascular thrombi. Only positive history found was ingestion of high dose nonsteroidal anti-inflammatory analgesics.

Patient recovered slowly but well and discharged after two weeks of hospital stay. After six weeks ileostomy reversal was done without any complications and remained healthy till now (six months postoperatively)

The differential diagnosis of nonspecific erosions, ulcerations and perforation of the small intestine includes Crohn's disease, Typhoid fever trauma (from ingested toothpicks or bones), infection (cytomegalovirus, tuberculosis, or Yersinia), Vasculitides (such as lupus, rheumatoid, or periarteritis nodosa) postradiation therapy, ischemia, and various medications (like enteric-coated potassium). In certain case reports, rheumatoid vasculitis and other collagen vascular diseases are supposed to be responsible for described intestinal strictures and inflammation, therefore, patients suffering from such diseases should be thoroughly examined, as NSAIDs are usually mainstay to treat these disorders [3] [4].

In contrast to the prevoiusly accepted belief, recently, it is documented that NSAID-induced gastrointestinal injury occurs more frequently in the small bowel than in the stomach [4] [5]. (NSAID) induced enteropathy may manifest acutely as well as after chronic use, being five patients described in one study after use of medication for less than 4 weeks [6][7]. Like-wise, the development of enteropathy does not seem to be related to the route of administration of NSAIDs, because, use of Osmosin, a now obsolete indomethacin rectal suppository, was also associated with ileal perforations [8]. However, the effect of intravenous route has yet to be established. Furthermore, in another study, majority of patients with NSAID-induced enteropathy were taking either indomethacin or piroxicam preparations for more than a month. Among these patient, 40% had intestinal obstruction, 40% had ulceration and anemia, and 12% had intestinal perforation, suggesting the NSAIDs as a possible cause. In a separate autopsy series, undiagnosed small bowel perforations was found to be the cause of death in three patients who had received long-term Aspirin therapy, that is, for six months or more [9]. In the study described previously, most of the patient underwent intestinal resection while in about one-fifth of them, the only treatment was discontinuation of use of NSAIDs [9]. Considering that, if the disease is suspected and treated early, it may preclude the need of surgery, thus, considerably reducing the associated morbidity and mortality.

In the case described here, the patient high doses of diclofenac sodium orally for two weeks. The subsequent laboratory and histopathologic findings were unable to identify any etiology for his ileal perforations other than NSAID-induced enteropathy, including inflammatory bowel disease, trauma, typhoid, tuberculosis and amoebiasis. Therefore, a diagnosis of diclofenac sodium-induced multiple ileal perforation was reached.

In another retrospective study, it is noted that those patients who were taking NSAIDs were twice as likely to have small and large bowel perforations or hemorrhage in comparison with control patients [10], further supporting our presumption in this case.

High doses of nonsteriodal anti-inflammatory drugs can cause multiple ileal erosions and perforation and should be considered in the the differential diagnosis, if other possibilities are excluded. Early suspicion and timely intervention may reduce the associated morbidity and mortality.

1. Kim JW. NSAID-induced gastroenteropathy. Korean J Gastroenterol 2008 Sep;52(3):134–41.   [Pubmed]    
2. Shioya N, Shibata S, Kojika M, Endo S. Multiple transverse colonic perforations associated with slow-release nonsteroidal anti-inflammatory drugs and corticosteroids: a case report. Case Rep Crit Care 2011;2011:824639.   [CrossRef]   [Pubmed]    
3. Saw KC, Quick CR, Higgins AF. Ileocaecal perforation and bleeding--are non-steroidal anti-inflammatory drugs (NSAIDs) responsible? J R Soc Med 1990 Feb;83(2):114–5.   [Pubmed]    
4. Deakin M. Small bowel perforation associated with an excessive dose of slow release diclofenac sodium. BMJ 1988 Aug 13;297(6646):488–9.   [CrossRef]   [Pubmed]    
5. Cree IA, Walker MA, Wright M, Forrester JC. Osmosin and ileal ulceration: a case report. Scott Med J 1985 Jan;30(1):40–1.   [Pubmed]    
6. Gibson GR, Whitacre EB, Ricotti CA. Colitis induced by nonsteroidal anti-inflammatory drugs. Report of four cases and review of the literature. Arch Intern Med 1992 Mar;152(3):625–32.   [CrossRef]   [Pubmed]    
7. Kuehne SE, Gauvin GP, Shortsleeve MJ. Small bowel stricture caused by rheumatoid vasculitis. Radiology 1992 Jul;184(1):215–6.   [CrossRef]   [Pubmed]    
8. Okuda Y, Takasugi K, Imai A, et al. Two cases of rheumatoid arthritis complicated with vasculitis-induced ischemic enterocolitis. Ryumachi 1990 Oct;30(5):403-7, 408; discussion 407–8.   [Pubmed]    
9. llison MC, Howatson AG, Torrance CJ, Lee FD, Russell RI. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 1992 Sep 10;327(11):749–54.   [CrossRef]   [Pubmed]    
10. Langman MJ, Morgan L, Worrall A. Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage. Br Med J (Clin Res Ed) 1985 Feb 2;290(6465):347–9.   [CrossRef]   [Pubmed]