Despite the constant attack on the gastroduodenal mucosa by a host of noxious agents (acid, pepsin, bile acids, pancreatic enzymes, drugs, and bacteria), integrity is maintained by an intricate system that provides mucosal defense and repair.
The gastric epithelial lining consists of rugae that contain microscopic gastric pits, each branching into four or five gastric glands made up of highly specialized epithelial cells. The makeup of gastric glands varies with their anatomic location. Glands within the gastric cardia comprise <5% of the gastric gland area and contain mucous and endocrine cells. The 75% of gastric glands are found within the oxyntic mucosa and contain mucous neck, parietal, chief, endocrine, enterochromaffin, and enterochromaffin-like (ECL) cells (Fig. 293-1). Pyloric glands contain mucous and endocrine cells (including gastrin cells) and are found in the antrum.
Diagrammatic representation of the oxyntic gastric gland. (Adapted from S Ito, RJ Winchester: Cell Biol 16:541, 1963. © The Rockefeller University Press.)
The parietal cell, also known as the oxyntic cell, is usually found in the neck, or isthmus, or in the oxyntic gland. The resting, or unstimulated, parietal cell has prominent cytoplasmic tubulovesicles and intracellular canaliculi containing short microvilli along its apical surface (Fig. 293-2). H+,K+-adenosine triphosphatase (ATPase) is expressed in the tubulovesicle membrane; upon cell stimulation, this membrane, along with apical membranes, transforms into a dense network of apical intracellular canaliculi containing long microvilli. Acid secretion, a process requiring high energy, occurs at the apical canalicular surface. Numerous mitochondria (30–40% of total cell volume) generate the energy required for secretion.
Gastric parietal cell undergoing transformation after secretagogue-mediated stimulation. cAMP, cyclic adenosine monophosphate. (Adapted from SJ Hersey, G Sachs: Physiol Rev 75:155, 1995.)
Gastroduodenal Mucosal Defense
The gastric epithelium is under constant assault by a series of endogenous noxious factors, including hydrochloric acid (HCl), pepsinogen/pepsin, and bile salts. In addition, a steady flow of exogenous substances such as medications, alcohol, and bacteria encounter the gastric mucosa. A highly intricate biologic system is in place to provide defense from mucosal injury and to repair any injury that may occur.
The mucosal defense system can be envisioned as a three-level barrier, composed of preepithelial, epithelial, and subepithelial elements (Fig. 293-3). The first line of defense is a mucus-bicarbonate-phospholipid layer, which serves as a physicochemical barrier to multiple molecules, including hydrogen ions. Mucus is secreted in a regulated fashion by gastroduodenal surface epithelial cells. It consists primarily of water (95%) and a mixture of phospholipids and glycoproteins (mucin). The mucous gel functions as a nonstirred water layer impeding diffusion of ions and molecules such as pepsin. Bicarbonate, secreted in a regulated manner by surface epithelial cells of the gastroduodenal mucosa into the mucous gel, forms a pH gradient ranging from 1 to 2 at the gastric luminal surface and reaching 6 to 7 along the epithelial cell surface.
Components involved in providing gastroduodenal mucosal defense and repair. CCK, cholecystokinin; CRF, corticotropin-releasing factor; EGF, epidermal growth factor; HCl, hydrochloride; IGF, insulin-like growth factor; TGFα, transforming growth factor α; TRF, thyrotropin releasing factor. (Modified and updated from Tarnawski A. Cellular and molecular mechanisms of mucosal defense and repair. In: Yoshikawa T, Arakawa T. Bioregulation and Its Disorders in the Gastrointestinal Tract. Tokyo, Japan: Blackwell Science, 1998:3–17.)
Surface epithelial cells provide the next line of defense through several factors, including mucus production, epithelial cell ionic transporters that maintain intracellular pH and bicarbonate production, and intracellular tight junctions. Surface epithelial cells generate heat shock proteins that prevent protein denaturation and protect cells from certain factors such as increased temperature, cytotoxic agents, or oxidative stress. Epithelial cells also generate trefoil factor family peptides and cathelicidins, which also play a role in surface cell protection and regeneration. If the preepithelial barrier were breached, gastric epithelial cells bordering a site of injury can migrate to restore a damaged region (restitution). This process occurs independent of cell division and requires uninterrupted blood flow and an alkaline pH in the surrounding environment. Several growth factors, including epidermal growth factor (EGF), transforming growth factor (TGF) α, and basic fibroblast growth factor (FGF), modulate the process of restitution. Larger defects that are not effectively repaired by restitution require cell proliferation. Epithelial cell regeneration is regulated by prostaglandins and growth factors such as EGF and TGF-α. In tandem with epithelial cell renewal, formation of new vessels (angiogenesis) within the injured microvascular bed occurs. Both FGF and vascular endothelial growth factor (VEGF) are important in regulating angiogenesis in the gastric mucosa.
An elaborate microvascular system within the gastric submucosal layer is the key component of the subepithelial defense/repair system, providing HCO3–, which neutralizes the acid generated by the parietal cell. Moreover, this microcirculatory bed provides an adequate supply of micronutrients and oxygen while removing toxic metabolic by-products.
Prostaglandins play a central role in gastric epithelial defense/repair (Fig. 293-4). The gastric mucosa contains abundant levels of prostaglandins that regulate the release of mucosal bicarbonate and mucus, inhibit parietal cell secretion, and are important in maintaining mucosal blood flow and epithelial cell restitution. Prostaglandins are derived from esterified arachidonic acid, which is formed from phospholipids (cell membrane) by the action of phospholipase A2. A key enzyme that controls the rate-limiting step in prostaglandin synthesis is cyclooxygenase (COX), which is present in two isoforms (COX-1, COX-2), each having distinct characteristics regarding structure, tissue distribution, and expression. COX-1 is expressed in a host of tissues, including the stomach, platelets, kidneys, and endothelial cells. This isoform is expressed in a constitutive manner and plays an important role in maintaining the integrity of renal function, platelet aggregation, and gastrointestinal (GI) mucosal integrity. In contrast, the expression of COX-2 is inducible by inflammatory stimuli, and it is expressed in macrophages, leukocytes, fibroblasts, and synovial cells. The beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on tissue inflammation are due to inhibition of COX-2; the toxicity of these drugs (e.g., GI mucosal ulceration and renal dysfunction) is related to inhibition of the COX-1 isoform. The highly COX-2–selective NSAIDs have the potential to provide the beneficial effect of decreasing tissue inflammation while minimizing toxicity in the GI tract. Selective COX-2 inhibitors have had adverse effects on the cardiovascular system, leading to increased risk of myocardial infarction. Therefore, the FDA has removed two of these agents (valdecoxib and rofecoxib) from the market (see below).
Schematic representation of the steps involved in synthesis of prostaglandin E2 (PGE2) and prostacyclin (PGI2). Characteristics and distribution of the cyclooxygenase (COX) enzymes 1 and 2 are also shown. TXA2, thromboxane A2.
Nitric oxide (NO) is important in the maintenance of gastric mucosal integrity. The key enzyme NO synthase is constitutively expressed in the mucosa and contributes to cytoprotection by stimulating gastric mucus, increasing mucosal blood flow and maintaining epithelial cell barrier function. The central nervous system (CNS) and hormonal factors also play a role in regulating mucosal defense through multiple pathways (Fig. 293-3).
Physiology of Gastric Secretion
Hydrochloric acid and pepsinogen are the two principal gastric secretory products capable of inducing mucosal injury. Gastric acid and pepsinogen play a physiologic role in protein digestion, absorption of iron and vitamin B12 as well as killing ingested bacteria. Acid secretion should be viewed as occurring under basal and stimulated conditions. Basal acid production occurs in a circadian pattern, with highest levels occurring during the night and lowest levels during the morning hours. Cholinergic input via the vagus nerve and histaminergic input from local gastric sources are the principal contributors to basal acid secretion. Stimulated gastric acid secretion occurs primarily in three phases based on the site where the signal originates (cephalic, gastric, and intestinal). Sight, smell, and taste of food are the components of the cephalic phase, which stimulates gastric secretion via the vagus nerve. The gastric phase is activated once food enters the stomach. This component of secretion is driven by nutrients (amino acids and amines) that directly stimulate the G cell to release gastrin, which in turn activates the parietal cell via direct and indirect mechanisms. Distention of the stomach wall also leads to gastrin release and acid production. The last phase of gastric acid secretion is initiated as food enters the intestine and is mediated by luminal distention and nutrient assimilation. A series of pathways that inhibit gastric acid production are also set into motion during these phases. The GI hormone somatostatin is released from endocrine cells found in the gastric mucosa (D cells) in response to HCl. Somatostatin can inhibit acid production by both direct (parietal cell) and indirect mechanisms (decreased histamine release from ECL cells and gastrin release from G cells). Additional neural (central and peripheral) and humoral [amylin, atrial natriuretic peptide (ANP), cholecystokinin, ghrelin, obestatin, secretin, and serotonin] factors play a role in counterbalancing acid secretion. Under physiologic circumstances, these phases occur simultaneously. Ghrelin, the appetite-regulating hormone expressed in stomach, may stimulate gastric acid secretion through a vagal-mediated mechanism, but this remains to be confirmed.
The acid-secreting parietal cell is located in the oxyntic gland, adjacent to other cellular elements (ECL cell, D cell) important in the gastric secretory process (Fig. 293-5). This unique cell also secretes intrinsic factor (IF). The parietal cell expresses receptors for several stimulants of acid secretion, including histamine (H2), gastrin (cholecystokinin B/gastrin receptor), and acetylcholine (muscarinic, M3). Binding of histamine to the H2 receptor leads to activation of adenylate cyclase and an increase in cyclic adenosine monophosphate (AMP). Activation of the gastrin and muscarinic receptors results in activation of the protein kinase C/phosphoinositide signaling pathway. Each of these signaling pathways in turn regulates a series of downstream kinase cascades that control the acid-secreting pump, H+,K+-ATPase. The discovery that different ligands and their corresponding receptors lead to activation of different signaling pathways explains the potentiation of acid secretion that occurs when histamine and gastrin or acetylcholine are combined. More importantly, this observation explains why blocking one receptor type (H2) decreases acid secretion stimulated by agents that activate a different pathway (gastrin, acetylcholine). Parietal cells also express receptors for ligands that inhibit acid production (prostaglandins, somatostatin, and EGF). Histamine also stimulates gastric acid secretion indirectly by activating the histamine H3 receptor on D-cells, which inhibits somatostatin release.
Regulation of gastric acid secretion at the cellular level. ACh, acetylcholine; ANP, atrial natriuretic peptide; CGRP, calcitoningene-related peptide; EC, enterochromaffin; ECL, enterochromaffin-like; GRP, gastrin-releasing peptide; PACAP, pituitary adenylate-cyclase activating peptide; SST, somatostatin; VIP, vasoactive intestinal peptide.
The enzyme H+,K+-ATPase is responsible for generating the large concentration of H+. It is a membrane-bound protein that consists of two subunits, α and β. The active catalytic site is found within the α subunit; the function of the β subunit is unclear. This enzyme uses the chemical energy of adenosine triphosphate (ATP) to transfer H+ ions from parietal cell cytoplasm to the secretory canaliculi in exchange for K+. The H+,K+-ATPase is located within the secretory canaliculus and in nonsecretory cytoplasmic tubulovesicles. The tubulovesicles are impermeable to K+, which leads to an inactive pump in this location. The distribution of pumps between the nonsecretory vesicles and the secretory canaliculus varies according to parietal cell activity (Fig. 293-2). Proton pumps are recycled back to the inactive state in cytoplasmic vesicles once parietal cell activation ceases.
The chief cell, found primarily in the gastric fundus, synthesizes and secretes pepsinogen, the inactive precursor of the proteolyticenzyme pepsin. The acid environment within the stomach leads to cleavage of the inactive precursor to pepsin and provides the low pH (<2) required for pepsin activity. Pepsin activity is significantly diminished at a pH of 4 and irreversibly inactivated and denatured at a pH of ≥7. Many of the secretagogues that stimulate acid secretion also stimulate pepsinogen release. The precise role of pepsin in the pathogenesis of PUD remains to be established.
Pathophysiologic Basis of Peptic Ulcer Disease
PUD encompasses both gastric and duodenal ulcers. Ulcers are defined as breaks in the mucosal surface >5 mm in size, with depth to the submucosa. Duodenal ulcers (DUs) and gastric ulcers (GUs); share many common features in terms of pathogenesis, diagnosis, and treatment, but several factors distinguish them from one another.
DUs are estimated to occur in 6–15% of the Western population. The incidence of DUs declined steadily from 1960 to 1980 and has remained stable since then. The death rates, need for surgery, and physician visits have decreased by >50% over the past 30 years. The reason for the reduction in the frequency of DUs is likely related to the decreasing frequency of Helicobacter pylori. Before the discovery of H. pylori, the natural history of DUs was typified by frequent recurrences after initial therapy. Eradication of H. pylori has greatly reduced these recurrence rates.
GUs tend to occur later in life than duodenal lesions, with a peak incidence reported in the sixth decade. More than one-half of GUs occur in males and are less common than DUs, perhaps due to the higher likelihood of GUs being silent and presenting only after a complication develops. Autopsy studies suggest a similar incidence of DUs and GUs.
DUs occur most often in the first portion of the duodenum (>95%), with ˜90% located within 3 cm of the pylorus. They are usually ≤1 cm in diameter but can occasionally reach 3–6 cm (giant ulcer). Ulcers are sharply demarcated, with depth at times reaching the muscularis propria. The base of the ulcer often consists of a zone of eosinophilic necrosis with surrounding fibrosis. Malignant DUs are extremely rare.
In contrast to DUs, GUs can represent a malignancy and should be biopsied upon discovery. Benign GUs are most often found distal to the junction between the antrum and the acid secretory mucosa. Benign GUs are quite rare in the gastric fundus and are histologically similar to DUs. Benign GUs associated with H. pylori are also associated with antral gastritis. In contrast, NSAID-related GUs are not accompanied by chronic active gastritis but may instead have evidence of a chemical gastropathy, typified by foveolar hyperplasia, edema of the lamina propria, and epithelial regeneration in the absence of H. pylori. Extension of smooth-muscle fibers into the upper portions of the mucosa, where they are not typically found, may also occur.
H. pylori and NSAID-induced injury account for the majority of DUs. Many acid secretory abnormalities have been described in DU patients. Of these, average basal and nocturnal gastric acid secretion appears to be increased in DU patients as compared to controls; however, the level of overlap between DU patients and control subjects is substantial. The reason for this altered secretory process is unclear, but H. pylori infection may contribute. Accelerated gastric emptying of liquids has been noted in some DU patients, but its role in DU formation, if any, is unclear. Bicarbonate secretion is significantly decreased in the duodenal bulb of patients with an active DU as compared to control subjects. H. pylori infection may also play a role in this process (see below).
As in DUs, the majority of GUs can be attributed to either H. pylori or NSAID-induced mucosal damage. GUs that occur in the prepyloric area or those in the body associated with a DU or a duodenal scar are similar in pathogenesis to DUs. Gastric acid output (basal and stimulated) tends to be normal or decreased in GU patients. When GUs develop in the presence of minimal acid levels, impairment of mucosal defense factors may be present. Gastric ulcers have been classified based on their location: Type I occur in the gastric body and tend to be associated with low gastric acid production; type II occur in the antrum and gastric acid can vary from low to normal; type III occur within 3 cm of the pylorus and are commonly accompanied by duodenal ulcers and normal or high gastric acid production; and type IV are found in the cardia and are associated with low gastric acid production.
Abnormalities in resting and stimulated pyloric sphincter pressure with a concomitant increase in duodenal gastric reflux have been implicated in some GU patients. Although bile acids, lysolecithin, and pancreatic enzymes may injure gastric mucosa, a definite role for these in GU pathogenesis has not been established. Delayed gastric emptying of solids has been described in GU patients but has not been reported consistently
H. Pylori and Acid Peptic Disorders
Gastric infection with the bacterium H. pylori accounts for the majority of PUD (Chap. 151). This organism also plays a role in the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma and gastric adenocarcinoma. Although the entire genome of H. pylori has been sequenced, it is still not clear how this organism, which resides in the stomach, causes ulceration in the duodenum, or whether its eradication will lead to a decrease in gastric cancer.
The bacterium, initially named Campylobacter pyloridis, is a gram-negative microaerophilic rod found most commonly in the deeper portions of the mucous gel coating the gastric mucosa or between the mucous layer and the gastric epithelium. It may attach to gastric epithelium but under normal circumstances does not appear to invade cells. It is strategically designed to live within the aggressive environment of the stomach. It is S-shaped (˜0.5–3 μm in size) and contains multiple sheathed flagella. Initially, H. pylori resides in the antrum but, over time, migrates toward the more proximal segments of the stomach. The organism is capable of transforming into a coccoid form, which represents a dormant state that may facilitate survival in adverse conditions. The genome of H. pylori (1.65 million base pairs) encodes ˜1500 proteins. Among this multitude of proteins there are factors that are essential determinants of H. pylori–mediated pathogenesis and colonization such as the outer membrane protein (Hop proteins), urease, and the vacuolating cytotoxin (Vac A). Moreover, the majority of H. pylori strains contain a genomic fragment that encodes the cag pathogenicity island (cag-PAI). Several of the genes that make up cag-PAI encode components of a type IV secretion island that translocates Cag A into host cells. Once in the cell, Cag A activates a series of cellular events important in cell growth and cytokine production. H. pylori also has extensive genetic diversity that in turn enhances its ability to promote disease. The first step in infection by H. pylori is dependent on the bacteria's motility and its ability to produce urease. Urease produces ammonia from urea, an essential step in alkalinizing the surrounding pH. Additional bacterial factors include catalase, lipase, adhesins, platelet-activating factor, and pic B (induces cytokines). Multiple strains of H. pylori exist and are characterized by their ability to express several of these factors (Cag A, Vac A, etc.). It is possible that the different diseases related to H. pylori infection can be attributed to different strains of the organism with distinct pathogenic features.
The prevalence of H. pylori varies throughout the world and depends largely on the overall standard of living in the region. In developing parts of the world, 80% of the population may be infected by the age of 20, whereas the prevalence is 20–50% in industrialized countries. In contrast, in the United States this organism is rare in childhood. The overall prevalence of H. pylori in the United States is ˜30%, with individuals born before 1950 having a higher rate of infection than those born later. About 10% of Americans <30 years of age are colonized with the bacteria. The rate of infection with H. pylori in industrialized countries has decreased substantially in recent decades. The steady increase in the prevalence of H. pylori noted with increasing age is due primarily to a cohort effect, reflecting higher transmission during a period in which the earlier cohorts were children. It has been calculated through mathematical models that improved sanitation during the latter half of the nineteenth century dramatically decreased transmission of H. pylori. Moreover, with the present rate of intervention, the organism will be ultimately eliminated from the United States. Two factors that predispose to higher colonization rates include poor socioeconomic status and less education. These factors, not race, are responsible for the rate of H. pylori infection in blacks and Hispanic Americans being double the rate seen in whites of comparable age. Other risk factors for H. pylori infection are (1) birth or residence in a developing country, (2) domestic crowding, (3) unsanitary living conditions, (4) unclean food or water, and (5) exposure to gastric contents of an infected individual.
Transmission of H. pylori occurs from person to person, following an oral-oral or fecal-oral route. The risk of H. pylori infection is declining in developing countries. The rate of infection in the United States has fallen by >50% when compared to 30 years ago.
H. pylori infection is virtually always associated with a chronic active gastritis, but only 10–15% of infected individuals develop frank peptic ulceration. The basis for this difference is unknown, but is likely due to a combination of host and bacterial factors some of which are outlined below. Initial studies suggested that >90% of all DUs were associated with H. pylori, but H. pylori is present in only 30–60% of individuals with GUs and 50–70% of patients with DUs. The pathophysiology of ulcers not associated with H. pylori or NSAID ingestion [or the rare Zollinger-Ellison syndrome (ZES)] is becoming more relevant as the incidence of H. pylori is dropping, particularly in the Western world (see below).
The particular end result of H. pylori infection (gastritis, PUD, gastric MALT lymphoma, gastric cancer) is determined by a complex interplay between bacterial and host factors (Fig. 293-6).
Bacterial factors: H. pylori is able to facilitate gastric residence, induce mucosal injury, and avoid host defense. Different strains of H. pylori produce different virulence factors. A specific region of the bacterial genome, the pathogenicity island (cag-PAI), encodes the virulence factors Cag A and pic B. Vac A also contributes to pathogenicity, although it is not encoded within the pathogenicity island. These virulence factors, in conjunction with additional bacterial constituents, can cause mucosal damage, in part through their ability to target the host immune cells. For example, Vac A targets human CD4 T cells, inhibiting their proliferation and in addition can disrupt normal function of B cells, CD8 T cells, macrophages and mast cells. Multiple studies have demonstrated that H. pylori strains that are cag-PAI positive are associated with a higher risk of peptic ulcer disease, premalignant gastric lesions and gastric cancer than are strains that lack the cag-PAI. Urease, which allows the bacteria to reside in the acidic stomach, generates NH3, which can damage epithelial cells. The bacteria produce surface factors that are chemotactic for neutrophils and monocytes, which in turn contribute to epithelial cell injury (see below). H. pylori makes proteases and phospholipases that break down the glycoprotein lipid complex of the mucous gel, thus reducing the efficacy of this first line of mucosal defense. H. pylori expresses adhesins (OMPs like BabA), which facilitate attachment of the bacteria to gastric epithelial cells. Although lipopolysaccharide (LPS) of gram-negative bacteria often plays an important role in the infection, H. pylori LPS has low immunologic activity compared to that of other organisms. It may promote a smoldering chronic inflammation.
Host factors: Studies in twins suggest that there may be genetic predisposition to acquire H. pylori. The inflammatory response to H. pylori includes recruitment of neutrophils, lymphocytes (T and B), macrophages, and plasma cells. The pathogen leads to local injury by binding to class II major histocompatability complex (MHC) molecules expressed on gastric epithelial cells, leading to cell death (apoptosis). Moreover, bacterial strains that encode cag-PAI can introduce Cag A into the host cells, leading to further cell injury and activation of cellular pathways involved in cytokine production. Elevated concentrations of multiple cytokines are found in the gastric epithelium of H. pylori–infected individuals, including interleukin (IL) 1α/β, IL-2, IL-6, IL-8, tumor necrosis factor (TNF) α, and interferon (IFN-γ). H. pylori infection also leads to both a mucosal and a systemic humoral response, which does not lead to eradication of the bacteria but further compounds epithelial cell injury. Additional mechanisms by which H. pylori may cause epithelial cell injury include (1) activated neutrophil-mediated production of reactive oxygen or nitrogen species and enhanced epithelial cell turnover and (2) apoptosis related to interaction with T cells (T helper 1, or TH1, cells) and IFN-γ.
Outline of the bacterial and host factors important in determining H. pylori–induced gastrointestinal disease. MALT, mucosal-associated lymphoid tissue.
The reason for H. pylori–mediated duodenal ulceration remains unclear. Studies suggest that H. pylori associated with duodenal ulceration may be more virulent. In addition, certain specific bacterial factors such as the duodenal ulcer-promoting gene A (dupA), may be associated with the development of duodenal ulcers. Another potential contributing factor is that gastric metaplasia in the duodenum of DU patients, which may be due to high acid exposure (see below), permits H. pylori to bind to it and produce local injury secondary to the host response. Another hypothesis is that H. pylori antral infection could lead to increased acid production, increased duodenal acid, and mucosal injury. Basal and stimulated [meal, gastrin-releasing peptide (GRP)] gastrin release are increased in H. pylori–infected individuals, and somatostatin-secreting D cells may be decreased. H. pylori infection might induce increased acid secretion through both direct and indirect actions of H. pylori and proinflammatory cytokines (IL-8, TNF, and IL-1) on G, D, and parietal cells (Fig. 293-7). Gastric ulcers, in contrast, are associated with H. pylori induced pangastritis and normal or low gastric acid secretion. H. pylori infection has also been associated with decreased duodenal mucosal bicarbonate production. Data supporting and contradicting each of these interesting theories have been demonstrated. Thus, the mechanism by which H. pylori infection of the stomach leads to duodenal ulceration remains to be established.
Summary of potential mechanisms by which H. pylori may lead to gastric secretory abnormalities. D, somatostatin cell; ECL, enterochromaffin-like cell; G, G cell. (Adapted from J Calam et al: Gastroenterology 113:543, 1997.)
In summary, the final effect of H. pylori on the GI tract is variable and determined by microbial and host factors. The type and distribution of gastritis correlate with the ultimate gastric and duodenal pathology observed. Specifically, the presence of antral-predominant gastritis is associated with DU formation; gastritis involving primarily the corpus predisposes to the development of GUs, gastric atrophy, and ultimately gastric carcinoma (Fig. 293-8).
Natural history of H. pylori-infection. (Used with permission from S Suerbaum, P Michetti: N Engl J Med 347:1175, 2002.)
NSAIDs represent a group of the most commonly used medications in the United States. More than 30 billion over-the-counter tablets and over 100 million prescriptions are sold yearly in the United States alone. In fact, after the introduction of COX-2 inhibitors in the year 2000, the number of prescriptions written for NSAIDs was >111 million at a cost of $4.8 billion. Side effects and complications due to NSAIDs are considered the most common drug-related toxicities in the United States. The spectrum of NSAID-induced morbidity ranges from nausea and dyspepsia (prevalence reported as high as 50–60%) to a serious GI complication such as endoscopy-documented peptic ulceration (15–30% of individuals taking NSAIDs regularly) complicated by bleeding or perforation in as many as 1.5% of users per year. It is estimated that NSAID-induced GI bleeding accounts for 60,000 to 120,000 hospital admissions per year, and deaths related to NSAID-induced toxicity may be as high as 16,000 per year in the United States. Approximately 4–5% of patients develop symptomatic ulcers within 1 year. Unfortunately, dyspeptic symptoms do not correlate with NSAID-induced pathology. Over 80% of patients with serious NSAID-related complications did not have preceding dyspepsia. In view of the lack of warning signs, it is important to identify patients who are at increased risk for morbidity and mortality related to NSAID usage. Even 75 mg/d of aspirin may lead to serious GI ulceration; thus, no dose of NSAID is completely safe. Established risk factors include advanced age, history of ulcer, concomitant use of glucocorticoids, high-dose NSAIDs, multiple NSAIDs, concomitant use of anticoagulants, clopidogrel, and serious or multisystem disease. Possible risk factors include concomitant infection with H. pylori, cigarette smoking, and alcohol consumption.
Prostaglandins play a critical role in maintaining gastroduodenal mucosal integrity and repair. It therefore follows that interruption of prostaglandin synthesis can impair mucosal defense and repair, thus facilitating mucosal injury via a systemic mechanism. Animal studies have demonstrated that neutrophil adherence to the gastric microcirculation plays an essential role in the initiation of NSAID-induced mucosal injury. A summary of the pathogenetic pathways by which systemically administered NSAIDs may lead to mucosal injury is shown in Fig. 293-9.
Mechanisms by which NSAIDs may induce mucosal injury. (Adapted from J Scheiman et al: J Clin Outcomes Management 3:23, 1996. Copyright 2003 Turner White Communications, Inc., www.turner-white.com. Used with permission.)
Injury to the mucosa also occurs as a result of the topical encounter with NSAIDs. Aspirin and many NSAIDs are weak acids that remain in a nonionized lipophilic form when found within the acid environment of the stomach. Under these conditions, NSAIDs migrate across lipid membranes of epithelial cells, leading to cell injury once trapped intracellularly in an ionized form. Topical NSAIDs can also alter the surface mucous layer, permitting back diffusion of H+ and pepsin, leading to further epithelial cell damage. Moreover, enteric-coated or buffered preparations are also associated with risk of peptic ulceration.
The interplay between H. pylori and NSAIDs in the pathogenesis of PUD is complex. Meta-analysis supports the conclusion that each of these aggressive factors is independent and synergistic risk factors for PUD and its complications such as GI bleeding. For example, eradication of H. pylori reduces the likelihood of GI complications in high-risk individuals to levels observed in individuals with average risk of NSAID-induced complications.
Pathogenetic Factors Unrelated to H. Pylori and NSAID in Acid Peptic Disease
Cigarette smoking has been implicated in the pathogenesis of PUD. Not only have smokers been found to have ulcers more frequently than do nonsmokers, but smoking appears to decrease healing rates, impair response to therapy, and increase ulcer-related complications such as perforation. The mechanism responsible for increased ulcer diathesis in smokers is unknown. Theories have included altered gastric emptying, decreased proximal duodenal bicarbonate production, increased risk for H. pylori infection, and cigarette-induced generation of noxious mucosal free radicals. Genetic predisposition may play a role in ulcer development. First-degree relatives of DU patients are three times as likely to develop an ulcer; however, the potential role of H. pylori infection in contacts is a major consideration. Increased frequency of blood group O and of the nonsecretor status have also been implicated as genetic risk factors for peptic diathesis. However, H. pylori preferentially binds to group O antigens. Psychological stress has been thought to contribute to PUD, but studies examining the role of psychological factors in its pathogenesis have generated conflicting results. Although PUD is associated with certain personality traits (neuroticism), these same traits are also present in individuals with nonulcer dyspepsia (NUD) and other functional and organic disorders.
Diet has also been thought to play a role in peptic diseases. Certain foods and beverages can cause dyspepsia, but no convincing studies indicate an association between ulcer formation and a specific diet. Specific chronic disorders have been shown to have a strong association with PUD: (1) systemic mastocytosis, (2) chronic pulmonary disease, (3) chronic renal failure, (4) cirrhosis, (5) nephrolithiasis, and (6) α1-antitrypsin deficiency. Those with a possible association are (1) hyperparathyroidism, (2) coronary artery disease, (3) polycythemia vera, and (4) chronic pancreatitis.
Multiple factors play a role in the pathogenesis of PUD. The two predominant causes are H. pylori infection and NSAID ingestion. PUD not related to H. pylori or NSAIDs is increasing. Other less common causes of PUD are shown in Table 293-1. These etiologic agents should be considered as the incidence of H. pylori is decreasing. Independent of the inciting or injurious agent, peptic ulcers develop as a result of an imbalance between mucosal protection/repair and aggressive factors. Gastric acid plays an essential role in mucosal injury.
Table 293-1 Causes of Ulcers Not Caused by Helicobacter Pylori and NSAIDs |Favorite Table|Download (.pdf)
Table 293-1 Causes of Ulcers Not Caused by Helicobacter Pylori and NSAIDs
|Pathogenesis of Non-Hp and Non-NSAID Ulcer Disease|
|Herpes simplex virus|
|Glucocorticoids (when combined with NSAIDs)|
|Basophilia in myeloproliferative disease|
|Duodenal obstruction (e.g., annular pancreas)|
|Idiopathic hypersecretory state|
Abdominal pain is common to many GI disorders, including DU and GU, but has a poor predictive value for the presence of either DU or GU. Up to 10% of patients with NSAID-induced mucosal disease can present with a complication (bleeding, perforation, and obstruction) without antecedent symptoms. Despite this poor correlation, a careful history and physical examination are essential components of the approach to a patient suspected of having peptic ulcers.
Epigastric pain described as a burning or gnawing discomfort can be present in both DU and GU. The discomfort is also described as an ill-defined, aching sensation or as hunger pain. The typical pain pattern in DU occurs 90 minutes to 3 hours after a meal and is frequently relieved by antacids or food. Pain that awakes the patient from sleep (between midnight and 3 a.m.) is the most discriminating symptom, with two-thirds of DU patients describing this complaint. Unfortunately, this symptom is also present in one-third of patients with NUD. The pain pattern in GU patients may be different from that in DU patients, where discomfort may actually be precipitated by food. Nausea and weight loss occur more commonly in GU patients. Endoscopy detects ulcers in <30% of patients who have dyspepsia.
The mechanism for development of abdominal pain in ulcer patients is unknown. Several possible explanations include acid-induced activation of chemical receptors in the duodenum, enhanced duodenal sensitivity to bile acids and pepsin, or altered gastroduodenal motility.
Variation in the intensity or distribution of the abdominal pain, as well as the onset of associated symptoms such as nausea and/or vomiting, may be indicative of an ulcer complication. Dyspepsia that becomes constant, is no longer relieved by food or antacids, or radiates to the back may indicate a penetrating ulcer (pancreas). Sudden onset of severe, generalized abdominal pain may indicate perforation. Pain worsening with meals, nausea, and vomiting of undigested food suggest gastric outlet obstruction. Tarry stools or coffee-ground emesis indicate bleeding.
Epigastric tenderness is the most frequent finding in patients with GU or DU. Pain may be found to the right of the midline in 20% of patients. Unfortunately, the predictive value of this finding is rather low. Physical examination is critically important for discovering evidence of ulcer complication. Tachycardia and orthostasis suggest dehydration secondary to vomiting or active GI blood loss. A severely tender, board like abdomen suggests a perforation. Presence of a succussion splash indicates retained fluid in the stomach, suggesting gastric outlet obstruction.
GI bleeding is the most common complication observed in PUD. It occurs in ˜15% of patients and more often in individuals >60 years of age. The mortality rate is as high as 5–10%. The higher incidence in the elderly is likely due to the increased use of NSAIDs in this group. Up to 20% of patients with ulcer-related hemorrhage bleed without any preceding warning signs or symptoms.
The second most common ulcer-related complication is perforation, being reported in as many as 6–7% of PUD patients. As in the case of bleeding, the incidence of perforation in the elderly appears to be increasing secondary to increased use of NSAIDs. Penetration is a form of perforation in which the ulcer bed tunnels into an adjacent organ. DUs tend to penetrate posteriorly into the pancreas, leading to pancreatitis, whereas GUs tend to penetrate into the left hepatic lobe. Gastrocolic fistulas associated with GUs have also been described.
Gastric Outlet Obstruction
Gastric outlet obstruction is the least common ulcer-related complication, occurring in 1–2% of patients. A patient may have relative obstruction secondary to ulcer-related inflammation and edema in the peripyloric region. This process often resolves with ulcer healing. A fixed, mechanical obstruction secondary to scar formation in the peripyloric areas is also possible. The latter requires endoscopic (balloon dilation) or surgical intervention. Signs and symptoms relative to mechanical obstruction may develop insidiously. New onset of early satiety, nausea, vomiting, increase of postprandial abdominal pain, and weight loss should make gastric outlet obstruction a possible diagnosis.
The list of gastrointestinal and nongastrointestinal disorders that can mimic ulceration of the stomach or duodenum is quite extensive. The most commonly encountered diagnosis among patients seen for upper abdominal discomfort is NUD. NUD, also known as functional dyspepsia or essential dyspepsia, refers to a group of heterogeneous disorders typified by upper abdominal pain without the presence of an ulcer. Dyspepsia has been reported to occur in up to 30% of the U.S. population. Up to 60% of patients seeking medical care for dyspepsia have a negative diagnostic evaluation. The etiology of NUD is not established, and the potential role of H. pylori in NUD remains controversial.
Several additional disease processes that may present with “ulcer-like” symptoms include proximal GI tumors, gastroesophageal reflux, vascular disease, pancreaticobiliary disease (biliary colic, chronic pancreatitis), and gastroduodenal Crohn's disease.
In view of the poor predictive value of abdominal pain for the presence of a gastroduodenal ulcer and the multiple disease processes that can mimic this disease, the clinician is often confronted with having to establish the presence of an ulcer. Documentation of an ulcer requires either a radiographic (barium study) or an endoscopic procedure. However, a large percentage of patients with symptoms suggestive of an ulcer have NUD; empirical therapy is appropriate for individuals who are otherwise healthy and <45 years of age, before embarking on a diagnostic evaluation (Chap. 39).
Barium studies of the proximal GI tract are still commonly used as a first test for documenting an ulcer. The sensitivity of older single-contrast barium meals for detecting a DU is as high as 80%, with a double-contrast study providing detection rates as high as 90%. Sensitivity for detection is decreased in small ulcers (<0.5 cm), presence of previous scarring, or in postoperative patients. A DU appears as a well-demarcated crater, most often seen in the bulb (Fig. 293-10A). A GU may represent benign or malignant disease. Typically, a benign GU also appears as a discrete crater with radiating mucosal folds originating from the ulcer margin (Fig. 293-10B). Ulcers >3 cm in size or those associated with a mass are more often malignant. Unfortunately, up to 8% of GUs that appear to be benign by radiographic appearance are malignant by endoscopy or surgery. Radiographic studies that show a GU must be followed by endoscopy and biopsy.
Barium study demonstrating: A. a benign duodenal ulcer; B. a benign gastric ulcer.
Endoscopy provides the most sensitive and specific approach for examining the upper GI tract (Fig. 293-11). In addition to permitting direct visualization of the mucosa, endoscopy facilitates photographic documentation of a mucosal defect and tissue biopsy to rule out malignancy (GU) or H. pylori. Endoscopic examination is particularly helpful in identifying lesions too small to detect by radiographic examination, for evaluation of atypical radiographic abnormalities, or to determine if an ulcer is a source of blood loss.
Endoscopy demonstrating: A. a benign duodenal ulcer; B. a benign gastric ulcer.
Although the methods for diagnosing H. pylori are outlined in Chap. 144, a brief summary will be included here (Table 293-2). Several biopsy urease tests have been developed (PyloriTek, CLOtest, Hpfast, Pronto Dry) that have a sensitivity and specificity of >90–95%. Several noninvasive methods for detecting this organism have been developed. Three types of studies routinely used include serologic testing, the 13C- or 14C-urea breath test, and the fecal H. pylori (Hp) antigen test. A urinary Hp antigen test, as well as a refined monoclonal antibody stool antigen test, appears promising.
Table 293-2 Tests for Detection of H. Pylori |Favorite Table|Download (.pdf)
Table 293-2 Tests for Detection of H. Pylori
|Invasive (Endoscopy/Biopsy Required)|
|Rapid urease||80–95/95–100||Simple, false negative with recent use of PPIs, antibiotics, or bismuth compounds|
|Histology||80–90/>95||Requires pathology processing and staining; provides histologic information|
|Culture||—/—||Time-consuming, expensive, dependent on experience; allows determination of antibiotic susceptibility|
|Serology||>80/>90||Inexpensive, convenient; not useful for early follow-up|
|Urea breath test||>90/>90||Simple, rapid; useful for early follow-up; false negatives with recent therapy (see rapid urease test); exposure to low-dose radiation with 14C test|
|Stool antigen||>90/>90||Inexpensive, convenient; not established for eradication but promising|
Occasionally, specialized testing such as serum gastrin and gastric acid analysis or sham feeding may be needed in individuals with complicated or refractory PUD [see “Zollinger-Ellison Syndrome (ZES),” below]. Screening for aspirin or NSAIDs (blood or urine) may also be necessary in refractory H. pylori–negative PUD patients.
Treatment: Peptic Ulcer Disease
Before the discovery of H. pylori, the therapy of PUD was centered on the old dictum by Schwartz of “no acid, no ulcer.” Although acid secretion is still important in the pathogenesis of PUD, eradication of H. pylori and therapy/prevention of NSAID-induced disease is the mainstay of treatment. A summary of commonly used drugs for treatment of acid peptic disorders is shown in Table 293-3.
Table 293-3 Drugs Used in the Treatment of Peptic Ulcer Disease
Acid Neutralizing/Inhibitory Drugs
Before we understood the important role of histamine in stimulating parietal cell activity, neutralization of secreted acid with antacids constituted the main form of therapy for peptic ulcers. They are now rarely, if ever, used as the primary therapeutic agent but instead are often used by patients for symptomatic relief of dyspepsia. The most commonly used agents are mixtures of aluminum hydroxide and magnesium hydroxide. Aluminum hydroxide can produce constipation and phosphate depletion; magnesium hydroxide may cause loose stools. Many of the commonly used antacids (e.g., Maalox, Mylanta) have a combination of both aluminum and magnesium hydroxide in order to avoid these side effects. The magnesium-containing preparation should not be used in chronic renal failure patients because of possible hypermagnesemia, and aluminum may cause chronic neurotoxicity in these patients.
Calcium carbonate and sodium bicarbonate are potent antacids with varying levels of potential problems. The long-term use of calcium carbonate (converts to calcium chloride in the stomach) can lead to milk-alkali syndrome (hypercalcemia, hyperphosphatemia with possible renal calcinosis and progression to renal insufficiency). Sodium bicarbonate may induce systemic alkalosis.
Four of these agents are presently available (cimetidine, ranitidine, famotidine, and nizatidine), and their structures share homology with histamine. Although each has different potency, all will significantly inhibit basal and stimulated acid secretion to comparable levels when used at therapeutic doses. Moreover, similar ulcer-healing rates are achieved with each drug when used at the correct dosage. Presently, this class of drug is often used for treatment of active ulcers (4–6 weeks) in combination with antibiotics directed at eradicating H. pylori (see below).
Cimetidine was the first H2 receptor antagonist used for the treatment of acid peptic disorders. The initial recommended dosing profile for cimetidine was 300 mg qid. Subsequent studies have documented the efficacy of using 800 mg at bedtime for treatment of active ulcer, with healing rates approaching 80% at 4 weeks. Cimetidine may have weak antiandrogenic side effects resulting in reversible gynecomastia and impotence, primarily in patients receiving high doses for prolonged periods of time (months to years, as in ZES). In view of cimetidine's ability to inhibit cytochrome P450, careful monitoring of drugs such as warfarin, phenytoin, and theophylline is indicated with long-term usage. Other rare reversible adverse effects reported with cimetidine include confusion and elevated levels of serum aminotransferases, creatinine, and serum prolactin. Ranitidine, famotidine, and nizatidine are more potent H2 receptor antagonists than cimetidine. Each can be used once a day at bedtime for ulcer prevention, which was commonly done before the discovery of H. pylori and the development of proton pump inhibitors (PPIs). Patients may develop tolerance to H2 blockers, a rare event with PPIs (see below). Comparable nighttime dosing regimens are ranitidine 300 mg, famotidine 40 mg, and nizatidine 300 mg.
Additional rare, reversible systemic toxicities reported with H2 receptor antagonists include pancytopenia, neutropenia, anemia, and thrombocytopenia, with a prevalence rate varying from 0.01–0.2%. Cimetidine and ranitidine (to a lesser extent) can bind to hepatic cytochrome P450; famotidine and nizatidine do not.
Proton Pump (H+,K+-ATPase) Inhibitors
Omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole are substituted benzimidazole derivatives that covalently bind and irreversibly inhibit H+,K+-ATPase. Esomeprazole, the newest member of this drug class, is the S-enantiomer of omeprazole, which is a racemic mixture of both S- and R-optical isomers. These are the most potent acid inhibitory agents available. Omeprazole and lansoprazole are the PPIs that have been used for the longest time. Both are acid-labile and are administered as enteric-coated granules in a sustained-release capsule that dissolves within the small intestine at a pH of 6. Lansoprazole is available in an orally disintegrating tablet that can be taken with or without water, an advantage for individuals who have significant dysphagia. Absorption kinetics are similar to the capsule. In addition, a lansoprazole-naproxen combination preparation that has been made available is targeted at decreasing NSAID-related GI injury (see below). Omeprazole is available as nonenteric-coated granules mixed with sodium bicarbonate in a powder form that can be administered orally or via gastric tube. The sodium bicarbonate has two purposes: to protect the omeprazole from acid degradation and to promote rapid gastric alkalinization and subsequent proton pump activation, which facilitates rapid action of the PPI. Pantoprazole and rabeprazole are available as enteric-coated tablets. Pantoprazole is also available as a parenteral formulation for intravenous use. These agents are lipophilic compounds; upon entering the parietal cell, they are protonated and trapped within the acid environment of the tubulovesicular and canalicular system. These agents potently inhibit all phases of gastric acid secretion. Onset of action is rapid, with a maximum acid inhibitory effect between 2 and 6 hours after administration and duration of inhibition lasting up to 72–96 hours. With repeated daily dosing, progressive acid inhibitory effects are observed, with basal and secretagogue-stimulated acid production being inhibited by >95% after 1 week of therapy. The half-life of PPIs is ˜18 hours; thus, it can take between 2 and 5 days for gastric acid secretion to return to normal levels once these drugs have been discontinued. Because the pumps need to be activated for these agents to be effective, their efficacy is maximized if they are administered before a meal (except for the immediate-release formulation of omeprazole) (e.g., in the morning before breakfast). Mild to moderate hypergastrinemia has been observed in patients taking these drugs. Carcinoid tumors developed in some animals given the drugs preclinically; however, extensive experience has failed to demonstrate gastric carcinoid tumor development in humans. Serum gastrin levels return to normal levels within 1–2 weeks after drug cessation. Rebound gastric acid hypersecretion has been described in H. pylori negative individuals after discontinuation of PPIs. It occurs even after relatively short-term usage (2 months) and may last for up to 2 months after the PPI has been discontinued. The mechanism involves gastrin-induced hyperplasia and hypertrophy of histamine-secreting ECL cells. The clinical relevance of this observation is that individuals may have worsening symptoms of gastroesophageal reflux disease (GERD) or dyspepsia upon stopping the PPI. Gradual tapering of the PPI and switching to an H2 receptor antagonist may prevent this from occurring. H. pylori-induced inflammation and concomitant decrease in acid production may explain why this does not occur in H. pylori-positive patients. IF production is also inhibited, but vitamin B12-deficiency anemia is uncommon, probably because of the large stores of the vitamin. As with any agent that leads to significant hypochlorhydria, PPIs may interfere with absorption of drugs such as ketoconazole, ampicillin, iron, and digoxin. Hepatic cytochrome P450 can be inhibited by the earlier PPIs (omeprazole, lansoprazole). Rabeprazole, pantoprazole, and esomeprazole do not appear to interact significantly with drugs metabolized by the cytochrome P450 system. The overall clinical significance of this observation is not definitely established. Caution should be taken when using theophylline, warfarin, diazepam, atazanavir, and phenytoin concomitantly with PPIs. Long-term acid suppression, especially with PPIs, has been associated with a higher incidence of community-acquired pneumonia as well as community and hospital acquired Clostridium difficile-associated disease. These observations require confirmation but should alert the practitioner to take caution when recommending these agents for long-term use, especially in elderly patients at risk for developing pneumonia or C. difficile infection. A population-based study revealed that long-term use of PPIs was associated with the development of hip fractures in older women. The absolute risk of fracture remained low despite an observed increase associated with the dose and duration of acid suppression. The mechanism for this observation is not clear and this finding must be confirmed before making broad recommendations regarding the discontinuation of these agents in patients who benefit from them. PPIs may exert a negative effect on the anti-platelet effect of clopidogrel. Although the evidence is mixed and inconclusive, a small increase in mortality and readmission rate for coronary events is seen in patients receiving a PPI while on clopidogrel. The mechanism involves the competition of the PPI and clopidogrel with the same cytochrome p450 (CYP2C19). Whether this is a class effect of PPIs is unclear; there appears to be at least a theoretical advantage of pantoprazole over the other PPIs, but this has not been confirmed. This drug interaction is particularly relevant in light of the common use of aspirin and clopidogrel for prevention of coronary events and the efficacy of PPIs in preventing GI bleeding in these patients. The FDA has made several recommendations while awaiting further evidence to clarify the impact of PPI therapy on clopidogrel use. Health care providers should continue to prescribe clopidogrel to patients who require it and should reevaluate the need for starting or continuing treatment with a PPI. From a practical standpoint additional recommendations to consider include: Patients taking clopidogrel with aspirin, especially with other GI risk factors for bleeding, should receive GI protective therapy. Although high-dose H2 blockers have been considered an option these do not appear to be as effective as PPIs. If PPIs are to be given, there should be a 12-h separation between administration of the PPI and clopidogrel to minimize competition of the two agents with the involved cytochrome p450. One option is to give the PPI 30 min before breakfast and the clopidogrel at bedtime. Insufficient data are available to firmly recommend one PPI over another.
Two new formulations of acid inhibitory agents are being developed. Tenatoprazole is a PPI containing an imidazopyridine ring instead of a benzimidazole ring, which promotes irreversible proton pump inhibition. This agent has a longer half-life than the other PPIs and may be beneficial for inhibiting nocturnal acid secretion, which has significant relevance in GERD. A second new class of agents is the potassium-competitive acid pump antagonists (P-CABs). These compounds inhibit gastric acid secretion via potassium competitive binding of the H+,K+-ATPase.
Sucralfate is a complex sucrose salt in which the hydroxyl groups have been substituted by aluminum hydroxide and sulfate. This compound is insoluble in water and becomes a viscous paste within the stomach and duodenum, binding primarily to sites of active ulceration. Sucralfate may act by several mechanisms: serving as a physicochemical barrier, promoting a trophic action by binding growth factors such as EGF, enhancing prostaglandin synthesis, stimulating mucus and bicarbonate secretion, and enhancing mucosal defense and repair. Toxicity from this drug is rare, with constipation being most common (2–3%). It should be avoided in patients with chronic renal insufficiency to prevent aluminum-induced neurotoxicity. Hypophosphatemia and gastric bezoar formation have also been reported rarely. Standard dosing of sucralfate is 1 g qid.
Sir William Osler considered bismuth-containing compounds the drug of choice for treating PUD. The resurgence in the use of these agents is due to their effect against H. pylori. Colloidal bismuth subcitrate (CBS) and bismuth subsalicylate (BSS, Pepto-Bismol) are the most widely used preparations. The mechanism by which these agents induce ulcer healing is unclear. Adverse effects with short-term usage include black stools, constipation, and darkening of the tongue. Long-term usage with high doses, especially with the avidly absorbed CBS, may lead to neurotoxicity. These compounds are commonly used as one of the agents in an anti-H. pylori regimen (see below).
In view of their central role in maintaining mucosal integrity and repair, stable prostaglandin analogues were developed for the treatment of PUD. The mechanism by which this rapidly absorbed drug provides its therapeutic effect is through enhancement of mucosal defense and repair. The most common toxicity noted with this drug is diarrhea (10–30% incidence). Other major toxicities include uterine bleeding and contractions; misoprostol is contraindicated in women who may be pregnant, and women of childbearing age must be made clearly aware of this potential drug toxicity. The standard therapeutic dose is 200 mu;g qid.
A number of drugs including anticholinergic agents and tricyclic antidepressants were used for treating acid peptic disorders but in light of their toxicity and the development of potent antisecretory agents, these are rarely, if ever, used today.
Extensive effort has been made in determining who of the many individuals with H. pylori infection should be treated. The common conclusion arrived at by multiple consensus conferences around the world is that H. pylori should be eradicated in patients with documented PUD. This holds true independent of time of presentation (first episode or not), severity of symptoms, presence of confounding factors such as ingestion of NSAIDs, or whether the ulcer is in remission. Some have advocated treating patients with a history of documented PUD who are found to be H. pylori–positive by serology or breath testing. Over one-half of patients with gastric MALT lymphoma experience complete remission of the tumor in response to H. pylori eradication. Treating patients with NUD, to prevent gastric cancer or patients with GERD requiring long-term acid suppression, remains controversial. Guidelines from the American College of Gastroenterology suggest eradication of H. pylori in patients who have undergone resection of early gastric cancer. The role of H. pylori eradication as a means to prevent gastric cancer is still controversial although data suggest a benefit of early eradication of H. pylori for prevention of gastric cancer in patients with peptic ulcer disease.
Multiple drugs have been evaluated in the therapy of H. pylori. No single agent is effective in eradicating the organism. Combination therapy for 14 days provides the greatest efficacy. A shorter course administration (7–10 days), although attractive, has not proved as successful as the 14-days regimens. The agents used with the greatest frequency include amoxicillin, metronidazole, tetracycline, clarithromycin, and bismuth compounds.
The physician's goal in treating PUD is to provide relief of symptoms (pain or dyspepsia), promote ulcer healing, and ultimately prevent ulcer recurrence and complications. The greatest impact of understanding the role of H. pylori in peptic disease has been the ability to prevent recurrence. Documented eradication of H. pylori in patients with PUD is associated with a dramatic decrease in ulcer recurrence to <10–20% as compared to 59% in GU patients and 67% in DU patients when the organism is not eliminated. Eradication of the organism may lead to diminished recurrent ulcer bleeding. The impact of its eradication on ulcer perforation is unclear.
Suggested treatment regimens for H. pylori are outlined in Table 293-4. Choice of a particular regimen will be influenced by several factors, including efficacy, patient tolerance, existing antibiotic resistance, and cost of the drugs. The aim for initial eradication rates should be 85–90%. Dual therapy [PPI plus amoxicillin, PPI plus clarithromycin, ranitidine bismuth citrate (Tritec) plus clarithromycin] are not recommended in view of studies demonstrating eradication rates of <80–85%. The combination of bismuth, metronidazole, and tetracycline was the first triple regimen found effective against H. pylori. The combination of two antibiotics plus either a PPI, H2 blocker, or bismuth compound has comparable success rates. Addition of acid suppression assists in providing early symptom relief and may enhance bacterial eradication.
Table 293-4 Regimens Recommended for Eradication of H. Pylori Infection
Triple therapy, although effective, has several drawbacks, including the potential for poor patient compliance and drug-induced side effects. Compliance is being addressed by simplifying the regimens so that patients can take the medications twice a day. Simpler (dual therapy) and shorter regimens (7 and 10 days) are not as effective as triple therapy for 14 days. Two anti-H. pylori regimens are available in prepackaged formulation: Prevpac (lansoprazole, clarithromycin, and amoxicillin) and Helidac (BSS, tetracycline, and metronidazole). The contents of the Prevpac are to be taken twice per day for 14 days, whereas Helidac constituents are taken four times per day with an antisecretory agent (PPI or H2 blocker), also for at least 14 days.
Side effects have been reported in up to 20–30% of patients on triple therapy. Bismuth may cause black stools, constipation, or darkening of the tongue. The most feared complication with amoxicillin is pseudomembranous colitis, but this occurs in <1–2% of patients. Amoxicillin can also lead to antibiotic-associated diarrhea, nausea, vomiting, skin rash, and allergic reaction. Tetracycline has been reported to cause rashes and, very rarely, hepatotoxicity and anaphylaxis.
One important concern with treating patients who may not need therapy is the potential for development of antibiotic-resistant strains. The incidence and type of antibiotic-resistant H. pylori strains vary worldwide. Strains resistant to metronidazole, clarithromycin, amoxicillin, and tetracycline have been described, with the latter two being uncommon. Antibiotic-resistant strains are the most common cause for treatment failure in compliant patients. Unfortunately, in vitro resistance does not predict outcome in patients. Culture and sensitivity testing of H. pylori is not performed routinely. Although resistance to metronidazole has been found in as many as 30% of isolates in North America and 80% in developing countries, triple therapy is effective in eradicating the organism in >50% of patients infected with a resistant strain. Clarithromycin resistance is seen in 13% of individuals in the United States, with resistance to amoxicillin being <1% and resistance to both metronidazole and clarithromycin in the 5% range.
Failure of H. pylori eradication with triple therapy in a compliant patient is usually due to infection with a resistant organism. Quadruple therapy (Table 293-4), where clarithromycin is substituted for metronidazole (or vice versa), should be the next step. The combination of pantoprazole, amoxicillin, and rifabutin for 10 days has also been used successfully (86% cure rate) in patients infected with resistant strains. Additional regimens considered for second-line therapy include levofloxacin-based triple therapy (levofloxacin, amoxicillin, PPI) for 10 days and furazolidone-based triple therapy (furazolidone, amoxicillin, PPI) for 14 days. Unfortunately, there is no universally accepted treatment regimen recommended for patients who have failed two courses of antibiotics. If eradication is still not achieved in a compliant patient, then culture and sensitivity of the organism should be considered. Additional factors that may lower eradication rates include the patient's country of origin (higher in Northeast Asia than other parts of Asia or Europe) and cigarette smoking. In addition, meta-analysis suggests that even the most effective regimens (quadruple therapy including PPI, bismuth, tetracycline, and metronidazole and triple therapy including PPI, clarithromycin, and amoxicillin) may have suboptimal eradication rates (<80%), thus demonstrating the need for the development of more efficacious treatments.
In view of the observation that 15–25% of patients treated with first-line therapy may still remain infected with the organism, new approaches to treatment have been explored. One promising approach is sequential therapy. This regimen consists of 5 days of amoxicillin and a PPI, followed by an additional 5 days of PPI plus tinidazole and clarithromycin. Initial studies have demonstrated eradication rates of >90% with good patient tolerance. Confirmation of these findings and applicability of this approach in the United States are needed.
Reinfection after successful eradication of H. pylori is rare in the United States (<1% per year). If recurrent infection occurs within the first 6 months after completing therapy, the most likely explanation is recrudescence as opposed to reinfection.
Therapy of NSAID-Related Gastric or Duodenal Injury
Medical intervention for NSAID-related mucosal injury includes treatment of an active ulcer and primary prevention of future injury. Recommendations for the treatment and primary prevention of NSAID-related mucosal injury are listed in Table 293-5. Ideally, the injurious agent should be stopped as the first step in the therapy of an active NSAID-induced ulcer. If that is possible, then treatment with one of the acid inhibitory agents (H2 blockers, PPIs) is indicated. Cessation of NSAIDs is not always possible because of the patient's severe underlying disease. Only PPIs can heal GUs or DUs, independent of whether NSAIDs are discontinued.
Table 293-5 Recommendations for Treatment of NSAID-Related Mucosal Injury |Favorite Table|Download (.pdf)
Table 293-5 Recommendations for Treatment of NSAID-Related Mucosal Injury
|NSAID discontinued||H2 receptor antagonist or PPI|
|Selective COX-2 inhibitor|
|H. pylori infection||Eradication if active ulcer present or there is a past history of peptic ulcer disease|
The approach to primary prevention has included avoiding the agent, using NSAIDs that are theoretically less injurious, and/or the use of concomitant medical therapy to prevent NSAID-induced injury. Several nonselective NSAIDs that are associated with a lower likelihood of GI toxicity include diclofenac, aceclofenac, and ibuprofen, although the beneficial effect may be eliminated if higher dosages of the agents are used. Primary prevention of NSAID-induced ulceration can be accomplished by misoprostol (200 μg qid) or a PPI. High-dose H2 blockers (famotidine, 40 mg bid) have also shown some promise in preventing endoscopically documented ulcers, although PPIs are superior. The highly selective COX-2 inhibitors, celecoxib and rofecoxib, are 100 times more selective inhibitors of COX-2 than standard NSAIDs, leading to gastric or duodenal mucosal injury that is comparable to placebo; their utilization led to an increase in cardiovascular events and withdrawal from the market. Additional caution was engendered when the CLASS study demonstrated that the advantage of celecoxib in preventing GI complications was offset when low-dose aspirin was used simultaneously. Therefore, gastric protection therapy is required in individuals taking COX-2 inhibitors and aspirin prophylaxis. Finally, much of the work demonstrating the benefit of COX-2 inhibitors and PPIs on GI injury has been performed in individuals of average risk; it is unclear if the same level of benefit will be achieved in high-risk patients. For example, concomitant use of warfarin and a COX-2 inhibitor was associated with rates of GI bleeding similar to those observed in patients taking nonselective NSAIDs. A combination of factors, including withdrawal of the majority of COX-2 inhibitors from the market, the observation that low-dose aspirin appears to diminish the beneficial effect of COX-2 selective inhibitors, and the growing use of aspirin for prophylaxis of cardiovascular events, have significantly altered the approach to gastric protective therapy during the use of NSAIDs. A set of guidelines for the approach to the use of NSAIDs was published by the American College of Gastroenterology and is shown in Table 293-6. Individuals who are not at risk for cardiovascular events, do not use aspirin, and are without risk for GI complications can receive nonselective NSAIDs without gastric protection. In those without cardiovascular risk factors but with a high potential risk (prior GI bleeding or multiple GI risk factors) for NSAID-induced GI toxicity, cautious use of a selective COX-2 inhibitor and co-therapy with misoprostol or high-dose PPI is recommended. Individuals at moderate GI risk without cardiac risk factors can be treated with a COX-2 inhibitor alone or with a nonselective NSAID with misoprostol or a PPI. Individuals with cardiovascular risk factors, who require low-dose aspirin and have low potential for NSAID-induced toxicity, should be considered for a non-NSAID agent or use of a traditional NSAID in combination with gastric protection, if warranted. Finally, individuals with cardiovascular and GI risks, who require aspirin must be considered for non-NSAID therapy, but if that is not an option, then gastric protection with any type of NSAID must be considered. Any patient, regardless of risk status, who is being considered for long-term traditional NSAID therapy, should also be considered for H. pylori testing and treatment if positive.
Table 293-6 Guide to NSAID Therapy |Favorite Table|Download (.pdf)
Table 293-6 Guide to NSAID Therapy
|No/Low NSAID GI Risk||NSAID GI Risk|
|No CV risk (no aspirin)||Traditional NSAID||Coxib or|
|Traditional NSAID + PPI or misoprostol|
|Consider non-NSAID therapy|
|CV risk (consider aspirin)||Traditional NSAID + PPI or misoprostol if GI risk warrants gastroprotection||A gastroprotective agent must be added if a traditional NSAID is prescribed|
|Consider non-NSAID therapy||Consider non-NSAID therapy|
Approach and Therapy: Summary
Controversy continues regarding the best approach to the patient who presents with dyspepsia (Chap. 39). The discovery of H. pylori and its role in pathogenesis of ulcers has added a new variable to the equation. Previously, if a patient <50 years of age presented with dyspepsia and without alarming signs or symptoms suggestive of an ulcer complication or malignancy, an empirical therapeutic trial with acid suppression was commonly recommended. Although this approach is practiced by some today, an approach presently gaining approval for the treatment of patients with dyspepsia is outlined in Fig. 293-12. The referral to a gastroenterologist is for the potential need of endoscopy and subsequent evaluation and treatment if the endoscopy is negative.
Overview of new-onset dyspepsia. Hp, Helicobacter pylori; UBT, urea breath test; IBS, irritable bowel syndrome. (Adapted from BS Anand and DY Graham: Endoscopy 31:215, 1999.)
Once an ulcer (GU or DU) is documented, the main issue at stake is whether H. pylori or an NSAID is involved. With H. pylori present, independent of the NSAID status, triple therapy is recommended for 14 days, followed by continued acid-suppressing drugs (H2 receptor antagonist or PPIs) for a total of 4–6 weeks. Selection of patients for documentation of H. pylori eradication (organisms gone at least 4 weeks after completing antibiotics) is an area of some debate. The test of choice for documenting eradication is the urea breath test (UBT). The stool antigen assay may also hold promise for this purpose, but the data have not been as clear cut as in the case of using the stool antigen test for primary diagnosis, especially if one considers patients who live in areas of low H. pylori prevalence. Further studies are warranted, but if the UBT is not available, a stool antigen should be considered to document eradication. The patient must be off antisecretory agents when being tested for eradication of H. pylori with UBT or stool antigen. Serologic testing is not useful for the purpose of documenting eradication since antibody titers fall slowly and often do not become undetectable. Two approaches toward documentation of eradication exist: (1) Test for eradication only in individuals with a complicated course or in individuals who are frail or with multisystem disease who would do poorly with an ulcer recurrence, and (2) test all patients for successful eradication. Some recommend that patients with complicated ulcer disease, or who are frail, should be treated with long-term acid suppression, thus making documentation of H. pylori eradication a moot point. In view of this discrepancy in practice, it would be best to discuss with the patient the different options available.
Several issues differentiate the approach to a GU versus a DU. GUs, especially of the body and fundus, have the potential of being malignant. Multiple biopsies of a GU should be taken initially; even if these are negative for neoplasm, repeat endoscopy to document healing at 8–12 weeks should be performed, with biopsy if the ulcer is still present. About 70% of GUs eventually found to be malignant undergo significant (usually incomplete) healing.
The majority (>90%) of GUs and DUs heal with the conventional therapy outlined above. A GU that fails to heal after 12 weeks and a DU that does not heal after 8 weeks of therapy should be considered refractory. Once poor compliance and persistent H. pylori infection have been excluded, NSAID use, either inadvertent or surreptitious, must be excluded. In addition, cigarette smoking must be eliminated. For a GU, malignancy must be meticulously excluded. Next, consideration should be given to a gastric acid hypersecretory state such as ZES (see “Zollinger-Ellison Syndrome,” below) or the idiopathic form, which can be excluded with gastric acid analysis. Although a subset of patients have gastric acid hypersecretion of unclear etiology as a contributing factor to refractory ulcers, ZES should be excluded with a fasting gastrin or secretin stimulation test (see below). More than 90% of refractory ulcers (either DUs or GUs) heal after 8 weeks of treatment with higher doses of PPI (omeprazole, 40 mg/d; lansoprazole 30–60 mg/d). This higher dose is also effective in maintaining remission. Surgical intervention may be a consideration at this point; however, other rare causes of refractory ulcers must be excluded before recommending surgery. Rare etiologies of refractory ulcers that may be diagnosed by gastric or duodenal biopsies include ischemia, Crohn's disease, amyloidosis, sarcoidosis, lymphoma, eosinophilic gastroenteritis, or infection [cytomegalovirus (CMV), tuberculosis, or syphilis].
Surgical intervention in PUD can be viewed as being either elective, for treatment of medically refractory disease, or as urgent/emergent, for the treatment of an ulcer-related complication. The development of pharmacologic and endoscopic approaches for the treatment of peptic disease and its complications has led to a substantial decrease in the number of operations needed for this disorder. Refractory ulcers are an exceedingly rare occurrence. Surgery is more often required for treatment of an ulcer-related complication.
Hemorrhage is the most common ulcer-related complication, occurring in ˜15–25% of patients. Bleeding may occur in any age group but is most often seen in older patients (sixth decade or beyond). The majority of patients stop bleeding spontaneously, but endoscopic therapy (Chap. 291) is necessary in some. Parenterally and orally administered PPIs also decrease ulcer rebleeding in patients who have undergone endoscopic therapy. Patients unresponsive or refractory to endoscopic intervention will require surgery (˜5% of transfusion-requiring patients).
Free peritoneal perforation occurs in ˜2–3% of DU patients. As in the case of bleeding, up to 10% of these patients will not have antecedent ulcer symptoms. Concomitant bleeding may occur in up to 10% of patients with perforation, with mortality being increased substantially. Peptic ulcer can also penetrate into adjacent organs, especially with a posterior DU, which can penetrate into the pancreas, colon, liver, or biliary tree.
Pyloric channel ulcers or DUs can lead to gastric outlet obstruction in ˜2–3% of patients. This can result from chronic scarring or from impaired motility due to inflammation and/or edema with pylorospasm. Patients may present with early satiety, nausea, vomiting of undigested food, and weight loss. Conservative management with nasogastric suction, intravenous hydration/nutrition, and antisecretory agents is indicated for 7–10 days with the hope that a functional obstruction will reverse. If a mechanical obstruction persists, endoscopic intervention with balloon dilation may be effective. Surgery should be considered if all else fails.
Specific Operations for Duodenal Ulcers
Surgical treatment is designed to decrease gastric acid secretion. Operations most commonly performed include (1) vagotomy and drainage (by pyloroplasty, gastroduodenostomy, or gastrojejunostomy), (2) highly selective vagotomy (which does not require a drainage procedure), and (3) vagotomy with antrectomy. The specific procedure performed is dictated by the underlying circumstances: elective vs. emergency, the degree and extent of duodenal ulceration, and the expertise of the surgeon. Moreover, the trend has been toward minimally invasive and anatomy-preserving operations.
Vagotomy is a component of each of these procedures and is aimed at decreasing acid secretion through ablating cholinergic input to the stomach. Unfortunately, both truncal and selective vagotomy (preserves the celiac and hepatic branches) result in gastric atony despite successful reduction of both basal acid output (BAO, decreased by 85%) and maximal acid output (MAO, decreased by 50%). Drainage through pyloroplasty or gastroduodenostomy is required in an effort to compensate for the vagotomy-induced gastric motility disorder. This procedure has an intermediate complication rate and a 10% ulcer recurrence rate. To minimize gastric dysmotility, highly selective vagotomy (also known as parietal cell, super-selective, or proximal vagotomy) was developed. Only the vagal fibers innervating the portion of the stomach that contains parietal cells is transected, thus leaving fibers important for regulating gastric motility intact. Although this procedure leads to an immediate decrease in both BAO and stimulated acid output, acid secretion recovers over time. By the end of the first postoperative year, basal and stimulated acid output are ˜30 and 50%, respectively, of preoperative levels. Ulcer recurrence rates are higher with highly selective vagotomy (≥10%), although the overall complication rates are the lowest of the three procedures.
The procedure that provides the lowest rates of ulcer recurrence (1%) but has the highest complication rate is vagotomy (truncal or selective) in combination with antrectomy. Antrectomy is aimed at eliminating an additional stimulant of gastric acid secretion, gastrin. Two principal types of reanastomoses are used after antrectomy: gastroduodenostomy (Billroth I) or gastrojejunostomy (Billroth II) (Fig. 293-13). Although Billroth I is often preferred over II, severe duodenal inflammation or scarring may preclude its performance. Prospective, randomized studies confirm that partial gastrectomy followed by Roux-en-Y reconstruction leads to a significantly better clinical, endoscopic, and histologic outcome than Billroth II reconstruction.
Schematic representation of Billroth I and II procedures.
Of these procedures, highly selective vagotomy may be the one of choice in the elective setting, except in situations where ulcer recurrence rates are high (prepyloric ulcers and those refractory to medical therapy). Selection of vagotomy and antrectomy may be more appropriate in these circumstances.
These procedures have been traditionally performed by standard laparotomy. The advent of laparoscopic surgery has led several surgical teams to successfully perform highly selective vagotomy, truncal vagotomy/pyloroplasty, and truncal vagotomy/antrectomy through this approach. An increase in the number of laparoscopic procedures for treatment of PUD has occurred. Laparoscopic repair of perforated peptic ulcers is safe, feasible for the experienced surgeon and is associated with decreased postoperative pain although it does take longer than an open approach. Moreover, no difference between the two approaches is noted in postoperative complications or length of hospital stay.
Specific Operations for Gastric Ulcers
The location and the presence of a concomitant DU dictate the operative procedure performed for a GU. Antrectomy (including the ulcer) with a Billroth I anastomosis is the treatment of choice for an antral ulcer. Vagotomy is performed only if a DU is present. Although ulcer excision with vagotomy and drainage procedure has been proposed, the higher incidence of ulcer recurrence makes this a less desirable approach. Ulcers located near the esophagogastric junction may require a more radical approach, a subtotal gastrectomy with a Roux-en-Y esophagogastrojejunostomy (Csende's procedure). A less aggressive approach, including antrectomy, intraoperative ulcer biopsy, and vagotomy (Kelling-Madlener procedure), may be indicated in fragile patients with a high GU. Ulcer recurrence approaches 30% with this procedure.
Complications seen after surgery for PUD are related primarily to the extent of the anatomic modification performed. Minimal alteration (highly selective vagotomy) is associated with higher rates of ulcer recurrence and less GI disturbance. More aggressive surgical procedures have a lower rate of ulcer recurrence but a greater incidence of GI dysfunction. Overall, morbidity and mortality related to these procedures are quite low. Morbidity associated with vagotomy and antrectomy or pyloroplasty is ≤5%, with mortality ˜1%. Highly selective vagotomy has lower morbidity and mortality rates of 1 and 0.3%, respectively.
In addition to the potential early consequences of any intraabdominal procedure (bleeding, infection, thromboembolism), gastroparesis, duodenal stump leak, and efferent loop obstruction can be observed.
The risk of ulcer recurrence is directly related to the procedure performed. Ulcers that recur after partial gastric resection tend to develop at the anastomosis (stomal or marginal ulcer). Epigastric abdominal pain is the most frequent presenting complaint (>90%). Severity and duration of pain tend to be more progressive than observed with DUs before surgery.
Ulcers may recur for several reasons, including incomplete vagotomy, inadequate drainage, retained antrum, and, less likely, persistent or recurrent H. pylori infection. ZES should have been excluded preoperatively. Surreptitious use of NSAIDs is an important reason for recurrent ulcers after surgery, especially if the initial procedure was done for an NSAID-induced ulcer. Once H. pylori and NSAIDs have been excluded as etiologic factors, the question of incomplete vagotomy or retained gastric antrum should be explored. For the latter, fasting plasma gastrin levels should be determined. If elevated, retained antrum or ZES (see below) should be considered. Incomplete vagotomy can be ruled out by gastric acid analysis coupled with sham feeding. In this test, gastric acid output is measured while the patient sees, smells, and chews a meal (without swallowing). The cephalic phase of gastric secretion, which is mediated by the vagus, is being assessed with this study. An increase in gastric acid output in response to sham feeding is evidence that the vagus nerve is intact. A rise in serum pancreatic polypeptide >50% within 30 min of sham feeding is also suggestive of an intact vagus nerve.
Medical therapy with H2 blockers will heal postoperative ulceration in 70–90% of patients. The efficacy of PPIs has not been fully assessed in this group, but one may anticipate greater rates of ulcer healing compared to those obtained with H2 blockers. Repeat operation (complete vagotomy, partial gastrectomy) may be required in a small subgroup of patients who have not responded to aggressive medical management.
Two types of afferent loop syndrome can occur in patients who have undergone partial gastric resection with Billroth II anastomosis. The more common of the two is bacterial overgrowth in the afferent limb secondary to stasis. Patients may experience postprandial abdominal pain, bloating, and diarrhea with concomitant malabsorption of fats and vitamin B12. Cases refractory to antibiotics may require surgical revision of the loop. The less common afferent loop syndrome can present with severe abdominal pain and bloating that occur 20–60 minutes after meals. Pain is often followed by nausea and vomiting of bile-containing material. The pain and bloating may improve after emesis. The cause of this clinical picture is theorized to be incomplete drainage of bile and pancreatic secretions from an afferent loop that is partially obstructed. Cases refractory to dietary measures may need surgical revision.
Dumping syndrome consists of a series of vasomotor and GI signs and symptoms and occurs in patients who have undergone vagotomy and drainage (especially Billroth procedures). Two phases of dumping, early and late, can occur. Early dumping takes place 15–30 minutes after meals and consists of crampy abdominal discomfort, nausea, diarrhea, belching, tachycardia, palpitations, diaphoresis, light-headedness, and, rarely, syncope. These signs and symptoms arise from the rapid emptying of hyperosmolar gastric contents into the small intestine, resulting in a fluid shift into the gut lumen with plasma volume contraction and acute intestinal distention. Release of vasoactive GI hormones (vasoactive intestinal polypeptide, neurotensin, motilin) is also theorized to play a role in early dumping.
The late phase of dumping typically occurs 90 min to 3 h after meals. Vasomotor symptoms (light-headedness, diaphoresis, palpitations, tachycardia, and syncope) predominate during this phase. This component of dumping is thought to be secondary to hypoglycemia from excessive insulin release.
Dumping syndrome is most noticeable after meals rich in simple carbohydrates (especially sucrose) and high osmolarity. Ingestion of large amounts of fluids may also contribute. Up to 50% of postvagotomy and drainage patients will experience dumping syndrome to some degree. Signs and symptoms often improve with time, but a severe protracted picture can occur in up to 1% of patients.
Dietary modification is the cornerstone of therapy for patients with dumping syndrome. Small, multiple (six) meals devoid of simple carbohydrates coupled with elimination of liquids during meals is important. Antidiarrheals and anticholinergic agents are complementary to diet. Guar and pectin, which increase the viscosity of intraluminal contents, may be beneficial in more symptomatic individuals. Acarbose, an α-glucosidase inhibitor that delays digestion of ingested carbohydrates, has also been shown to be beneficial in the treatment of the late phases of dumping. The somatostatin analogue octreotide has been successful in diet-refractory cases. This drug is administered subcutaneously (50 μg tid), titrated according to clinical response. A long-acting depot formulation of octreotide can be administered once every 28 days and provides symptom relief comparable to the short-acting agent. In addition, patient weight gain and quality of life appear to be superior with the long-acting form.
Up to 10% of patients may seek medical attention for the treatment of postvagotomy diarrhea. This complication is most commonly observed after truncal vagotomy. Patients may complain of intermittent diarrhea that occurs typically 1–2 hours after meals. Occasionally the symptoms may be severe and relentless. This is due to a motility disorder from interruption of the vagal fibers supplying the luminal gut. Other contributing factors may include decreased absorption of nutrients (see below), increased excretion of bile acids, and release of luminal factors that promote secretion. Diphenoxylate or loperamide is often useful in symptom control. The bile salt–binding agent cholestyramine may be helpful in severe cases. Surgical reversal of a 10-cm segment of jejunum may yield a substantial improvement in bowel frequency in a subset of patients.
A subset of postpartial gastrectomy patients who present with abdominal pain, early satiety, nausea, and vomiting will have mucosal erythema of the gastric remnant as the only finding. Histologic examination of the gastric mucosa reveals minimal inflammation but the presence of epithelial cell injury. This clinical picture is categorized as bile or alkaline reflux gastropathy/gastritis. Although reflux of bile is implicated as the reason for this disorder, the mechanism is unknown. Prokinetic agents, cholestyramine, and sucralfate have been somewhat effective treatments. Severe refractory symptoms may require using either nuclear scanning with 99mTc-HIDA to document reflux or an alkaline challenge test, where 0.1 N NaOH is infused into the stomach in an effort to reproduce the patient's symptoms. Surgical diversion of pancreaticobiliary secretions away from the gastric remnant with a Roux-en-Y gastrojejunostomy consisting of a long (50–60 cm) Roux limb has been used in severe cases. Bilious vomiting improves, but early satiety and bloating may persist in up to 50% of patients.
Maldigestion and Malabsorption
Weight loss can be observed in up to 60% of patients after partial gastric resection. A significant component of this weight reduction is due to decreased oral intake. However, mild steatorrhea can also develop. Reasons for maldigestion/malabsorption include decreased gastric acid production, rapid gastric emptying, decreased food dispersion in the stomach, reduced luminal bile concentration, reduced pancreatic secretory response to feeding, and rapid intestinal transit.
Decreased serum vitamin B12 levels can be observed after partial gastrectomy. This is usually not due to deficiency of IF, since a minimal amount of parietal cells (source of IF) are removed during antrectomy. Reduced vitamin B12 may be due to competition for the vitamin by bacterial overgrowth or inability to split the vitamin from its protein-bound source due to hypochlorhydria.
Iron-deficiency anemia may be a consequence of impaired absorption of dietary iron in patients with a Billroth II gastrojejunostomy. Absorption of iron salts is normal in these individuals; thus, a favorable response to oral iron supplementation can be anticipated. Folate deficiency with concomitant anemia can also develop in these patients. This deficiency may be secondary to decreased absorption or diminished oral intake.
Malabsorption of vitamin D and calcium resulting in osteoporosis and osteomalacia is common after partial gastrectomy and gastrojejunostomy (Billroth II). Osteomalacia can occur as a late complication in up to 25% of postpartial gastrectomy patients. Bone fractures occur twice as commonly in men after gastric surgery as in a control population. It may take years before x-ray findings demonstrate diminished bone density. Elevated alkaline phosphatase, reduced serum calcium, bone pain, and pathologic fractures may be seen in patients with osteomalacia. The high incidence of these abnormalities in this subgroup of patients justifies treating them with vitamin D and calcium supplementation indefinitely. Therapy is especially important in females.
The incidence of adenocarcinoma in the gastric stump is increased 15 years after resection. Some have reported a four- to fivefold increase in gastric cancer 20–25 years after resection. The pathogenesis is unclear but may involve alkaline reflux, bacterial proliferation, or hypochlorhydria. The role of endoscopic screening is not clear, and most guidelines do not support its use.