Acute nonsteroidal anti-inflammatory drug-induced colitis.

Resulting from direct toxicity on the bowel mucosa, nonsteroidal anti-inflammatory drug (NSAID)-induced colitis is an underestimated although potentially serious condition. Plain abdominal radiographs and multidetector computed tomography allow to identify a right-sided acute colitis with associated pericolonic inflammation, progressively diminished changes along the descending and sigmoid colon, and rectal sparing, consistent with the hypothesized pathogenesis of NSAID colitis. Increased awareness of this condition should reduce morbidity through both prevention and early recognition. High clinical suspicion and appropriate patient questioning, together with consistent instrumental findings, negative biochemistry, and stool investigations should help physicians not to miss this important diagnosis.

A 41-year-old man with no medical history was admitted to emergency department complaining of severe abdominal pain associated with blood-stained diarrhea. Physical examination revealed a body temperature of 37°C, diffuse tenderness at deep abdominal palpation, appreciable bowel peristalsis, negative peritonism signs, and fresh blood in the rectum at digital exploration. Laboratory tests disclosed mild leukocytosis and raised (18.4 mg/l) C-reactive protein.

On plain abdominal radiographs [Figure 1], the “thumbprinting" sign was identified throughout the transverse colon, suggested a marked haustral thickening condition involving most of the large bowel. Urgent-setting multidetector computed tomography (MDCT) was requested to investigate clinical and radiographic suspicion of severe infectious colitis, and to rule out possible surgical complications such as perforation, abscess collections, or gangrene. MDCT [Figure 2] confirmed severe mural thickening throughout the right hemicolon, with a stratified appearance (“target” or “water halo” sign) corresponding to enhancing hyperemic mucosa and hypoattenuating edematous submucosal, plus ancillary findings of pericolonic fat inflammatory changes and minimal peritoneal effusion. Similar changes indicating acute colitis of a significantly lesser entity involved the terminal ileum, descending and sigmoid colon, with sparing of the rectum.

Figure 1

(a) Supine and (b) upright plain abdominal radiographs. The “thumbprinting” sign corresponding to thickened haustra (arrowheads in a) is seen throughout the transverse colon, indicating a marked thickening condition involving most of the large bowel, associated with some enteric air-fluid levels (arrows in b)

Figure 2

Contrast-enhanced multidetector computed tomography. Coronal reformatted (a) and axial (b, d in craniocaudal order) images show marked (up to 2 cm) mural thickening of entire right colon (arrowheads in a, b, and c) with a stratified appearance (“target” sign) including enhancing mucosa and hypoattenuating submucosa. Associated findings indicating acute colitis include pericolonic fat inflammatory changes, minimal parietocolic and pelvic peritoneal effusion (*). Similar changes of a significantly lesser entity involve the terminal ileum, descending and sigmoid colon (arrowhead in d), with spared rectum

Colonoscopy was deemed contraindicated by the attending endoscopist because of the severity of clinical symptoms and imaging findings. Empiric, broad spectrum intravenous antibiotic treatment with piperacilline/tazobactam was started. On further questioning, the patient disclosed recent abuse of mixed nonsteroidal anti-inflammatory drug (NSAID) medications to treat postoperative pain following facial and eyelid surgery during the last 6 weeks.

Extensive biochemical assays and stool cultures yielded negative results. Clostridium, Salmonella spp., Shigella, and Entamoeba infections were excluded. Following withdrawal of anti-inflammatory medications, a week later resolution of clinical manifestations, laboratory and imaging abnormalities allowed patient discharge, thus validating the diagnosis of acute NSAID-induced colitis.

In recent years, evidence is mounting that NSAID-related bowel injury is not site-specific to the gastroduodenal mucosa, and that NSAIDs may cause or exacerbate injury in the small intestine and colon as well. Despite the extensive use of these medications in the general population, NSAID-induced colitis is very scarcely reported in medical literature and underestimated by most clinicians.[123456]

Elderly people and patients on long-term treatment are at highest risk. Among published series of NSAID colitis, the most commonly reported indications for medication intake include arthritis or osteoarthritis, other musculoskeletal disorders, toothache or headache, sinusitis, postoperative or postpartum pain, lumbar pain, dysmenorrhea, and prophylaxis against vascular disease. Oral, intramuscular, rectal, and topical preparations may be involved. Ibuprofen, diclofenac, and aspirin account for approximately 85% of cases. Interestingly, the toxic effect is not dose related.[47]

The mechanisms underlying NSAID-associated colitis are still unclear. Its probable multifactorial pathogenesis includes inhibition of cyclooxygenase and prostaglandin synthesis, and impairment of oxidative phosphorylation. The role of direct drug toxicity on the intestinal wall is suggested by the fact that intestinal changes are mostly limited to the right hemicolon, with usual rectal sparing.[16] Since most NSAIDs undergo enterohepatic circulation, the proximal colon is directly exposed to intact drug following bacterial breakdown in the distal ileum, and the cecum acts as a reservoir. Furthermore, the use of slow release and enteric-coated preparations allows more drugs to reach the colon.[16]

As described in sparse case reports and some case series, the natural history of NSAID-induced colitis is poorly understood. Presenting symptoms may include diffuse abdominal pain, diarrhea, lower gastrointestinal bleeding, occasionally ulceration or perforation. Subacute and chronic forms manifest with weight loss, symptomatic iron-deficiency anemia, and long-term development of diaphragm-like fibrotic strictures. Hospitalization is necessary in up to 20% of cases.[123457]

Endoscopy may be normal in up to 45% of cases or reveal nonspecific changes including mucosal inflammation, erosions, superficial solitary or multiple ulcerations, or concentric diaphragm-like strictures. Histology from biopsy specimens may show mixed inflammatory cell infiltrates, crypt distortion and microabscesses, mucus depletion, and mucosal erosions. Not surprisingly, misinterpretation as Crohn's disease, ulcerative or ischemic colitis and even colon cancer has been reported.[257]

Despite their limited sensitivity and specificity, plain abdominal radiographs are often obtained as the screening emergency diagnostic study, particularly to exclude perforation and bowel obstruction. Identification of the uncommon “thumbprinting” sign, consisting of sharply contoured finger-like indentations of the large bowel that correspond to thickened haustra, suggests an acute colonic disease. Currently, MDCT is increasingly adopted and highly valuable for the detection and characterization of inflammatory conditions involving the large bowel. MDCT comprehensively provides assessment of severity and longitudinal extent of colitis, differentiation from malignancy, and exclusion of complications requiring surgery.[8]

In this case of severe NSAID-induced colitis, MDCT findings included marked circumferential mural thickening with enhancing hyperemic mucosa and low-attenuation edematous, inflamed submucosa, also known as the radiological “target” or “water halo” sign. The observed distribution of bowel changes with predominant right colon and terminal ileum involvement, decreasing abnormalities along the transverse, descending and sigmoid tracts and rectal sparing may reflect the above-discussed pathogenesis of NSAID colitis.[16] These appearances are similar to those observed in the most serious forms of infectious colitis, such as pseudomembranous colitis (PMC) from Clostridium difficile overgrowth, with the exception that PMC does not involve the distal ileum. Although significant overlap exists between the imaging appearances of most colonic infections, right-sided predominance favors Salmonella, Yersinia, Mycobacterium tuberculosis, and Entamoeba infections that should be considered in the differential diagnosis and need laboratory and microbiological verifications. Associated findings such as peritoneal effusion and pericolonic fat stranding indicate an acute intestinal inflammation. Furthermore, MDCT allows post-treatment follow-up with the drawback of ionizing radiation use.[8]

Because NSAID(s) are so widely prescribed and even available as over-the-counter medications, we believe that increased awareness of this largely underestimated clinical condition is necessary to reduce morbidity both by prevention and early recognition. The diagnosis of NSAID colitis is made on the basis of positive drug history, consistent endoscopic, imaging, and pathological changes, and associated negative stool cultures and insignificant biochemical abnormalities in contrast with troublesome symptoms. The appropriate treatment including withdrawal of the involved medications plus antibiotics allows resolution of symptoms while avoiding the potential side effects of other unnecessary therapies such as corticosteroids of azathioprine.[136]