NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies

Abstract

The mechanisms underlying the ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to cause ulceration in the stomach and proximal duodenum are well understood, and this injury can largely be prevented through suppression of gastric acid secretion (mainly with proton pump inhibitors). In contrast, the pathogenesis of small intestinal injury induced by NSAIDs is less well understood, involving more complex mechanisms than those in the stomach and proximal duodenum. There is clear evidence for important contributions to NSAID enteropathy of enteric bacteria, bile and enterohepatic recirculation of the NSAID. There is no evidence that suppression of gastric acid secretion will reduce the incidence or severity of NSAID enteropathy. Indeed, clinical data suggest little, if any, benefit. Animal studies suggest a significant exacerbation of NSAID enteropathy when proton pump inhibitors are co-administered with the NSAID. This worsening of damage appears to be linked to changes in the number and types of bacteria in the small intestine during proton pump inhibitor therapy. The distinct mechanisms of NSAID-induced injury in the stomach/proximal duodenum versus the more distal small intestine likely dictate distinct strategies for prevention.

Figure 1

Pathogenesis of NSAID enteropathy. NSAIDs that undergo enterohepatic recirculation exhibit much greater capacity to induce small intestinal injury than those that are not absorbed and delivered into the upper small intestine in bile. Inhibition of PG synthesis and increased intestinal permeability can be observed with all NSAIDs, but only those that undergo enterohepatic recirculation will cause significant ulceration. It is likely that NSAIDs, particularly when combined with bile, can directly damage epithelial cells in the intestine. Neutrophil infiltration and release of TNF-α contribute to injury, but the increase in gram-negative bacteria in the small intestine is particularly important for the generation of ulcers. Thus, broad-spectrum antibiotics can prevent experimental NSAID enteropathy, and germ-free rodents do not develop intestinal ulcers when given NSAIDs.