NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity

Author:: Mark Feldman, MD, MACP, AGAF, FACG
Section Editor:: J Thomas Lamont, MD
Deputy Editor:: Shilpa Grover, MD, MPH, AGAF

Literature review current through: Jan 2024.

This topic last updated: Jun 23, 2022.

INTRODUCTION — Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used because of their versatile effectiveness as analgesics, antipyretics, and antiinflammatory agents. Aspirin is also used in relatively low doses as an antiplatelet agent [1]. However, even very low doses of oral aspirin and other NSAIDs can injure the gastric and duodenal mucosa, with the potential for considerable morbidity and mortality [2].

This topic will review the pathogenesis and risk factors for gastroduodenal toxicity due to the use of NSAIDs and aspirin. The clinical presentation of NSAID-induced gastrointestinal injury and recommendations for the prevention and treatment of NSAID-induced gastroduodenal injury are discussed elsewhere. (See "NSAIDs: Adverse effects on the distal small bowel and colon" and "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity".)

OVERVIEW OF CYCLOOXYGENASE AND MUCOSAL PROSTAGLANDIN BIOLOGY

Role of cyclooxygenase — Cyclooxygenase (COX), the rate-limiting enzyme in prostaglandin (PG) synthesis, converts the unsaturated fatty acid arachidonic acid (C20:4; derived from phospholipids in cell membranes) into PGG2 and then to PGH2 (figure 1). The gastric and duodenal mucosa proceed to convert PGH2 to various prostanoids (prostaglandins and thromboxane A2). PGs such as PGE2 and PGI2protect the mucosal lining from injury by luminal acid-pepsin.

There are two functional forms of COX in the human body, COX-1 and COX-2 [3]. These two proteins are 50 to 60 percent homologous and are coded on chromosomes 9 and 1, respectively. COX-1 is a constitutive enzyme with a fairly steady rate of expression in most cells of the body. In contrast, COX-2 is produced in many cells only when bacterial polysaccharides (endotoxin), pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta, or growth factors (mitogens) induce COX-2 expression. The healthy gastric and duodenal mucosa constitutively use COX-1 to produce its mucosal-protective PGs [4]. (See "Overview of COX-2 selective NSAIDs", section on 'COX-2 selective NSAIDs (coxibs)'.)

Mechanism of mucosal protection

Prostaglandins — Several mucosal functions are altered by endogenous PGs and by exogenously administered PGs. These changes may contribute to the mucosal protective effects of PGs. While it is true that certain PGs such as PGE2 reduce gastric acid secretion, hypochlorhydria does not entirely explain the mucosal protection observed with PGE2. In animals, for example, doses of PGE2 far too low to inhibit gastric acid secretion profoundly protect against gastric injury induced by aspirin, alcohol, and other gastric irritants. This non-antisecretory effect of PGs is referred to as "cytoprotection."

Some of the cytoprotective mechanisms of PGs include:

●Stimulation of mucin, bicarbonate, and phospholipid secretion by gastroduodenal epithelial cells

●Enhancement of mucosal blood flow and the delivery of oxygen to epithelial cells via local vasodilation

●Increased epithelial cell migration towards the luminal surface (epithelial restitution)

●Enhanced epithelial cell proliferation

Epithelial mucin and bicarbonate combine to form an alkaline, unstirred water layer on the surface of the gastric mucosa, which retards diffusion of acid-pepsin from the lumen into the mucosa.

Nitric oxide — Generation of nitric oxide (NO) by NO synthase (NOS) may be a key intermediate in cytoprotection. Similar to the role of COX-1, constitutive NOS is important in the maintenance of an intact mucosal lining. Two enzymes contribute to the basal, constitutive NOS activity: neuronal NOS (nNOS; type I) and endothelial NOS (eNOS; type III). The cytoprotective mechanisms of NO parallel PG effects and include:

●Stimulation of gastric mucin and bicarbonate secretion

●Enhancement of mucosal blood flow

●Maintenance of epithelial barrier function

In some but not all models, an inducible NOS (iNOS; type II) produces high levels of NO leading to physiologic responses that are often quite different than seen in the basal state. Inducible NOS is generally associated with inflammatory states, similar to COX-2 [5]. However, the relationship between the various NOS forms and COX enzymes has not been fully elucidated. Most studies implicate both constitutive and inducible enzymes in the maintenance of gastric mucosal integrity as well as in epithelial restitution [6,7]. Manipulation of NO levels in models of nonsteroidal antiinflammatory drug (NSAID)-induced mucosal damage suggests a protective role for both NO and PGs [8,9].

PATHOGENESIS OF GASTRODUODENAL TOXICITY

Mechanism of action of NSAIDs — The primary effect of NSAIDs is to inhibit cyclooxygenase (COX; prostaglandin [PG] synthase), thereby impairing the ultimate transformation of arachidonic acid to PGs, prostacyclin, and thromboxanes. Many nonsteroidal antiinflammatory drugs (NSAIDs) block COX-1 and COX-2 more or less equally (ie, are nonselective) and thus may impair gastric PG production at low tissue concentrations (table 1). Selective inhibitors of COX-2 may better preserve PG-mediated gastrointestinal mucosal protection (table 1). However, COX-2 selective inhibitors (eg, celecoxib) may still block COX-1 in the stomach and duodenum at clinically recommended doses and thus have the potential to cause mucosal injury.

COX-1 mediated NSAID injury — Gastric and duodenal injury by acid and pepsin may occur when the protective functions of PGs are compromised as a consequence of PG deficiency induced by COX-1 inhibiting NSAIDs [10]. Injury to the stomach or duodenum can range from subtle alterations in gastric mucosal barrier function, microscopic damage to surface cells, or even to gross injury. The most subtle change is disruption of mucosal barrier function, manifesting as increased mucosal permeability to hydrogen ions (which then diffuse more rapidly from the lumen into the mucosa) and sodium ions (which then diffuse more rapidly from the mucosa into the lumen). Disruption of the gastric mucosal barrier and the resultant damage to surface cells by gastric acid may result in macroscopic injury over time if repair mechanisms are ineffective.

Repair mechanisms include rapid migration of deeper epithelial cells lining gastric pits to cover the damaged surface (restitution) and less rapid regeneration of new epithelial cells from progenitor cells (proliferation). Epithelial restitution and proliferation both require adequate amounts of well-oxygenated blood at a pH close to 7.4. PGs and nitric oxide (NO) have important roles in these repair mechanisms, while COX inhibitors can disrupt these PG-dependent reparative processes. Gastric restitution has been associated with induction of COX-2 [11]. Aspirin-induced gastric injury is also associated with inhibition of vascular endothelial growth factor (VEGF), which may reduce angiogenesis, inhibit autophagy (an adaptive response to cell stress that can promote cell survival), and enhance gastric cell apoptosis [12,13].

Macroscopic injury by NSAIDs ranges from edema, erythema, subepithelial hemorrhage, erosions (mucosal breaks, without visible depth to the lesion), and ulcers (mucosal breaks, with visible depth to the lesion). Only erosive/ulcerative lesions are considered clinically important, although lesser lesions may be precursors of erosive lesions if reparative mechanisms fail. Development of the full spectrum of lesions in the PG-depleted stomach or duodenum requires acid and pepsin; potent acid inhibition (eg, with proton pump inhibitors [PPIs]) markedly protects against their development. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Gastric damage — The gastrointestinal mucosa uses COX-1 to generate mucosal-protective PGs. Aspirin doses as low as 10 mg/day inhibit gastric PG generation considerably and can damage the stomach [14]. Epidemiologic and placebo-controlled studies indicate that the risk of serious, clinically-relevant gastrointestinal damage increases as the aspirin dose is raised [15-17].

After low-dose aspirin therapy is stopped, the human stomach requires five to eight days to recover its COX-1 activity and its ability to synthesize protective PGs, suggesting a very slow turnover of gastric COX-1 [18]. Thus, gastric mucosa somewhat resembles the megakaryocyte/platelet, which requires 10 to 14 days to recover from aspirin.

Although aspirin inhibits COX-1 and also COX-2 (table 1), certain COX-2-mediated reactions can still occur after aspirin has been given, such as the conversion of arachidonic acid to the fatty acid 15-hydroxyeicosatetraenoic acid (15-HETE); 15-HETE is then converted to 15-epi lipoxin A4 by another enzyme, 5-lipoxygenase (5-LOX). Studies in animals have demonstrated enhanced production of 15-epi lipoxin A4 following aspirin exposure [19]. Furthermore, this lipoxin minimizes gastric damage by aspirin (ie, it is cytoprotective). This protective effect of 15-epi lipoxin A4 can be abolished (with more gastric damage resulting) by administering a selective COX-2 inhibitor [19]. Therefore, the combination of low-dose aspirin and a COX-2 selective inhibitor may lead to more gastrointestinal damage than low-dose aspirin alone.

In contrast to aspirin, which acetylates COX irreversibly, most NSAIDs inhibit COX-1 and COX–2 reversibly [3]. Nevertheless, even transient but repeated COX inhibition in the gastric mucosa by an NSAID is sufficient to predispose the stomach to injury. That this injury is due to loss of PG-mediated cytoprotection is supported by the observation that NSAID-related gastric damage is prevented by exogenous PGE analogs (drugs) such as misoprostol [20].

Misoprostol does not primarily protect the stomach by inhibiting the stomach's ability to produce hydrochloric acid because drugs that inhibit gastric acid secretion to the same or slightly greater extent as misoprostol, such as histamine-2 receptor antagonists (H2RAs), have little or no protective effect against NSAID-induced gastric damage. Fortunately, the relative failure of H2RAs to protect the stomach from damage by NSAIDs may be overcome by using higher H2RA doses or by using more potent acid-inhibitory compounds such as PPIs. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Duodenal damage — Aspirin doses as low as 325 mg every other day increase the risk of duodenal ulcers [21]. In contrast to the stomach, damage to the duodenal mucosa by aspirin and NSAIDs seems to depend highly upon gastric acid. Thus, not only misoprostol but also by histamine-2 blockers with their modest acid inhibition can largely prevent endoscopic evidence of duodenal mucosal injury by NSAIDs. PPIs are also highly effective. These observations related to the pathogenesis of gastric and duodenal injury lay the groundwork for using either a PPI or misoprostol in the prevention of NSAID-induced gastroduodenal ulcers. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Non-COX-1 mediated injury — NSAIDs probably interfere with growth factors and other mediators responsible for restitution and adaptive protection. Adaptive protection refers to the observation that mild gastric irritants induce enhanced cytoprotection. In addition to COX-1, COX-2, and NO, various growth factors such as transforming growth factor (TGF)-beta and TGF-alpha appear to participate in adaptive protection [22]. Endogenous trefoil factor proteins are also associated with mucosal protection in indomethacin-induced injury in rats [23].

RISK FACTORS FOR NSAID-INDUCED GASTRODUODENAL TOXICITY

NSAID dose and duration — Ulcer risk increases with dose of therapy. However, gastroduodenal toxicity may develop even in patients taking low doses of aspirin [24], which can be associated with a significant decrease in gastric mucosal prostaglandin [PG] concentrations [14]. Gastroduodenal complications are most common within the first three months after the initiation of therapy, but longer duration of therapy is associated with an increased risk of developing ulcer complications [21,24-39]. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Potential risks'.)

Helicobacter pylori infection — The role of H. pylori infection in nonsteroidal antiinflammatory drug (NSAID)-induced gastritis or ulcer formation is complex [40-48]. NSAID use and H. pylori infection represent independent yet synergistic risk factors for uncomplicated and bleeding peptic ulcer disease [PUD] [49,50]. In a systematic review with a total of 21 studies, the risk of uncomplicated PUD among NSAID users was significantly higher among H. pylori positive compared with H. pylori negative individuals (odds ratio [OR] 1.81) [50]. Ulcers were more common in H. pylori positive compared with H. pylori negative patients irrespective of NSAID use (OR 4.03) and in NSAID users compared with nonusers irrespective of H. pylori status (OR 3.10). Eradication of H. pylori prior to NSAID treatment can reduce the risk of PUD [44-46,51]. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Role of helicobacter pylori'.)

Other risk factors — Other important risk factors for gastroduodenal toxicity of NSAIDs include increasing age, a past history of gastroduodenal toxicity from NSAIDs, a past history of PUD, and concurrent use of glucocorticoids, anticoagulants, and clopidogrel and probably bisphosphonates and selective serotonin reuptake inhibitors [SSRIs] [21,25,37,39,52].

SSRIs are associated with an increased risk of upper gastrointestinal bleeding, particularly in patients taking NSAIDs [53-58]. A possible mechanism is platelet serotonin depletion, which may adversely influence the hemostatic response to vascular injury [37]. In a meta-analysis that included 15 case-control studies and four cohort studies, the use of SSRIs was associated with an increased risk of upper gastrointestinal bleeding compared with not using an SSRI (OR for case-control studies 1.7, 95% CI 1.4-1.9; OR for cohort studies 1.7, 95% CI 1.1-2.5) [59]. When the analysis was confined to patients receiving NSAIDs, the risk was even higher (OR 4.3, 95% CI 2.8-6.4). However, the risk of toxicity may not be uniform among the NSAIDs. The gastrointestinal toxicity of different NSAIDs is discussed in detail separately. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Nonselective NSAIDs'.)

Genetic predisposition to gastroduodenal injury due to polymorphism of cytochrome P450 2C9 may delay the metabolism of several NSAIDs, with a prolonged duration of drug exposure enhancing their ulcerogenic effect [60].

ASSESSMENT OF GASTRODUODENAL TOXICITY RISK — The risk of gastroduodenal toxicity in patients taking nonsteroidal antiinflammatory drugs (NSAIDs) can be categorized as being as high, moderate, or low based on the presence of a complicated ulcer and the following risk factors [61]:

●History of an uncomplicated ulcer

●Age >65 years

●High-dose NSAID therapy

●Concurrent use of aspirin (including low dose), glucocorticoids, or anticoagulants

Based on these risk factors, magnitude of risk can be assessed as follows:

●High risk – Presence of ≥3 risk factors or history of a complicated ulcer

●Moderate risk – Presence of one or two risk factors

●Low risk – None of the four risk factors listed

Strategies to avoid mucosal damage in patients on NSAIDs based on their risk of toxicity are discussed in detail separately. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Nonsteroidal antiinflammatory drugs (NSAIDs) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Role of cyclooxygenase – Cyclooxygenase (COX), the rate-limiting enzyme in prostaglandin (PG) synthesis, converts the unsaturated fatty acid arachidonic acid (C20:4; derived from phospholipids in cell membranes) into PGG2 and then to PGH2 (figure 1). The gastric and duodenal mucosa proceed to convert PGH2 to various prostanoids (PGs and thromboxane A2). PGs such as PGE2 protect the mucosal lining from injury by luminal acid-pepsin. (See 'Role of cyclooxygenase' above.)

●Mucosal protection by prostaglandins – Certain PGs such as PGE2 reduce gastric acid secretion. Other cytoprotective mechanisms of PGs include (see 'Mechanism of mucosal protection' above):

•Stimulation of mucin, bicarbonate, and phospholipid secretion by epithelial cells

•Enhancement of mucosal blood flow and the delivery of oxygen to epithelial cells via local vasodilation

•Increased epithelial cell migration towards the luminal surface (epithelial restitution)

•Enhanced epithelial cell proliferation

●Mechanism of NSAID injury – Mucosal damage by aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) is primarily a consequence of inhibition of COX-1 in the upper gastrointestinal tract, although COX-2 inhibition may also play a role. COX inhibition reduces mucosal generation of protective PGs such as PGE2. NSAIDs may also interfere with growth factors and other mediators responsible for restitution and adaptive protection. (See 'Mechanism of action of NSAIDs' above.)

●Risk factors for NSAID-induced gastroduodenal toxicity – Ulcer risk increases with dose and duration of NSAID therapy. NSAID use and H. pylori infection represent independent yet synergistic risk factors for uncomplicated and bleeding peptic ulcer disease. Other important risk factors for gastroduodenal toxicity of NSAIDs include increasing age, a past history of gastroduodenal toxicity from NSAIDs, a past history of peptic ulcer disease, and concurrent use of glucocorticoids, anticoagulants, and clopidogrel and possibly bisphosphonates and selective serotonin reuptake inhibitors [SSRIs]. Genetic predisposition to gastroduodenal injury due to polymorphism of cytochrome P450 2C9 may delay the metabolism of several NSAIDs, with a prolonged duration of drug exposure enhancing their ulcerogenic effect. (See 'Other risk factors' above.)

●Assessment of gastroduodenal toxicity risk – The risk of gastroduodenal toxicity in patients taking NSAIDs can be categorized as high, moderate, or low based on the presence of the following risk factors:

•History of an uncomplicated ulcer

•Age >65 years

•High-dose NSAID therapy

•Concurrent use of aspirin (including low dose), glucocorticoids, or anticoagulants

Based on these risk factors, magnitude of risk is categorized as follows:

•High risk – Presence of ≥3 risk factors or history of a complicated ulcer

•Moderate risk – Presence of one or two risk factors

•Low risk – None of the four risk factors listed (see 'Assessment of gastroduodenal toxicity risk' above)

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NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity

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