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Gastrointestinal System
Gastrointestinal System MJ Fedoruk, University of California, Irvine, CA, USA S Hong, Exponent Health Sciences, Irvine, CA, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by M. Joseph Fedoruk and Tee L. Guidotti, volume 2, pp 410–416, Ó 2005, Elsevier Inc.
Introduction This article provides an overview of the anatomy, physiology, and potential toxic effects that can affect the gastrointestinal (GI) system. The GI system consists of a luminal GI tract lined by mucous membranes and associated digestive organs, including the liver, exocrine pancreas, and gallbladder. The liver and endocrine pancreas (e.g., endocrine system) are discussed in other sections of this encyclopedia. The primary function of the GI tract is digestion and absorption of nutrients, ions, and water from food and liquids. Digestion involves the breakdown or hydrolysis of food into smaller molecules for absorption. Absorption refers to the transport of nutrients, ions, and water across intestinal cells into the body for metabolism. The autonomic nervous system innervates the GI tract via direct and indirect pathways. Increased parasympathetic tone leads to enhanced GI function, favoring digestion and peristalsis. Increased sympathetic tone results in a fight or flight type response and inhibition of peristalsis and digestion. The human GI tract or tube forms the largest mucosal surface in the body. The tract consists of (1) an inner mucosal layer containing mucus-secreting and other specialized cells; (2) a submucosal layer consisting of loose connective tissue with blood and lymphatic vessels, inflammatory cells, and nerve fibers; (3) a muscular layer containing smooth muscles, which produce peristalsis; and (4) a serosal layer or covering that encloses the tube. The GI mucosal cells have very rapid turnover rates, making them especially susceptible to ionizing radiation and cancer chemotherapeutic agents. About 60–75% of small intestinal cells and 10% of colonic mucosal cells turnover daily. The tract tube consists of five segments, each with various specialized cell types that perform unique functions described next.
action. Chief cells secrete the proteolytic precursor enzymes pepsinogen 1 and 11, which further digest foods. Pepsinogen is activated by the stomach’s low pH environment and inactivated by the high pH (6) in the duodenum mast cells and enterochromaffin-like cells release histamine, which acts on parietal cell H2 receptors to release hydrochloric acid. H2 blockers such as cimetidine are widely used to treat gastric hyperacidity. The factors associated with the regulation of gastric acid secretion are complex and involve chemical, neural, and hormonal influences. The stomach and small intestine contain several endocrine cells that affect gastric acid release. A principal factor that stimulates hydrochloric acid release is gastrin, a hormone released into the circulation by G cells located in the epithelial lining in the stomach, duodenum, and proximal jejunum. Gastrin is released in response to food in the stomach and small intestine. Stimulation of the vagus nerve results in hydrochloric acid release via muscarinic cholinergic receptors located on parietal cells. Vagal stimulation is also thought to stimulate gastrin release and lower the threshold for gastrin release. Gastric acid secretion is inhibited by several mechanisms, including increased gastric acidity (pH of 3 or less inhibits gastrin release), acid in the duodenum, hypertonic fluids, and hyperglycemia. Somatostatin, a hormone produced by gastric mucosal endocrine cells (D cells), inhibits gastrin release. Gastric acid secretion is not the primary cause of peptic ulcer disease except in conditions that result in extreme overproduction, such as the Zolinger–Ellison syndrome. Infection with Helicobacter pylori, a small, flagellated, gram-negative spiral bacillus that produces urease, which serves to neutralize acidity in the gastric mucus, is primary cause for peptic ulcer. Peptic ulcers are now routinely treated with antibiotics directed against H. pylori. H. pylori infection is also associated with an increased risk gastric carcinoma. H. pylori is a common infection worldwide, especially in many developing countries.
Oral Cavity, Hypopharynx, and Esophagus The oral cavity and hypopharynx initiate the process of digestion by mechanically breaking down and mixing food with salivary enzymes, including amylase, which breaks down starch. The esophagus propels food and liquids from the hypopharynx to the stomach. The esophagus has two sphincters (i.e., areas of increased pressure) that prevent reflux of gastric contents. During swallowing the sphincters relax to enable food propulsion. Aspiration of gastric contents can result in significant lung damage.
Stomach The stomach further digests food by several processes. Food is mechanically churned into smaller sizes through peristaltic
702
Small Intestine The primary function of the small intestine, which is composed of three segments, duodenum, ileum, and jejunum, is nutrient absorption. Pancreatic enzymes, including amylase, lipase, and trypsin, are secreted into the proximal small intestine (duodenum), where they break down nutrients into smaller molecules that can be directly absorbed. Bile acids are secreted through the bile duct into the duodenum and help form micelles, which emulsify fats and facilitate lipid absorption. Most nutrient absorption occurs in the jejunum and ileum. A characteristic feature of the small intestine is a mucosal lining that is principally composed of enterocytes, which contain numerous villi that serve as absorptive areas. The villi extend into the lumen and appear as fingerlike projections
Encyclopedia of Toxicology, Volume 2
http://dx.doi.org/10.1016/B978-0-12-386454-3.00026-9
Gastrointestinal System
covered with epithelial cells. The villi also contain microvilli, which are also composed of microfilaments that form a brush border. Absorption of nutrients is also enhanced by motility of the small intestine and direct movement of villi, which place food in proximity to capillaries and lymphatic lacteals, which serve as absorptive channels. Several types of absorptive mechanisms exist for nutrients, including active transport, passive diffusion, facilitated diffusion, and endocytosis. Endocytosis occurs when the outer plasma cell membrane surrounds a soluble or particulate nutrient and engulfs the contents. This process is similar to phagocytosis. Complex polysaccharides, i.e., carbohydrates, or starches, are hydrolyzed to oligosaccharides and disaccharides by pancreatic amylase. Disaccharides, including lactase, sucrase, and maltase, are enzymatically split by enzymes contained in microvilli of enterocytes. Glucose and other monosaccharides are absorbed by an active transport mechanism that is coupled to energy derived from a sodium pump mechanism. Proteins are initially broken down in the stomach by pepsins, but completion of digestion occurs in the duodenum by pancreatic enzymes trypsin and chymotrypsin. This results in the formation of oligopeptides, dipeptides, and amino acids. Dipeptides are broken down by dipeptidases located on microvilli. Amino acids are absorbed rapidly in the duodenum and jejunum by active transport mechanisms. Most dietary fat is composed of long-chain triglycerides, which contain saturated and unsaturated fats. Hydrolysis of triglycerides occurs in the duodenum, through the action of pancreatic enzymes, including lipase, colipase, and bile salts. Bile salts, which are synthesized by the liver, have detergent properties and enable the formation of micelles, which are emulsions of triglycerides or fats with bile salts. The micelles enable lipase enzyme to access the water–fat insoluble phase. Colipase, a pancreatic enzyme, acts to place the pancreatic lipase in close proximity to the surface of a triglyceride droplet and is necessary for the action of lipase. Lipase hydrolyzes the triglyceride to form 2-monoglycerides and fatty acids. Monoglycerides released from micelles come into contact with cell surfaces, where they are absorbed by diffusion. Once inside the cell, metabolism is dependent on chain length. Long-chain fatty acids are esterified to triglycerides by enzymes in the endoplasmic reticulum and interact with cholesterol phospholipids and apoproteins to form chylomicrons and very low-density lipoproteins. Medium-chain fatty acids are not reesterified and enter the portal venous system, where they are transported and bound by albumen. Other nutrients absorbed in the small intestine include fat-soluble vitamins, iron, calcium, water, and sodium. Bile salts are absorbed from the ileum or terminal portion of the small intestine and are recirculated via the portal vein. If the ileum is diseased, as in Crohn’s disease, bile salts may not be absorbed, and fat absorption, including absorption of fatsoluble vitamins, may be impaired. Endocrine cells are scattered among walls of the small intestine, including the villi. The cells release a large array of secretory products into the bloodstream. Products include gastrin, somatostatin, secretin, cholecystokinin, neurotensin, enteroglucagon, vasoactive intestinal polypeptide, GI polypeptide, and other agents that can act by neurocrine and paracrine mechanisms and play a key role in digestion.
703
The small intestine, in addition to other portions of the mucosa and submucosa of the GI tract, contains a large numbers of T and B cells, macrophages, and plasma cells. This lymphoid tissue forms unencapsulated nodules in the ileum, which are macroscopically visible and known as Peyer’s patches. M or microfold cells are specialized cells found in epithelial tissue overlaying the GI tract that function to transport macromolecules by transcytosis from the intestinal lumen to intraepithelial macrophages and lymphocytes and play a key role in defense against external pathogens. Other mucosal epithelial surfaces in the body (e.g., respiratory tract and genitourinary tract) contain similar populations of lymphocytes that serve to protect pathogenic organisms.
Large Intestine The principal function of the colon is to reabsorb water and electrolytes that are present inside a liquid luminal stream. In contrast to the small intestinal mucosa, the lining of the colon is composed of columnar absorptive cells that have shorter, flat epithelial cells with no villi, although some absorptive cells have microvilli. The mucosa is punctuated by tubular crypts that extend to the mucosal layer and contain goblet cells, which secrete mucus; Paneth cells, which secrete lysozyme; endocrine cells; and undifferentiated goblet cells. Cellular proliferation is confined to the crypts, and cells differentiate and migrate to the surface to replace superficial epithelial cells lost to surface abrasion or degeneration. Lymphoid tissue is found in the mucosa and submucosa.
Intestinal Flora The GI tract is colonized by endogenous bacteria or host flora that include over 40 types of bacteria. There are approximately 10 times more bacteria in the gut than human cells in the body. Host flora perform metabolic functions and serve to ferment undigested carbohydrates in the colon into short-chain fatty acids, which can be used for energy by colon cells. Host flora also play a role in immunity, including growth repression of harmful microorganisms and growth of epithelial cells. Intestinal bacteria may contain several enzymes, including b-glucosidase, which are involved in the biotransformation of xenobiotics. Loss of intestinal flora following antibiotic therapy can lead to overgrowth of pathogenic organisms. Probiotic formulations of bacteria that are nonpathogenic and part of the human flora may be used as prophylactics or therapeutic agents for certain GI conditions Some bacteria, like Lactobacilli, may serve to decrease the risk of cancer.
Exocrine Pancreas The pancreas contains cells that have endocrine and exocrine functions. The gland is largely formed of acinar cells, which secrete digestive enzymes or their precursor into the duodenum. Exocrine function is subject to hormonal and neural regulation. The islets of Langerhans contain strands of cells, including B and A cells that secrete insulin and
704
Gastrointestinal System
glucagon, respectively, and form the endocrine portion of the gland.
Toxicant Effects on the GI System Toxic effects can be mediated in the GI system by several mechanisms, which are discussed next.
Direct Mucosal or Cellular Injury Xenobiotics that contact the mucosal or other cells of the GI tract produce irritation characterized by inflammation, degeneration, and/or proliferation. The type of toxic effect that is manifest is dependent on several factors, including chemical characteristics of the agent, dose or magnitude of exposure, and type of tissue involved. Erosions or a superficial ulceration of the mucosa can occur focally or diffusely. Erosions are due to focal necrosis of the epithelium and associated stroma and are restricted to the superficial layers. Diffuse irritation accompanied by an inflammatory reaction is called enteritis. Ulcers, in contrast, are deeper lesions extending beyond the mucosa and penetrating into the adjacent tissue layers. Chronic irritation can lead to proliferative lesions, including dysplasia, which potentially can become malignant. Ingestion of strong alkali and acids has the potential to produce severe tissue destruction or liquefaction necrosis. Alkali with a pH of 11.5–12 and acids with a pH <2 can produce significant corrosive injury. Other substances such as phenol may not be highly alkaline but can still produce corrosive injury. Alkali are found in many commercial products, such as household and industrial cleaners, dishwasher soaps and drain openers, and low-phosphate detergents. Factors affecting the degree of tissue injury or destruction include the amount ingested, the duration of contact with tissue, concentration, pH, physical form, titratable alkaline, and acid reserve. A frequent injury following alkali ingestion is esophageal burns. Diffuse circumferential esophageal burns are more common in patients ingesting concentrated liquid alkaline corrosives, while granular forms tend to produce patchy or streaky oral and esophageal burns. Ingestion of capsules containing liquid alkaline corrosives or solids can result in gastric injuries. From a clinical perspective, the absence of visible oral burns does not reliably exclude the presence of esophageal burns, and persons ingesting such formulations may need to undergo endoscopy to determine the extent of esophageal injury to enable proper patient care. Complications of caustic ingestion include tracheoesophageal and aortoesophageal fistulae; strictures of the mouth, esophagus, and stomach; and esophageal carcinoma. In severe cases, GI bleeding or perforated viscus with mediastinitis or peritonitis may develop and can be fatal. Strictures are more likely to develop after second- or third-degree or circumferential burns. GI tract irritation can occur when xenobiotics interfere with the gastric mucosal barrier. Gastric ulcers have been associated with anti-inflammatory medications, including aspirin and nonsteroidal anti-inflammatory drugs. The mechanism is
thought to be the inhibition of cyclooxygenase, which is required for prostaglandin secretion. Prostaglandins play a key role in maintaining mucosal defenses of the stomach. Other agents that can cause severe injury to the GI tract include salicylates, heavy metals, and iron. Acute pancreatitis is an inflammatory disorder that results in abdominal pain and elevated blood levels of pancreatic enzymes. The condition can be mild, but about 15–25% cases are severe, with 5% mortality from multiorgan failure. Chronic alcohol abuse accounts for about 30% of cases in the United States. Drug-induced pancreatitis is thought to be an uncommon cause of pancreatitis, with an estimated incidence of 0.1–2%. A wide array of medications has been associated with pancreatitis, but the scientific literature is limited and consists primarily of case reports. Medications commonly reported to cause pancreatitis include didanosine, sulfonamides, thiazide diuretics, tetracycline, azathioprine, estrogens, and valproic acid. Potential mechanisms vary for different agents, but include direct toxic effects, ischemia, immunologic reactions, intravascular thrombosis, and altered viscosity of pancreatic juices.
Interaction with GI Tract Receptors Gastrointestinal function can be affected by interaction with cellular receptors. Stimulation of cholinergic muscarinic receptors by agents such as cholinesterase inhibitors (e.g., organophosphate pesticides) and nicotine can lead to nausea, vomiting, and diarrhea. Similarly, the administration of drugs that block with cholinergic muscarinic receptor functioning (e.g., atropine, tricyclic antidepressants, opiates, and sedative hypnotic medications) can slow motility and lead to constipation. Opioid withdrawal can lead to an increase in motility and secretions of the GI tract.
Indirect Effects Vomiting can occur as a consequence of the interaction of a chemical with the central chemoreceptor zone or vomiting center in the fourth ventricle of the brain. Glycosides, opiates, nicotine, and possibly carbon monoxide may act in this manner. Vomiting can also occur as a consequence of local GI tract stimulation from a wide array of agents, including soaps, detergents, solvents, metals (including arsenic and thallium), and toxins associated with several types of food poisonings.
Allergic Reactions The GI tract can be a site of hypersensitivity reactions. Angioedema of the mouth, including the pharynx, can occur following use of several medications such as angiotensin-convertingenzyme (ACE) inhibitors. The reaction is mediated via IgE.
Carcinogenesis GI tract cancers comprise about 20% of all cancer death in the United States. Epidemiological studies provide strong evidence
Gastrointestinal System
that GI tract cancers are affected by environmental factors. Migration studies demonstrate that immigrants and to a degree their offspring begin to experience the cancer rates similar to the population of the host country rather than their country of origin for cancers of the same organ. The incidence of GI tract cancers demonstrates considerable geographical variation for the same organ, supporting the conclusion that environmental factors play a causal role. Colorectal cancer is the second most common malignancy in the United States, accounting for about nearly 10%, of all cancer death. Although genetic factors play a role, including family polyposis and familial cancer syndrome, environmental risk factors, including ionizing radiation exposure, high dietary fat and meat intake, nitrosamines, and limited physical activity, provide evidence for an environmental cause. Fat intake has been postulated to increase cancer risk by changing the composition of intestinal flora, which can affect metabolism of xenobiotics, or by increasing concentrations of bile salts. Cancer of the rectum shares some risk factors with the colon cancer but also has distinct characteristics possibly related to sexually transmitted infections, chronic inflammation, and cigarette smoking. Gastric neoplasms were among the most frequent malignancies at the turn of the century, but the incidence has decreased in the past 50 years. Risk factors include nitrate ingestion and persons with hypochlorhydria who have a relative lack of stomach acid. This may be secondary to the presence of bacteria, which are normally killed in an acidic gastric environment and that transform nitrates to nitrites, which can eventually form carcinogenic nitrosamines. Oral cavity cancers have been associated with cigarettes, alcohol, and chewing tobacco or snuff or betel nut quid (popular in parts of Asia) and infection with human papilloma
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virus. Cancer of the oral cavity is not common in the Western world, but is frequently found in some developing countries, including India, where it accounts for approximately 8% of all malignancies. Other factors include a history of ionizing radiation exposure and nutritional deficiencies including iron in association with Plummer–Vinson syndrome. Esophageal cancer is associated with the use of alcohol and nitrosamines, ingestion of alkaline corrosive agents, and possibly chewing betel nut (popular in parts of Asia). Nutritional deficiencies have also been linked to this type of malignancy.
See also: Absorption; Acids; Alkalies; Carbamate Pesticides; Carcinogenesis; Corrosives; Endocrine System; Liver; Metals; Organophosphorus Compounds; Poisoning Emergencies in Humans.
Further Reading Kapp Jr., R.W., 2008. Gastrointestinal toxicology. In: Hayes, A.W. (Ed.), Principles and Methods of Toxicology, fifth ed. CRC Press/Taylor & Francis Group, Boca Raton, FL (Chapter 31). Kotler, K., Flomenbaum, N., 2006. Gastrointestinal principles. In: Flomenbaum, N.E., Goldfrank, L.R., Hoffman, R.S., Howland, M.A., Lewin, N.A., Nelson, L.S. (Eds.), Goldfrank’s Toxicologic Emergencies, eighth ed. McGraw-Hill, New York (Chapter 25). Parfitt, J.R., Driman, D.K., 2007. Pathological effects of drugs on the gastrointestinal tract: a review. Hum. Pathol. 38 (4), 527–536. Robbins, S.L., Kumar, V., Abbas, A.K., Cotran, R.S., Fausto, N., 2010. Robbins and Cotran Pathologic Basis of Disease. Saunders/Elsevier. Shottenfeld, D., Fraumeni, J., 2006. Cancer Epidemiology and Prevention, second ed. Oxford University Press, New York.
Introduction This article provides an overview of the anatomy, physiology, and potential toxic effects that can affect the gastrointestinal (GI) system. The GI system consists of a luminal GI tract lined by mucous membranes and associated digestive organs, including the liver, exocrine pancreas, and gallbladder. The liver and endocrine pancreas (e.g., endocrine system) are discussed in other sections of this encyclopedia. The primary function of the GI tract is digestion and absorption of nutrients, ions, and water from food and liquids. Digestion involves the breakdown or hydrolysis of food into smaller molecules for absorption. Absorption refers to the transport of nutrients, ions, and water across intestinal cells into the body for metabolism. The autonomic nervous system innervates the GI tract via direct and indirect pathways. Increased parasympathetic tone leads to enhanced GI function, favoring digestion and peristalsis. Increased sympathetic tone results in a fight or flight type response and inhibition of peristalsis and digestion. The human GI tract or tube forms the largest mucosal surface in the body. The tract consists of (1) an inner mucosal layer containing mucus-secreting and other specialized cells; (2) a submucosal layer consisting of loose connective tissue with blood and lymphatic vessels, inflammatory cells, and nerve fibers; (3) a muscular layer containing smooth muscles, which produce peristalsis; and (4) a serosal layer or covering that encloses the tube. The GI mucosal cells have very rapid turnover rates, making them especially susceptible to ionizing radiation and cancer chemotherapeutic agents. About 60–75% of small intestinal cells and 10% of colonic mucosal cells turnover daily. The tract tube consists of five segments, each with various specialized cell types that perform unique functions described next.
action. Chief cells secrete the proteolytic precursor enzymes pepsinogen 1 and 11, which further digest foods. Pepsinogen is activated by the stomach’s low pH environment and inactivated by the high pH (6) in the duodenum mast cells and enterochromaffin-like cells release histamine, which acts on parietal cell H2 receptors to release hydrochloric acid. H2 blockers such as cimetidine are widely used to treat gastric hyperacidity. The factors associated with the regulation of gastric acid secretion are complex and involve chemical, neural, and hormonal influences. The stomach and small intestine contain several endocrine cells that affect gastric acid release. A principal factor that stimulates hydrochloric acid release is gastrin, a hormone released into the circulation by G cells located in the epithelial lining in the stomach, duodenum, and proximal jejunum. Gastrin is released in response to food in the stomach and small intestine. Stimulation of the vagus nerve results in hydrochloric acid release via muscarinic cholinergic receptors located on parietal cells. Vagal stimulation is also thought to stimulate gastrin release and lower the threshold for gastrin release. Gastric acid secretion is inhibited by several mechanisms, including increased gastric acidity (pH of 3 or less inhibits gastrin release), acid in the duodenum, hypertonic fluids, and hyperglycemia. Somatostatin, a hormone produced by gastric mucosal endocrine cells (D cells), inhibits gastrin release. Gastric acid secretion is not the primary cause of peptic ulcer disease except in conditions that result in extreme overproduction, such as the Zolinger–Ellison syndrome. Infection with Helicobacter pylori, a small, flagellated, gram-negative spiral bacillus that produces urease, which serves to neutralize acidity in the gastric mucus, is primary cause for peptic ulcer. Peptic ulcers are now routinely treated with antibiotics directed against H. pylori. H. pylori infection is also associated with an increased risk gastric carcinoma. H. pylori is a common infection worldwide, especially in many developing countries.
Oral Cavity, Hypopharynx, and Esophagus The oral cavity and hypopharynx initiate the process of digestion by mechanically breaking down and mixing food with salivary enzymes, including amylase, which breaks down starch. The esophagus propels food and liquids from the hypopharynx to the stomach. The esophagus has two sphincters (i.e., areas of increased pressure) that prevent reflux of gastric contents. During swallowing the sphincters relax to enable food propulsion. Aspiration of gastric contents can result in significant lung damage.
Stomach The stomach further digests food by several processes. Food is mechanically churned into smaller sizes through peristaltic
702
Small Intestine The primary function of the small intestine, which is composed of three segments, duodenum, ileum, and jejunum, is nutrient absorption. Pancreatic enzymes, including amylase, lipase, and trypsin, are secreted into the proximal small intestine (duodenum), where they break down nutrients into smaller molecules that can be directly absorbed. Bile acids are secreted through the bile duct into the duodenum and help form micelles, which emulsify fats and facilitate lipid absorption. Most nutrient absorption occurs in the jejunum and ileum. A characteristic feature of the small intestine is a mucosal lining that is principally composed of enterocytes, which contain numerous villi that serve as absorptive areas. The villi extend into the lumen and appear as fingerlike projections
Encyclopedia of Toxicology, Volume 2
http://dx.doi.org/10.1016/B978-0-12-386454-3.00026-9
Gastrointestinal System
covered with epithelial cells. The villi also contain microvilli, which are also composed of microfilaments that form a brush border. Absorption of nutrients is also enhanced by motility of the small intestine and direct movement of villi, which place food in proximity to capillaries and lymphatic lacteals, which serve as absorptive channels. Several types of absorptive mechanisms exist for nutrients, including active transport, passive diffusion, facilitated diffusion, and endocytosis. Endocytosis occurs when the outer plasma cell membrane surrounds a soluble or particulate nutrient and engulfs the contents. This process is similar to phagocytosis. Complex polysaccharides, i.e., carbohydrates, or starches, are hydrolyzed to oligosaccharides and disaccharides by pancreatic amylase. Disaccharides, including lactase, sucrase, and maltase, are enzymatically split by enzymes contained in microvilli of enterocytes. Glucose and other monosaccharides are absorbed by an active transport mechanism that is coupled to energy derived from a sodium pump mechanism. Proteins are initially broken down in the stomach by pepsins, but completion of digestion occurs in the duodenum by pancreatic enzymes trypsin and chymotrypsin. This results in the formation of oligopeptides, dipeptides, and amino acids. Dipeptides are broken down by dipeptidases located on microvilli. Amino acids are absorbed rapidly in the duodenum and jejunum by active transport mechanisms. Most dietary fat is composed of long-chain triglycerides, which contain saturated and unsaturated fats. Hydrolysis of triglycerides occurs in the duodenum, through the action of pancreatic enzymes, including lipase, colipase, and bile salts. Bile salts, which are synthesized by the liver, have detergent properties and enable the formation of micelles, which are emulsions of triglycerides or fats with bile salts. The micelles enable lipase enzyme to access the water–fat insoluble phase. Colipase, a pancreatic enzyme, acts to place the pancreatic lipase in close proximity to the surface of a triglyceride droplet and is necessary for the action of lipase. Lipase hydrolyzes the triglyceride to form 2-monoglycerides and fatty acids. Monoglycerides released from micelles come into contact with cell surfaces, where they are absorbed by diffusion. Once inside the cell, metabolism is dependent on chain length. Long-chain fatty acids are esterified to triglycerides by enzymes in the endoplasmic reticulum and interact with cholesterol phospholipids and apoproteins to form chylomicrons and very low-density lipoproteins. Medium-chain fatty acids are not reesterified and enter the portal venous system, where they are transported and bound by albumen. Other nutrients absorbed in the small intestine include fat-soluble vitamins, iron, calcium, water, and sodium. Bile salts are absorbed from the ileum or terminal portion of the small intestine and are recirculated via the portal vein. If the ileum is diseased, as in Crohn’s disease, bile salts may not be absorbed, and fat absorption, including absorption of fatsoluble vitamins, may be impaired. Endocrine cells are scattered among walls of the small intestine, including the villi. The cells release a large array of secretory products into the bloodstream. Products include gastrin, somatostatin, secretin, cholecystokinin, neurotensin, enteroglucagon, vasoactive intestinal polypeptide, GI polypeptide, and other agents that can act by neurocrine and paracrine mechanisms and play a key role in digestion.
703
The small intestine, in addition to other portions of the mucosa and submucosa of the GI tract, contains a large numbers of T and B cells, macrophages, and plasma cells. This lymphoid tissue forms unencapsulated nodules in the ileum, which are macroscopically visible and known as Peyer’s patches. M or microfold cells are specialized cells found in epithelial tissue overlaying the GI tract that function to transport macromolecules by transcytosis from the intestinal lumen to intraepithelial macrophages and lymphocytes and play a key role in defense against external pathogens. Other mucosal epithelial surfaces in the body (e.g., respiratory tract and genitourinary tract) contain similar populations of lymphocytes that serve to protect pathogenic organisms.
Large Intestine The principal function of the colon is to reabsorb water and electrolytes that are present inside a liquid luminal stream. In contrast to the small intestinal mucosa, the lining of the colon is composed of columnar absorptive cells that have shorter, flat epithelial cells with no villi, although some absorptive cells have microvilli. The mucosa is punctuated by tubular crypts that extend to the mucosal layer and contain goblet cells, which secrete mucus; Paneth cells, which secrete lysozyme; endocrine cells; and undifferentiated goblet cells. Cellular proliferation is confined to the crypts, and cells differentiate and migrate to the surface to replace superficial epithelial cells lost to surface abrasion or degeneration. Lymphoid tissue is found in the mucosa and submucosa.
Intestinal Flora The GI tract is colonized by endogenous bacteria or host flora that include over 40 types of bacteria. There are approximately 10 times more bacteria in the gut than human cells in the body. Host flora perform metabolic functions and serve to ferment undigested carbohydrates in the colon into short-chain fatty acids, which can be used for energy by colon cells. Host flora also play a role in immunity, including growth repression of harmful microorganisms and growth of epithelial cells. Intestinal bacteria may contain several enzymes, including b-glucosidase, which are involved in the biotransformation of xenobiotics. Loss of intestinal flora following antibiotic therapy can lead to overgrowth of pathogenic organisms. Probiotic formulations of bacteria that are nonpathogenic and part of the human flora may be used as prophylactics or therapeutic agents for certain GI conditions Some bacteria, like Lactobacilli, may serve to decrease the risk of cancer.
Exocrine Pancreas The pancreas contains cells that have endocrine and exocrine functions. The gland is largely formed of acinar cells, which secrete digestive enzymes or their precursor into the duodenum. Exocrine function is subject to hormonal and neural regulation. The islets of Langerhans contain strands of cells, including B and A cells that secrete insulin and
704
Gastrointestinal System
glucagon, respectively, and form the endocrine portion of the gland.
Toxicant Effects on the GI System Toxic effects can be mediated in the GI system by several mechanisms, which are discussed next.
Direct Mucosal or Cellular Injury Xenobiotics that contact the mucosal or other cells of the GI tract produce irritation characterized by inflammation, degeneration, and/or proliferation. The type of toxic effect that is manifest is dependent on several factors, including chemical characteristics of the agent, dose or magnitude of exposure, and type of tissue involved. Erosions or a superficial ulceration of the mucosa can occur focally or diffusely. Erosions are due to focal necrosis of the epithelium and associated stroma and are restricted to the superficial layers. Diffuse irritation accompanied by an inflammatory reaction is called enteritis. Ulcers, in contrast, are deeper lesions extending beyond the mucosa and penetrating into the adjacent tissue layers. Chronic irritation can lead to proliferative lesions, including dysplasia, which potentially can become malignant. Ingestion of strong alkali and acids has the potential to produce severe tissue destruction or liquefaction necrosis. Alkali with a pH of 11.5–12 and acids with a pH <2 can produce significant corrosive injury. Other substances such as phenol may not be highly alkaline but can still produce corrosive injury. Alkali are found in many commercial products, such as household and industrial cleaners, dishwasher soaps and drain openers, and low-phosphate detergents. Factors affecting the degree of tissue injury or destruction include the amount ingested, the duration of contact with tissue, concentration, pH, physical form, titratable alkaline, and acid reserve. A frequent injury following alkali ingestion is esophageal burns. Diffuse circumferential esophageal burns are more common in patients ingesting concentrated liquid alkaline corrosives, while granular forms tend to produce patchy or streaky oral and esophageal burns. Ingestion of capsules containing liquid alkaline corrosives or solids can result in gastric injuries. From a clinical perspective, the absence of visible oral burns does not reliably exclude the presence of esophageal burns, and persons ingesting such formulations may need to undergo endoscopy to determine the extent of esophageal injury to enable proper patient care. Complications of caustic ingestion include tracheoesophageal and aortoesophageal fistulae; strictures of the mouth, esophagus, and stomach; and esophageal carcinoma. In severe cases, GI bleeding or perforated viscus with mediastinitis or peritonitis may develop and can be fatal. Strictures are more likely to develop after second- or third-degree or circumferential burns. GI tract irritation can occur when xenobiotics interfere with the gastric mucosal barrier. Gastric ulcers have been associated with anti-inflammatory medications, including aspirin and nonsteroidal anti-inflammatory drugs. The mechanism is
thought to be the inhibition of cyclooxygenase, which is required for prostaglandin secretion. Prostaglandins play a key role in maintaining mucosal defenses of the stomach. Other agents that can cause severe injury to the GI tract include salicylates, heavy metals, and iron. Acute pancreatitis is an inflammatory disorder that results in abdominal pain and elevated blood levels of pancreatic enzymes. The condition can be mild, but about 15–25% cases are severe, with 5% mortality from multiorgan failure. Chronic alcohol abuse accounts for about 30% of cases in the United States. Drug-induced pancreatitis is thought to be an uncommon cause of pancreatitis, with an estimated incidence of 0.1–2%. A wide array of medications has been associated with pancreatitis, but the scientific literature is limited and consists primarily of case reports. Medications commonly reported to cause pancreatitis include didanosine, sulfonamides, thiazide diuretics, tetracycline, azathioprine, estrogens, and valproic acid. Potential mechanisms vary for different agents, but include direct toxic effects, ischemia, immunologic reactions, intravascular thrombosis, and altered viscosity of pancreatic juices.
Interaction with GI Tract Receptors Gastrointestinal function can be affected by interaction with cellular receptors. Stimulation of cholinergic muscarinic receptors by agents such as cholinesterase inhibitors (e.g., organophosphate pesticides) and nicotine can lead to nausea, vomiting, and diarrhea. Similarly, the administration of drugs that block with cholinergic muscarinic receptor functioning (e.g., atropine, tricyclic antidepressants, opiates, and sedative hypnotic medications) can slow motility and lead to constipation. Opioid withdrawal can lead to an increase in motility and secretions of the GI tract.
Indirect Effects Vomiting can occur as a consequence of the interaction of a chemical with the central chemoreceptor zone or vomiting center in the fourth ventricle of the brain. Glycosides, opiates, nicotine, and possibly carbon monoxide may act in this manner. Vomiting can also occur as a consequence of local GI tract stimulation from a wide array of agents, including soaps, detergents, solvents, metals (including arsenic and thallium), and toxins associated with several types of food poisonings.
Allergic Reactions The GI tract can be a site of hypersensitivity reactions. Angioedema of the mouth, including the pharynx, can occur following use of several medications such as angiotensin-convertingenzyme (ACE) inhibitors. The reaction is mediated via IgE.
Carcinogenesis GI tract cancers comprise about 20% of all cancer death in the United States. Epidemiological studies provide strong evidence
Gastrointestinal System
that GI tract cancers are affected by environmental factors. Migration studies demonstrate that immigrants and to a degree their offspring begin to experience the cancer rates similar to the population of the host country rather than their country of origin for cancers of the same organ. The incidence of GI tract cancers demonstrates considerable geographical variation for the same organ, supporting the conclusion that environmental factors play a causal role. Colorectal cancer is the second most common malignancy in the United States, accounting for about nearly 10%, of all cancer death. Although genetic factors play a role, including family polyposis and familial cancer syndrome, environmental risk factors, including ionizing radiation exposure, high dietary fat and meat intake, nitrosamines, and limited physical activity, provide evidence for an environmental cause. Fat intake has been postulated to increase cancer risk by changing the composition of intestinal flora, which can affect metabolism of xenobiotics, or by increasing concentrations of bile salts. Cancer of the rectum shares some risk factors with the colon cancer but also has distinct characteristics possibly related to sexually transmitted infections, chronic inflammation, and cigarette smoking. Gastric neoplasms were among the most frequent malignancies at the turn of the century, but the incidence has decreased in the past 50 years. Risk factors include nitrate ingestion and persons with hypochlorhydria who have a relative lack of stomach acid. This may be secondary to the presence of bacteria, which are normally killed in an acidic gastric environment and that transform nitrates to nitrites, which can eventually form carcinogenic nitrosamines. Oral cavity cancers have been associated with cigarettes, alcohol, and chewing tobacco or snuff or betel nut quid (popular in parts of Asia) and infection with human papilloma
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virus. Cancer of the oral cavity is not common in the Western world, but is frequently found in some developing countries, including India, where it accounts for approximately 8% of all malignancies. Other factors include a history of ionizing radiation exposure and nutritional deficiencies including iron in association with Plummer–Vinson syndrome. Esophageal cancer is associated with the use of alcohol and nitrosamines, ingestion of alkaline corrosive agents, and possibly chewing betel nut (popular in parts of Asia). Nutritional deficiencies have also been linked to this type of malignancy.
See also: Absorption; Acids; Alkalies; Carbamate Pesticides; Carcinogenesis; Corrosives; Endocrine System; Liver; Metals; Organophosphorus Compounds; Poisoning Emergencies in Humans.
Further Reading Kapp Jr., R.W., 2008. Gastrointestinal toxicology. In: Hayes, A.W. (Ed.), Principles and Methods of Toxicology, fifth ed. CRC Press/Taylor & Francis Group, Boca Raton, FL (Chapter 31). Kotler, K., Flomenbaum, N., 2006. Gastrointestinal principles. In: Flomenbaum, N.E., Goldfrank, L.R., Hoffman, R.S., Howland, M.A., Lewin, N.A., Nelson, L.S. (Eds.), Goldfrank’s Toxicologic Emergencies, eighth ed. McGraw-Hill, New York (Chapter 25). Parfitt, J.R., Driman, D.K., 2007. Pathological effects of drugs on the gastrointestinal tract: a review. Hum. Pathol. 38 (4), 527–536. Robbins, S.L., Kumar, V., Abbas, A.K., Cotran, R.S., Fausto, N., 2010. Robbins and Cotran Pathologic Basis of Disease. Saunders/Elsevier. Shottenfeld, D., Fraumeni, J., 2006. Cancer Epidemiology and Prevention, second ed. Oxford University Press, New York.