20: Gastrointestinal Principles

Humans are in constant contact with a variety of xenobiotics. In addition to its critical role in absorbing nutrients, the gastrointestinal (GI) tract forms the initial functional barrier between ingested material and the body. An understanding of the GI tract’s structure, physiology, and innervation is critical to the toxicologic concepts of absorption, motility, and toxic insult. This chapter discusses the normal role of the GI tract and its relationship to toxicology. Anatomic, pathologic, and microbiologic principles are discussed, including the role of the GI tract in the metabolism of xenobiotics. Examples of GI pathologies and their clinical manifestations are discussed, with examples when appropriate.

The luminal GI tract can be divided into five distinct structures: oral cavity and hypopharynx, esophagus, stomach, small intestine, and colon (Fig. 20–1). These environments differ in luminal pH, specific epithelial cell receptors, and endogenous flora. The transitional areas between these distinct organs have specialized epithelia and muscular sphincters with specific functions and vulnerabilities. Knowledge of the anatomy of these transition zones is particularly important for the localization and management of foreign bodies. The functions of the pancreas and liver are closely integrated with those of the luminal organs. The pancreas is discussed here; the liver and its metabolic functions are discussed in Chaps. 13 and 23.

The visceral structures of the GI tract are composed of several layers, including the epithelium, lamina propria, submucosa, muscle layers, and serosa (the last of which is only present in intraperitoneal organs). As the transition is made throughout the GI tract, differences in luminal pH, epithelial cell receptors, muscularity, and endogenous flora are encountered, affecting the absorption and metabolism of individual xenobiotics.

The epithelium, the innermost layer of the GI tract, is the most specialized cell type in the intestine and is composed of epithelial, endocrine, and receptor cells. Epithelial cells have polarity, with the basal surface facing the lamina propria and the apical surface facing the lumen. They are further specialized for specific functions of secretion or absorption. Additionally, the epithelial cells form part of the mucosal immune defense, where they are able to detect the presence of microbial pathogens and downregulate the immune system in the presence of nonpathogenic or probiotic microbes. The major barrier to penetration of xenobiotics and microbes is the GI epithelium, a single-cell-thick membrane. The cell membrane is a semipermeable lipid bilayer that contains aqueous pores through which certain materials can pass, depending on their on size or molecular structure. The membrane is not continuous because it consists of individual epithelial cells; however, these cells are joined to each other by structures known as tight junctions. The tight junctions have a gap of about 8 Å, which allows passage only of water, ions, and low-molecular-weight substances.

The muscle layer found beneath the lamina propria is made up of the muscularis mucosa, the circular muscles, and the longitudinal muscles. Contraction of the muscularis mucosa causes a change in the surface area of the gut lumen that alters secretion or absorption of nutrients. Whereas depolarization of circular muscle leads to contraction of a ring of smooth muscle and a decrease in the diameter of that segment of the GI tract, depolarization of longitudinal muscle leads to contraction in the longitudinal direction and a decrease in the length of that segment. The function of the muscle layers is integrated with the enteric nervous system to provide for a coordinated movement of luminal contents through the GI tract so as to maximize absorption and minimize bacterial growth. This integration facilitates the flow of chyme (undigested food) via a coordinated sequence of muscular contractions and relaxations, leading to segmentation of luminal contents, peristaltic movements, and unidirectional flow through the intestine.

The GI tract is innervated by the autonomic nervous system via both extrinsic and intrinsic pathways (Fig. 20–2). The extrinsic innervation permits communication among the brain, spinal cord, and chemoreceptors and mechanoreceptors located in the gut. Parasympathetic stimulation in the extrinsic pathway tends to be excitatory (“rest and digest”) and is carried via the vagus, splanchnic, and pelvic nerves to the myenteric and submucosal plexuses. In contrast, increased sympathetic tone (“fight or flight”) inhibits digestive and peristaltic activity via fibers that originate in the thoracolumbar cord and terminate in the myenteric and submucosal plexuses. The intrinsic innervation of the GI tract, or enteric nervous system, constitutes a reflex arc that modulates both peristalsis (via the myenteric plexus) and secretion (via the submucosal plexus) in response to parasympathetic and sympathetic tone.

An elaborate mucosal immune system has evolved to protect the GI tract from pathogens.⁴⁵ Mucosal immunity can be divided into an afferent limb, which recognizes a pathogen and induces the proliferation and differentiation of immunocompetent cells, and an efferent limb, which coordinates and affects the immune response. The afferent system includes the lymphoid ­follicles and specialized M-cells found therein that promote transit of antigens to antigen-presenting cells.³⁰ After being sensitized, immune cells undergo a complicated process of clonal expansion and differentiation, which occurs in mucosal and mesenteric lymphoid follicles, as well as in extraintestinal sites. Immunocompetent cells then return to the intestine and other mucous membranes and are scattered diffusely within the epithelial and lamina propria compartments.

The normal endogenous flora in the GI tract includes more than 400 species of bacteria along with a small number of fungi and viruses; the intestinal mucosa is normally colonized by large numbers of nonpathogenic anaerobic strains of Bacteroides spp, Eubacterium spp, Clostridium spp as well as aerobic strains of Escherichia coli, Proteus spp, Enterobacter spp, Serratia spp, Lactobacillus spp, and Klebsiella spp.¹⁸ The concentration of luminal bacteria varies by site, from lowest in the proximal small intestine to highest in the large intestine. En masse, these bacteria are more metabolically active than the liver. Endogenous bacteria occupy unique niches related to host physiology, environmental pressures, and microbial interactions, which result in long-term stability. The flora may be altered by various insults (particularly antibiotics) but usually returns to baseline after the insult is removed. Indeed, the cumulative total of microbial species in the enteric system (or enterotype) is remarkably consistent across countries and continents.²

The endogenous flora has multiple metabolic functions. A primary function in the colon is the salvage of malabsorbed carbohydrates by fermentation and production of short-chain fatty acids, a preferred substrate for colonic epithelial cells. This increased metabolic efficiency is best demonstrated when mice grown in germ-free conditions require a higher caloric intake to maintain weight.³⁷ This has led to some conjecture about the link between human flora and obesity, although this has yet to be born out.

Bacterial metabolism can significantly affect the disposition of enteral compounds. For example, the bacterial metabolism of digoxin contributes to its steady-state concentrations, and antibiotic treatment may reduce or eradicate the intestinal flora, predisposing to digoxin toxicity.⁹ Bacterial contribution to vitamin K metabolism is also demonstrated, necessitating dose adjustments of warfarin during and after antibiotic therapy. The metabolic activity of intraluminal bacteria is exploited in some treatment strategies. For example, sulfasalazine, used in the treatment of ulcerative colitis, is created through the linkage of 5-aminosalicylic acid to sulfapyridine. The azo bonds of the nonabsorbable sulfasalazine are broken by bacterial azoreductases, permitting the absorption of active metabolites in the colon at the site of inflammation.³³

The normal flora of the gut consists of probiotics—live, nonpathogenic bacteria and fungi that can also be used as prophylactic or therapeutic xenobiotics. These bacteria compete for and displace pathogenic bacteria, directly modulate intestinal immune function, and exert a trophic effect on the GI tract. They are used to decrease traveler’s diarrhea, suppress antibiotic-induced diarrhea, and reduce inflammation in ileal pouches after colectomy in patients with ulcerative colitis.^17,19,20

There are three groups of regulatory peptide hormones that act on target cells within the GI tract. These are released from endocrine cells in the GI mucosa into the portal circulation and enter the systemic circulation to affect target cells. Gastrin, cholecystokinin (CCK), secretin, and glucose-dependent insulinotropic polypeptide (GIP; formerly gastric inhibitory peptide) are considered the primary GI hormones. Somatostatin and histamine make up the paracrines, hormones that are released from endocrine cells and diffuse over short distances to act on target cells located in the GI tract. Vasoactive intestinal peptide (VIP), gastrin-releasing peptide (GRP), and enkephalins compose the last group known as neurocrines; substances that are synthesized in neurons of the GI tract, move by axonal transport down the axon, and are then released by action potentials in the nerves. The effects of these regulators are summarized in Table 20–1.²⁶

Xenobiotic effects on GI regulation can lead to intended or unintended consequences. Somatostatins reduce splanchnic blood flow and portal blood pressure, leading to their use as therapeutics for bleeding esophageal varices. Erythromycin agonizes motilin receptors, leading to increased GI propulsion, cramping, and diarrhea.

Oropharynx and Hypopharynx

The main functions of the mouth and oropharynx are chewing, lubrication of food with saliva, and swallowing. Saliva initiates digestion of starch by α-amylase (ptyalin), triglyceride digestion by lingual lipase, lubrication of ingested food by mucus, and protection of the mouth and esophagus by dilution and buffering of ingested foods.

Saliva production is unique in that it is increased by both parasympathetic and sympathetic activity. Parasympathetic stimulation, via cranial nerves VII and IX, acts on muscarinic cholinergic receptors on acinar and ductal cells, increasing saliva production via vasodilation and increasing transport processes. Parasympathetic pathways are stimulated by food in the mouth, smells, conditioned reflexes, and nausea and are inhibited by sleep, dehydration, and fear. Sympathetic stimulation originates from preganglionic nerves in the thoracic segments T1 to T3. When β-adrenergic receptors are triggered by norepinephrine, production of saliva increases but at a rate less than that of parasympathetic stimulation.¹¹ It is theorized that the hypersalivation, or sialorrhea, associated with clozapine use may be related to agonism of parasympathetic muscarinic receptors or antagonism of adrenergic α receptors (resulting in unopposed β-adrenergic receptor–mediated vasodilation).⁵ Conversely, dysfunction of saliva production, via the anticholinergic side effects of other antipsychotics, can lead to dry mouth, or xerostomia.

Esophagus

The esophagus is a distensible muscular tube that extends from the epiglottis to the gastroesophageal junction. The lumen of the esophagus narrows at several points along its course, first at the cricopharyngeus muscle, then midway down alongside the aortic arch, and then distally where it crosses the diaphragm. The upper esophageal sphincter (UES) and lower esophageal sphincter (LES) are physiologic high-pressure regions that remain closed except during swallowing. Although the LES is a functional segment without anatomic features, the UES is marked by the presence of striated muscle.

The wall of the esophagus reflects the general structural organization of the GI tract noted previously, consisting of mucosa, submucosa, muscularis propria, and adventitia. The mucosal layer has three components. The nonkeratinizing stratified squamous epithelial layer faces the lumen; provides protection for underlying tissue; and houses several specialized cell types such as melanocytes, endocrine cells, dendritic cells, and lymphocytes. The lamina propria is the nonepithelialized portion of the mucosa, and the muscularis mucosa, a layer of longitudinally oriented smooth muscle bundles, is the third component.

The submucosa consists of loose connective tissue, and submucosal glands secrete a mucin-containing fluid via squamous epithelium-lined ducts, which facilitates lubrication of the esophageal lumen. The muscularis propria consists of an inner circular and outer longitudinal coat of smooth muscle; this layer also contains striated muscle fibers in the proximal esophagus that are responsible for voluntary swallowing.

The esophagus has no serosal lining. Only small segments of the intra-abdominal esophagus are covered by adventitia, a sheathlike structure that also surrounds the adjacent great vessels, tracheobronchial tree, and other structures of the mediastinum.

The esophagus provides a conduit for food and fluids from the pharynx to the stomach, and the sphincters generally prevent reflux of gastric contents into the esophagus. Normal transit of food involves coordinated motor activity, including a wave of peristaltic contraction, relaxation of the LES (facilitated by nitric oxide and VIP), and subsequent closure of the LES (facilitated by several hormones and neurotransmitters such as gastrin, acetylcholine, serotonin, and motilin). Xenobiotics can alter muscle tone in various segments of the esophagus, altering function. Caffeine is associated with relaxation of the LES and decreased peristalsis, increasing incidence of acid reflux.²⁹ Additionally, sildenafil, via its effect on nitric oxide, relaxes esophageal smooth muscle, decreasing the pathologically elevated esophageal tone common to patients with achalasia.⁷ Because of the rapid transit time of swallowed substances through this portion of the GI tract, digestion does not take place, and passive diffusion of substances from the food into the bloodstream is prevented.^11,46

Stomach

The stomach is a saccular organ covered entirely by peritoneum that has a capacity greater than 3 L. The stomach is divided into five anatomic regions: the cardia, fundus, corpus or body, antrum, and pyloric sphincter. The gastric wall consists of mucosa, submucosa, muscularis propria, and serosa. The interior surface of the stomach is marked by coarse rugae, or longitudinal folds. The mucosa is made up of a superficial epithelial cell compartment and a deep glandular compartment. The glandular compartment consists of gastric glands, which vary between regions of the stomach. The mucus glands of the cardia, fundus, and body secrete mucus and pepsinogen. Oxyntic, or acid-forming, glands found in the fundus and body contain parietal, chief, and endocrine cells. The parietal cells contain vesicles that house hydrochloric acid–secreting proton pumps and secrete intrinsic factor, a substance necessary for the ileal absorption of vitamin B₁₂. Chief cells secrete the proteolytic proenzyme pepsinogen, which is cleaved to its active form, pepsin, upon exposure to the low luminal gastric pH of 3 to 4. Pepsin is subsequently inactivated in the duodenum when the pH increases to 6.0. The endocrine, or enterochromaffinlike (ECL), cells found in the mucosa of the body of the stomach produce histamine, which increases acid production and decreases gastric pH by stimulating H₂ receptors on the parietal cells. Somatostatin and endothelin, both modulators of acid production, are also produced in ECL cells (Fig. 49–4).

Hydrochloric acid is secreted when cephalic, gastric, and intestinal signals converge on the gastric parietal cells to activate proton pumps and release hydrochloric acid in an adenosine triphosphate–dependent process. During the cephalic phase, or the preparatory phase of the brain for eating and digestion, acetylcholine is released from vagal afferents in response to sight, smell, taste, and chewing. Acetylcholine stimulates the parietal cells via muscarinic receptors, resulting in an increase in cytosolic calcium and activation of the proton pump. G cells, located in the antrum of the stomach, produce and release gastrin in response to luminal amino acids and peptides. Gastrin activates receptors within parietal cells, leading to a similar increase in cytosolic calcium. Additionally, gastrin and vagal afferents induce the release of histamine from ECL cells, which stimulates parietal cell H₂ receptors. Lastly, the intestinal phase is initiated when food containing digested protein enters the proximal small intestine and involves gastrin as well as a number of other polypeptides in the secretion of hydrochloric acid from the stomach⁴⁶ (Fig. 20–3).

The gastric mucosa is protected from gastric acidic secretions by ­several mechanisms, including a thin layer of surface mucus and channels that allow acid- and pepsin-containing fluids to exit glands without contact with the surface epithelium. Additionally, the surface epithelium secretes bicarbonate, raising the pH at the cell surface. Prostaglandins produced in the mucosal cells stimulate production of bicarbonate and mucus, and inhibit parietal cell production of acid; prostaglandin inhibition by nonsteroidal antiinflammatory drugs (NSAIDs) plays an important role in the pathogenesis of peptic ulcer disease.⁴⁶

In the stomach, ingested products are ground to particle sizes of less than 0.2 mm, which are then further processed and digested in preparation for absorption of nutrients in the small intestine. Many xenobiotics are weak acids that are no longer ionized in the acidic environment of the stomach, facilitating absorption through the lipid bilayer at the level of the stomach. Other factors that affect xenobiotic absorption include particle size, transit time, and type of drug delivery system. Different drug formulations, such as time release, enteric coating, slowly dissolving matrices, dissolution control via osmotic pumps, ion exchange resins, and pH-sensitive mechanisms, can affect bioavailability and the site of maximal release within the GI tract.

The time required for gastric emptying is determined by the complex interplay of innervation, muscle action, underlying illness, and xenobiotic exposure. Digestion and absorption are time-dependent processes, and optimal absorption requires adjustment of the luminal environment through secretion of ions and water, to accommodate meals that vary considerably in nutrient composition, water content, and density. Osmoreceptors and chemoreceptors in the GI tract fine tune the digestive and absorptive processes by regulating transit and secretion using a variety of neurocrine, paracrine, and endocrine mechanisms. Interference with this integrated response may lead to stasis and bacterial overgrowth or rapid transit with decreased absorption and development of diarrhea. A large number of mediators affect motility, including common neurotransmitters, such as acetylcholine and norepinephrine; hormones; cytokines; inflammatory compounds; and others. In general, whereas parasympathetic impulses promote motility, sympathetic stimulation inhibits motility. Other transmitters, such as serotonin, promote transit, but dopamine and enkephalins can slow motility. Some xenobiotics, such as opioids and diphenhydramine, delay gastric emptying, but other xenobiotics, such as metoclopramide, may enhance gastric emptying. Our understanding of the complex neuroendocrine gastric axis continues to evolve in attempts to explain new phenomenon, such as the cannabinoid hyperemesis syndrome, which may be caused by cannabinoid receptors in the brain or gut.⁴¹

Small and Large Intestines

In an average adult, the small intestine is approximately 6 m in length and begins retroperitoneally as the duodenum, becoming intraperitoneal at the jejunum and ileum. The boundary between the small intestine and large intestine is the ileocecal valve, and the large intestine typically measures 1.5 m in an adult. The large intestine (or colon) is further divided into cecal, ascending, transverse, descending, and sigmoid segments. The sigmoid colon is continuous with the rectum and terminates at the anus. Whereas anterograde and retrograde peristalsis occurs in the small intestine, anterograde peristalsis predominates in the large intestine. This movement allows for mixing of food, maximizes contact with the mucosa, and is mediated by both the extrinsic and intrinsic nervous systems. The remarkable absorptive capacity of the small intestine is made possible by innumerable villi of the intestinal wall, which extend into the lumen and increase absorptive area. The epithelial border of the small intestine also contains mucin-secreting goblet cells, endocrine cells, and specialized absorptive cells; functionally, these cells create an ideal environment for nutrient absorption. The mucosa of the large intestine is devoid of villi. The large intestine functions primarily to absorb electrolytes and water, secrete potassium, salvage any remaining nutrients, and store and release waste. Intestinal epithelial cells also ­metabolize xenobiotics, a function typically attributed to the liver (see below).

Regeneration of injured or senescent intestinal epithelial cells begins in the crypts, with differentiation occurring as these cells migrate toward the intestinal lumen. This process occurs rapidly, with turnover of the small intestinal epithelium occurring every 4 to 6 days and large intestinal ­epithelium turnover occurring every 3 to 8 days. This rapid regeneration leaves the intestinal epithelium vulnerable to processes that interfere with cell replication (eg, radiation, chemotherapy). Sloughing of GI epithelium, typically manifested by hemorrhagic enteritis, is a valuable marker for xenobiotic insults that lead to mitotic arrest.

Anatomic and functional changes after bariatric surgery and bowel resection have important effects on drug bioavailability and toxicity. The common Roux-en-Y gastric bypass surgery, which diverts gastric contents into distal small bowel, may increase bioavailability by bypassing intestinal CYP3A or decrease bioavailability by bypassing the proximal jejunum as an area of drug absorption.¹⁶ Alterations in stomach and bowel pH after surgery may affect absorption of ionized drugs. Disruption of the enterohepatic recirculation may enhance elimination of drugs such as digoxin.⁴⁸ Many xenobiotics, such as ethanol, oral morphine, and caffeine, achieve maximum serum concentrations faster because of rapid transit. However, studies evaluating serum concentrations of known CYP substrates (caffeine [CYP1A2], tolbutamide [CYP2C9], omeprazole [CYP219], and midazolam [CYP3A]) in patients with gastric bypass surgery have not found any clinically significant changes in drug metabolism.⁴³ Because specific data are limited, current recommendations for dosing in postoperative patients are based on extrapolating from a xenobiotic site of absorption and kinetics and a particular patient’s functional GI anatomy.

Pancreas

The pancreas is a retroperitoneal organ that serves both exocrine and endocrine functions. The exocrine portion of the gland produces digestive enzymes and occupies more than 80% to 85% of the mass of the pancreas. The exocrine pancreas is composed of acinar cells, specialized epithelial cells housing zymogen granules that release digestive enzymes and proenzymes into the duodenum. Columnar epithelial cells produce mucin and ductal cuboidal epithelial cells secrete a bicarbonate-rich fluid that neutralizes gastric acids. The pancreas secretes 2 to 2.5 L/day of this mixed solution. Typically, the digestive enzymes are released as proenzymes, such as trypsinogen, chymotrypsinogen, and procarboxypeptidase, which are activated upon contact with the higher pH of the duodenum; this process usually helps to prevent autodigestion of the pancreas itself. Enzymes on the brush border of the duodenum, including enteropeptidase, cleave proenzymes to their active forms. Only pancreatic amylase and lipase are secreted in their active forms.

Secretion of pancreatic enzymes is regulated by multiple factors, the most important of which are cholecystokinin and secretin, both produced in the duodenum. Cholecystokinin is released from the duodenum in response to fatty acids and the products of protein catabolism such as peptides and amino acids. Cholecystokinin stimulates acinar cells to release digestive enzymes and proenzymes. Secretin is released by the duodenum in the presence of lowered pH caused by gastric acids and luminal fatty acids. Secretin triggers ductal cells to secrete bicarbonate and water. Acetylcholine also plays a role in the regulation of pancreatic exocrine function by stimulating digestive enzyme secretion from the acinus and potentiating the effects of secretin. Vagal reflexes increase acetylcholinergic tone in the setting of decreased pH, protein breakdown products, and fatty acids in the duodenal lumen.

The endocrine portion of the pancreas is composed of approximately one million clusters of cells known as the islets of Langerhans that secrete insulin, glucagon, and somatostatin. Other products of the endocrine pancreas include serotonin and VIP. Injury to the endocrine pancreas can result in impaired glucose homeostasis. In one study, more than one third of patients with an episode of alcoholic pancreatitis subsequently developed impaired glucose tolerance.³⁶

Although the liver is usually identified as the site of xenobiotic metabolism, similar functions occur in the luminal GI tract (including hydroxylation, sulfation, acetylation, and glucuronidation). Biotransformation is a property both of luminal bacteria and enterocytes. Metabolism by the intestine affects the amount of orally administered xenobiotic that actually enters the body and therefore contributes to the first-pass effect, or presystemic disposition.

One of the most well-described families of export proteins, P-glycoprotein (PGP), is found in the mucosa of the small and large intestines, hepatocytes, adrenal cortex, renal tubules, and capillary cells lining the blood–brain barrier.⁴⁹ The PGPs are susceptible to induction and inhibition in a manner similar to hepatic cytochrome oxidase enzymes. Many of the substrates of CYP3A have inhibitory effects on PGPs. Inhibitors of PGPs may raise serum concentrations of a xenobiotic, although inducers of PGPs may prevent therapeutic drug concentrations from ever reaching the target cell. The PGP system is important in drug interactions and drug resistance (Chap. 9).

Pathologic Conditions of the Gastrointestinal Tract

Oral Pathology.

Discoloration of the teeth is reported with a number of medications, most notably tetracyclines (Table 20–2). Gingival hyperplasia, overgrowth of the gums around the teeth, is an uncommon adverse effect from chronic use of several xenobiotics. Some medications implicated in causing gingival hyperplasia include calcium channel blockers, cyclosporine, lithium, phenobarbital, phenytoin, topiramate, and valproic acid.¹ Xerostomia, or pathologic dryness of the mouth, is an uncomfortable effect of many xenobiotics that can lead to increased dental decay. The list of xenobiotics that can cause xerostomia is extensive, but the most commonly implicated classes of xenobiotics causing xerostomia are listed in Table 20–3. Chronic methamphetamine use is linked to characteristic oral pathology known as “meth mouth.” This condition, which is common in both inhalational and intravenous users, is characterized by extensive and severe tooth decay and is linked to poor hygiene, bruxism, and xerostomia associated with methamphetamine use.¹²

Esophagitis and Dysphagia.

Xenobiotic-induced esophageal injury includes esophagitis (including pill esophagitis), ulceration, perforation, and stricture. The most common presenting complaint is a foreign body sensation in the throat.²³ Xenobiotics commonly implicated in esophagitis and esophageal ulcerations are listed in Table 20–4. Patients with preexisting esophageal motility disorders are at higher risk of esophageal pathology. Additionally, xenobiotics with a gelatin matrix, rapid dissolvability, and large size predispose to esophageal injury. Although most symptoms resolve with withdrawal of the offending xenobiotics, patients with persistent or severe odynophagia should be evaluated with endoscopy to identify pathology and prevent perforation caused by retained pills.¹³

Webs, Strictures, and Esophageal Malignancy.

Caustic injury is one of the most common causes of esophageal strictures and malignancies. Some authors have also postulated the role of pill esophagitis in the evolution of esophageal strictures.⁶ As many as 4% of patients with esophageal cancer report a history of caustic injury, and patients with a history of caustic ingestion may have more than a 1000-fold higher risk of developing an esophageal malignancy than the general population.²⁴ Other xenobiotics known to cause esophageal strictures include aluminum phosphide and ionizing radiation.⁴²

Gastritis and Peptic Ulcer Disease.

Gastritis, or inflammation of the gastric mucosa, and peptic ulcer disease (PUD) are commonly related to xenobiotic exposure (Table 20–5). Symptoms of gastritis and PUD include epigastric pain, nausea, and vomiting but may also include hematemesis and melena.³² The primary distinction between gastritis and PUD is appearance at endoscopy: whereas gastritis is characterized by diffuse inflammation of the gastric mucosa, an ulcer is a discrete lesion of the mucosa. NSAIDs remain an important part of the pathogenesis of gastritis and PUD by interfering with prostaglandin synthesis and subsequently impairing the integrity of the gastric mucosal barrier to acid. Cyclooxygenase-2 (COX-2) selective inhibitors promised to decrease the incidence of gastric pathology caused by chronic NSAID use; however, unexpected cardiovascular side effects have limited their utility. New xenobiotics are focusing on inhibition of other inflammatory mediators that may have been previously overlooked, and co-administration of protective xenobiotics. 5-Lipoxygenase (5-LOX) inhibitors may reduce production of proinflammatory leukotrienes, and when co-administered with COX inhibitors, decrease gastric toxicity. Other reformulated NSAIDs are designed to release molecules of NO and H₂S, which help maintain gastric mucosal integrity. These next generation of drugs may preserve systemic antiinflammatory effects while enhancing the gastric safety profile.¹⁰

Chronic treatment of peptic ulcer disease with antacids, H₂ blockers, or proton pump inhibitors can lead to hypochlorhydria or achlorhydria, the reduction or absence of gastric acid, respectively. By increasing the pH of the stomach, these conditions increase risk of bacterial overgrowth, atrophic gastritis, osteoporosis, hip fracture (via impaired calcium absorption), Salmonella and Vibrio cholerae infection, and gastric carcinoma.⁴⁷

Enteritis and Diarrhea.

The symptoms of GI distress are nonspecifically associated with xenobiotic exposure. However, certain xenobiotics that increase peristalsis or impair fluid absorption can result in significant diarrhea. Opioid withdrawal, colchicine overdose, and serotonin toxicity are important toxidromes that may feature diarrhea as a prominent symptom. The rapid turnover of the GI mucosa makes it uniquely susceptible to xenobiotics that cause cell death and mitotic arrest. Hemorrhagic enteritis, manifested by hematochezia, can be a characteristic finding of certain exposures (Table 20–6).

Bezoars.

The term bezoar refers to a concretion formed anywhere in the alimentary system and may be a complication of overdose. The risk of bezoar formation is increased in cases of massive pill ingestion and varies according to tablet size, adhesiveness, and liquid viscosity.⁴⁰ Comorbid illnesses or toxicities that delay gastric emptying and bowel transit time may increase the risk of bezoar formation. Effects from bezoars can range from mechanical obstruction to severe local irritation (and stricture formation) to continuous delayed absorption of xenobiotics and resulting toxicity. Suspicion for bezoar formation is raised in patients after ingestion who develop signs of obstruction (vomiting, abdominal pain, constipation) and in patients with delayed or prolonged toxicity (eg, rising serum iron concentrations 8 hours after ingestion) after overdose.⁴⁰ Depending on the nature of the bezoar, they may be diagnosed using plain radiography; however, in some instances, computed tomography (CT) with oral contrast can increase sensitivity. Recent studies have had limited success with ultrasonography as a diagnostic adjuvant, although this requires further study. Ultimately, a high suspicion of bezoar with negative radiographic evaluation findings may prompt direct visualization with endoscopy and colonoscopy or exploratory surgery. Bezoars frequently require surgical intervention, and several cases report dramatic recovery after removal.

Pancreatitis.

Pancreatitis is an acute inflammatory process that results in autolysis of the pancreas from digestive enzymes. Cases range from mild to severe, with an overall mortality rate of 5%.¹⁶ The most common causes of pancreatitis are alcohol abuse and gallbladder disease; however, nonalcoholic xenobiotic-induced pancreatitis accounts for 0.1% to 2% of cases of acute pancreatitis.³ Populations at higher risk of drug-induced pancreatitis include children, women, elderly adults, and patients with HIV and inflammatory bowel disease.³ Acute pancreatitis is defined as having two of the following three criteria: (1) abdominal pain characteristic of acute pancreatitis, (2) serum amylase or lipase greater than three times the upper limit of normal (although amylase is less specific and may be unnecessary), and (3) characteristic findings of acute pancreatitis on CT scan.⁴ The diagnosis of xenobiotic-induced pancreatitis can be impossible to confirm because no diagnostic test or pattern of injury distinguishes xenobiotic-induced pancreatitis from other etiologies. However, the symptoms and laboratory abnormalities associated with xenobiotic-induced pancreatitis tend to resolve shortly after withdrawal of the offending xenobiotic; again, this can be challenging to differentiate from the natural course of mild to moderate disease. It is unclear whether rechallenge with an offending xenobiotic will cause pancreatitis again; however, any xenobiotic suspected of causing pancreatitis should be withheld unless the benefits outweigh this risk. The management of xenobiotic-induced pancreatitis does not differ from other causes and hinges on volume resuscitation, bowel rest, and careful monitoring.

Numerous xenobiotics are associated with pancreatitis, each with varying levels of quality and quantity of evidence; representative xenobiotics are listed in Table 20–7.^3,21 The pathogenic mechanism varies among xenobiotics. The nucleoside reverse transcriptase inhibitor didanosine and dioxin may promote pancreatitis as a result of mitochondrial injury.^31,35,38 Cholinergic xenobiotics, such as parathion and certain scorpion venoms, may result in pancreatitis caused by overstimulation.^25,34 Vasospasm and ischemia are also purported as a mechanism, as in cases of pancreatitis secondary to ergot alkaloids.¹⁴

The endocrine functions of the pancreas are also susceptible to injury from pancreatitis or toxic insult. Typically, this results from injury to pancreatic β cells leading to impaired glucose homeostasis, similar to diabetes. Streptozotocin is notable for its toxicity to pancreatic β cells and ability to induce diabetes in animal models. In one study of patients after episodes of alcoholic pancreatitis, more than one third developed impaired glucose tolerance.³⁶ There are rare xenobiotics that can cause damage to α cells in animal models; however, they do not consistently cause hypoglycemia (Table 20–8).

Constipation.

Decreased stooling (fewer than three bowel movements a week) associated with abdominal pain is a major source of morbidity for patients taking opioids and other drugs that slow gastric emptying and decrease gut motility. It is estimated that opioid-induced bowel dysfunction affects up to 40% of patients on long-term opioids.⁸ In its most extreme form, severe constipation is associated with bowel obstruction and perforation. Novel therapeutics for this include locally acting opioid receptor antagonists (eg, prolonged-release naloxone and methylnatrexone) that may alleviate GI effects without decreasing analgesic effects.¹⁵

Foreign Bodies

The esophagus is the most common site of impaction from symptomatic foreign bodies. They tend to be found just proximal to a pathologic esophageal narrowing or in one of three anatomic places: at the cervical esophagus near the cricopharyngeus muscle, at the level of the aortic notch, or just above the gastroesophageal junction. The likelihood that a foreign object will lodge in the esophagus is related to its size and shape. The major complications of foreign bodies in the esophagus include pain, bleeding, obstruction, or perforation, which may lead to subsequent mediastinitis or fistula. The general rule is that conservative means can be used for up to 12 hours after ingestion of the esophageal foreign body. If serial radiographs demonstrate no movement after 12 hours, endoscopic retrieval or surgery should be considered because the risk of perforation increases after that time; some authors extend this observation period to 24 hours.²² Ingestion of button batteries proves an important exception to this rule. Esophageal button batteries can cause significant mucosal injury in 2 to 4 hours, with perforation in as little as 6 hours.²⁸ Proposed mechanisms for the rapid development of esophageal injury include alkaline burn, local current, and pressure necrosis.²⁸ Most recently, almost all button battery ingestions associated with serious or fatal outcomes were 20-mm lithium batteries, dangerous for their large size and higher voltage.^27,28,39 Of note, lithium batteries do not contain an alkali solution, lending support to the concept that electrical current results in morbidity rather than leakage of caustic battery contents. All suspected esophageal button batteries should therefore undergo immediate endoscopic removal within 2 hours; success rates with this modality are reported as excellent. Button batteries that are in the stomach or beyond may be left to pass spontaneously in asymptomatic patients.

Foreign bodies are also commonly found in the stomach. Many small foreign bodies pass through the stomach and the remainder of the GI tract without difficulty. Objects greater than 5 cm in length or 2 cm in diameter may be unable to traverse the duodenum and may require endoscopic or surgical removal. Foreign bodies beyond the duodenum may not require any intervention except observation; however, some objects may become lodged at the ileocecal valve. Serial examinations and radiographs can be appropriate for asymptomatic patients; however, increasing abdominal pain or tenderness may mandate further imaging and surgical consultation. Recent increase in pediatric ingestion of strong, small magnets may be one exception to these recommendations. Multiple magnets may attract across bowel walls, preventing transit and leading to intestinal perforation. Ingestion of a single magnet may not increase morbidity and may be managed as above, but the ingestion of multiple magnets should be managed aggressively with surgical consultation for removal.⁴⁴ Body packers represent an unusual exception to these rules. Patients who are discovered to be internally concealing large quantities of illicit drugs may require whole-bowel irrigation to facilitate transit of colonic packets and even emergency laparotomy for obstruction or suspected packet rupture in cases of cocaine or methamphetamine smuggling³⁹ (Special Considerations: SC5).

• The GI tract is vulnerable to a wide variety of pathogenic organisms.

• The GI tract modulates absorption and metabolism of xenobiotics.

• Endogenous flora contribute greatly to the function and pathology of the GI tract with both host and microbial components acting as one organ system.

• The GI tract involves a complex interplay of regulatory hormones.

• As function follows structure, effects of various xenobiotics are often related to the specific parts of the GI tract that are affected.

Acknowledgment

Kavita Babu, MD; Neal E. Flomenbaum, MD; Donald P. Kotler, MD; and Martin Jay Smilkstein, contributed to this chapter in previous editions.

References