PDF: Chapter 16 Peptic Ulcer Disease

ITESM Access Provided by: Greenberger's CURRENT Diagnosis & Treatment Gastroenterology, Hepatology, & Endoscopy, 4e Chapter 16: Peptic Ulcer Disease Edwar...

ITESM Access Provided by: Greenberger's CURRENT Diagnosis & Treatment Gastroenterology, Hepatology, & Endoscopy, 4e Chapter 16: Peptic Ulcer Disease Edward Lew ESSENTIALS OF DIAGNOSIS ESSENTIALS OF DIAGNOSIS Peptic ulcers are mucosal defects in the stomach or small intestine. Helicobacter pylori infection, nonsteroidal anti­inflammatory drugs (NSAIDs), and aspirin use are the most common causes. Patients may have epigastric pain or complications such as gastrointestinal (GI) bleeding, perforation, and obstruction. Diagnosis is often made by endoscopy or radiologic studies. GENERAL CONSIDERATIONS Peptic ulcers are defects or breaks in the gastric or small intestinal mucosa that have depth and extend through the muscularis mucosae. In contrast to erosions, which are small and superficial mucosal lesions, peptic ulcers can vary in size from 5 mm to several centimeters and may lead to complications such as GI bleeding, obstruction, penetration, and perforation. The pathogenesis of peptic ulcers is multifactorial and arises from an imbalance of protective and aggressive factors such as when GI mucosal defense mechanisms are impaired in the presence of gastric acid and pepsin. Peptic ulcer disease was long considered an idiopathic and lifelong disorder. This paradigm changed dramatically in 1984 when Marshall and Warren reported that a curved bacillus, initially named Campylobacter pyloridis and subsequently classified as H pylori, was linked to ulcers. Multiple studies have since shown that eradication of H pylori significantly reduces the rate of ulcer recurrence. Another major risk factor for peptic ulcers is the use of NSAIDs and aspirin. These medications generally exert their therapeutic and toxic effects by inhibiting the enzymes cyclooxygenase­1 (COX­1) and cyclooxygenase­2 (COX­2), which, in turn, impair mucosal protection and promote ulcers. The treatment of ulcer patients has been revolutionized since the development of the acid­suppressive medications such as the histamine­2 (H2)­receptor blockers and proton pump inhibitors (PPIs), the synthetic prostaglandin misoprostol, and the selective COX­2 inhibitors. Only a small fraction of ulcers is associated with neoplasia or caused by acid hyper­secretory states such as Zollinger­Ellison syndrome and other rare disorders. The incidence of both gastric and duodenal ulcers in developed countries rapidly increased throughout the 19th century and peaked during the first half of the 20th century. Since the 1950s, however, the incidence and prevalence of both ulcers have steadily declined. There has also been a decrease in the prevalence of H pylori over recent decades, attributed to improved hygiene and widespread use of antibiotics in developed countries. Hospital discharge data for the general U.S. population showed that the age­adjusted hospitalization rates for peptic ulcer disease and H pylori were highest among adults age 65 years and older and decreased with each subsequent age group. These trends are thought to reflect an underlying birth cohort effect with a decrease in H pylori incidence among younger generations. The lifetime prevalence of peptic ulcers in the general population is estimated to be about 5–10% with an incidence of 0.1–0.3% per year. The development of peptic ulcer increases with age, with most ulcers occurring between 25 and 64 years of age. A systematic review of the literature on the epidemiology of peptic ulcer disease estimated an annual incidence ranging from 0.10% to 0.19% for physician­diagnosed peptic ulcers and from 0.03% to 0.17% for peptic ulcers diagnosed during hospitalization. However, more current estimates are likely to be lower especially in developed countries because of a declining incidence of peptic ulcers during the past 20 to 30 years along with a decline in H pylori infection. GI bleeding, perforation, and gastric outlet obstruction are the main complications of peptic ulcers. The incidence of bleeding ulcers in the general population ranges from 0.27 Downloaded and 1.0611:0 2025­2­19 per A 1000 Yourperson­years, IP is while that of perforated ulcers is 0.03 to 0.30 per 1000 person­years. Although hospital admissions Chapter 16: Peptic Ulcer Disease, Edward Lew Page for peptic ulcer bleeding have steadily declined, the case fatality rate remains as high as 5–10%. Peptic ulcer complications can also adversely 1 / 16 affect ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility functional status and quality of life. The lifetime prevalence of peptic ulcers in the general population is estimated to be about 5–10% with an incidence of 0.1–0.3% per year. The ITESMon the development of peptic ulcer increases with age, with most ulcers occurring between 25 and 64 years of age. A systematic review of the literature epidemiology of peptic ulcer disease estimated an annual incidence ranging from 0.10% to 0.19% for physician­diagnosed peptic ulcers and from Access Provided by: 0.03% to 0.17% for peptic ulcers diagnosed during hospitalization. However, more current estimates are likely to be lower especially in developed countries because of a declining incidence of peptic ulcers during the past 20 to 30 years along with a decline in H pylori infection. GI bleeding, perforation, and gastric outlet obstruction are the main complications of peptic ulcers. The incidence of bleeding ulcers in the general population ranges from 0.27 and 1.06 per 1000 person­years, while that of perforated ulcers is 0.03 to 0.30 per 1000 person­years. Although hospital admissions for peptic ulcer bleeding have steadily declined, the case fatality rate remains as high as 5–10%. Peptic ulcer complications can also adversely affect functional status and quality of life. Gurusamy KS, Pallari E. Medical versus surgical treatment for refractory or recurrent peptic ulcer. Cochrane Database Syst Rev. 2016;3(3): CD011523. [PubMed: 27025289] Lanas A, Chan FKL. Peptic ulcer disease. Lancet. 2017;390:613–624. [PubMed: 28242110] Malmi H, Kautiainen H, Virta LJ, Färkkilä N, Koskenpato J, Färkkilä MA. Incidence and complications of peptic ulcer disease requiring hospitalisation have markedly decreased in Finland. Aliment Pharmacol Ther. 2014;39(5):496–506 [PubMed: 24461085] Sverdén E, Agréus L, Dunn JM, Lagergren J. Peptic ulcer disease. BMJ. 2019;367:l5495. [PubMed: 31578179] PATHOGENESIS A. Causes of Peptic Ulcers H pylori infection and the use of NSAIDs and aspirin have numerous effects on the GI tract and are the most common causes of peptic ulcers (Table 16– 1). In general, both factors disrupt normal mucosal defenses and repair, making the mucosa more susceptible to acid. Suppression of gastric acid secretion using pharmacologic agents heals ulcers and reduces future complications. Only a few patients have an underlying acid hypersecretory state causing ulcers. For example, less than 1% of patients with duodenal ulcers have a gastrin­secreting tumor causing profound acid secretion as part of the Zollinger­Ellison syndrome. Approximately 3–5% of gastric ulcers represent malignancy including adenocarcinoma, lymphoma, or metastatic lesions. Other infections and conditions that increase ulcer formation include cytomegalovirus or herpes simplex (especially among immunosuppressed patients), tuberculosis, Crohn’s disease, the use of other non­NSAID medications, hyperparathyroidism, sarcoidosis, myeloproliferative disorder, and systemic mastocytosis. Table 16–1. Risk factors for peptic ulcers. Helicobacter pylori infection NSAIDs and aspirin use Other medications (eg, potassium chloride, concomitant use of corticosteroids with NSAIDs, bisphosphonates, selective serotonin reuptake inhibitors, sirolimus, mycophenolate mofetil, 5­fluorouracil) Neoplasia Acid hypersecretory disorders (eg, Zollinger­Ellison syndrome) Hyperparathyroidism Crohn’s disease Sarcoidosis Myeloproliferative disorder Systemic mastocytosis Other rare infections (eg, cytomegalovirus, herpes simplex, tuberculosis) Critically ill patients with severe burns, head injury, physical trauma, or multiple organ failure Downloaded 2025­2­19 NSAIDs, nonsteroidal 11:0 A Your IP anti­inflammatory is drugs. Chapter 16: Peptic Ulcer Disease, Edward Lew Page 2 / 16 ©2025 McGraw Cigarette smokingHill. alsoAllpromotes Rights Reserved. Terms of the development of ulcers Use Privacy and mayPolicy Notice interact with H pylori Accessibility and NSAIDs to increase mucosal injury. Smoking also impairs ulcer healing and increases ulcer recurrence. Several studies suggest that alcohol use and diet do not appear to increase ulcer formation, whereas emotional stress may predispose some individuals to ulcers. Critically ill patients with severe burns, physical trauma, or multiple organ failure  Myeloproliferative disorder Systemic mastocytosis ITESM Other rare infections (eg, cytomegalovirus, herpes simplex, tuberculosis) Access Provided by: Critically ill patients with severe burns, head injury, physical trauma, or multiple organ failure NSAIDs, nonsteroidal anti­inflammatory drugs. Cigarette smoking also promotes the development of ulcers and may interact with H pylori and NSAIDs to increase mucosal injury. Smoking also impairs ulcer healing and increases ulcer recurrence. Several studies suggest that alcohol use and diet do not appear to increase ulcer formation, whereas emotional stress may predispose some individuals to ulcers. Critically ill patients with severe burns, physical trauma, or multiple organ failure also have an increased risk of developing gastroduodenal ulcers and associated complications. There is also an association of peptic ulcers with medical conditions such as chronic obstructive lung disease and chronic renal failure, but the mechanisms are unclear. A genetic susceptibility has been reported but is thought to stem mainly from intra familial infection with H pylori. Recent studies suggest that an increasing proportion of ulcers are idiopathic, as they are not related to H pylori, NSAIDs, aspirin, acid hypersecretion, or any other known cause. In a pooled analysis of six clinical trials, for example, 27% of duodenal ulcers had no etiologic cause identified. In other studies, the proportion of idiopathic ulcers that is H pylori negative and NSAID negative without any other detectable causes ranges from 20% to 44%. Patients who develop bleeding from H pylori negative and non­NSAID idiopathic ulcers have also been shown to have a nearly four­fold increased risk of recurrent GI bleeding and higher mortality as compared to patients with bleeding from H pylori associated ulcers. These idiopathic ulcers appear to be more common in older people with comorbid conditions and have a high rate of relapse. Emma S, Lars A, Jason MD, Jesper L. Peptic ulcer disease BMJ. 2019;367:l5495. [PubMed: 31578179] Kavitt RT, Lipowska AM, Anyane­Yeboa A, Gralnek IM. Diagnosis and treatment of peptic ulcer disease. Am J Med. 2019;132(4):447–456. [PubMed: 30611829] Crooks CJ1, West J, Card TR. Comorbidities affect risk of nonvariceal upper gastrointestinal bleeding. Gastroenterology. 2013;144:1384–1393. [PubMed: 23470619] B. Helicobacter pylori Infection H pylori is a spiral gram­negative urease­producing bacterium that can be found in the mucus coating the gastric mucosa or between the mucus layer and gastric epithelium. Multiple factors enable the bacterium to live in the hostile stomach acid environment, including its ability to produce urease, which helps alkalinize the surrounding pH. H pylori infection is most commonly acquired in childhood and results in a chronic active gastritis that is usually lifelong without specific treatment. Risk factors for acquiring H pylori include low socioeconomic status, household crowding, and country of origin. In most regions, the main mechanism of spread is intrafamilial transmission. The prevalence of H pylori varies among different countries and remains high in most developing countries and is generally related to socioeconomic status and levels of hygiene. Most infected persons remain asymptomatic, but approximately 10–15% develop peptic ulcer disease during their lifetime. In addition to causing chronic gastritis and peptic ulcers, H pylori has been associated with the development of gastric adenocarcinoma and gastric mucosa­associated lymphoid tissue (MALT) lymphoma. A study from Japan with a mean follow­up of 7.8 years reported that gastric cancer developed in 2.9% of patients with peptic ulcer, dyspepsia, and gastric hyperplasia who had H pylori infection but in none of the uninfected patients with these conditions. There is an increased incidence of gastric cancer associated with H pylori in other areas including the Middle East, Southeast Asia, the Mediterranean, Eastern Europe, Central America, and South America. In 1994, the International Agency for Research on Cancer classified H pylori as a group 1 carcinogen and a definite cause of gastric cancer in humans. Infection with H pylori increases the risk of peptic ulcers and GI bleeding from threefold to sevenfold. Depending on the population, H pylori is present in up to 70–90% of patients with duodenal ulcers and up to 30–60% of gastric ulcers. Multiple clinical studies show that H pylori eradication reduces ulcer recurrence to less than 10% as compared with recurrences of 70% with acid suppression alone. H pylori generally causes mucosal injury and ulcer complications through inflammation and cytokines. Despite a vigorous systemic and mucosal humoral response, antibody production does not lead to eradication of the infection. H pylori is a highly heterogeneous bacterium. A combination of microbial and host factors determines the outcome of H pylori infection. The virulence of the organism, host genetics, and environmental factors affect the distribution and severity of gastric inflammation and level of acid secretion. The ability of H pylori strains to produce different proteins has been linked to their virulence and affects the host immune response. Several H pylori virulence factors have been associated with gastric atrophy, intestinal metaplasia, and risk of disease. For example, the presence of H pylori virulence Downloaded 2025­2­19 11:0 A Your IP is factors that affect the induction of proinflammatory cytokine release or adhesion to the epithelial cell partly explain geographic differences in the Chapter 16: Peptic Ulcer Disease, Edward Lew Page 3 / 16 incidence ©2025 McGrawof gastric Hill.cancer. Several All Rights of these bacterial Reserved. Terms of virulence factors Use Privacy include Policy the Cag Notice patho­genicity island (cagPAI), PicB, and the vacuolating Accessibility cytotoxin (VacA). H pylori also expresses adhesins such as blood group antigen­binding adhesin (BabA) and outer inflammatory protein adhesion (OipA) which facilitate attachment of the bacteria to gastric epithelium. H pylori that express the cytotoxin­associated gene A (CagA­positive strains) lead to eradication of the infection. ITESM H pylori is a highly heterogeneous bacterium. A combination of microbial and host factors determines the outcome of H pylori infection. The virulence Access Provided by: of the organism, host genetics, and environmental factors affect the distribution and severity of gastric inflammation and level of acid secretion. The ability of H pylori strains to produce different proteins has been linked to their virulence and affects the host immune response. Several H pylori virulence factors have been associated with gastric atrophy, intestinal metaplasia, and risk of disease. For example, the presence of H pylori virulence factors that affect the induction of proinflammatory cytokine release or adhesion to the epithelial cell partly explain geographic differences in the incidence of gastric cancer. Several of these bacterial virulence factors include the Cag patho­genicity island (cagPAI), PicB, and the vacuolating cytotoxin (VacA). H pylori also expresses adhesins such as blood group antigen­binding adhesin (BabA) and outer inflammatory protein adhesion (OipA) which facilitate attachment of the bacteria to gastric epithelium. H pylori that express the cytotoxin­associated gene A (CagA­positive strains) reportedly represent virulent strains having greater interactions with humans. Several genes in a genomic fragment that make up a Cag pathogenicity island encode components of a type IV secretion island that translocates CagA in host cells and affects cell growth and cytokine production. CagA is a highly antigenic protein that is associated with a prominent inflammatory response by eliciting interleukin­8 production. H pylori strains that also express active forms of VacA or the outer membrane proteins BabA and OipA are similarly associated with a higher risk of diseases than are strains that lack these factors. Blaser MJ. Heterogeneity of Helicobacter pylori. Eur J Gastroenterol Hepatol. 2012;9(suppl 1):S3–S6. [PubMed: 22498905] Hooi JKY, Lai WY, Ng WK, et al. Global prevalence of Helicobacter pylori infection: systematic review and meta­analysis. Gastroenterology. 2017;153:420–429. [PubMed: 28456631] Robinson K, John C, Atherton JC. The spectrum of Helicobacter­mediated diseases. Annu Rev Pathol. 2021;16:123–144. [PubMed: 33197219] Sheila EC. Helicobacter pylori infection. N Engl J Med. 2019;380(12):1158–1165. [PubMed: 30893536] C. Aspirin & NSAIDS Aspirin and NSAIDs are among the most frequently used drugs worldwide. NSAIDs are used to treat pain and inflammation, whereas aspirin is being increasingly used for primary and secondary prevention of cardiovascular events. Unfortunately, these drugs have substantial GI toxicity and are associated with the development of peptic ulcers and life­threatening GI bleeding. Endoscopic studies have shown that up to 15–30% of patients on NSAIDs develop gastric and duodenal ulcers. Epidemiologic studies also suggest that the risks of ulcer complications and death among regular NSAID users are 3–10 times higher as compared with those not taking these drugs. The elderly are at particularly increased risk, and one study found that the adjusted hospitalization rate for ulcer complications was 16.7 per 1000 person­years among elderly Medicaid patients on NSAIDs, in contrast to a rate of 4.2 among nonusers, with an attributable rate of 12.5 excess hospitalizations for ulcer disease per 1000 person­years among users. Aspirin and other NSAIDs generally exert their therapeutic and toxic effects by inhibiting COX­1 and COX­2 isoenzymes, which, in turn, decrease prostaglandin synthesis. COX­1 is the rate­limiting enzyme for GI prostaglandins that normally help maintain mucosal blood flow and increase secretion of mucus and bicarbonate. Inhibition of COX­1 impairs mucosal protection and leads to ulcers. The risks of peptic ulcers and GI bleeding are dependent on the dose, duration, and type of NSAID. Older age and a previous history of GI bleeding or ulcers significantly increase the development of peptic ulcers among NSAID users. In a meta­analysis, the pooled relative risks for ulcer complications ranged from 1.6 to 9.2, according to the individual NSAID, with a pooled relative risk of 1.6 for aspirin. Even very low doses of aspirin have been associated with ulcers and GI bleeding, suggesting that there are no true safe doses of aspirin. A case­control study, for example, found that low­dose aspirin and nonaspirin NSAIDs both significantly increased the risk of ulcer bleeding with odds ratios of 2.4 and 7.4, respectively. Concomitant use of NSAIDs or aspirin with corticosteroids, selective serotonin­reuptake inhibitors, aldosterone antagonists, or anticoagulants significantly increase the risk of upper GI bleeding. Laine L, Curtis SP, Cryer B, et al. Risk factors for NSAID­associated upper GI clinical events in a long­term prospective study of 34 701 arthritis patients. Aliment Pharmacol Ther. 2010;32:1240–1248. [PubMed: 20955443] Lanas A, Chan FKL. Peptic ulcer disease. Lancet. 2017;390:613–624. [PubMed: 28242110] Downloaded 2025­2­19 11:0 A Your IP is Chapter 16: Peptic Ulcer Disease, Edward Lew Page 4 / 16 MascleeMcGraw ©2025 GM, Valkhoff Hill. AllVE, Coloma Rights PM, et al.Terms Reserved. Risk ofofupper Use gastrointestinal Privacy Policy bleeding Notice from different drug combinations. Gastroenterology. Accessibility 2014;147(4):784–792. [PubMed: 24937265] Laine L, Curtis SP, Cryer B, et al. Risk factors for NSAID­associated upper GI clinical events in a long­term prospective study of 34 701 arthritis patients. Aliment Pharmacol Ther. 2010;32:1240–1248. ITESM Access Provided by: [PubMed: 20955443] Lanas A, Chan FKL. Peptic ulcer disease. Lancet. 2017;390:613–624. [PubMed: 28242110] Masclee GM, Valkhoff VE, Coloma PM, et al. Risk of upper gastrointestinal bleeding from different drug combinations. Gastroenterology. 2014;147(4):784–792. [PubMed: 24937265] CLINICAL FINDINGS A. Symptoms & Signs Epigastric pain is the classic symptom associated with peptic ulcer disease. The pain is often described as a gnawing, dull, aching, “empty,” or “hunger­ like” sensation. The classic pain associated with duodenal ulcer is sometimes relieved with ingestion of milk, food, or antacids but recurs 2–4 hours after eating and may also awaken the patient at night. In contrast, most patients with gastric ulcers report that eating exacerbates the pain. During fasting, they may have relief of their symptoms, which then recur shortly after eating. As a result, some gastric ulcer patients experience nausea, avoidance of food/anorexia, and even weight loss. Peptic ulcer symptoms tend to recur at intervals of weeks or months due to healing and relapse while patients continue to have H pylori infection or use NSAIDs. An acute worsening or change in the pain characteristic such as generalized pain may arise from ulcer penetration or perforation. Alarm symptoms such as melena, hematemesis, guaiac­positive stools, and unexplained anemia suggest possible ulcer bleeding, while persistent vomiting may represent obstruction. Early satiety, anorexia, and unexplained weight loss may arise from cancer. Patients with upper abdominal pain with radiation to the back may have penetration, while those with severe or worsening abdominal pain may have perforation. However, many ulcer patients present with few or no symptoms until the development of complications such as GI bleeding, perforation, penetration, and obstruction. In one study, abdominal pain was absent in over 30% of older patients with peptic ulcers seen on upper endoscopy. Less common symptoms such as nausea and vomiting may arise from a gastric outlet obstruction with ulcer edema or scarring. The physical examination is unreliable and often normal, although some ulcer patients have epigastric tenderness to deep palpation. Occult or gross blood may be detected in the setting of bleeding ulcers. Tachycardia and orthostasis may be found in patients with significant bleeding or dehydration, while a rigid abdomen with diffuse rebound tenderness may reflect ulcer perforation with peritonitis. Rarely, a distended abdomen or a succession splash can be noted in patients with an ulcer that is complicated by outlet obstruction. Most duodenal ulcers develop in the bulb or pylori channel. Patients with duodenal ulcers tend to have a younger age of onset, often between 30 and 55 years of age on average. These duodenal ulcer patients also have an increased parietal cell mass and acid secretion (with increased average basal and nocturnal gastric acid secretion). Bicarbonate secretion has been reported to be impaired among patients with active duodenal ulcers. It is thought that the imbalance between duodenal acid load and buffering capacity leads to the development of small islands of gastric metaplasia in the duodenal bulb. Colonization of these islands by H pylori subsequently leads to duodenitis and duodenal ulcer. In the stomach, most benign ulcers are found in the antrum and lesser curvature of the stomach at the junction of the body and antrum. Gastric ulcers often occur later in life, usually among patients between the ages of 55 and 70 years with a peak incidence in the sixth decade. Patients with gastric ulcers often have normal or decreased acid secretion. A few patients present with both gastric and duodenal ulcers are found to have increased acid secretion. The gastric ulcers in these patients tend to be in the distal antrum or pyloric channel. B. Endoscopy Definitive diagnosis of peptic ulcers can be made using upper endoscopy. Endoscopy has a much higher diagnostic yield than barium contrast radiology and enables biopsy specimens to be obtained for evaluation of H pylori infection and underlying malignancy. Because up to 5% of gastric ulcers are malignant, it is generally recommended that biopsy samples be taken from the ulcer margin or that a follow­up endoscopy be scheduled 12 weeks after starting acid­suppressive medications to document complete healing. Ulcers greater than 3 cm in size and those that are associated with a mass are more likely to be malignant. In contrast, the incidence of malignant duodenal ulcers is extremely low; thus, they do not routinely require biopsy. Actively bleeding ulcers or ulcers at high risk for rebleeding can also be treated during endoscopy with hemostasis therapy. Patients suspected of having an ulcer who present with alarm symptoms, such as GI bleeding, early satiety, and unexplained weight loss, and those Downloaded 2025­2­19 who are elderly 11:0 A prompt should undergo Your IPevaluation is with endoscopy. Patients who are found to have multiple ulcers, refractory ulcers, or ulcers in Chapter 16: Peptic Ulcer Disease, Edward Lew or who have diarrhea and weight loss should also be considered for evaluation of Zollinger­Ellison unusual locations, such as postbulbar or jejunum, Page 5 / 16 ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility syndrome. In contrast, there is some controversy as to the best approach for initial evaluation and treatment of young patients under the age of 50–55 years who ulcers are malignant, it is generally recommended that biopsy samples be taken from the ulcer margin or that a follow­up endoscopy be scheduled 12 ITESM weeks after starting acid­suppressive medications to document complete healing. Ulcers greater than 3 cm in size and those that are associated with a Access Provided by: mass are more likely to be malignant. In contrast, the incidence of malignant duodenal ulcers is extremely low; thus, they do not routinely require biopsy. Actively bleeding ulcers or ulcers at high risk for rebleeding can also be treated during endoscopy with hemostasis therapy. Patients suspected of having an ulcer who present with alarm symptoms, such as GI bleeding, early satiety, and unexplained weight loss, and those who are elderly should undergo prompt evaluation with endoscopy. Patients who are found to have multiple ulcers, refractory ulcers, or ulcers in unusual locations, such as postbulbar or jejunum, or who have diarrhea and weight loss should also be considered for evaluation of Zollinger­Ellison syndrome. In contrast, there is some controversy as to the best approach for initial evaluation and treatment of young patients under the age of 50–55 years who present with ulcer­like symptoms or dyspepsia without alarm symptoms, in an area with a low incidence of gastric cancer and a prevalence of H pylori over 20%. Possible options include (1) testing and treating for H pylori, (2) treating with acid­suppressive medications and monitoring response, or (3) making a direct referral for evaluation with upper endoscopy. Prompt endoscopy potentially offers a small benefit in terms of finding a specific diagnosis and directing treatment but is not cost effective for the initial management of dyspepsia as compared to the other strategies. Instead, several other studies recommend that young patients with undifferentiated dyspepsia initially undergo noninvasive testing for H pylori followed by treatment if this infection is present. Successful cure of H pylori potentially reduces the need for endoscopy as well as ulcer recurrence, and clinical studies suggest that this strategy does not adversely affect outcomes. Further evaluation with endoscopy is recommended for patients with persistent symptoms despite therapy. Alternatively, young patients with a presentation suggestive of uncomplicated ulcers may first be given empiric treatment with acid­suppressive medications. Further evaluation is recommended if these patients continue to have persistent or recurrent symptoms 2–4 weeks later. All patients should discontinue aspirin and NSAIDs if possible, as well as stop alcohol, smoking, and use of illicit drugs. In one large clinical trial, patients having dyspepsia without alarm symptoms were randomized to testing and treating for H pylori versus empiric PPI therapy. After 1 year of follow­up, patients in the two groups had a similar rate of persistent dyspeptic symptoms, and both strategies were found to be equally cost effective in the initial management of dyspepsia. It is notable that over 80% of these patients continued to experience dyspeptic symptoms despite eradication of H pylori (82%) or acid­suppressive therapy (83%). Delaney BC, Qume M, Moayyedi P, et al. Helicobacter pylori test and treat versus proton pump inhibitor in initial management of dyspepsia in primary care: multicentre randomized controlled trial (MRC­CUBE trial). BMJ. 2008;336:651–654. [PubMed: 18310262] Eusebi LH, Black CJ, Howden CW, et al. Effectiveness of management strategies for uninvestigated dyspepsia: systematic review and network meta­ analysis. BMJ. 2019;367:l6483s. [PubMed: 31826881] C. Barium Studies Barium upper GI studies are safer and cheaper than endoscopy, but they have limited accuracy for detecting ulcers and other mucosal lesions. In contrast to endoscopy, barium upper GI studies do not permit biopsy and other specimens to be obtained for histologic evaluation or allow immediate treatment of bleeding ulcers. D. Tests to Diagnose Helicobacter pylori Infection Several methods are available to detect H pylori infection (Table 16–2). The noninvasive tests include serologic testing, urea breath test, and stool antigen test. Infection can also be detected during endoscopy in which a biopsy sample is obtained for a rapid urease testing, histologic study, or even culture. Serum immunoassays for immunoglobulin G (IgG) antibodies to H pylori are inexpensive but have a reported sensitivity of 85% and specificity of 79%. As a result, the positive predictive value of serologic testing is limited in populations with a low pretest probability of having the infection such as areas in which the prevalence is 30% or less. The prevalence of H pylori in the United States is estimated to be 30%. Moreover, serologic testing should not be used to determine the success of H pylori cure after treatment since antibody titers can persist for years and do not always become negative. The urea breath test or the stool antigen test can be used for both the initial diagnosis and follow­up of eradication therapy because they have excellent sensitivities and specificities. Urea breath testing is based on detecting H pylori­derived urease activity in the stomach (with a sensitivity and specificity exceeding 95%), whereas the stool antigen test uses polyclonal anti­H pylori capture antibody adsorbed to microwells (with sensitivity and specificity exceeding 92%). It is generally recommended to wait at least 4 weeks or more after completing eradication therapy to confirm successful cure. To help minimize false­negative results, PPIs should be withheld for at least 2–4 weeks and antibiotics and bismuth compounds for 4 weeks prior to testing, as these drugs have suppressive effects on H pylori. Since the use of H2­receptor blockers does not need to be restricted, they may be used to help manage heartburn and other GI symptoms prior to H pylori testing. Downloaded 2025­2­19 11:0 A Your IP is Chapter 16: Peptic Ulcer Disease, Edward Lew Table 16–2. Page 6 / 16 ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Diagnostic tests for Helicobacter pylori. have excellent sensitivities and specificities. Urea breath testing is based on detecting H pylori­derived urease activity in the stomach (with a sensitivity and specificity exceeding 95%), whereas the stool antigen test uses polyclonal anti­H pylori capture antibody adsorbed to microwells (withITESM sensitivity and specificity exceeding 92%). It is generally recommended to wait at least 4 weeks or more after completing eradication therapy to confirm successful Access Provided by: cure. To help minimize false­negative results, PPIs should be withheld for at least 2–4 weeks and antibiotics and bismuth compounds for 4 weeks prior to testing, as these drugs have suppressive effects on H pylori. Since the use of H2­receptor blockers does not need to be restricted, they may be used to help manage heartburn and other GI symptoms prior to H pylori testing. Table 16–2. Diagnostic tests for Helicobacter pylori. Sensitivity Specificity Test Comments (%) (%) Noninvasive Urea breath 95–100 91–98 Recommended for both screening and confirming cure; recent use of antibiotics, bismuth, and PPIs can test increase false­negative results H pylori stool 91–96 93–97 Can be used for initial diagnosis and to confirm successful cure; recent use of antibiotics, bismuth, and antigen test PPIs can decrease antigen load in stool Serologic ELISA 85–92 79–83 Detects exposure to H pylori but cannot be used to confirm successful cure after treatment. May remain positive for years after eradication of H. pylori infection. However, test not influenced by recent use of PPI or antibiotics. Invasive Endoscopy with biopsy Histology >95 >95–98 Widely used method of diagnosis during endoscopy; sensitivity is improved by taking at least 2 biopsies from antrum and 1 from body of stomach Rapid 93–97 95–100 Reduced accuracy reported among patients with GI bleeding urease test (CLO test) Culture 70–80 100 Technically demanding; sensitivity varies among laboratories CLO, Campylobacter­like organism; ELISA, enzyme­linked immunosorbent assay; GI, gastrointestinal; PPI, proton pump inhibitor. Note: Patients are recommended to stop bismuth, antibiotics, and proton pump inhibitors at least 4 weeks before H. pylori testing for active infection using either urea breath test, stool antigen test, and histology. In patients who undergo endoscopy, an antral biopsy can be obtained for rapid urease testing, which has a sensitivity of 89–100% and specificity of 92– 100%. Biopsies can also be performed, and specimens sent for histologic examination using routine hematoxylin and eosin staining. The presence of polymorphonuclear leukocytes in inflamed gastric tissue is suggestive of H pylori gastritis. In biopsy specimens in which H pylori cannot be found, the use of modified Giemsa, Warthin­Starry, Genta, and other stains may be helpful. Culture of H pylori from biopsy samples has a specificity of 100% if results are positive, but it is not routinely performed. Because culture is difficult to perform and expensive, it is usually reserved to determine antibiotic susceptibilities for patients who fail to respond to second­line eradication therapy. DIFFERENTIAL DIAGNOSIS In some studies, only half of patients with peptic ulcer present with classic symptoms. Unfortunately, the history and physical examination are neither Downloaded 2025­2­19 11:0 A Your IP is sensitive nor Peptic Chapter 16: specificUlcer enough to accurately Disease, Edwarddiagnose Lew peptic ulcers or distinguish between duodenal and gastric ulcers. A diagnosis of a peptic ulcer Page 7 / 16 may be McGraw ©2025 suspected in selected Hill. All Rightspatients presenting Reserved. Termswith epigastric of Use pain, Privacy but the Policy differential Notice is broad and includes gastroesophageal reflux disease, Accessibility biliary tract disease, hepatitis, pancreatitis, abdominal aortic aneurysm, gastroparesis, functional dyspepsia, neoplasia, mesenteric ischemia, and myocardial ischemic pain, among others. results are positive, but it is not routinely performed. Because culture is difficult to perform and expensive, it is usually reserved to determine antibiotic susceptibilities for patients who fail to respond to second­line eradication therapy. ITESM Access Provided by: DIFFERENTIAL DIAGNOSIS In some studies, only half of patients with peptic ulcer present with classic symptoms. Unfortunately, the history and physical examination are neither sensitive nor specific enough to accurately diagnose peptic ulcers or distinguish between duodenal and gastric ulcers. A diagnosis of a peptic ulcer may be suspected in selected patients presenting with epigastric pain, but the differential is broad and includes gastroesophageal reflux disease, biliary tract disease, hepatitis, pancreatitis, abdominal aortic aneurysm, gastroparesis, functional dyspepsia, neoplasia, mesenteric ischemia, and myocardial ischemic pain, among others. Although peptic ulcers can be diagnosed during upper endoscopy, laboratory and radiologic tests may help narrow the differential diagnosis. Some ulcer patients are anemic due to acute bleeding or chronic blood loss from benign or malignant ulcers. Liver function tests and levels of amylase and lipase should be checked to help evaluate for hepatitis and pancreatitis. An abdominal ultrasound may show gallstone disease or an abdominal aortic aneurysm. An electrocardiogram and measurement of cardiac enzymes help evaluate myocardial causes of pain. Finally, an acute abdominal series with upright and lateral decubitus views showing free air suggests perforation. COMPLICATIONS The most common complication associated with peptic ulcers is the development of GI hemorrhage. Up to 15% of peptic ulcers bleed, and affected patients have a mortality rate of 4.5–8.5%. Patients older than 60 years of age have a higher incidence of bleeding ulcers and mortality. Those who also have a large initial bleed, continued or recurrent bleeding, or severe comorbid illnesses have the greatest risk of death. Patients with bleeding ulcers can present with hematemesis or coffee ground emesis, passage of black tarry stool, and rarely, hematochezia. Up to 7% of ulcer patients have perforation with severe abdominal pain and a rigid abdomen from peritonitis. Owing to the widespread use of NSAIDs among the elderly, they are at increased risk, and many do not present with antecedent ulcer pain or peritoneal findings. Penetration occurs when the ulcer crater erodes into an adjacent organ as, for example, when a duodenal ulcer penetrates the pancreas leading to pancreatitis or a gastric ulcer penetrates the left hepatic lobe. Gastric outlet obstruction occurs in less than 2% of ulcer patients and may arise from ulcer inflammation and edema in the prepyloric area. Chronic ulcer scarring in the prepyloric area can also lead to a fixed mechanical obstruction that may require endoscopic balloon dilation or surgical therapy. This diagnosis should be suspected in patients who complain of nausea, vomiting, early satiety, and weight loss, especially if they also have dehydration and electrolyte imbalances. TREATMENT A. General Principles Treatment of peptic ulcers consists of healing the ulcer and preventing ulcer recurrences and future complications. All ulcer patients should be tested and treated for H pylori even if they have a clear history of NSAID or aspirin use. It is not clinically possible to determine whether ulcers arise directly from H pylori, NSAID/aspirin use, or a combination of these factors. Although H pylori and NSAID use cause most ulcers, the level of acid secretion still plays a role in pathogenesis and healing. Multiple studies show that the administration of acid­suppressive medications promotes active ulcer healing. Bleeding peptic ulcers account for 40–60% of patients presenting with acute upper GI bleeding. Please refer to Chapter 20 for further details on the diagnosis and management of these patients. In summary, patients suspected of having significant ulcer bleeding should be started on an intravenous PPI followed by prompt endoscopy within 24 hours of presentation. Patients with tachycardia (heart rate ≥100 beats per minute), hypotension (systolic blood pressure ≤100 mm Hg), age older than 60 years, and major coexisting conditions are at increased risk for further bleeding and death. There are several risk­assessment tools such as the Glasgow­Blatchford score that help stratify low­ and high­risk patients. Using a restrictive blood transfusion strategy to target a hemoglobin >7 g/dL has been associated with a lower risk of further bleeding and all cause mortality. However, a higher hemoglobin threshold may be considered for symptomatic patients or those with underlying cardiovascular disease. The administration of intravenous PPIs before endoscopy downstages the ulcer lesion and the need for hemostasis therapy as compared to placebo. After endoscopic hemostasis, PPIs have also been shown to significantly reduce rebleeding, the need for repeat endoscopic therapy, and surgery. Intravenous therapy also reduced mortality in Asian trials and in a subgroup of ulcer patients having active bleeding or a nonbleeding visible vessel. Intravenous PPI therapy should be maintained for the first 72 hours in high­risk patients since most rebleeding occurs during this time. Other meta­analyses suggest that intermittent or twice daily dosing of an intravenous PPI is not inferior to a high dose continuous infusion. The promotility agent, erythromycin at 250 mg given intravenously 30 minutes prior to endoscopy increases gastric motility and visualization of the mucosa, which may reduce the need for blood transfusions and repeat endoscopy. Downloaded 2025­2­19 11:0 A Your IP is Chapter 16: Peptic Ulcer Disease, Edward Lew Page 8 / 16 A recentMcGraw ©2025 randomized clinical Hill. All trial Rights reported no Reserved. outcome Terms differences of Use Privacybetween Policy urgent Notice versus early endoscopy (defined as endoscopy within 6 hours Accessibility versus 6–24 hours after GI consultation, respectively) for 30­day all­cause mortality, recurrent bleeding, transfusion requirement, or length of hospital stay. In multiple studies, endoscopic hemostasis has been shown to significantly reduce rebleeding, surgery, and mortality and is recommended for hemostasis, PPIs have also been shown to significantly reduce rebleeding, the need for repeat endoscopic therapy, and surgery. Intravenous therapy ITESM also reduced mortality in Asian trials and in a subgroup of ulcer patients having active bleeding or a nonbleeding visible vessel. Intravenous PPI therapy should be maintained for the first 72 hours in high­risk patients since most rebleeding occurs during this time. Other meta­analyses suggest Access Provided by: that intermittent or twice daily dosing of an intravenous PPI is not inferior to a high dose continuous infusion. The promotility agent, erythromycin at 250 mg given intravenously 30 minutes prior to endoscopy increases gastric motility and visualization of the mucosa, which may reduce the need for blood transfusions and repeat endoscopy. A recent randomized clinical trial reported no outcome differences between urgent versus early endoscopy (defined as endoscopy within 6 hours versus 6–24 hours after GI consultation, respectively) for 30­day all­cause mortality, recurrent bleeding, transfusion requirement, or length of hospital stay. In multiple studies, endoscopic hemostasis has been shown to significantly reduce rebleeding, surgery, and mortality and is recommended for high­risk ulcers, based on their endoscopic appearance and likelihood of further bleeding. High­risk ulcers include those that are actively spurting or oozing blood, those that have a nonbleeding visible vessel, or those that have an adherent clot. Please refer to Chapter 20: Acute Upper Gastrointestinal Bleeding for more details on the various hemostasis strategies, which may include a combination of thermocoagulation therapy (using bipolar electrocoagulation probes or heater probes), placement of hemoclips (mechanical therapy), and injection of epinephrine, alcohol, or a sclerosant (injection therapy). Thermocoagulation or clip placement, either alone or with epinephrine injection, are effective, but epinephrine injection alone is not recommended. Instead, adding a second modality to epinephrine injection is superior to epinephrine injection alone in reducing recurrent bleeding, surgery, and mortality. Endoscopic therapy should be repeated if bleeding recurs. Surgery or transcatheter arterial embolization can be performed if repeat endoscopic therapy fails. Complications of bleeding or perforation occur in about 0.5% of patients undergoing endoscopic therapy. Second­look endoscopy may be useful in selected patients but is not routinely recommended. Nonhealing gastric ulcers should be biopsied or closely followed to exclude underlying neoplasia. After discharge, patients having high­risk ulcers and clinical factors such as tachycardia and hypotension, older age, or major coexisting conditions should receive PPI therapy twice daily for 2 weeks followed by once daily dosing. In contrast, patients having erosions or ulcers without high­risk endoscopic findings and no hemodynamic instability or major coexisting conditions can be given once daily PPI therapy. Barkun AN, Almadi M, Kuipers EJ, et al. Management of nonvariceal upper gastrointestinal bleeding: guideline recommendations from the International Consensus Group. Ann Intern Med. 2019;171:805–822. [PubMed: 31634917] Laine L. Upper gastrointestinal bleeding due to a peptic ulcer. N Engl J Med. 2016;375(12):1198. [PubMed: 27653581] Lau JY, Yu Y, Tang RS, et al. Timing of endoscopy for acute upper gastrointestinal bleeding. N Engl J Med. 2020;382:1299–1308. [PubMed: 32242355] Sung JJ, Chiu PW, Chan FKL, et al. Asia­Pacific working group consensus on non­variceal upper gastrointestinal bleeding: an update 2018. Gut. 2018;67(10):1757–1768. [PubMed: 29691276] B. Peptic Ulcers in Patients Requiring Chronic NSAIDs Patients who develop peptic ulcers while using NSAIDs should be tested and treated for H pylori and the NSAID should be discontinued if possible. H pylori eradication alone is insufficient to completely prevent recurrent GI complications among ulcer patients who continue to take NSAIDs. Acid­ suppressive medication, usually with a PPI, should also be administered to help the ulcer. PPIs block acid secretion by irreversibly binding and inhibiting the hydrogen­potassium ATPase that resides on the luminal surface of the parietal cell. Commonly used PPIs include omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole. Potassium­competitive acid blockers such as vonoprazan are also now being developed that reportedly have a more rapid onset of action, longer duration and more effective acid suppression than the PPIs. Among different patients, there may be less pharmacokinetic variation than the PPI since clinical efficacy is not altered by CYP2C19 polymorphisms. If patients cannot switch to acetaminophen and require chronic NSAIDs, they should consider taking the lowest effective NSAID dose along with co­ therapy with either a PPI or a prostaglandin analog called misoprostol. These drugs have been shown to significantly reduce recurrent ulcer complications among chronic NSAID users. Unfortunately, misoprostol at 200 mcg four times daily is often associated with cramps, diarrhea, and poor patient compliance. Drugs that selectively inhibit COX­2 were developed to have similar analgesic and anti­inflammatory effects as traditional NSAIDs but with a reduced risk of GI complications. Several studies have suggested that COX­2 inhibitors help treat musculoskeletal as well as arthritic conditions with fewer ulcer complications because they do not inhibit the gastric mucosal prostaglandins. Among healed ulcer patients, the use of a COX­2 inhibitor had a lower rate of adverse upper and lower GI events as compared to the strategy of providing a traditional NSAID with PPI co­therapy. Another trial has also shown that combining Downloaded 2025­2­19 a selective COX­2 11:0 A Your IPinhibitor is with a PPI was even more effective in preventing recurrent ulcer bleeding than taking a COX­2 Chapter 16: Peptic Ulcer Disease, Edward Lew Page 9 / 16 inhibitor alone. However, COX­2 inhibitors have been also associated with an increased risk of cardiovascular and thrombotic events. The exact ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility mechanisms for this are not clear but may be related to the fact that thromboxane A2 is a COX­1­mediated product that causes irreversible platelet aggregation, vasoconstriction, and smooth muscle proliferation. In contrast, prostacyclin is synthesized from COX­2 and is an inhibitor of platelet patient compliance. ITESM Drugs that selectively inhibit COX­2 were developed to have similar analgesic and anti­inflammatory effects as traditional NSAIDs but with a reduced Access Provided by: risk of GI complications. Several studies have suggested that COX­2 inhibitors help treat musculoskeletal as well as arthritic conditions with fewer ulcer complications because they do not inhibit the gastric mucosal prostaglandins. Among healed ulcer patients, the use of a COX­2 inhibitor had a lower rate of adverse upper and lower GI events as compared to the strategy of providing a traditional NSAID with PPI co­therapy. Another trial has also shown that combining a selective COX­2 inhibitor with a PPI was even more effective in preventing recurrent ulcer bleeding than taking a COX­2 inhibitor alone. However, COX­2 inhibitors have been also associated with an increased risk of cardiovascular and thrombotic events. The exact mechanisms for this are not clear but may be related to the fact that thromboxane A2 is a COX­1­mediated product that causes irreversible platelet aggregation, vasoconstriction, and smooth muscle proliferation. In contrast, prostacyclin is synthesized from COX­2 and is an inhibitor of platelet aggregation while causing vasodilation and inhibition of smooth muscle proliferation. Selective inhibition of COX­2 may lead to an imbalance in these products that promotes thrombosis. Thus, clinicians must be judicious when prescribing these drugs. COX­2 inhibitors should be considered for chronic NSAID patients who have a substantial risk of ulcer complications but a low risk of cardiovascular disease. The addition of low­dose aspirin to a COX­2 inhibitor increases the ulcer rate to that seen with nonselective NSAIDs. A recent randomized clinical trial found that among patients with cardio­ thrombotic diseases and a history of upper GI bleeding combining a COX­2 inhibitor plus proton­pump inhibitor is superior to using a nonselective NSAIDs plus proton­pump inhibitor for prevention of recurrent upper GI bleeding. As a result, this strategy should be considered for patients at high risk of both cardiovascular and GI events who require aspirin and NSAID for cardiovascular and anti­inflammatory therapies. Barkun AN, Almadi M, Kuipers EJ, et al. Management of nonvariceal upper gastrointestinal bleeding: guideline recommendations from the International Consensus Group. Ann Intern Med. 2019;171:805–822. [PubMed: 31634917] Chan FKL, Ching JYL, Tse YK, et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (concern): an industry­independent, double­blind, double­dummy, randomised trial. The Lancet. 2017;389:2375– 2382. [PubMed: 31924632] Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J Gastroenterol. 2012;107(3):345–360. [PubMed: 22310222] C. Peptic Ulcers in Patients Requiring Chronic Antiplatelet Therapy or Antithrombotic Therapy The use of enteric­coated or buffered aspirin does not substantially reduce the risk of ulcer complications compared to noncoated aspirin due to the systemic effects of these drugs. There are also other widely used antiplatelet drugs such as clopidogrel that selectively and irreversibly block the adenosine diphosphate receptor on platelets. Clopidogrel, with or without aspirin, has been shown to be beneficial in the treatment of acute coronary syndrome and in the prevention of ischemic events among patients with atherosclerotic diseases. As expected, the combined use of clopidogrel with aspirin causes a greater increase in GI bleeding risk compared to aspirin alone. Patients who are taking aspirin and present with potential ulcer complications such as GI bleeding should receive intravenous PPI therapy and undergo upper endoscopy. Ulcers that are found to have high­risk bleeding stigmata are then treated with hemostasis therapy. Testing and treating for H pylori as well as providing secondary prophylaxis with a PPI have been shown to be effective in reducing recurrent aspirin­induced GI complications. The coadministration of an acid lowering medication such as a PPI with aspirin greatly reduces recurrent ulcer bleeding as compared to switching patients to clopidogrel alone. One randomized trial reported that PPIs were superior to high­dose H2­receptor antagonists in preventing recurrent aspirin­related ulcers and erosions. However, another randomized clinical trial of high­risk aspirin users found no significant difference in using a H2­ receptor antagonist versus a PPI to prevent recurrent upper GI bleeding and ulcers. In this study, a slightly lower proportion of patients receiving a PPI along with aspirin developing recurrent bleeding or ulcer than did patients receiving a H2­receptor antagonist with aspirin, but this difference was not statistically significant. Among patients requiring chronic aspirin therapy who suffer an acute ulcer bleed, it had been unclear when to safely resume aspirin. Restarting aspirin before the ulcer has adequately healed potentially increases recurrent bleeding, but delayed administration of aspirin may also lead to greater cardiovascular or ischemic events in high­risk patients. This issue has been addressed in a large study of aspirin patients with a bleeding ulcer who underwent endoscopic hemostasis followed by maintenance therapy with a PPI. These patients were then randomized to promptly resuming aspirin versus withholding aspirin for 8 weeks after endoscopy. Patients who continued taking aspirin had no significant increase in rebleeding but had significantly lower mortality at 30 days (1% vs 9%) and 8 weeks (1% vs 13%). The protective effects of aspirin appear to outweigh its potential for further short­term GI complications that mainly occurred within 5 days after the index bleed. Aspirin should thus be restarted as soon as the risk for Downloaded 2025­2­19 cardiovascular 11:0 A Your events outweighs IP is the risk for recurrent ulcer complications. Current recommendations include resuming aspirin 1–7 days after the Chapter bleeding stops and providing co­therapy withLew 16: Peptic Ulcer Disease, Edward a PPI to reduce rebleeding. Page 10 / 16 ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility The management of patients requiring other antiplatelet or antithrombotic therapy who develop peptic ulcers and GI bleeding should be tailored to individual patients based on the severity of bleeding and risk of thromboembolism. For example, patients receiving dual antiplatelet therapy for a aspirin before the ulcer has adequately healed potentially increases recurrent bleeding, but delayed administration of aspirin may also lead to greater ITESM cardiovascular or ischemic events in high­risk patients. This issue has been addressed in a large study of aspirin patients with a bleeding ulcer who underwent endoscopic hemostasis followed by maintenance therapy with a PPI. These patients were then randomized to promptly resuming Accessaspirin Provided by: versus withholding aspirin for 8 weeks after endoscopy. Patients who continued taking aspirin had no significant increase in rebleeding but had significantly lower mortality at 30 days (1% vs 9%) and 8 weeks (1% vs 13%). The protective effects of aspirin appear to outweigh its potential for further short­term GI complications that mainly occurred within 5 days after the index bleed. Aspirin should thus be restarted as soon as the risk for cardiovascular events outweighs the risk for recurrent ulcer complications. Current recommendations include resuming aspirin 1–7 days after the bleeding stops and providing co­therapy with a PPI to reduce rebleeding. The management of patients requiring other antiplatelet or antithrombotic therapy who develop peptic ulcers and GI bleeding should be tailored to individual patients based on the severity of bleeding and risk of thromboembolism. For example, patients receiving dual antiplatelet therapy for a drug­eluding stent should not stop both antiplatelet drugs because of a high rate of stent thrombosis. Patients receiving warfarin but develop severe ulcer bleeding exacerbated by coagulopathy may be managed using various approaches that include vitamin K, fresh frozen plasma, prothrombin complex concentrates, or recombinant factor VIIa, and each have different advantages and disadvantages for the individual patient. Warfarin should be resumed once adequate hemostasis has been achieved. The use of direct oral anticoagulants (DOACs) has been shown to be more effective than warfarin in reducing thromboembolism risk, however, DOACs cannot be reversed by vitamin K and some agents have a higher risk of major GI bleeding than warfarin. Decisions regarding management of acute GI bleeding from DOACs depends on the severity of bleeding, timing of the last dose, creatinine clearance and hepatic function. DOACs have a rapid onset of action and restarting these drugs should be delayed until adequate hemostasis has been achieved. For example, the Asian Pacific Association of Gastroenterology and the Asian Pacific Society for Digestive Endoscopy recommend resuming DOACs by day 3 once hemostasis is achieved, and without bridging therapy. The following guidelines are also from an international consensus group for the management of upper GI bleeding that are conditional recommendations based on low­quality evidence: 1) In patients with previous ulcer bleeding receiving cardiovascular prophylaxis with single­ or dual­antiplatelet therapy, the use of PPI therapy is recommended over no therapy. 2) In patients with previous ulcer bleeding requiring continued cardiovascular prophylaxis with anticoagulant therapy (vitamin K antagonists, DOACs), the use of PPI therapy is recommended over no therapy. This international consensus group also commented on weighing the risks and benefits of PPI therapy. They acknowledged that meta­analyses of primarily observational studies have suggested possible associations between PPI therapy and adverse effects, including community­acquired pneumonia, hip fracture, colorectal cancer, chronic kidney disease, community­acquired enteric infection, and Clostridium difficile infection. However, their analysis of factors, such as consistency, specificity, temporality, and biological plausibility, as well as confounding factors, showed that the evidence for causality is very weak. The consensus group felt that for high­risk patients with an ongoing need for anticoagulants, the evidence suggests that the benefits of secondary prophylaxis outweigh the risks. They concluded that the unproven potential and rare safety concerns should not prevent treatment for patients at risk for life­threatening consequences. Barkun AN, Almadi M, Kuipers EJ, et al. Management of nonvariceal upper gastrointestinal bleeding: guideline recommendations from the International Consensus Group. Ann Intern Med. 2019;171:805–822. [PubMed: 31634917] Chan FKL, Goh KL, Reddy N, et al. Management of patients on antithrombotic agents undergoing emergency and elective endoscopy: joint Asian Pacific Association of Gastroenterology (APAGE) and Asian Pacific Society for Digestive Endoscopy (APSDE) practice guidelines. Gut. 2018;67:405–417 [PubMed: 29331946] Chan FK, Kyaw M, Tanigawa T, et al. Similar efficacy of proton­pump inhibitors vs H2­receptor antagonists in reducing risk of upper gastrointestinal bleeding or ulcers in high­risk users of low­dose aspirin. Gastroenterology. 2017;152(1):105–110. [PubMed: 27641510] Lanas A, Chan FKL. Peptic ulcer disease. Lancet. 2017;390:613–624. [PubMed: 28242110] Sengupta N, Marshall AL, Jones BA, et al. Rebleeding vs thromboembolism after hospitalization for gastrointestinal bleeding in patients on direct oral anticoagulants. Clin Gastroenterol Hepatol. 2018;16(12):1893–1900. [PubMed: 29775794] D. Eradication Therapy for Helicobacter pylori Infection Patients with active duodenal or gastric ulcers and those with a prior ulcer history should be tested and treated for H pylori. The number of patients who would need to be treated for H pylori infection to prevent a recurrent duodenal ulcer is two and for recurrent gastric ulcer is three. After successful cure, reinfection with H pylori is considered rare. In the United States, the estimated incidence is approximately 1 reinfection per 100 patients per year. Patients with early stage MALT lymphoma (type I or II) should also be tested and treated for H pylori since eradication of this infection can induce Downloaded 2025­2­19 11:0 A Your IP is remission in many patients when the tumor is limited to the stomach. However, the treatment of more advanced stages of MALToma may also involve Chapter 16: Peptic Ulcer Disease, Edward Lew Page 11 / 16 chemotherapy, radiation, and surgery. There are several GI consensus groups, including the ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Maastricht V Consensus Report that recommend testing and treating several other groups of patients for H pylori, but there is limited evidence of benefit. This includes patients diagnosed with gastric adenocarcinoma, especially those with early­stage disease undergoing resection. In a randomized clinical trial among patients with early gastric cancer D. Eradication Therapy for Helicobacter pylori Infection ITESM Patients with active duodenal or gastric ulcers and those with a prior ulcer history should be tested and treated for H pylori. The number of patients Access Provided by: who would need to be treated for H pylori infection to prevent a recurrent duodenal ulcer is two and for recurrent gastric ulcer is three. After successful cure, reinfection with H pylori is considered rare. In the United States, the estimated incidence is approximately 1 reinfection per 100 patients per year. Patients with early stage MALT lymphoma (type I or II) should also be tested and treated for H pylori since eradication of this infection can induce remission in many patients when the tumor is limited to the stomach. However, the treatment of more advanced stages of MALToma may also involve chemotherapy, radiation, and surgery. There are several GI consensus groups, including the Maastricht V Consensus Report that recommend testing and treating several other groups of patients for H pylori, but there is limited evidence of benefit. This includes patients diagnosed with gastric adenocarcinoma, especially those with early­stage disease undergoing resection. In a randomized clinical trial among patients with early gastric cancer or high grade adenoma who underwent endoscopic resection, those who received H pylori treatment had a lower incidence of metachronous gastric cancer and improvement from baseline in the grade of gastric glandular atrophy at the corpus than did patients who received placebo. Other groups who should be considered for H pylori testing and treating include patients found to have atrophic gastritis or intestinal metaplasia, and first­degree relatives of patients with gastric adenocarcinoma since the relatives themselves are at increased risk of gastric cancer partly due to the intra familial transmission of H pylori. Although the mechanisms are unknown, a few studies suggest that H pylori may play a role in autoimmune disorders such as idiopathic thrombocytopenic purpura. Eradication of H pylori has been shown to increase the platelet count in these patients. It is also recommended to consider testing and treating for H pylori among patients with vitamin B12 deficiency and otherwise unexplained iron deficiency anemia. Successful H. pylori eradication among patients with unexplained iron deficiency anemia may reverse the anemia and improve iron absorption. Some studies also suggest that screening and treating for H pylori among patients who are starting or taking long­term NSAID therapy or those taking long­term aspirin may reduce the risk of peptic ulcer disease or ulcer bleeding. To date, it remains controversial whether to test and treat all patients with functional dyspepsia, gastroesophageal reflux disease, or other non­GI disorders as well as asymptomatic individuals. The success of H pylori eradication depends on bacterial factors as well as the type and duration of therapy, and patient compliance. Patients most often fail to respond to initial H pylori therapy because of antibiotic resistance and/or noncompliance with taking the prescribed regimen. The appropriate treatment regimen for eradication of H. pylori should be tailored according to local prevalence of antibiotic resistance if available. Antibiotic resistance to H pylori is categorized as primary if there has not been any previous eradication therapy, or as secondary if resistance was acquired as a result of ineffective eradication attempts. A careful patient history including any penicillin allergies and inquiry about prior use of specific antibiotics such as macrolide antibiotics (eg, clarithromycin, azithromycin, and erythromycin) should be obtained to assess for possible resistance. Prior to initiating eradication therapy, patients should also be given careful instructions not to arbitrarily miss any doses. There are multiple treatment regimens for H pylori eradication and most include a PPI combined with 2 or more antibiotics for 7–14 days (Table 16–3). Some commonly prescribed antibiotics include amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin; studies often report cure rates ranging from 70% to 90% with these agents. Meta­analyses suggest that a 14­day treatment regimen has higher eradication rates and is more cost effective compared with 7­day therapy. Due to regional antibiotic resistance differences, a 14­day regimen is more effective in the United States and is recommended by the U.S. Food and Drug Administration. Triple therapy was previously a commonly prescribed regimen that uses a PPI (given twice daily) along with clarithromycin (500 mg twice daily) and amoxicillin (1 g twice daily) or metronidazole (500 mg twice daily, for penicillin­allergic patients). Unfortunately, H pylori is becoming increasingly resistant to clarithromycin, metronidazole, and levofloxacin in many areas of the world. A clarithromycin­based regimen should not be used in areas where the resistance rate is known to be greater than 15%. In contrast to metronidazole, H pylori resistance to clarithromycin cannot be easily overcome by increasing the dose of the drug. Clarithromycin­resistance has been reported to be as high as 30% in Southern Europe and even 50% in China. The clarithromycin resistance rates in many different geographic regions in the United States are not known and thus many authorities have advocated for surveillance registries for H pylori resistance and local therapy success rates. Table 16–3. Common treatment regimens for Helicobacter pylori. Treatment Regimen Duration Comments Quadruple bismuth therapy PPI twice daily 14 days Recommended for first line therapy as well as for second line or rescue therapy, Tetracycline, 500 mg four times daily especially in areas with high resistance to clarithromycin. Metronidazole, 250­500 mg four times daily or 500 mg three times daily Bismuth four times daily: ­Bismuth subcitrate 120­300 mg or 420 mg ­Bismuth subsalicylate 300 or 524 mg Downloaded 2025­2­19 11:0 A Your IP is Chapter 16: Peptic Ulcer Disease, Edward Lew Page 12 / 16 ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Concomitant therapy nonbismuth quadruple therapy  Tetracycline, 500 mg four times daily especially in areas with high resistance to clarithromycin. Metronidazole, 250­500 mg four times daily or 500 ITESM mg three times daily Access Provided by: Bismuth four times daily: ­Bismuth subcitrate 120­300 mg or 420 mg ­Bismuth subsalicylate 300 or 524 mg Concomitant therapy nonbismuth quadruple therapy PPI twice daily 14 days First line therapy in areas with low primary resistance to clarithromycin. Also Amoxicillin 1000 mg twice daily recommended for rescue therapy. Metronidazole 500 mg or Tinidazole 500 mg twice daily Clarithromycin 500 mg twice daily Triple therapy PPI twice daily 14 days Restricted use for first line therapy if the clarithromycin resistance rate is less than Clarithromycin 500 mg twice daily, or 15% in the community. Metronidazole, 500 mg twice daily Amoxicillin 1000 mg twice daily PPI twice daily 14 days Restricted use for first­line therapy in penicillin­allergic patients if the clarithromycin Clarithromycin 500 mg twice daily resistance rate is less than 15% in the community. Metronidazole 500 mg twice daily Levofloxacin­based triple therapy PPI twice daily 10–14 Recommended for second­line or rescue therapy but ACG states may also consider Levofloxacin 250 mg twice daily or 500 mg once days for first line. daily Amoxicillin 1000 mg twice daily for 10 days Sequential nonbismuth quadruple PPI twice daily 10–14 ACG states may consider for first line therapy. The efficacy of clarithromycin Amoxicillin 1000 mg twice daily for the first half days sequential therapy may be suboptimal in areas with a high rate of triple therapy only failure. Metronidazole 500 mg + Clarithromycin 500 mg twice daily for the second half of therapy only Hybrid nonbismuth quadruple therapy PPI twice daily 14 days Hybrid therapy is not widely endorsed for first line therapy. Amoxicillin 1000 mg twice daily Metronidazole 500 mg + Clarithromycin 500 mg twice daily for the second half of therapy only High­dose dual therapy Rabeprazole 20 mg four times daily 14 days Recommended option for second­line or rescue therapy. Amoxicillin 75 mg four times daily Downloaded 2025­2­19 Rifabutin therapy 11:0 A Your IP is Chapter 16: Peptic Ulcer Disease, Edward Lew Page 13 / 16 ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility PPI twice daily 10 days Recommended option for third or fourth­line rescue therapy if susceptibility testing is Amoxicillin, 1000 mg twice daily not available.  High­dose dual therapy ITESM Access Provided by: Rabeprazole 20 mg four times daily 14 days Recommended option for second­line or rescue therapy. Amoxicillin 75 mg four times daily Rifabutin therapy PPI twice daily 10 days Recommended option for third or fourth­line rescue therapy if susceptibility testing is Amoxicillin, 1000 mg twice daily not available. Rifabutin 150 mg twice daily or 300 mg daily ACG, American College of Gastroenterology; PPI, proton pump inhibitor. The dose of PPI will depend on brand used. In many regimens, metronidazole can be substituted by tinidazole. The eradication rate is significantly affected by the regional variation in H. pylori resistance patterns. The best strategy is to achieve successful cure of H pylori on the first attempt to minimize costs and to avoid retreating, retesting, and potential adverse effects on other gut microbiota. The use of antibiotic susceptibility data would help limit inappropriate antibiotic use, prevent widespread resistance in other organisms and reduce costs, but these data are typically not available in the US or many other parts of the world. Several experts and consensus groups have reviewed the best available evidence and published treatment guidelines including the American College of Gastroenterology (ACG), the European Helicobacter and Microbiota Study Group (Maastricht V/Florence report), and the Canadian Association of Gastroenterology/Canadian Helicobacter Study Group (Toronto Consensus). To maximize successful eradication on the first attempt, most experts agree that quadruple therapy should have a more prominent role and most treatments should be given for 14 days. For first line therapy, bismuth quadruple therapy is recommended especially in areas with resistance to clarithromycin and metronidazole while concomitant therapy is useful for patients from areas of low resistance to clarithromycin where bismuth is not available. Bismuth quadruple therapy, for example, includes a PPI twice daily and four­times­daily dosing of antibiotics with tetracycline (500 mg) and metronidazole (250–500 mg), along with bismuth subsalicylate or subcitrate. Patients with a true penicillin allergy should use the bismuth quadruple therapy or the clarithromycin based triple therapy with metronidazole if there is no prior use of macrolides and the patient is from an area of low clarithromycin resistance. If a patient fails an initial treatment for H pylori eradication, it is generally recommended to avoid re­using the antibiotics in that failed regimen, especially if it included clarithromycin and levofloxacin. However, it is reasonable to consider re­using metronidazole in a bismuth regimen due to a synergistic effect as well as re­using amoxicillin and tetracycline because resistance to these agents is rare. Depending on what agents were used, an acceptable second line therapy includes the bismuth quadruple therapy or levofloxacin triple therapy. After failure of a second attempt or subsequent attempts, it is then highly recommended to consider culture with susceptibility testing if possible. If this is not available, then again depending on the prior regimens, it is acceptable to consider bismuth quadruple therapy (if patients were on clarithromycin triple therapy and then levofloxacin­based therapy), as well as concomitant therapy. There are also recommendations for a high­dose dual therapy with amoxicillin (750 mg qid) and a PPI (20 mg qid) as well as regimens using rifabutin as salvage treatment for H pylori. Unfortunately, rifabutin has been associated with 2% incidence of myelotoxicity among patients being treated for H pylori which appears to be reversible and does not appear to increase susceptibility to infections. However, because of this risk, the ACG recommends prescribing the rifabutin regimen for 10 days. Otherwise, most authorities recommend 14 days for all salvage therapies. To date, the evidence for any benefit in using adjunct probiotics to improve eradication rates or reduce treatment­associated side effects remains low but is still being studied. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: treatment of Helicobacter pylori infection. Am J Gastroenterol. 2017;112(2):212–239. [PubMed: 28071659] Choi IJ, Kook MC, Kim YI, et al. Helicobacter pylori therapy for the prevention of metachronous gastric cancer. N Engl J Med. 2018;378(12):1085–1095. [PubMed: 29562147] Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection­the Maastricht V/Florence Consensus Report. Gut. 2017;66(1):6–30. [PubMed: 27707777] Fallone CA, Chiba N, van Zanten SV, et al. The Toronto consensus for the treatment of Helicobacter pylori infection in adults. Gastroenterology. Downloaded 2025­2­19 11:0 A Your IP is 2016;151(1):51–69. Chapter 16: Peptic Ulcer Disease, Edward Lew Page 14 / 16 [PubMed: 27102658] ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Fallone CA, Moss SF, Malfertheiner P. Reconciliation of recent Helicobacter pylori treatment guidelines in a time of increasing resistance to  ITESM Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection­the Maastricht V/Florence Consensus Report. Gut. Access Provided by: 2017;66(1):6–30. [PubMed: 27707777] Fallone CA, Chiba N, van Zanten SV, et al. The Toronto consensus for the treatment of Helicobacter pylori infection in adults. Gastroenterology. 2016;151(1):51–69. [PubMed: 27102658] Fallone CA, Moss SF, Malfertheiner P. Reconciliation of recent Helicobacter pylori treatment guidelines in a time of increasing resistance to antibiotics. Gastroenterology. 2019;157(1):44–53. [PubMed: 30998990] E. Helicobacter pylori & Gastric Adenocarcinoma Up to 5% of gastric ulcers represent underlying neoplasia in some countries. Although the incidence of gastric cancer has steadily declined over the past few decades, it remains a major cause of cancer death worldwide. There is wide regional variation in the incidence of gastric cancer. High incidence rates have been reported in Japan, Eastern Asia, Eastern Europe, and parts of Latin America, while low incidence rates have been reported in the United States and Western Europe. Gastric carcinogenesis, especially for intestinal type gastric cancer is a multistep process, starting from chronic gastritis and progressing over many years to atrophy, intestinal metaplasia, dysplasia, and eventually adenocarcinoma. In animal studies, long­term infection with H pylori in Mongolian gerbils has been shown to induce gastric adenocarcinoma. Three meta­analyses of case­control and cohort studies report summary odds ratios for H pylori and gastric adenocarcinoma of 1.92 (95% confidence interval [CI], 1.32–2.78), 2.5 (95% CI, 1.90–3.40), and 2.04 (95% CI, 1.69–2.45). It is believed that the chronic gastric inflammation from H pylori infection can promote gastric carcinogenesis and progress to the precancerous changes of atrophic gastritis and intestinal metaplasia. The risk of gastric cancer increases in relation to the severity and extent of those precancerous changes. Chronic H pylori infection also contributes to gastric mucosal genetic instability by reducing gastric acid secretion, which can promote the growth of gastric microbiome that processes dietary components into carcinogens. Studies show that eradicating H pylori can resolve the gastric inflammation. This can potentially stop further gastric mucosal damage, prevent further H pylori induced DNA damage, improve gastric acid secretion, and restore the microbiome toward normal. Early data supporting a direct association of H pylori and gastric cancer in humans comes from a long­term cohort study from Japan by Uemura and colleagues. In this study, 1526 patients with various GI disorders, including duodenal ulcers, gastric ulcers, gastric hyperplasia, and nonulcer dyspepsia, underwent endoscopy with biopsy at enrollment and then 1–3 years after enrollment. There were 1246 H pylori­infected and 280 uninfected patients followed for a mean duration of 7.8 years. Among the H pylori patients, 253 received eradication therapy at an early stage of follow­up. Gastric cancer developed in approximately 3% of the infected patients but in none of the uninfected patients. In addition, none of the H pylori patients who received eradication therapy developed gastric cancer. H pylori patients with severe gastric atrophy, corpus­predominant gastritis, and intestinal metaplasia were at significantly higher risk for gastric cancer. The risk was also increased in almost all subgroups of H pylori­infected patients (those with gastric ulcers, gastric hyperplastic polyps, or nonulcer dyspepsia) but not in those with duodenal ulcers. It is noteworthy that infected patients who received eradication therapy did not develop gastric cancer. These results support the notion that eradication of H pylori may potentially prevent or delay the development of cancer. In a systematic review and meta­analysis of 24 studies, eradication of H pylori infection reduced the incidence of gastric cancer. After adjustment for baseline gastric cancer incidence, individuals with eradication of H pylori infection had a lower incidence of gastric cancer than those who did not receive eradication therapy (pooled incidence rate ratio = 0.53; 95% CI: 0.44–0.64). Eradication provided significant benefit for asymptomatic infected individuals (pooled incidence rate ratio, 0.62; 95% CI: 0.49–0.79) and individuals after endoscopic resection of gastric cancers (pooled incidence rate ratio, 0.46; 95% CI: 0.35–0.60). It is known that the risk of gastric cancer is greater in patients with low gastric acidity such as those with severe atrophic gastritis with intestinal metaplasia and pernicious anemia. Patients who have had a partial gastrectomy are also at risk for gastric cancer after a long latency period, but their risk appears greater after an additional acid­reducing procedure such as vagotomy. Low acid secretion has been hypothesized to predispose to gastric cancer by affecting vitamin C absorption and overgrowth of salivary and intestinal bacteria in the stomach, which potentially promote the formation of carcinogenic nitrosamines. Chronic inflammation with alterations to DNA or changes in expression of cytokines and chemokines may also affect early progression. Host genetics also play a key role, and studies have shown how human genetic polymorphisms profoundly affect gastric carcinogenesis. For example, interleukin­1β is an important proinflammatory cytokine and a powerful inhibitor of acid secretion. Levels of interleukin­1β within the gastric mucosa are increased by H pylori infection. Genetic polymorphisms that promote high expression of interleukin­1β help explain why some H pylori–infected patients develop gastric cancer while others do not. Downloaded 2025­2­19 11:0 A Your IP is Chapter 16: Peptic Ulcer Disease, Edward Lew Page 15 / 16 Cover TL, Blaser MJ. Helicobacter pylori in health and disease. Gastroenterology. 2009;136:1863–1873. ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility [PubMed: 19457415] cancer by affecting vitamin C absorption and overgrowth of salivary and intestinal bacteria in the stomach, which potentially promote the formation of carcinogenic nitrosamines. Chronic inflammation with alterations to DNA or changes in expression of cytokines and chemokines may alsoITESM affect early progression. Host genetics also play a key role, and studies have shown how human genetic polymorphisms profoundly affect gastric carcinogenesis. Access Provided by: For example, interleukin­1β is an important proinflammatory cytokine and a powerful inhibitor of acid secretion. Levels of interleukin­1β within the gastric mucosa are increased by H pylori infection. Genetic polymorphisms that promote high expression of interleukin­1β help explain why some H pylori–infected patients develop gastric cancer while others do not. Cover TL, Blaser MJ. Helicobacter pylori in health and disease. Gastroenterology. 2009;136:1863–1873. [PubMed: 19457415] Lee YC, Chiang TH, Chou CK, et al. Association between Helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta­ analysis. Gastroenterology. 2016;150(5):1113–1124. [PubMed: 26836587] Sheila EC. Helicobacter pylori infection. N Engl J Med. 2019;380(12):1158–1165. [PubMed: 30893536] Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345(11):784–9. [PubMed: 11556297] F. Helicobacter pylori & Gastric MALT Lymphoma Gastric MALT lymphoma is a clonal B­cell neoplasm arising from postgerminal center B­cells in the marginal zone of lymphoid follicles. There is strong evidence supporting a causative role of H pylori infection in the development of gastric low­grade B­cell lymphoma from MALT. Epidemiologic studies have shown that significantly more patients with gastric MALT lymphomas than matched controls have had H pylori infection. In addition, H pylori gastritis has been associated with the induction of gastric lymphoid follicles. It is thought that the H pylori–generated immune responses leads to lymphoid hyperplasia, which along with genetic aberrations activates intracellular survival pathways. The disease can then progress due to proliferation and resistance to apoptosis, and the emergence of a malignant clone. A proliferation­inducing ligand (APRIL) produced by macrophages in the H pylori–infected gastric mucosa also plays an important role in promoting the survival and proliferation of neoplastic B cells. Several investigators have even been able to detect the lymphoma B­cell clone in the chronic H pylori gastritis that preceded the lymphoma. Nevertheless, the strongest evidence of a causal association is that H pylori eradication can induce remission in these patients. Several studies suggested that eradication of H pylori leads to a complete remission of the lymphoma in 60–90% of cases and a pooled data analysis of 34 studies showed that successful cure of H pylori infection was associated with remission of gastric MALT lymphoma in 78% of patients. Many of these patients remain in remission for years. Filip PV, Cuciureanu D, Laura Sorina Diaconu LS, et al. MALT lymphoma: epidemiology, clinical diagnosis and treatment. J Med Life. 2018;11(3):187– 193. [PubMed: 30364585] Nakamura S, Matsumoto T. Treatment strategy for gastric mucosa­associated lymphoid tissue lymphoma. Gastroenterol Clin North Am. 2015;44(3):649–660. [PubMed: 26314674] Munari F, Lonardi S, Cassatella MA, et al. Tumor­associated macrophages as major source of APRIL in gastric MALT lymphoma. Blood. 2011;117:6612–6616. [PubMed: 21527528] Zullo A, Hassan C, Ridola L, et al. Gastric MALT lymphoma: old and new insights. Ann Gastroenterol. 2014;27:27–33. [PubMed: 24714739] Downloaded 2025­2­19 11:0 A Your IP is Chapter 16: Peptic Ulcer Disease, Edward Lew Page 16 / 16 ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility