# 05 - 335 Peptic Ulcer Disease and Related Disorders

### 335 Peptic Ulcer Disease and Related Disorders

the need for diagnostic testing in most patients. When endoscopy is 
performed, localized ulceration or inflammation is evident. Histologi­
cally, acute inflammation is typical. Chest CT imaging will sometimes 
reveal esophageal thickening consistent with transmural inflammation. 
Although the condition usually resolves within days to weeks, symp­
toms may persist for months and stricture can develop in severe cases. 
No specific therapy is known to hasten the healing process, but antise­
cretory medications are frequently prescribed to remove concomitant 
reflux as an aggravating factor. When healing results in stricture forma­
tion, dilation is indicated.

■
■FOREIGN BODIES AND FOOD IMPACTION
Food or foreign bodies may lodge in the esophagus, causing complete 
obstruction, which in turn can cause an inability to handle secretions 
(foaming at the mouth) and severe chest pain. Food impaction may 
occur due to peptic stricture, carcinoma, Schatzki ring, EoE, achala­
sia, or simply inattentive eating. If it does not resolve spontaneously, 
impacted food should be removed endoscopically. Use of meat ten­
derizer enzymes to facilitate passage of a meat bolus is discouraged 
because of potential esophageal injury. Glucagon (1 mg IV) is some­
times tried before endoscopic dislodgement. After emergent treatment, 
patients should be evaluated for potential causes of the impaction with 
treatment rendered as indicated.
ESOPHAGEAL MANIFESTATIONS OF 
SYSTEMIC DISEASE
■
■SCLERODERMA AND CONNECTIVE 

TISSUE DISORDERS
Scleroderma esophagus (hypotensive LES and absent esophageal con­
tractility) was initially described as a manifestation of scleroderma or 
other collagen vascular diseases and thought to be specific for these 
disorders. However, this nomenclature subsequently has been dis­
carded because an estimated half of qualifying patients do not have an 
identifiable rheumatologic disease, and reflux disease is often the only 
identifiable association. When scleroderma esophagus occurs as a man­
ifestation of a connective tissue disorder, the histopathologic findings 
are of infiltration and destruction of the esophageal muscularis propria 
with collagen deposition and fibrosis and reduction in the number of 
interstitial cells of Cajal. The pathogenesis of absent peristalsis and LES 
hypotension in the absence of a connective tissue disorder is unknown. 
Regardless of the underlying cause, the manometric abnormalities pre­
dispose patients to severe GERD due to inadequate LES barrier function 
combined with poor esophageal clearance of refluxed acid. Dysphagia 
may also be manifest but is generally mild and alleviated by eating in an 
upright position and using liquids to facilitate solid transit.
PART 10
Disorders of the Gastrointestinal System
■
■DERMATOLOGIC DISEASES
A host of dermatologic disorders (lichen planus, pemphigus vulgaris, 
bullous pemphigoid, cicatricial pemphigoid, Behçet’s syndrome, and 
epidermolysis bullosa) can affect the oropharynx and esophagus, 
particularly the proximal esophagus, with blisters, bullae, ulceration, 
webs, and strictures. Topical or systemic anti-inflammatory therapy 
is effective for mucosal healing. Stevens-Johnson syndrome and graftversus-host disease can also involve the esophagus. Esophageal dilation 
may be necessary to treat strictures.
■
■FURTHER READING
Hirano I et al: American Gastroenterological Institute and the joint 
task force on allergy-immunology practice parameters clinical guide­
lines for the management of eosinophilic esophagitis. Gastroenterol­
ogy 158:1776, 2020.
Kahrilas PJ et al: Advances in the management of oesophageal motil­
ity disorders in the era of high-resolution manometry: A focus on 
achalasia syndromes. Nat Rev Gastroenterol Hepatol 15:323, 2018.
Katzka DA, Kahrilas PJ: Advances in the diagnosis and manage­
ment of gastroesophageal reflux disease. BMJ 23:371, 2020.
Katzka DA et al: Phenotypes of gastroesophageal reflux disease: 
Where Rome, Lyon, and Montreal meet. Clin Gastroenterol Hepatol 
18:767, 2020.

Shaheen NJ et al: Diagnosis and management of Barrett’s esophagus: 
An updated ACG guideline. Am J Gastroenterol 117:559, 2022.
Straumann A, Katzka DA: Diagnosis and treatment of eosinophilic 
esophagitis. Gastroenterology 154:346, 2018.
Von Arnim U et al: Monitoring patients with eosinophilic esophagitis 
in routine clinical practice – international expert recommendations. 
Clin Gastroenterol Hepatol 21:2526, 2023.
John Del Valle

Peptic Ulcer Disease 

and Related Disorders
PEPTIC ULCER DISEASE
A peptic ulcer is defined as disruption of the mucosal integrity of the 
stomach and/or duodenum leading to a local defect or excavation due 
to active inflammation. Although burning epigastric pain exacerbated 
by fasting and improved with meals is a symptom complex associated 
with peptic ulcer disease (PUD), it is now clear that >90% patients with 
this symptom complex (dyspepsia) do not have ulcers and that the 
majority of patients with peptic ulcers may be asymptomatic. Ulcers 
occur within the stomach and/or duodenum and are often chronic in 
nature. Acid peptic disorders are very common in the United States, 
with 4 million individuals (new cases and recurrences) affected per 
year. Lifetime overall prevalence of PUD in the United States is ~8.4% 
with a slightly higher prevalence in men. PUD significantly affects 
quality of life by impairing overall patient well-being and contribut­
ing substantially to work absenteeism. Moreover, an estimated 15,000 
deaths per year occur as a consequence of complicated PUD. The 
financial impact of these common disorders has been substantial, with 
an estimated burden on direct and indirect health care costs of ~$6 bil­
lion per year in the United States, with $3 billion spent on hospitaliza­
tions, $2 billion on physician office visits, and $1 billion in decreased 
productivity and days lost from work.
■
■GASTRIC PHYSIOLOGY
Gastric Anatomy 
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. 335-1). Highly specialized tuft cells are located in the neck 
region of the gastric gland. These specialized cells are thought to 
sample luminal contents, which in turn may be important in regulating 
gastric acid secretion. Pyloric glands contain mucous and endocrine 
cells (including gastrin cells) and are found in the antrum.
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 unstimu­
lated, parietal cell has prominent cytoplasmic tubulovesicles and intra­
cellular canaliculi containing short microvilli along its apical surface 
(Fig. 335-2). 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 api­
cal 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.

Corpus gland
Human
Corpus
Antrum
Mouse
Antral gland
Corpus
Antrum
FIGURE 335-1  Diagrammatic representation of the oxyntic gastric gland. Cellular constituents of the stomach. The human stomach is divided into three components the 
cardia, the corpus and the antrum. The oxyntic gland which contains the majority of the acid producing cells are located in the corpus.  Glands located in the antrum secrete 
predominantly mucus and also contain the important gastrin producing cells.  It is also important to note that key progenitor cells are located within both the gastric corpus 
and antral glands. (Reproduced with permission from AC Engevik et al: The physiology of the gastric parietal cell. Physiol Rev 100:573, 2020, Figure 1.)
Resting
Stimulated
Canaliculus
HCl
H+,K+–ATPase
KCl
Tubulovesicles
KCl
Active
pump
H3O+
Active
pump
Ca
–
cAMP
Gastrin
ACh
Histamine
FIGURE 335-2  Gastric parietal cell undergoing transformation after secretagoguemediated stimulation. cAMP, cyclic adenosine monophosphate. (Reproduced with 
permission from SJ Hersey, G Sachs: Gastric acid secretion. Am Physiol Soc 75:155, 
1995.)

Surface cells
(MUC5AC)
Progenitor cells
Pit (foveolus)
Mucous neck cells
(MUC6, TFF2)
Parietal cells
(Н/К-АТРаsе)
Isthmus
D cells
(Somatostatin)
ECL cells
(Histidine decarboxylase)
Neck
EC cells
(Serotonin)
X Cell
(Ghrelin)
Base
Chief cells
(MIST1, PGC)
Surface cells
(MUC5AC)
CHAPTER 335
G cells
(Gastrin)
D cells
(Somatostatin)
Pit
ECL cells
(Histidine decarboxylase)
Peptic Ulcer Disease and Related Disorders 
EC cells
(Serotonin)
Progenitor zone
Progenitor cells
(LRIG1, LGR5)
Base
Deep mucous
gland cells
(MUC6, TFF2, CD44v9)
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 ele­
ments (Fig. 335-3). The first line of defense is a mucus-bicarbonatephospholipid 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 glyco­
proteins (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 gastro­
duodenal mucosa into the mucous gel, forms a pH gradient ranging

PART 10
Disorders of the Gastrointestinal System
FIGURE 335-3  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. (Republished with permission of 
John Wiley and Son’s Inc, from Bioregulation and Its Disorders in the Gastrointestinal Tract, T Yoshikawa, T Arakawa [eds]: 1998; permission conveyed through Copyright 
Clearance Center, Inc.)
from 1 to 2 at the gastric luminal surface and reaching 6–7 along the 
epithelial cell surface.
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 intracel­
lular 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. Epi­
thelial cells also generate trefoil factor family peptides and cathelicidins, 
which also play a role in surface cell protection and regeneration. If the 
preepithelial barrier is 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), transform­
ing 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 regenera­
tion 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 regulat­
ing angiogenesis in the gastric mucosa. In addition, the gastric peptide 
gastrin (see below) has been found to stimulate cell proliferation, migra­
tion, invasion, angiogenesis, and autophagy. Finally, gastric parietal cells 
(see below) express sonic hedgehog, a family of proteins important in 
regulating cell lineage in multiple organs. This latter finding suggests 
that parietal cells may also have the ability to regulate gastric stem cells.

Membrane phospholipids
Phospholipase A2
Arachidonic acid
Stomach
Kidney
Platelets
Endothelium
Macrophages
Leukocytes
Fibroblasts
Endothelium
COX-1
housekeeping
COX-2
inflammation
PGI2, PGE2
  Inflammation
  Mitogenesis
  Bone formation
  Other functions?
TXA2, PGI2, PGE2
  Gastrointestinal mucosal integrity
  Platelet aggregation
  Renal function
FIGURE 335-4  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.
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 byproducts. Several locally produced factors including nitric oxide (NO) 
(see below), hydrogen sulfide, and prostacyclin contribute to the vas­
cular protective pathway through vasodilation of the microcirculation.
Prostaglandins play a central role in gastric epithelial defense/
repair (Fig. 335-4). 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 phos­
pholipids (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 tis­
sue inflammation while minimizing toxicity in the GI tract. Selective 
COX-2 inhibitors have had adverse effects on the cardiovascular (CV) 
system, leading to increased risk of myocardial infarction. Therefore, 
the U.S. Food and Drug Administration (FDA) has removed two of 
these agents (valdecoxib and rofecoxib) from the market (see below).
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. 335-3).
Since the discovery of Helicobacter pylori and its impact on gastric 
pathology, it has become clear that the stomach has an elaborate and 
complex inherent immunologic system in place. Although a detailed 
description of the gastric immune system is beyond the scope of this 
chapter, several features are worth highlighting. The gastric immune 

response to certain pathogens such as H. pylori (see below) involves 
extensive interplay between innate (dendritic cells, epithelial cells, 
neutrophils, and macrophages) and adaptive (B and T cells) compo­
nents. Helper T cells (TH and TH regulatory cells) have been extensively 
studied and appear to play an important role in a broad array of gastric 
physiology extending from gastric secretion to epithelial cell turnover 
via production of a number of cytokines.

The discovery of H. pylori has also led to the understanding that 
the stomach, once thought to be devoid of microorganisms due to its 
highly adverse environment (acid and pepsin), can serve as host for 
bacterial communities consisting of hundreds of phylotypes, otherwise 
known as its microbiota. The conceptual framework of the microbiome 
has been receiving extensive attention in light of its importance in 
human health and disease. The overall relevance of the gastric microbi­
ome and its impact on gastric pathology remain to be established, but it 
is likely that alteration of microorganism homeostasis will play a role in 
aspects of certain disorders such as PUD, gastritis, and gastric cancer.
Physiology of Gastric Secretion 
Understanding of the physiol­
ogy of gastric secretion is important when considering the pathophysi­
ology of PUD and the therapeutic options available. A detailed review of 
the many components of gastric acid secretion is beyond the scope of 
this chapter, and the reader is referred to Engevik et al (see Further 
Reading) for a comprehensive discussion on this very important topic. 
For the purposes of this chapter, a brief review of acid secretion will 
follow. HCl and pepsinogen are the two principal gastric secretory 
products capable of inducing mucosal injury. Gastric acid and pepsino­
gen play a physiologic role in protein digestion; absorption of iron, cal­
cium, magnesium, and vitamin B12; and killing ingested bacteria. Acid 
secretion should be viewed as occurring under basal and stimulated 
conditions. Basal acid production occurs in a circadian pattern, with 
the highest levels occurring during the night and lowest levels during 
the morning hours. Cholinergic input via the vagus nerve and hista­
minergic input from local gastric sources are the principal contribu­
tors 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 (via peptone and amino acid receptors) 
and indirectly (via stimulation of intramural gastrin-releasing peptide 
neurons) 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 (pari­
etal cell) and indirect mechanisms (decreased histamine release from 
ECL cells, ghrelin release from Gr cells, and gastrin release from G cells). 
Additional neural (central and peripheral) and humoral (amylin, 
atrial natriuretic peptide [ANP], cholecystokinin, ghrelin, interleukin 
11 [IL-11], 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 Gr cells in the stomach, and its related peptide 
motilin (released from the duodenum) may increase gastric acid secre­
tion through stimulation of histamine release from ECL cells, but this 
remains to be confirmed.
CHAPTER 335
Peptic Ulcer Disease and Related Disorders 
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. 335-5). This unique cell also secretes 
intrinsic factor (IF) and IL-11. The parietal cell expresses receptors for 
several stimulants of acid secretion, including histamine (H2), gastrin 
(cholecystokinin 2/gastrin receptor), and acetylcholine (muscarinic, 
M3). Binding of histamine to the H2 receptor and activation of the

CGRP
PACAP
ACh
ACh
ACh
ACh
ACh
GRP
VIP
+
+
+
–
–
–
–
+
EC Cell
(ANP)
D Cell
(SST)
G Cell
(Gastrin)
D Cell
(SST)
–
+
+
–
HP
(Chronic Antrum)
Acid
HP (Acute)
FIGURE 335-5  Regulation of gastric acid secretion at the cellular level. ACh, acetylcholine; ANP, atrial natriuretic peptide; CGRP, calcitonin gene-related peptide; EC, 
enterochromaffin; ECL, enterochromaffin-like; GRP, gastrin-releasing peptide; PACAP, pituitary adenylate-cyclase activating peptide; SST, somatostatin; VIP, vasoactive 
intestinal peptide.
gastrin and muscarinic receptors result in stimulation of downstream 
signaling pathways, which in turn regulates the acid-secreting pump, 
H+,K+-ATPase. Parietal cells also express receptors for ligands that 
inhibit acid production (glucagon-like peptide 1, prostaglandins, 
somatostatin, EGF, neurotensin, and urocortin). Histamine also stimu­
lates gastric acid secretion indirectly by activating the histamine H3 
receptor on D cells, which inhibits somatostatin release.
PART 10
Disorders of the Gastrointestinal System
The enzyme H+,K+-ATPase is responsible for generating the large 
concentration of H+ ions. 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. 335-2). Proton pumps are 
recycled back to the inactive state in cytoplasmic vesicles once parietal 
cell activation ceases. In addition, acid secretion requires a number of 
apical and basolateral parietal cell membrane chloride and potassium 
channels. Parietal cells also express members of the sonic hedgehog 
(Shh) family proteins, which play an important role in regulating cell 
types in multiple organs. This family of proteins may also regulate cell 
differentiation as well as restitution of mucosal defense in the gastric 
epithelium.
The chief cell, found primarily in the gastric fundus, synthesizes and 
secretes pepsinogen, the inactive precursor of the proteolytic enzyme 
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 PUD
PUD encompasses both gastric ulcers (GUs) and duodenal ulcers 
(DUs). Ulcers are defined as breaks in the mucosal surface >5 mm in 
size, with depth to the submucosa. DUs and GUs share many common 
features in terms of pathogenesis, diagnosis, and treatment, but several 
factors distinguish them from one another. H. pylori and NSAIDs are 
the most common risk factors for PUD, with estimated odds ratios in 
the United States of 3.7 and 3.3, respectively. Additional risk factors 
(odds ratio) include chronic obstructive lung disease (2.34), chronic 
renal insufficiency (2.29), current tobacco use (1.99), former tobacco 
use (1.55), older age (1.67), three or more doctor visits in a year (1.49), 

Vagus
+
+
–
Parietal
Cell
+
+
H3
H2
+
–
–
+
ECL Cell
(Histamine)
Fundus
Antrum
coronary heart disease (1.46), former alcohol use (1.29), AfricanAmerican race (1.20), obesity (1.18), and diabetes (1.13). Selective 
serotonin reuptake inhibitors (SSRIs) and gastric bypass surgery are 
also associated with an increased incidence of PUD. A rise in idio­
pathic PUD has also been noted. The mechanisms by which some of 
these risk factors lead to ulcer disease are highlighted below.
Epidemiology 
• 
DUODENAL ULCERS  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 
H. pylori in turn associated with overall improved sanitary conditions 
across the world. Before the discovery of H. pylori, the natural history 
of DUs was typified by frequent recurrences after initial therapy. Eradi­
cation of H. pylori has reduced these recurrence rates by >80%.
GASTRIC ULCERS  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, per­
haps 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.
Pathology 
• 
DUODENAL ULCERS  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.
GASTRIC ULCERS  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 secre­
tory 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.
Pathophysiology 
• 
DUODENAL ULCERS  H. pylori and NSAIDinduced injuries 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. Bicarbonate secretion is significantly decreased in the duo­
denal bulb of patients with an active DU as compared to control sub­
jects. H. pylori infection may also play a role in this process (see below).
GASTRIC ULCERS  As in DUs, the majority of GUs can be attributed to 
either H. pylori or NSAID-induced mucosal damage. Prepyloric GUs 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.
H. PYLORI AND ACID PEPTIC DISORDERS  Although gastric infection 
with the bacterium H. pylori was once thought to account for the 
majority of PUD (Chap. 168), more recent studies suggest that only 
one-fourth of DUs and one-sixth of GUs were associated with H. pylori 
infection. These changes are likely due to successful rates of eradica­
tion of the organism coupled with improved sanitary conditions. It 
appears that NSAIDs have become the most common cause of PUD 
(see below). 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. H. pylori eradication 
efforts may lead to a decrease in gastric cancer in high-risk popula­
tions, particularly in individuals who have not developed chronic 
atrophic gastritis and gastric metaplasia.
The Bacterium  The bacterium, initially named Campylobacter pylori­
dis, 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, some fac­
tors 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 cagPAI 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 cellu­
lar 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 surround­
ing pH. Additional bacterial factors include but are not limited to, 
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.
Epidemiology  The prevalence of H. pylori varies throughout the world 
and depends largely on the overall standard of living in the region, 
with overall global prevalence decreasing. The global prevalence of 
H. pylori infection in adults has declined from 50–55% to 43% dur­
ing 2014 to 2020. Contributing factors to these changes likely include 

improvement of socioeconomic status and living standards as well as 
enhanced hygiene conditions. It is also possible that the increased use 
of antibiotics specifically with eradication therapies in individuals with 
infection could be a contributing factor to the overall decrease in global 
prevalence with a high variability in H. pylori infection throughout the 
world. 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 industri­
alized 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 infec­
tion 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 interven­
tion, the organism ultimately will be eliminated from the United States. 
Two factors that predispose to higher colonization rates include poor 
socioeconomic status and less education about the organism. 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) expo­
sure to gastric contents of an infected individual.

CHAPTER 335
Transmission of H. pylori occurs from person to person, following 
an oral-oral or fecal-oral route. The risk of H. pylori infection is declin­
ing in developing countries. The rate of infection in the United States 
has fallen by >50% when compared to 30 years ago.
Pathophysiology  H. pylori infection is virtually always associated with 
a chronic active gastritis, but only 10–15% of infected individu­
als develop frank peptic ulceration. The basis for this difference is 
unknown but is likely due to a combination of host and bacterial fac­
tors, 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 one-sixth of individuals with GUs and one-fourth 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).
Peptic Ulcer Disease and Related Disorders 
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. 335-6).
Bacterial factors
    Structure
    Adhesins
    Porins
    Enzymes
      (urease, vac A, cag A, etc.)
Host factors
    Duration
    Location
    Inflammatory response
    Genetics??
Chronic gastritis
Peptic ulcer disease
Gastric MALT lymphoma
Gastric cancer
FIGURE 335-6  Outline of the bacterial and host factors important in determining 
H. pylori–induced gastrointestinal disease. MALT, mucosal-associated lymphoid 
tissue.

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 including γ-glutamyl 
transpeptidase (GGT), cytotoxin-associated gene A (Cag A) product, 
and virulence components vacuolating toxin (Vac A), in addition to 
pathogen-associated molecular patterns (PAMPs) such as flagella and 
lipopolysaccharide (LPS). 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 muco­
sal 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 dem­
onstrated that H. pylori strains that are cag-PAI positive are associated 
with a higher risk of PUD, premalignant gastric lesions, and gastric 
cancer than are strains that lack the cag-PAI. In addition, H. pylori 
may directly inhibit parietal cell H+,K+-ATPase activity through a Cag 
A–dependent mechanism, leading in part to the low acid production 
observed after acute infection with the organism. 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 (outer membrane proteins like 
BabA), which facilitate attachment of the bacteria to gastric epithelial 
cells. Although LPS of gram-negative bacteria often plays an important 
role in the infection, H. pylori LPS has low immunologic activity com­
pared to that of other organisms. It may promote a smoldering chronic 
inflammation.

PART 10
Disorders of the Gastrointestinal System
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 histocompatibility 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 and repression of 
tumor-suppressor genes. 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 fac­
tor (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 epithe­
lial 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 [TH1] cells) and IFN-γ. Finally, the human stomach is colonized 
by a host of commensal organisms that may affect the likelihood of 

H. pylori infection and subsequent mucosal injury. Moreover, coloniza­
tion of the stomach with H. pylori likely alters the composition of the 
gastric microbiota. The impact of the latter on gastric pathophysiology 
remains unknown but some studies suggest a potential increase in the 
development of gastric cancer. H. pylori also appears to regulate NO 
formation via different mechanisms that in turn may contribute to the 
organism’s cytotoxic effects. Specifically, H. pylori–derived factors, such as 
urease, or the bacterium itself, stimulate NO synthase (NOS2) expression 
in macrophages and in gastric epithelial cells leading to NO release and 
subsequent cytotoxic effect on surrounding cells. H. pylori also leads to 
the formation of 8-nitroguanine (8-NO2-Gua), which in conjunction with 
oncoprotein Cag A, may contribute to the development of gastric cancer.
The basis for H. pylori–mediated duodenal ulceration remains 
unclear. Studies suggest that H. pylori associated with duodenal ulcer­
ation may be more virulent. In addition, certain specific bacterial 

Parietal cell
FUNDUS
Vagus
Canaliculus
Acetylcholine
Histamine
+
+
H, K ATPase
Tubulovesicles
ECL cell
+
Histamine
+
–
–
Somatostatin
Somatostatin
ECL cell
D cell
+
Gastrin
ANTRUM
Blood vessel
Gastrin
D cell
G cell
–
Somatostatin
FIGURE 335-7  Summary of potential mechanisms by which H. pylori may lead 
to gastric secretory abnormalities. D, somatostatin cell; ECL, enterochromaffinlike cell; G, G cell. (Reproduced with permission from J Calam et al: How does 
Helicobacter pylori cause mucosal damage? Its effect on acid and gastrin 
physiology. Gastroenterology 113:543, 1997.)
factors such as the DU-promoting gene A (dupA) may be associated 
with the development of DUs. 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 is 
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. 335-7). GUs, in contrast, are associated with H. pylori–
induced pangastritis and normal or low gastric acid secretion. The 
H. pylori–mediated decrease in gastric acid secretion after long-term 
infection may be due to the bacterium’s ability to inhibit H+,K+-ATPase 
expression. H. pylori infection has also been associated with decreased 
duodenal mucosal bicarbonate production. Data supporting and con­
tradicting 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. The development of 
in vitro organoids, a unique tool that replicates in part the multicellular 
structure of the intact organ, provides a more physiologic model for 
experimentation in an in vitro system. Moreover, the development of 
advanced microscopic optical imaging techniques will lead to increased 
understanding of parietal cell adaptation to H. pylori infection.
In summary, the final effect of H. pylori on the GI tract is variable 
and determined by microbial and host factors. The type and distri­
bution 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. 335-8).
NSAID-INDUCED DISEASE 
Epidemiology  NSAIDs represent a group of the most commonly used 
medications in the world and the United States. It is estimated that 

7 billion dollars per year are spent on NSAIDs worldwide, with >30 bil­
lion over-the-counter tablets sold. More than 30 million individuals take 
NSAIDs, with >100 million prescriptions sold yearly in the United States

High level of acid production
Duodenal ulcer
MALT
lymphoma
Antralpredominant
gastritis
Chronic
H. pylori
infection
Asymptomatic
H. pylori
infection
Nonatrophic
pangastritis
Normal gastric
mucosa
Corpuspredominant
atrophic
gastritis
Gastric ulcer
Acute
H. pylori
infection
Intestinal metaplasia
Dysplasia
Gastric
cancer
Low level of acid production
Childhood
Advanced age
FIGURE 335-8  Natural history of H. pylori infection. MALT, mucosal-associated 
lymphoid tissue. (From The New England Journal of Medicine, Medical progress: 
Helicobacter pylori infection, S Suerbaum, P Michetti: 347:1175-1186. Copyright @2002 
Massachusetts Medical Society. Reprinted with permission from Massachusetts 
Medical Society.)
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), which 
is 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 60,000–120,000 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. In fact, the incidence of mucosal injury 
(ulcers and erosions) in patients taking low-dose aspirin (75–325 mg) has 
been estimated to range from as low as 8 to as high as 60%. It appears 
that H. pylori infection increases the risk of PUD-associated GI bleeding in chronic users of low-dose aspirin. Established risk factors include 
advanced age, history of ulcer, concomitant use of glucocorticoids, highdose NSAIDs, multiple NSAIDs, concomitant use of anticoagulants or 
clopidogrel, and serious or multisystem disease. Possible risk factors 
include concomitant infection with H. pylori, cigarette smoking, and 
alcohol consumption. SSRIs have a synergistic effect on the induction of 
GI bleeding believed to be due in part to this agent’s ability to decrease 
platelet aggregation by decreasing serotonin content in platelets.
Pathophysiology  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. 335-9. Single nucleotide polymorphisms (SNPs) 
have been found in several genes, including those encoding certain subtypes of cytochrome P450 (see below), IL-1β (IL-1β), angiotensinogen 

Gastrointestinal mucosal injury
Mitochondrial uncoupling
Reactive prooxidants
MOS
ATP
Mitochondrial fission
Mucosal PGHS-1
PGE 2
Mucosal defense
Intestinal mucosal barrier function
Mucosal inflammation
Apoptosis
FIGURE 335-9  Effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on different 
target organs. The action of NSAIDs on major organs including stomach, small 
intestine, heart, liver, kidney, respiratory tract, and brain is mainly mediated through 
prostaglandin endoperoxide synthase (PGHS)–dependent prostanoid modulation 
and alteration of mitochondrial functional integrity leading to mitochondrial 
oxidative stress (MOS) generation, depolarization of mitochondrial transmembrane 
potential (ΔΨm), and consequent cell death. However, in heart, low-dose aspirin 
actually offers cardioprotection through antithrombotic effect. Upward arrows 
indicate upregulation/elevation; downward arrows indicate downregulation/
depletion. (From S Bindu et al: Non-steroidal anti-inflammatory drugs (NSAIDs) and 
organ damage: A current perspective. Biochem Pharmacol 180:114147, 2020.)
(AGT), and an organic ion transporting polypeptide (SLCO1B1), but 
these findings need confirmation in larger-scale studies.
CHAPTER 335
Injury to the mucosa also occurs as a result of the topical use of 
NSAIDs, leading to increased epithelial surface permeability. 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. NSAIDs can also lead to 
mucosal injury via production of additional proinflammatory mediators such as TNF and leukotrienes through simultaneous activation of 
the lipoxygenase pathway.
Peptic Ulcer Disease and Related Disorders 
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 an independent and synergistic risk factor 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.
In summary, NSAID-induced mucosal injury is a multifaceted process involving the interaction of multiple, often synergistic pathophysiologic processes at the epithelium and surrounding interfaces.
PATHOGENETIC FACTORS UNRELATED TO H. PYLORI AND NSAIDS 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 ulcerrelated 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 frequencies 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. 
Additional genetic factors have been postulated to predispose certain

individuals to developing PUD and/or upper GI bleeding. Specifically, 
genes encoding the NSAID-metabolizing enzymes cytochrome P450 
2C9 and 2C8 (CYP2C9 and CYP2C8) are potential susceptibility genes 
for NSAID-induced PUD, but unfortunately, the studies have not been 
consistent in demonstrating this association. In a United Kingdom 
study, the CYP2C19*17 gain-of-function polymorphism was associated 
with PUD in a Caucasian cohort, irrespective of ulcer etiology. These 
findings need to be confirmed in broader studies. 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 asso­
ciation with PUD: (1) advanced age, (2) chronic pulmonary disease, 
(3) chronic renal failure, (4) cirrhosis, (5) nephrolithiasis, (6) α1antitrypsin deficiency, and (7) systemic mastocytosis. Disorders with 
a possible association are (1) hyperparathyroidism, (2) coronary artery 
disease, (3) polycythemia vera, (4) chronic pancreatitis, (5) former 
alcohol use, (6) obesity, (7) African-American race, and (8) three or 
more doctor visits in a year.
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 335-1. 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 important role in mucosal injury.
PART 10
Disorders of the Gastrointestinal System
■
■CLINICAL FEATURES
History 
Abdominal pain is common to many GI disorders, includ­
ing DU and GU, but it has a poor predictive value for the presence 
TABLE 335-1  Causes of Ulcers Not Caused by Helicobacter pylori 

and NSAIDs
Pathogenesis of Non-Hp and Non-NSAID Ulcer Disease
Infection
  Cytomegalovirus
  Herpes simplex virus
  Helicobacter heilmannii
Drug/Toxin
  Bisphosphonates
  Checkpoint inhibitor
  Chemotherapy
  Clopidogrel
  Crack cocaine
  Glucocorticoids (when combined with NSAIDs)
  Mycophenolate mofetil
  Potassium chloride
Miscellaneous
  Basophilia in myeloproliferative disease
  Duodenal obstruction (e.g., annular pancreas)
  Infiltrating disease
  Ischemia
  Radiation therapy
  Eosinophilic infiltration
  Sarcoidosis
  Crohn’s disease
  Idiopathic hypersecretory state
Abbreviations: Hp, H. pylori; NSAIDs, nonsteroidal anti-inflammatory drugs.

of either DU or GU. Approximately two-thirds of patients with PUD 
do not have abdominal pain, and up to 87% of patients with NSAIDinduced 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 pat­
tern in DU occurs 90 min to 3 h 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 twothirds of DU patients describing this complaint. Unfortunately, this 
symptom is also present in one-third of patients with NUD (see below). 
Elderly patients are less likely to have abdominal pain as a manifesta­
tion of PUD and may instead present with a complication such as 
ulcer bleeding or perforation. 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 activa­
tion of chemical receptors in the duodenum, enhanced duodenal sen­
sitivity to bile acids and pepsin, and 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 radi­
ates 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.
Physical Examination 
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 low. Physical examination is critically important for dis­
covering 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, suggest­
ing gastric outlet obstruction.
PUD-Related Complications 
• 
GASTROINTESTINAL BLEEDING  

GI bleeding is the most common complication observed in PUD. 
Bleeding is estimated to occur in 19.4–57 per 100,000 individuals in a 
general population or in ~15% of patients. Bleeding and complications 
of ulcer disease occur more often in individuals >60 years of age. The 
30-day mortality rate is as high as 2.5–10%. The higher incidence in 
the elderly is likely due to the increased use of NSAIDs in this group. 
In addition, up to 80% of the mortality in PUD-related bleeding is due 
to nonbleeding causes such as multiorgan failure (24%), pulmonary 
complications (24%), and malignancy (34%).
Greater than 50% of patients with ulcer-related hemorrhage bleed 
without any preceding warning signs or symptoms.
PERFORATION  The second most common ulcer-related complication 
is perforation, being reported in as many as 6–7% of PUD patients 
with an estimated 30-day mortality of >20%. Acute abdominal pain, 
tachycardia, and abdominal rigidity compose the classic triad associ­
ated with this complication. It is essential to remember that elderly 
patients or individuals who are immunosuppressed may not have this 
classic presentation. As in the case of bleeding, the incidence of perfo­
ration in the elderly appears to be increasing secondary to increased 
use of NSAIDs. Perforation of DUs has become less common in light 
of the increased rates of H. pylori eradication, with NSAID-induced 
GUs leading to perforation occurring more commonly. 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. 
Mortality for this complication can be >20% within 30 days.
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 ulcerrelated inflammation and edema in the peripyloric and duodenal 
region. This process often resolves with ulcer healing. A fixed, mechan­
ical obstruction secondary to scar formation in the peripyloric areas 
is also possible. The latter requires endoscopic (balloon dilation with 
or without placement of a biodegradable stent) or surgical interven­
tion with a stricturoplasty or gastrojejunostomy. 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.
Differential Diagnosis 
The list of GI and non-GI 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 functional dyspepsia (FD) or essential 
dyspepsia, which refers to a group of heterogeneous disorders typified 
by upper abdominal pain without the presence of an ulcer. The symp­
toms can range from postprandial fullness and early satiety to epigas­
tric burning pain. The dichotomy of this symptom complex has led to 
the identification of two subcategories of FD including postprandial 
distress syndrome (PDS) and epigastric pain syndrome (EPS). Dyspep­
sia has been reported to occur in up to 30% of the U.S. population. Up 
to 80% of patients seeking medical care for dyspepsia have a negative 
diagnostic evaluation. The etiology of FD is not established, but postin­
fectious states, certain foods, and H. pylori infection may contribute to 
the pathogenesis of this common disorder.
Several additional disease processes that may present with “ulcerlike” symptoms include proximal GI tumors, gastroesophageal reflux, 
vascular disease, pancreaticobiliary disease (biliary colic, chronic pan­
creatitis), and gastroduodenal Crohn’s disease.
Diagnostic Evaluation 
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, rarely done in today’s environment) or an endoscopic procedure. 
However, a large percentage of patients with symptoms suggestive of an 
A
B
FIGURE 335-10  Barium study demonstrating (A) a benign duodenal ulcer and (B) a benign gastric ulcer.

ulcer have NUD; testing for H. pylori and antibiotic therapy (see below) 
are appropriate for individuals who are otherwise healthy, without 
red flag signs such as nausea, vomiting, weight loss, or evidence of GI 
bleeding and <60 years of age, before embarking on a diagnostic evalu­
ation (Chap. 48).

Barium studies of the proximal GI tract are rarely used as a first 
test for documenting an ulcer (Fig. 335-10). Endoscopy provides the 
most sensitive and specific approach for examining the upper GI 
tract (Fig. 335-11). 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.
Although the methods for diagnosing H. pylori are outlined in 
Chap. 168, a brief summary will be included here (Table 335-2). 
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-urea breath test, and the fecal H. pylori (Hp) antigen 
test (monoclonal antibody test). A urinary Hp antigen test and a home 
breath test appear promising.
Occasionally, specialized testing such as serum gastrin and gastric 
acid analysis may be needed in individuals with complicated or refrac­
tory PUD (see “Zollinger-Ellison Syndrome,” below). Screening for 
aspirin or NSAIDs (blood or urine) may also be necessary in refractory 
H. pylori–negative PUD patients.
CHAPTER 335
TREATMENT
Peptic Ulcer Disease
Peptic Ulcer Disease and Related Disorders 
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 335-3.
ACID-NEUTRALIZING/INHIBITORY DRUGS
Antacids  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

A
B
FIGURE 335-11  Endoscopy demonstrating (A) a benign duodenal ulcer and (B) a benign gastric ulcer.
but instead are often used by patients for symptomatic relief of 
dyspepsia. The most commonly used agents are mixtures of alumi­
num hydroxide and magnesium hydroxide. Aluminum hydroxide 
can produce constipation and phosphate depletion; magnesium 
hydroxide may cause loose stools. Many of the commonly used ant­
acids (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.
PART 10
Disorders of the Gastrointestinal System
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 and hyperphos­
phatemia with possible renal calcinosis and progression to renal 
insufficiency). Sodium bicarbonate may induce systemic alkalosis.
H2 Receptor Antagonists  Four of these agents are presently avail­
able (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).
TABLE 335-2  Tests for Detection of Helicobacter pylori
SENSITIVITY/
SPECIFICITY, % COMMENTS
TEST
Invasive (Endoscopy/Biopsy Required)
Rapid urease
80–95/95–100
Simple, false negative with recent use of 
PPIs, antibiotics, or bismuth compounds
Histology
60–90/>95
Requires pathology processing and staining; 
provides histologic information
Culture
76-90/100
Time-consuming, expensive, dependent 
on experience; allows determination of 
antibiotic susceptibility
Noninvasive
Serology
74.4/59
Inexpensive, convenient; not useful for early 
follow-up; cannot distinguish active and 
prior infection
Urea breath test
>95/>95
Simple, rapid; useful for early follow-up; 
false negatives with recent therapy (see 
rapid urease test)
Stool antigen
>95/>95
Inexpensive, convenient
Abbreviation: PPIs, proton pump inhibitors.

Cimetidine was the first H2 receptor antagonist used for the 
treatment of acid peptic disorders. 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). 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 cimeti­
dine include confusion and elevated levels of serum aminotransfer­
ases, creatinine, and serum prolactin. Famotidine is a more potent 
H2 receptor antagonists than cimetidine. It 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 cimetidine 800 mg and famotidine 40 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 to 
0.2%. Cimetidine can bind to hepatic cytochrome P450; famotidine 
does not.
Proton Pump (H+,K+-ATPase) Inhibitors  Omeprazole, esomepra­
zole, lansoprazole, rabeprazole, and pantoprazole are substituted 
TABLE 335-3  Drugs Used in the Treatment of Peptic Ulcer Disease
DRUG TYPE/
MECHANISM
EXAMPLES
DOSE
Acid-Suppressing Drugs
Antacids
Mylanta, Maalox, Tums, 
Gaviscon
100–140 meq/L 1 and 3 h 
after meals and hs
H2 receptor antagonists
Cimetidine
400 mg bid
 
Famotidine
40 mg hs
Proton pump inhibitors
Omeprazole
20 mg/d
 
Lansoprazole
30 mg/d
 
Rabeprazole
20 mg/d
 
Pantoprazole
40 mg/d
 
Esomeprazole
20 mg/d
 
Dexlansoprazole
30 mg/d
Mucosal Protective Agents
Sucralfate
Sucralfate
1 g qid
Prostaglandin analogue
Misoprostol
200 μg qid
Bismuth-containing 
compounds
Bismuth subsalicylate 
(BSS)
See anti–H. pylori 
regimens (Table 335-4)
Abbreviation: hs, at bedtime (hora somni).

Peptic Ulcer Disease and Related Disorders 

CHAPTER 335
benzimidazole derivatives that covalently bind and irreversibly 
inhibit H+,K+-ATPase. Esomeprazole is the S-enantiomer of omepra­
zole, which is a racemic mixture of both S- and R-optical isomers. 
The R-isomer of lansoprazole, dexlansoprazole, is the most recent 
PPI approved for clinical use. Its reported advantage is a dual 
delayed-release system aimed at improving treatment of gastro­
esophageal reflux disease (GERD). 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 sustainedrelease 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 
non–enteric-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 omepra­
zole from acid degradation and to promote rapid gastric alkaliniza­
tion 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 com­
pounds; 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 gas­
tric acid secretion. Onset of action is rapid, with a maximum acid 
inhibitory effect between 2 and 6 h after administration and dura­
tion of inhibition lasting up to 72–96 h. 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 h; 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 morn­
ing before breakfast). Mild to moderate hypergastrinemia has been 
observed in patients taking these drugs. Carcinoid tumors devel­
oped in some animals given the drugs chronically; however, exten­
sive 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 shortterm 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 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. Cau­
tion should be taken when using theophylline, warfarin, diazepam, 
atazanavir, and phenytoin concomitantly with PPIs.
The list of potential side effects with long-term PPI use has 
steadily grown over the years. These agents are commonly used 
since several formulations have become available as over-the-coun­
ter medications. Moreover, up to 70% of current prescriptions for 
long-term PPIs may be unwarranted and between 35 and 60% of 
in-hospital use of PPIs may be inappropriate. Interpretation of the 
multiple studies should take into consideration that the vast major­
ity were retrospective observational studies in which confounding 
factors could not be accounted for entirely.
Long-term acid suppression, especially with PPIs, has been asso­
ciated with a higher incidence of community-acquired pneumonia 
as well as community- and hospital-acquired Clostridioides difficile–
associated disease. A meta-analysis showed a 74% increased risk of 
C. difficile infection and a 2.5-fold higher risk of reinfection as com­
pared to nonusers. In light of these concerns, the FDA published a 
safety alert regarding the association between C. difficile infection 
and PPI use. Although the risk of spontaneous bacterial peritonitis 
in cirrhotics was thought to be increased, the data here are less 
supportive. The impact of PPI-induced changes in the host micro­
biome is postulated to play a role in the increased risk of infection, 
but this theory needs to be confirmed. 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.
Diarrhea is also associated with PPI use, which in some cases has 
been associated with the development of collagenous colitis (hazard 
ratio of 4.5), particularly with lansoprazole. The mechanism for 
PPI-induced collagenous colitis is unclear, but in vitro studies dem­
onstrate that PPIs may induce collagen gene expression. The colitis 
usually resolves with cessation of the PPI.
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 and may be zero 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 recommenda­
tions regarding the discontinuation of these agents in patients who 
benefit from them. Long-term use of PPIs has also been implicated 
in the development of iron, vitamin B12, and magnesium deficiency. 
A meta-analysis of nine observational studies found a 40% increase 
in hypomagnesemia in PPI users as compared to nonusers. One 
approach to consider in patients needing to take PPIs long term is to 
check a complete blood count looking for evidence of anemia due to 
iron or vitamin B12 deficiency, vitamin B12 level, and a magnesium 
level after 1–2 years of PPI use, but these recommendations are not 
evidence based or recommended by expert opinion. PPIs may exert 
a negative effect on the antiplatelet effect of clopidogrel. Although 
the evidence is mixed and inconclusive, a small increase in mortal­
ity and readmission rate for coronary events was seen in patients 
receiving a PPI while on clopidogrel in earlier studies. Subsequently, 
three meta-analyses reported an inverse correlation between clopi­
dogrel and PPI use; therefore, the influence of this drug interaction 
on mortality is not clearly established. 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 the following: 
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, 
some have recommended that there be a 12-h separation between

Bone fracture
C. difficile infection
Community-acquired
pneumonia
(2 studies)
Side effect
Hypomagnesemia
Acute interstitial
nephritis
Acute kidney disease
Chronic
kidney disease
2.00
2.50
3.00
1.50
1.00
0.50
5.00
5.50
6.00
4.50
4.00
3.50
0.00
Adjusted odds ratio (95% confidence interval)
FIGURE 335-12.  Evidence supporting the potential adverse effects of proton pump 
inhibitor drugs. (Adapted from AJ Schoenfeld, D Grady: Adverse effects associated 
with proton pump inhibitors. JAMA Intern Med 176:172, 2016.)
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 bed­
time. Insufficient data are available to firmly recommend one PPI 
over another. Additional concerning side effects with long-term PPI 
use include increased cardiac risks independent of clopidogrel use, 
dementia, and acute and chronic kidney injury. Again, the data are 
often retrospective and confounding variables were not consistently 
eliminated, thus making it difficult to establish a definitive association 
between PPIs and the toxicities outlined. A summary of the side 
effects with the corresponding relative risks is shown in Fig. 335-12. 
Ultimately, heightened awareness of inappropriate long-term use of 
PPIs is paramount. Patients aged ≥65 years of age have a higher risk 
for some of the long-term side effects of PPIs highlighted above, in 
part due to the higher prevalence of concomitant chronic diseases. 
It is therefore essential to carefully select individuals, especially 
among the elderly, who need long-term PPI therapy and discon­
tinue it in those individuals who do not need it. Abrupt withdrawal 
of a PPI in a long-term user may result in a component of rebound 
hyperacidity; thus, this agent should be tapered gradually over the 
course of 1–2 weeks with possible transition to an H2 blocker for a 
short period of time.
PART 10
Disorders of the Gastrointestinal System
Development of novel acid inhibitory agents continues in an 
attempt to primarily address the need for better agents to treat 
GERD. For example, modified H2 blockers with greater potency 
and duration as well as novel PPIs with longer half-life and potency 
are under study. For example, 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 inhib­
iting nocturnal acid secretion, which has significant relevance in 
GERD. Additional PPIs with longer half-life and combined with 
other agents are being studied, but the details are beyond the scope 
of this chapter. A second new class of agents is the potassiumcompetitive acid pump antagonists (P-CAPs). These compounds 
inhibit gastric acid secretion via potassium competitive binding 
of the H+,K+-ATPase. Revaprazan, vonoprazan and tegoprazan are 
agents approved for use in Korea and Japan, and vonoprazan has 
been approved by the FDA for use in the United States. Vonoprazan 
may be superior to PPIs when combined with antibiotics for the 
treatment of H. pylori, and this novel agent was awarded Fast Track 
status by the FDA for the treatment of H. pylori in combination with 
both amoxicillin and clarithromycin and with amoxicillin alone.
CYTOPROTECTIVE AGENTS
Sucralfate  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 prostaglan­
din 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.
Bismuth-Containing Preparations  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 prepara­
tions. The mechanism by which these agents induce ulcer healing 
is unclear. Adverse effects with short-term use include black stools, 
constipation, and darkening of the tongue. Long-term use with high 
doses, especially with the avidly absorbed CBS, may lead to neuro­
toxicity. These compounds are commonly used as one of the agents 
in an anti–H. pylori regimen (see below).
6.50
Prostaglandin Analogues  In view of their central role in main­
taining 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 μg qid.
Miscellaneous Drugs  A number of drugs including anticholiner­
gic 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. 
Newer agents such as teprenone, an acyclic polyisoprenoid com­
pound used as a gastric mucosal protector that is employed to treat 
gastritis and GUs outside of the United States; plant-based thera­
pies; and CCK2 receptor antagonists are intriguing therapies but 
require further evaluation.
THERAPY OF H. PYLORI
The physician’s goal in treating PUD is to provide relief of symp­
toms (pain or dyspepsia), promote ulcer healing, and ultimately 
prevent ulcer recurrence and complications. The greatest influence 
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. Eradica­
tion of the organism may lead to diminished recurrent ulcer bleed­
ing. The effect of its eradication on ulcer perforation is unclear.
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 docu­
mented PUD. This holds true independent of time of presentation 
(first episode or not), severity of symptoms, presence of confound­
ing 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 stool 
antigen or breath testing. Between 60 and 90% of patients with 
gastric MALT lymphoma experience complete remission of the 
tumor in response to H. pylori eradication. The Maastricht VI/Flor­
ence Consensus Report recommends a test-and-treat approach for 
patients with uninvestigated dyspepsia if the local incidence of H. 
pylori is >20%. The American College of Gastroenterology (ACG) 
clinical guidelines (developed for North America) recommend that 
individuals aged <60 years with uninvestigated dyspepsia should

be tested and treated for H. pylori. In addition, recommendations 
from this consensus report and the ACG clinical guidelines include 
testing and offering eradication of H. pylori in patients who will be 
using NSAIDs (including low-dose aspirin) on a long-term basis, 
especially if there is a prior history of PUD. These individuals will 
require continued PPI treatment as well as eradication treatment, 
because eradication of the organism alone does not eliminate the 
risk of gastroduodenal ulcers in patients already receiving longterm NSAIDs. Moreover, it appears that eradication of H pylori 
decreases NSAID-induced GI bleeding. Treating patients with 
NUD to prevent gastric cancer or patients with GERD requiring 
long-term acid suppression remains controversial. Guidelines from 
the ACG suggest eradication of H. pylori in patients who have 
undergone resection of early gastric cancer. The Maastricht VI/
Florence Consensus Report also evaluated H. pylori treatment in 
gastric cancer prevention and recommends that eradication should 
be considered in the following situations: first-degree relatives of 
family members with gastric cancer; patients with previous gastric 
neoplasm treated by endoscopic or subtotal resection; individuals 
with a risk of gastritis (severe pangastritis or body-predominant 
gastritis) or severe atrophy; patients with gastric acid inhibition 
for >1 year; individuals with strong environmental risk factors for 
gastric cancer (heavy smoking; high exposure to dust, coal, quartz, 
or cement; and/or work in quarries); and H. pylori–positive patients 
with a fear of gastric cancer. Finally, the ACG clinical guidelines 
recommend testing and offering H. pylori eradication to patients 
with unexplained iron-deficiency anemia and idiopathic thrombo­
cytopenic purpura. The Maastricht VI/Florence Consensus Report 
concurs with the ACG with the aforementioned recommendations 
and in addition recommends eradicating H. pylori in patients 
TABLE 335-4  Recommended First-Line Therapies for H. pylori Infection
REGIMEN
DRUGS (DOSES)
DOSING FREQUENCY
DURATION (DAYS)
FDA APPROVAL
Clarithromycin triple (Only in 
patients without prior exposure 
to macrolides, incidence of 
clarithromycin <15%, or either of 
the above unknown) 
PPI (standard or double dose)
bid

Yesa
Clarithromycin (500 mg)
 
 
 
Amoxicillin (1 g) or metronidazole (500 mg tid)
 
 
 
Bismuth quadruple (Now often 
recommended as first-line 
therapy)
PPI (standard dose)
bid
10–14
Nob
Bismuth subcitrate (120–300 mg) or subsalicylate (300 mg)
qid
 
 
Tetracycline (500 mg)
qid
 
 
Metronidazole (250–500 mg)
qid (250 mg)
tid to qid (500 mg)
Concomitant
PPI (standard dose)
bid
10–14
No
 
Clarithromycin (500 mg)
 
 
 
 
Amoxicillin (1 g)
 
 
 
 
Nitroimidazole (500 mg)c
 
 
 
Sequential
PPI (standard dose)
bid
5–7
No
 
PPI, clarithromycin (500 mg) + nitroimidazole (500 mg)c
bid
5–7
 
Hybrid
PPI (standard dose) + amoxicillin (1 g)
bid

No
 
PPI, amoxicillin, clarithromycin (500 mg), nitroimidazole (500 mg)c
bid

Levofloxacin triple
PPI (standard or double dose) + amoxicillin (1 g)
bid
5–7
No
 
Levofloxacin (500 mg)
qd
 
 
 
Amoxicillin (1 g)
bid
 
 
Levofloxacin sequential
PPI (standard or double dose) + amoxicillin (1 g)
bid
5–7
No
 
PPI, amoxicillin, levofloxacin (500 mg qd), nitroimidazole (500 mg)c
bid
5–7
 
LOAD
Levofloxacin (250 mg)
qd
7–10
No
 
PPI (double dose)
qd
 
 
 
Nitazoxanide (500 mg)
bid
 
 
 
Doxycycline (100 mg)
qd
 
 
aSeveral PPI, clarithromycin, and amoxicillin combinations have achieved FDA approval. The regimen of a PPI, clarithromycin, and metronidazole is not an FDA-approved 
treatment regimen. bThe regimen of a PPI, bismuth, tetracycline, and metronidazole combined with a PPI for 10 days is an FDA-approved treatment regimen. cMetronidazole 
or tinidazole.
Abbreviations: bid, twice daily; FDA, Food and Drug Administration; PPI, proton pump inhibitor; tid, three times daily; qd, once daily; qid, four times daily.
Source: Reproduced with permission from WD Chey et al: ACG clinical guideline: Treatment of Helicobacter pylori infection. Am J Gastroenterol 112:212, 2017.

with unexplained vitamin B12 deficiency. Despite this, concerns 
have been raised about the widespread use of antibiotics for the 
therapy of all cases of H. pylori positivity, including the potential 
for increased bacterial resistance rates, reported weight gain, and 
alteration of the microbiome. In fact, the increasing incidence of 
bacterial resistance to antibiotics coupled with variability in general 
prevalence of the organism worldwide and limitations in develop­
ing personalized H. pylori–driven sensitivity therapies have led to 
increasing challenges in effectively treating this organism.

Multiple drugs have been evaluated in the therapy of H. pylori. 
No single agent is effective in eradicating the organism. Combina­
tion therapy for 14 days provides the greatest efficacy, although 
regimens based on sequential administration of antibiotics also 
appear promising (see below). A shorter administration course 
(7–10 days), although attractive, has not proved as successful as 
the 14-day regimens. The agents used with the greatest frequency 
include amoxicillin, metronidazole, tetracycline, clarithromycin, 
and bismuth compounds. Moreover, the steady increase in H pylori 
resistance to antibiotics, in particular clarithromycin and metro­
nidazole, has significantly impacted the approach to eradication 
of this organism (see below). In addition, increasing resistance to 
antibiotics has led to a higher incidence of H. pylori infections that 
are refractory to first-line therapies.
Suggested treatment regimens for H. pylori are outlined in 
Table 335-4. Choice of a particular regimen will be influenced by 
several factors, including efficacy, patient tolerance, existing antibi­
otic resistance, prior antibiotic use, and cost of the drugs. The aim 
for initial eradication rates should be 85–90%. The combination 
of bismuth, metronidazole, and tetracycline was the first triple 
regimen found effective against H. pylori. The combination of two 
CHAPTER 335
Peptic Ulcer Disease and Related Disorders

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 enhances bacterial eradication.

Triple therapy, although effective, has several drawbacks, includ­
ing 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. One anti–H. pylori regimen is available in 
prepackaged formulation: Prevpac (lansoprazole, clarithromycin, and 
amoxicillin).The contents of the Prevpac are to be taken twice per day 
for 14 days, understanding that clarithromycin-based triple therapy 
should be avoided in settings where H. pylori resistance to this agent 
exceeds 15% or the patient has been recently exposed to macrolide 
antibiotics or if neither of these factors is known (see below).
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 amoxi­
cillin 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. Concomitant use 
of probiotics may ameliorate some of the antibiotic side effects (see 
below). 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, clar­
ithromycin, 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. In light of this, culture-independent methods are needed 
to determine antibiotic resistance. Detection of resistance toward 
several antibiotics can be achieved by detecting different H. pylori 
mutations or other genetic changes, but the accuracy of the molecu­
lar tools available vary widely between different antibiotics. There­
fore, a standardized approach to determine antibiotic resistance that 
is easy to use is still not readily available. In addition, the standard 
method of obtaining tissue through endoscopy is cost prohibitive 
when considering the widespread presence of this organism in 
certain parts of the world; thus, new efforts are aimed at develop­
ing techniques that capitalize on DNA extraction and performing 
polymerase chain reaction (PCR) on stool samples from patients 
infected with H. pylori. These diagnostic modalities are still in early 
phases of development. In light of this, most recommendations 
for treatment of H. pylori outline that if individual susceptibility 
testing is not available, first-line therapy in areas of a high inci­
dence of clarithromycin resistance (>15%) or in situations where 
resistance to clarithromycin is not known that bismuth quadruple 
therapy should be the first line of treatment. If not available, non­
bismuth concomitant quadruple therapy may be a consideration. 
An algorithmic approach to the therapy of H. pylori as outlined in 
the Maastricht VI/Florence Consensus Report is provided in Fig. 
335-13. 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 13–16% of individuals in the United States, 
with resistance to amoxicillin being <1% and resistance to both 
metronidazole and clarithromycin in the 5% range. Resistance to 
tetracycline and rifabutin (see below) is reported to be <2% in the 
United States. In light of the paucity of H. pylori antibiotic real-time 
resistance data, asking the patient about prior antibiotic exposure 
should be included in the decision-making and used as a surrogate for 
potential antibiotic resistance, especially when it comes to prior 
macrolide use. Clarithromycin use should be excluded in patients 
with prior macrolide usage.
PART 10
Disorders of the Gastrointestinal System

Failure of H. pylori eradication with triple therapy in a compliant 
patient is usually due to infection with a resistant organism. Addi­
tional important factors in treatment failure include inadequate acid 
suppression and inadequate adherence to the recommended regi­
men. Addressing both of these latter issues is critical before embark­
ing on selecting alternative antibiotics for eradication of H. pylori. 
An in-depth review of the approach to patients with refractory H. 
pylori is beyond the scope of this chapter, and readers are referred to 
the American Gastroenterological Association 2021 guidelines (see 
Further Reading) for in-depth discussion of this important topic. A 
series of salvage therapies for H. pylori are shown in Table 335-5. 
The combination of PPI, 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, no 
treatment regimen is universally accepted for patients in whom two 
courses of antibiotics have failed. If eradication is still not achieved 
in a compliant patient, then culture and sensitivity of the organism 
should be considered. One challenge with this approach is that 
culture and sensitivity testing is cumbersome and not widely avail­
able; thus, H. pylori resistance data within specific communities are 
often not available. Non-culture-based approaches using molecular 
markers to determine potential resistance through stool testing are 
being developed but are not widely available. 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. Regimens examined consist of 5 days 
of amoxicillin and a PPI, followed by an additional 5 days of PPI 
plus tinidazole and clarithromycin or levofloxacin. One promising 
regimen that has the benefit of being shorter in duration, easier 
to take, and less expensive is 5 days of concomitant therapy (PPI 
twice daily, amoxicillin 1 g twice daily, levofloxacin 500 mg twice 
daily, and tinidazole 500 mg twice daily). Initial studies have dem­
onstrated eradication rates of >90% with good patient tolerance. 
Confirmation of these findings and applicability of this approach 
in the United States are needed, although some experts are recom­
mending abandoning clarithromycin-based triple therapy in the 
United States for the concomitant therapy or the alternative sequen­
tial therapies highlighted above.
Innovative non-antibiotic-mediated approaches have been 
explored in an effort to improve eradication rates of H. pylori. 
Pretreatment of patients with N-acetylcysteine as a mucolytic agent 
to destroy the H. pylori biofilm and therefore impair antibiotic 
resistance has been examined, but more studies are needed to con­
firm the applicability of this approach. In vitro studies suggest that 
certain probiotics like Lactobacillus or its metabolites can inhibit 
H. pylori. Administration of probiotics has been attempted in sev­
eral clinical studies in an effort to maximize antibiotic-mediated 
eradication with varying results. Overall, it appears that the use of 
certain probiotics, such as Lactobacillus spp., Saccharomyces spp., 
Bifidobacterium spp., and Bacillus clausii, did not alter eradication 
rates but importantly decreased antibiotic-associated side effects 
including nausea, dysgeusia, diarrhea, and abdominal discomfort/
pain, resulting in enhanced tolerability of H. pylori therapies. 
Additional studies are needed to confirm the potential benefits 
of probiotics in this setting. Statins, specifically atorvastatin, have 
been used with some success as an adjunct to quadruple therapy 
in patients with NUD. Additional nonpharmacologic therapies are

Low (<15%)
clarithromycin resistance
Bismuth 4-drug
1st line
If fails
Levofloxacin 4- or
3-drug
OR
2nd line
If fails
If fails
If fails
Clarithromycin 3- or
4-drug
Levofloxacin 4- or
3-drug
Bismuth 4-drug
3rd line
If fails
If fails
Rifabutin 3-drug
Rifabutin 3-drug
Rifabutin 3-drug
4th line
A
High (>15%)
or unknown clarithromycin resistance
1st option
Bismuth 4-drug
1st line
If fails
Levofloxacin 4- or
3-drug
2nd line
If fails
Rifabutin 3-drug
3rd line
4th line
B
FIGURE 335-13  Empirical approach to Helicobacter pylori eradication if individual antibiotic susceptibility testing is not avaliable. A. Low <15% clarithromycin resistance; 
B. High >15% or unknown clarithromycin resistance. Treatment regimens: Bismuth 4-drug—proton pump inhibitor (PPI), bismuth, tetracycline, metronidazole; Clarithromycin 
3-drug—PPI, clarithromycin, amoxicillin (use only if clarithromycin sensitivity is known); Nonbismuth 4-drug—PPI, clarithromycin, amoxicillin, metronidazole; Levofloxacin 
4-drug—PPI, levofloxacin, amoxicillin, bismuth; Levofloxacin 3-drug—same as levofloxacin 4-drug omitting bismuth; Rifabutin 3-drug in the setting of high fluoroquinolone 
resistance—rifabutin, high dose PPI, amoxicillin. (modified from Malfetheiner P, et al: Gut 71:9, 2022). (Adapted from permission from P Malfertheiner et al: Management of 
Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 71:9, 2022.)
also being explored including oxygen-enriched environment or 
hyperbaric oxygen therapy, antimicrobial photodynamic therapy, 
nanomaterials, antimicrobial peptides, phase therapy, and modified 
lysins. Readers are referred to a recent comprehensive review on 
this topic (Luo et al in Further Reading).
Reinfection after successful eradication of H. pylori is rare in the 
United States (<1% per year). If recurrent infection occurs within 

OR
Clarithromycin 3-drug
If fails
Levofloxacin 4- or
3-drug
Bismuth 4-drug
If fails
CHAPTER 335
2nd option (bismuth 4-drug
locally unavailable)
Non-bismuth 4-drug
(concomitant)
Peptic Ulcer Disease and Related Disorders 
OR
Levofloxacin 4- or
3-drug
Bismuth 4-drug
If fails
If fails
Levofloxacin 4- or
3-drug
Bismuth 4-drug
If fails
If fails
Rifabutin 3-drug
Rifabutin 3-drug
the first 6 months after completing therapy, the most likely explana­
tion 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

TABLE 335-5  Salvage Therapies for H. pylori Infection
REGIMEN
DRUGS (DOSES)
DOSING FREQUENCY
DURATION (DAYS)
FDA APPROVAL
Bismuth quadruple
PPI (standard dose)
bid

Noa
 
Bismuth subcitrate (120–300 mg) or subsalicylate (300 mg)
qid
 
 
 
Tetracycline (500 mg)
qid
 
 
 
Metronidazole (500 mg)
tid or qid
 
 
Levofloxacin triple
PPI (standard dose)
bid

No
 
Levofloxacin (500 mg)
qd
 
 
 
Amoxicillin (1 g)
bid
 
 
Concomitant
PPI (standard dose)
bid
10–14
No
 
Clarithromycin (500 mg)
bid
 
 
 
Amoxicillin (1 g)
bid
 
 
 
Nitroimidazole (500 mg)
bid or tid
 
 
Rifabutin triple
PPI (standard dose)
bid

No
 
Rifabutin (300 mg)
qd
 
 
 
Amoxicillin (1 g)
bid
 
 
High-dose dual
PPI (standard to double dose)
tid or qid

No
 
Amoxicillin (1 g tid or 750 mg qid)
tid or qid
 
 
aPPI, bismuth, tetracycline, and metronidazole prescribed separately is not an FDA-approved treatment regimen. However, Pylera, a combination product containing bismuth 
subcitrate, tetracycline, and metronidazole, combined with a PPI for 10 days is an FDA-approved treatment regimen.
Abbreviations: bid, twice daily; FDA, Food and Drug Administration; PPI, proton pump inhibitor; tid, three times daily; qd, once daily; qid, four times daily.
Source: Reproduced with permission from WD Chey et al: ACG clinical guideline: Treatment of Helicobacter pylori infection. Am J Gastroenterol 112:212, 2017.
injury. Recommendations for the treatment and primary preven­
tion of NSAID-related mucosal injury are listed in Table 335-6. 
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.
PART 10
Disorders of the Gastrointestinal System
The widespread use of NSAIDs has created some concern due to 
the increasing likelihood of GI and CV side effects associated with 
these agents. The approach to primary prevention has included 
avoiding the agent, using the lowest possible dose of the agent for 
the shortest period of time possible, using NSAIDs that are theoret­
ically less injurious, using newer topical NSAID preparations, and/
or using concomitant medical therapy to prevent NSAID-induced 
injury. Several nonselective NSAIDs that are associated with a lower 
likelihood of GI and CV toxicity include naproxen 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 a PPI and, if not tolerated, 
misoprostol (200 μg qid). High-dose H2 blockers (famotidine 40 mg 
bid) have also shown some promise in preventing endoscopically 
documented ulcers, although PPIs are superior. The highly selec­
tive 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. 
TABLE 335-6  Recommendations for Treatment of NSAID-Related 
Mucosal Injury
CLINICAL SETTING
RECOMMENDATION
Active ulcer
 
  NSAID discontinued
H2 receptor antagonist or PPI
  NSAID continued
PPI
Prophylactic therapy
Misoprostol
 
PPI
 
Selective COX-2 inhibitor
H. pylori infection
Eradication if tests positive for H. pylori
Abbreviations: COX-2, isoenzyme of cyclooxygenase; NSAID, nonsteroidal antiinflammatory drug; PPI, proton pump inhibitor.

Their utilization led to an increase in CV events initially leading 
to both celecoxib and rofecoxib being withdrawn from the market. 
After continued analysis of available data, the FDA concluded that 
celecoxib is no less safe than several nonopioid pain killers and has 
been allowed to remain on the market with a warning label that 
it was associated with increased risk of heart attacks and strokes. 
Additional caution was engendered when the CLASS study demon­
strated that the advantage of celecoxib in preventing GI complica­
tions 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 CV events, has signifi­
cantly 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 ACG and is shown in Table 335-7. 
TABLE 335-7  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
Consider non-NSAID therapy
A gastroprotective agent must 
be added if a traditional NSAID 
is prescribed
Consider non-NSAID therapy
Abbreviations: CV, cardiovascular; GI, gastrointestinal; NSAID, nonsteroidal antiinflammatory drug; PPI, proton pump inhibitor.
Source: Reproduced with permission from AM Fendrick: Am J Manag Care 10:740, 
2004.

Individuals who are not at risk for CV events, do not use aspirin, 
and are without risk for GI complications can receive nonselective 
NSAIDs without gastric protection. In those without CV risk fac­
tors 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 high-dose PPI or 
misoprostol are recommended. Individuals at moderate GI risk 
without cardiac risk factors can be treated with a COX-2 inhibi­
tor alone or with a nonselective NSAID with PPI or misoprostol. 
Individuals with CV risk factors, who require low-dose aspirin and 
have low potential for NSAID-induced toxicity, should be consid­
ered for a non-NSAID agent or use of a traditional NSAID such 
as naproxen (lower CV side effects) in combination with gastric 
protection, if warranted. Finally, individuals with CV 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. Assuring the use of GI protective agents with NSAIDs is 
difficult, even in high-risk patients. This is in part due to under­
prescribing of the appropriate protective agent; other times, the 
difficulty is related to patient compliance. The latter may be due to 
patients forgetting to take multiple pills or preferring not to take the 
extra pill, especially if they have no GI symptoms. Several NSAID 
gastroprotective-containing combination pills are now commer­
cially available, including double-dose famotidine with ibuprofen, 
diclofenac with misoprostol, and naproxen with esomeprazole. 
Although initial studies suggested improved compliance and a 
cost advantage when taking these combination drugs, their clinical 
benefit over the use of separate pills has not been established. One 
additional concern with NSAID-induced GI complications is the 
relatively low rate of primary care provider compliance with estab­
lished guidelines outlining preventative measures. An intervention 
including professional education, informatics to facilitate review, 
and financial incentives for practices to review patients’ charts to 
assess appropriateness showed a reduced rate of high-risk prescrib­
ing of antiplatelet medications and NSAIDs with a tendency toward 
improved clinical outcomes. Efforts continue toward developing 
safer NSAIDs, including topical NSAIDs, NSAID formulations that 
are rapidly absorbed (diclofenac potassium powder mixed with a 
buffering agent, Prosorb and SoluMatrix technology), NO-releasing 
NSAIDs, hydrogen sulfide–releasing NSAIDs, dual COX/5-LOX 
inhibitors, NSAID prodrugs, and agents that can effectively seques­
ter unbound NSAIDs without interfering with their efficacy.
APPROACH AND THERAPY: SUMMARY
Controversy continues regarding the best approach to the patient 
who presents with dyspepsia (Chap. 48). The discovery of H. pylori 
and its role in pathogenesis of ulcers has added a new variable to 
the equation. Previously, if a patient <60 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; today, how­
ever, a test-and-treat approach with a noninvasive diagnostic tool 
for H. pylori and eradication of the organism, if positive, is recom­
mended (Fig. 335-14).
Once an ulcer (GU or DU) is documented, the main issue to 
consider is whether H. pylori or an NSAID is involved. With H. 
pylori present, independent of the NSAID status, triple or qua­
druple therapy is recommended for 14 days, followed by continued 
acid-suppressing drugs (H2 receptor antagonist or PPIs) for a 
total of 4–6 weeks. H. pylori eradication should be documented 
4 weeks after completing antibiotics. The test of choice for docu­
menting eradication is the laboratory-based validated monoclonal 
stool antigen test or a urea breath test (UBT). The patient must be 
off antisecretory agents for at least 7 days when being tested for 
eradication of H. pylori with UBT or stool antigen. Serologic testing 
is not useful for the purpose of documenting eradication because 

New-Onset Dyspepsia
>40 years old
Alarm symptoms
Exclude by history GERD, biliary
 pain, IBS, aerophagia,
 medication-related
–
Noninvasive Hp testing
+
–
+
or
Anti-Hp
therapy
Refer to
gastroenterologist
Empiric trial
H2 blocker
4 weeks
after therapy
Confirm eradication UBT
Symptoms remain or recur
FIGURE 335-14  Overview of new-onset dyspepsia. GERD, gastroesophageal reflux 
disease; Hp, Helicobacter pylori; IBS, irritable bowel syndrome; UBT, urea breath 
test. (Reproduced with permission from BS Anand, DY Graham: State-of-the-Art: 
Ulcer and Gastritis, Endoscopy 31:215, 1999. © Georg Thieme Verlag KG.)
CHAPTER 335
antibody titers fall slowly and often do not become undetectable. 
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.
Peptic Ulcer Disease and Related Disorders 
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. Repeat endos­
copy is warranted in patients with DU if symptoms persist despite 
medical therapy or a complication is suspected.
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 con­
sidered refractory. Once poor compliance and persistent H. pylori 
infection have been excluded, NSAID use, either inadvertent or sur­
reptitious, 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 has 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, amyloido­
sis, sarcoidosis, lymphoma, eosinophilic gastroenteritis, smoking 
crack cocaine, or infection (cytomegalovirus [CMV], tuberculosis, 
or syphilis).

SURGICAL THERAPY
Surgical intervention in PUD can be viewed as being either elec­
tive, 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 with a drop of >90% for elective ulcer surgery over the past 
four decades. 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. 333) is necessary in some. Paren­
terally and orally administered PPIs also decrease ulcer rebleed­
ing in patients who have undergone endoscopic therapy. Patients 
unresponsive or refractory to endoscopic intervention will require 
angiographic intervention or surgery (~5% of transfusion-requiring 
patients).
Free peritoneal perforation occurs in ~2–3% of DU patients, 
with NSAID-induced GU perforations occurring more commonly. 
Sudden onset of severe abdominal pain with peritoneal signs and 
evidence of pneumoperitoneum on abdominal imaging is the clas­
sic presentation of a perforated viscous, but this presentation occurs 
in only two-thirds of patients. The latter is especially true in elderly 
patients (>70 years old), obese individuals, and immunocompro­
mised patients. It is important to keep in mind that, as in the case 
of bleeding, up to 10% of these patients will not have antecedent 
ulcer symptoms. Delay in diagnosis clearly leads to higher mortal­
ity; thus, early suspicion and intervention with nasogastric suction, 
intravenous PPI, antibiotics, and surgical consultation are essential. 
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.
PART 10
Disorders of the Gastrointestinal System
Pyloric channel ulcers or DUs can lead to gastric outlet obstruc­
tion 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 man­
agement 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 obstruc­
tion persists, endoscopic intervention with balloon dilation may be 
effective. Surgery should be considered if all else fails.
Specific Operations for Duodenal Ulcers  Surgical treatment was 
originally 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 pro­
cedure), and (3) vagotomy with antrectomy. The specific procedure 
performed is dictated by the underlying circumstances: elective 
versus emergency, the degree and extent of duodenal ulceration, 
the etiology of the ulcer (H. pylori, NSAIDs, malignancy), and the 
expertise of the surgeon. Moreover, the trend has been toward a 
dramatic decrease in the need for surgery for treatment of refrac­
tory PUD, and when needed, minimally invasive and anatomypreserving operations are preferred.
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 com­
plication 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 are transected, thus leaving fibers important for regu­
lating 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%, respec­
tively, of preoperative levels. Ulcer recurrence rates are higher with 
highly selective vagotomy (≥10%), although the overall complica­
tion 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 (trun­
cal or selective) in combination with antrectomy. Antrectomy is 
aimed at eliminating an additional stimulant of gastric acid secre­
tion, gastrin. Two principal types of reanastomoses are used after 
antrectomy: gastroduodenostomy (Billroth I) or gastrojejunostomy 
(Billroth II) (Fig. 335-15). 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 sig­
nificantly better clinical, endoscopic, and histologic outcome than 
Billroth II reconstruction.
Of these procedures, highly selective vagotomy may be the pro­
cedure of choice in the elective setting, except in situations where 
ulcer recurrence rates are high (prepyloric ulcers and those refrac­
tory 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 
Antrum
Fundus
Duodenum
Billroth I
Billroth II
FIGURE 335-15  Schematic representation of Billroth I and II procedures.

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 sur­
geon, and 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 complica­
tions or length of hospital stay.
Specific Operations for GUs  The location and presence of a 
concomitant DU dictate the operative procedure performed for 
a GU. Antrectomy (including the ulcer) with a Billroth I anasto­
mosis 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 (Csendes’ procedure). A less aggres­
sive 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.
Surgery-Related Complications  Complications seen after surgery 
for PUD are related primarily to the extent of the anatomic modi­
fication 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 intraab­
dominal procedure (bleeding, infection, thromboembolism), gas­
troparesis, duodenal stump leak, and efferent loop obstruction can 
be observed.
Recurrent Ulceration  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 impor­
tant 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 ques­
tion 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 ulcer­
ation 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 oper­
ation (complete vagotomy, partial gastrectomy) may be required in 
a small subgroup of patients who have not responded to aggressive 
medical management.

Afferent Loop Syndromes  Although rarely seen today as a result 
of the decrease in the performance of Billroth II anastomosis, two 
types of afferent loop syndrome can occur in patients who have 
undergone this type of partial gastric resection. 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 min 
after meals. Pain is often followed by nausea and vomiting of bilecontaining material. The pain and bloating may improve after eme­
sis. 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 or conversion of the Billroth II anastomosis 
to a Roux-en-Y gastrojejunostomy.

Dumping Syndrome  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 pro­
cedures). Two phases of dumping, early and late, can occur. Early 
dumping takes place 15–30 min after meals and consists of crampy 
abdominal discomfort, nausea, diarrhea, belching, tachycardia, pal­
pitations, 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.
CHAPTER 335
The late phase of dumping typically occurs 90 min to 3 h after 
meals. Vasomotor symptoms (light-headedness, diaphoresis, palpi­
tations, tachycardia, and syncope) predominate during this phase. 
This component of dumping is thought to be secondary to hypogly­
cemia from excessive insulin release.
Peptic Ulcer Disease and Related Disorders 
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. After vagotomy and 
drainage, up to 50% of patients will experience dumping syndrome 
to some degree early on. 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 viscos­
ity of intraluminal contents, may be beneficial in more symptomatic 
individuals. Acarbose, an α-glucosidase inhibitor that delays diges­
tion 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.
Postvagotomy Diarrhea  Up to 10% of patients may seek medical 
attention for the treatment of postvagotomy diarrhea. This compli­
cation is most commonly observed after truncal vagotomy, which 
is rarely performed today. Patients may complain of intermittent 
diarrhea that occurs typically 1–2 h 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 rever­
sal of a 10-cm segment of jejunum may yield a substantial improve­
ment in bowel frequency in a subset of patients.

Bile Reflux Gastropathy  A subset of post–partial 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 effec­
tive treatments. Severe refractory symptoms may require using 
either nuclear scanning with 99mTc-HIDA to document reflux. 
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. Patients can 
experience a 10% loss of body weight, which stabilizes 3 months post­
operatively. 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.
PART 10
Disorders of the Gastrointestinal System
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) is 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 gastroje­
junostomy. 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 osteopo­
rosis and osteomalacia is common after partial gastrectomy and 
gastrojejunostomy (Billroth II). Osteomalacia can occur as a late 
complication in up to 25% of post–partial 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 justi­
fies treating them with vitamin D and calcium supplementation 
indefinitely. Therapy is especially important in females. Copper 
deficiency has also been reported in patients undergoing surgeries 
that bypass the duodenum, where copper is primarily absorbed. 
Patients may present with a rare syndrome that includes ataxia, 
myelopathy, and peripheral neuropathy.
Gastric Adenocarcinoma  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 alka­
line reflux, bacterial proliferation, or hypochlorhydria. The role 
of endoscopic screening is not clear, and most guidelines do not 
support its use.
Additional Complications  Reflux esophagitis and a higher inci­
dence of gallstones and cholecystitis have been reported in patients 

undergoing subtotal gastrectomy. The latter is thought to be due to 
decreased gallbladder contractility associated with vagotomy and 
bypass of the duodenum, leading to decreased postprandial release 
of cholecystokinin.
RELATED CONDITIONS
■
■ZOLLINGER-ELLISON SYNDROME
Severe peptic ulcer diathesis secondary to gastric acid hypersecretion due 
to unregulated gastrin release from a non–β-cell, often well-differentiated 
neuroendocrine tumor (NET; gastrinoma) defines the components of 
ZES. Initially, ZES was typified by aggressive and refractory ulceration 
in which total gastrectomy provided the only chance for enhancing 
survival. Today, it can be cured by surgical resection in up to 40% of 
patients with the sporadic form of the disease (see below).
Epidemiology 
The true incidence of ZES is unknown, but esti­
mates suggest that it varies from 0.1 to 1% of individuals presenting 
with PUD, with 0.1–3 individuals per year having this rare diagnosis. 
Others have estimated an incidence of 0.5–3 per million population. 
Females are slightly more commonly affected than males, and the 
majority of patients are diagnosed between ages 30 and 65. In addition, 
the time of diagnosis is estimated to be between 4 and 7 years after the 
onset of symptoms. Gastrinomas are classified into sporadic tumors 
(80%) and those associated with multiple endocrine neoplasia (MEN) 
type 1 (see below). The widespread availability and use of PPIs have 
led to a decreased patient referral for gastrinoma evaluation, delay in 
diagnosis, and an increase in false-positive diagnoses of ZES. In fact, 
diagnosis may be delayed for ≥6 years after symptoms consistent with 
ZES are displayed.
Pathophysiology 
Hypergastrinemia originating from an autono­
mous neoplasm is the driving force responsible for the clinical mani­
festations in ZES. Gastrin stimulates acid secretion through gastrin 
receptors on parietal cells and by inducing histamine release from ECL 
cells. Gastrin also has a trophic action on gastric epithelial cells. Longstanding hypergastrinemia leads to markedly increased gastric acid 
secretion through both parietal cell stimulation and increased parietal 
cell mass. The increased gastric acid output leads to peptic ulcer dia­
thesis, erosive esophagitis, and diarrhea.
Tumor Distribution 
Although early studies suggested that the 
vast majority of gastrinomas occurred within the pancreas, a signifi­
cant number of these lesions are extrapancreatic. Between 60 and 90% 
of these tumors are found within the hypothetical gastrinoma triangle 
(confluence of the cystic and common bile ducts superiorly, junction 
of the second and third portions of the duodenum inferiorly, and junc­
tion of the neck and body of the pancreas medially). Duodenal tumors 
constitute the most common nonpancreatic lesion; between 60 and 
100% of gastrinomas are found here. Duodenal tumors are smaller, 
slower growing, and less likely to metastasize than pancreatic lesions 
and occur primarily in the first and second portion of the duodenum 
(90%). Less common extrapancreatic sites include stomach, bones, 
ovaries, heart, liver, and lymph nodes. More than 60% of tumors are 
considered malignant (determined by local invasion and/or evidence 
of metastasis), with up to 30–50% of patients having multiple lesions 
or metastatic disease at presentation. Histologically, gastrin-producing 
cells appear well-differentiated (grade 1 or 2 histologically), expressing 
markers typically found in endocrine neoplasms (chromogranin, neuronspecific enolase). Although not clearly established in gastrinomas, 
histologic grade in pancreatic NETs generally is an important predictor 
of survival in these rare neoplasms (Chap. 89).
Clinical Manifestations 
Gastric acid hypersecretion is respon­
sible for the signs and symptoms observed in patients with ZES. 
The most common clinical presentation for gastrinoma patients is 
abdominal pain in the presence of acid peptic disorders. Peptic ulcer 
is the most common clinical manifestation, occurring in >90% of 
gastrinoma patients. Initial presentation and ulcer location (duodenal

bulb) may be indistinguishable from common PUD. Clinical situations 
that should create suspicion of gastrinoma are ulcers in unusual loca­
tions (second part of the duodenum and beyond), ulcers refractory to 
standard medical therapy, ulcer recurrence after acid-reducing surgery, 
ulcers presenting with frank complications (bleeding, obstruction, and 
perforation), or ulcers in the absence of H. pylori or NSAID ingestion. 
Symptoms of esophageal origin are present in up to two-thirds of 
patients with ZES, with a spectrum ranging from mild esophagitis to 
frank ulceration with stricture and Barrett’s mucosa.
Diarrhea, the next most common clinical manifestation, is found in 
up to 70% of patients. Although diarrhea often occurs concomitantly 
with acid peptic disease, it may also occur independent of an ulcer and 
classically will abate with PPI therapy. Etiology of the diarrhea is mul­
tifactorial, resulting from marked volume overload to the small bowel, 
pancreatic enzyme inactivation by acid, and damage of the intestinal 
epithelial surface by acid. The epithelial damage can lead to a mild 
degree of maldigestion and malabsorption of nutrients. The diarrhea 
may also have a secretory component due to the direct stimulatory 
effect of gastrin on enterocytes or the co-secretion of additional hor­
mones from the tumor such as vasoactive intestinal peptide.
Gastrinomas can develop in the presence of MEN 1 syndrome 
(Chaps. 89 and 400) in ~25% of patients. This autosomal dominant 
disorder involves primarily three organ sites: the parathyroid glands 
(80–90%), pancreas (40–80%), and pituitary gland (30–60%). The 
syndrome is caused by inactivating mutations of the MEN1 tumorsuppressor gene found on the long arm of chromosome 11q13. The 
gene encodes for menin, which has an important role in DNA replica­
tion and transcriptional regulation. A genetic diagnosis is obtained by 
sequencing of the MEN1 gene, which can reveal mutations in 70–90% 
of typical MEN 1 cases. A family may have an unknown mutation, 
making a genetic diagnosis impossible, and therefore, certain individu­
als will require a clinical diagnosis, which is determined by whether a 
patient has tumors in two of the three endocrine organs (parathyroid, 
pancreas/duodenum, or pituitary) or has a family history of MEN 1 
and one of the endocrine organ tumors. In view of the stimulatory 
effect of calcium on gastric secretion, the hyperparathyroidism and 
hypercalcemia seen in MEN 1 patients may have a direct effect on ulcer 
disease. Resolution of hypercalcemia by parathyroidectomy reduces 
gastrin and gastric acid output in gastrinoma patients. An additional 
distinguishing feature in ZES patients with MEN 1 is the higher inci­
dence of gastric carcinoid tumor development (as compared to patients 
with sporadic gastrinomas). ZES presents and is diagnosed earlier in 
MEN 1 patients, and they have a more indolent course as compared 
to patients with sporadic gastrinoma. Gastrinomas tend to be smaller, 
multiple, and located in the duodenal wall more often than is seen in 
patients with sporadic ZES. Establishing the diagnosis of MEN 1 is 
critical in order to provide genetic counseling to the patient and their 
family and also to determine the recommended surgical approach. 
Therefore, gastrinoma patients should be screened for MEN 1 by per­
forming a detailed family history and obtaining several serum markers 
including calcium, parathyroid, prolactin, and pancreatic polypeptide 
levels.
Diagnosis 
Establishing an early diagnosis is important in order to 
minimize the long-term sequelae of gastric acid hypersecretion, pre­
vent metastatic disease, and counsel family members if a diagnosis of 
MEN 1 is established. Biochemical measurements of gastrin and acid 
secretion in patients suspected of having ZES play an important role 
is establishing this rare diagnosis. Often, patients suspected of having 
ZES will be treated with a PPI in an effort to ameliorate symptoms 
and decrease the likelihood of possible acid-related complications. 
The presence of the PPI, which will lower acid secretion and poten­
tially elevate fasting gastrin levels in normal individuals, will make 
the diagnostic approach in these individuals somewhat difficult. 
Significant morbidity related to peptic diathesis has been described 
when stopping PPIs in gastrinoma patients; therefore, a systematic 
approach in stopping these agents is warranted (see below). The first 
step in the evaluation of a patient suspected of having ZES is to obtain 
a fasting gastrin level. A list of clinical scenarios that should arouse 

TABLE 335-8  When to Obtain a Fasting Serum Gastrin Level
Multiple ulcers
Ulcers in unusual locations; associated with severe esophagitis; resistant 
to therapy with frequent recurrences; in the absence of nonsteroidal antiinflammatory drug ingestion or Helicobacter pylori infection
Ulcer patients awaiting surgery
Severe or refractory GERD
GERD associated with diarrhea
Extensive family history for peptic ulcer disease
Postoperative ulcer recurrence
Basal hyperchlorhydria
Unexplained diarrhea or steatorrhea
Diarrhea improved with PPI
Hypercalcemia
Family history of pancreatic islet, pituitary, or parathyroid tumor
Prominent gastric or duodenal folds
suspicion regarding this diagnosis is shown in Table 335-8. Fasting 
gastrin levels obtained using a dependable assay are usually <150 pg/
mL. A normal fasting gastrin, on two separate occasions, especially 
if the patient is on a PPI, virtually excludes this diagnosis. Virtually 
all gastrinoma patients will have a gastrin level >150–200 pg/mL. 
Measurement of fasting gastrin should be repeated to confirm the 
clinical suspicion. Some of the commercial biochemical assays used 
for measuring serum gastrin may be inaccurate. Variable specificity of 
the antibodies used have led to both false-positive and false-negative 
fasting gastrin levels, placing in jeopardy the ability to make an accu­
rate diagnosis of ZES.
CHAPTER 335
Multiple processes can lead to an elevated fasting gastrin level, the 
most frequent of which are gastric hypochlorhydria and achlorhydria, 
with or without pernicious anemia. Gastric acid induces feedback 
inhibition of gastrin release. A decrease in acid production will subse­
quently lead to failure of the feedback inhibitory pathway, resulting in 
net hypergastrinemia. Gastrin levels will thus be high in patients using 
antisecretory agents for the treatment of acid peptic disorders and 
dyspepsia. H. pylori infection can also cause hypergastrinemia. Addi­
tional causes of elevated gastrin include retained gastric antrum; G-cell 
hyperplasia; gastric outlet obstruction; renal insufficiency; massive 
small-bowel obstruction; and conditions such as rheumatoid arthritis, 
vitiligo, diabetes mellitus, and pheochromocytoma. Although a fasting 
gastrin >10 times normal is highly suggestive of ZES, two-thirds of 
patients will have fasting gastrin levels that overlap with levels found 
in the more common disorders outlined above, especially if a PPI is 
being taken by the patient. The effect of the PPI on gastrin levels and 
acid secretion will linger several days after stopping the PPI; therefore, 
it should be stopped for a minimum of 7 days before testing. During 
this period, the patient should be placed on a histamine H2 antagonist, 
such as famotidine, twice to three times per day. Although this type of 
agent has a short-term effect on gastrin and acid secretion, it needs to 
be stopped 24 h before repeating fasting gastrin levels or performing 
some of the tests highlighted below. The patient may take antacids for 
the final day, stopping them ~12 h before testing is performed. Height­
ened awareness of complications related to gastric acid hypersecretion 
during the period of PPI cessation is critical.
Peptic Ulcer Disease and Related Disorders 
Historically the next study typically recommended for establish­
ing a biochemical diagnosis of gastrinoma is to assess acid secretion. 
Unfortunately, few centers perform this type of testing; thus, only 
a brief summary will be provided here. Typically, nothing further 
needs to be done if decreased acid output in the absence of a PPI is 
observed. A pH can be measured on gastric fluid obtained either dur­
ing endoscopy or through nasogastric aspiration; a pH <3 is suggestive 
of a gastrinoma, but a pH >3 is not helpful in excluding the diagnosis. 
In those situations where the pH is >3, formal gastric acid analysis 
should be performed if available. Normal BAO in nongastric surgery 
patients is typically <5 meq/h. A BAO >15 meq/h in the presence of

hypergastrinemia is considered pathognomonic of ZES, but up to 12% 
of patients with common PUD may have elevated BAO to a lesser 
degree that can overlap with levels seen in ZES patients. In an effort 
to improve the sensitivity and specificity of gastric secretory studies, a 
BAO/MAO ratio was established using pentagastrin infusion as a way 
to maximally stimulate acid production, with a BAO/MAO ratio >0.6 
being highly suggestive of ZES. Pentagastrin is no longer available in 
the United States, making measurement of MAO virtually impossible. 
An endoscopic method for measuring gastric acid output has been 
developed but requires further validation.

Gastrin provocative tests have been developed in an effort to dif­
ferentiate between the causes of hypergastrinemia and are especially 
helpful in patients with indeterminate acid secretory studies. The tests 
are the secretin stimulation test and the calcium infusion study; the 
latter is rarely, if ever, utilized in our current environment due to the 
cumbersome nature of the test and its lower sensitivity and specificity 
than secretin stimulation. The most sensitive and specific gastrin pro­
vocative test for the diagnosis of gastrinoma is the secretin study. An 
increase in gastrin of ≥120 pg within 15 min of secretin injection has a 
sensitivity and specificity of >90% for ZES. PPI-induced hypochlorhy­
dria or achlorhydria may lead to a false-positive secretin test; thus, this 
agent must be stopped for 1 week before testing.
In light of the limited availability of the biochemical studies outlined 
above, more studies make a diagnosis of gastrinoma based on the pres­
ence of elevated gastrin and low gastric pH in the right clinical setting 
coupled with tumor localization tests outlined below and positive 
histology by biopsy (difficult to obtain). Revised guidelines for the best 
approach to establishing a diagnosis of gastrinoma taking into consid­
eration the above outlined limitations are being considered, but none 
have replaced the established guidelines outlined earlier in this section 
(see Jensen et al in Further Reading).
PART 10
Disorders of the Gastrointestinal System
Tumor Localization 
Once the biochemical diagnosis of gastri­
noma has been confirmed (if possible), the tumor must be located. 
Multiple imaging studies have been used in an effort to enhance 
tumor localization (Table 335-9). The broad range of sensitivity is 
due to the variable success rates achieved by the different investiga­
tive groups. Endoscopic ultrasound (EUS) permits imaging of the 
pancreas with a high degree of resolution (<5 mm). This modality is 
particularly helpful in excluding small neoplasms within the pancreas 
and in assessing the presence of surrounding lymph nodes and vascu­
lar involvement, but it is not very sensitive (43%) for finding duode­
nal lesions. This latter observation has led some to not include EUS in 
the routine preoperative evaluation of a patient suspected of having 
a gastrinoma. Several types of endocrine tumors express cell-surface 
receptors for somatostatin, in particular the subtype 2 (SSTR2). 
This permits the localization, staging, and prediction of therapeutic 
response to somatostatin analogues (see below) by gastrinomas. 
The original functional scinitigraphic tool developed measuring 
TABLE 335-9  Sensitivity of Imaging Studies in Zollinger-Ellison 
Syndrome
 
SENSITIVITY, %
PRIMARY 
GASTRINOMA
HEPATIC METASTATIC 
GASTRINOMA
STUDY
Ultrasound
0–28
15–77
CT scan
0–59
99–100
Selective angiography
35–68
96–100
Portal venous sampling
70–90
N/A
SASI
55–78
N/A
MRI
20–25
88–100
OctreoScan
55–77
90–100
EUS
28–86
N/A
Abbreviations: CT, computed tomography; EUS, endoscopic ultrasonography; 
MRI, magnetic resonance imaging; N/A, not applicable; OctreoScan, imaging with 
111In-pentetreotide; SASI, selective arterial secretin injection.

the uptake of the stable somatostatin analogue 111In-pentetreotide 
(OctreoScan) has demonstrated sensitivity and specificity rates of 
>80%. Positron emission tomography (PET)–computed tomography 
(CT) with 68Ga-DOTATATE has been developed and is superior 
than OctreoScan for assessing tumor presence in patients with 
well-differentiated NETs such as gastrinomas, with sensitivity and 
specificity of >90%, making it the functional imaging study of choice 
when available. 18F-Fluordeoxyglucose (18F-FDG) PET imaging has 
been found to be useful in pancreatic NETs, including gastrinomas, 
particularly as a prognostic marker.
Up to 50% of patients have metastatic disease at diagnosis. Success 
in controlling gastric acid hypersecretion has shifted the emphasis of 
therapy toward providing a surgical cure. Detecting the primary tumor 
and excluding metastatic disease are critical in view of this paradigm 
shift. Once a biochemical diagnosis has been confirmed, the patient 
should first undergo an abdominal CT scan, magnetic resonance imag­
ing (MRI), or OctreoScan/PET-CT with 68Ga-DOTATATE (depending 
on availability) to exclude metastatic disease. Once metastatic disease 
has been excluded, an experienced endocrine surgeon may opt for 
exploratory laparotomy with intraoperative ultrasound or transillumi­
nation. In other centers, careful examination of the peripancreatic area 
with EUS, accompanied by endoscopic exploration of the duodenum 
for primary tumors, will be performed before surgery. Selective arterial 
secretin injection may be a useful adjuvant for localizing tumors in a 
subset of patients. The extent of the diagnostic and surgical approach 
must be carefully balanced with the patient’s overall physiologic condi­
tion and the natural history of a slow-growing gastrinoma.
TREATMENT
Zollinger-Ellison Syndrome
Treatment of functional endocrine tumors is directed at ameliorat­
ing the signs and symptoms related to hormone overproduction, 
curative resection of the neoplasm, and attempts to control tumor 
growth in metastatic disease.
PPIs are the treatment of choice and have decreased the need 
for total gastrectomy. Initial PPI doses tend to be higher than those 
used for treatment of GERD or PUD. The initial dose of omeprazole, 
lansoprazole, rabeprazole, or esomeprazole should be in the range of 
60 mg in divided doses in a 24-h period. When gastric acid analysis 
was more widely available, dosing was adjusted to achieve a BAO 
<10 meq/h (at the drug trough) in surgery-naive patients and to 

<5 meq/h in individuals who have previously undergone an acidreducing operation. Close monitoring of clinical symptoms when 
starting PPIs and increasing the dose accordingly are paramount. 
Although the somatostatin analogue has inhibitory effects on gastrin 
release from receptor-bearing tumors and inhibits gastric acid secre­
tion to some extent, PPIs have the advantage of reducing parietal 
cell activity to a greater degree. Despite this, octreotide or lanreotide 
may be considered as adjunctive therapy to the PPI in patients with 
tumors that express somatostatin receptors and have peptic symp­
toms that are difficult to control with high-dose PPI.
The ultimate goal of surgery would be to provide a definitive 
cure. Improved understanding of tumor distribution has led to 
immediate cure rates as high as 33% with 10-year disease-free inter­
vals as high as 95% in sporadic gastrinoma patients undergoing 
surgery. A positive outcome is highly dependent on the experience 
of the surgical team treating these rare tumors. Surgical therapy of 
gastrinoma patients with MEN 1 remains controversial because of 
the difficulty in rendering these patients disease-free with surgery. 
In contrast to the encouraging postoperative results observed in 
patients with sporadic disease, <5% of MEN 1 patients are diseasefree 5 years after an operation. Moreover, in contrast to patients 
with sporadic ZES, the clinical course of MEN 1 patients tends to be 
benign and rarely leads to disease-related mortality, recommending 
that early surgery be deferred. Some groups suggest surgery only if 
a clearly identifiable, nonmetastatic lesion is documented by struc­
tural studies. Others advocate a more aggressive approach, where

all patients free of hepatic metastasis are explored and all detected 
tumors in the duodenum are resected; this is followed by enucle­
ation of lesions in the pancreatic head, with a distal pancreatectomy 
to follow. The outcome of the two approaches has not been clearly 
defined. Laparoscopic surgical interventions may provide attractive 
approaches in the future but currently seem to be of some limited 
benefit in patients with gastrinoma because a significant percentage 
of the tumors may be extrapancreatic and difficult to localize with a 
laparoscopic approach. Finally, patients selected for surgery should 
be individuals whose health status would lead them to tolerate a 
more aggressive operation and obtain the long-term benefits from 
such aggressive surgery, which are often witnessed after 10 years.
Therapy of metastatic endocrine tumors in general remains sub­
optimal; gastrinomas are no exception. In light of the observation 
that in many instances tumor growth is indolent and that many 
individuals with metastatic disease remain relatively stable for 
significant periods of time, many advocate not instituting systemic 
tumor-targeted therapy until evidence of tumor progression or 
refractory symptoms not controlled with PPIs are noted. Medical 
approaches, including biologic therapy (IFN-α, long-acting soma­
tostatin analogues, and peptide receptor radionuclides), systemic 
chemotherapy (streptozotocin, 5-fluorouracil, and doxorubicin), 
and hepatic artery embolization, may lead to significant toxicity 
without a substantial improvement in overall survival. Use of temo­
zolomide with capecitabine has demonstrated radiographic regres­
sion and progression-free survival in patients with well-differentiated 
NETs in the range of 70% and 18 months, respectively. Systemic 
therapy with radiolabeled somatostatin analogues (peptide receptor 
radiotherapy [PRRT]) has been used in the therapy of metastatic 
NETs and appears to be very promising in terms of radiographic 
regression, symptoms, and progression-free survival, but addi­
tional studies are warranted. Several promising therapies are being 
explored, including radiofrequency ablation or cryoablation of liver 
lesions and use of agents that block the VEGF receptor pathway 
(sunitinib, surufatinib), the mammalian target of rapamycin, and 
immune checkpoint inhibitors (Chap. 89).
Surgical approaches, including debulking surgery and liver 
transplantation for hepatic metastasis, have also produced limited 
benefit.
The overall 5- and 10-year survival rates for gastrinoma patients 
are 62–75% and 47–53%, respectively. Individuals with the entire 
tumor resected or those with a negative laparotomy have 5- and 
10-year survival rates >90%. Patients with incompletely resected 
tumors have 5- and 10-year survival rates of 43 and 25%, respec­
tively. Patients with hepatic metastasis have <20% survival at 5 years. 
Favorable prognostic indicators include primary duodenal wall 
tumors, isolated lymph node tumor, the presence of MEN 1, and 
undetectable tumor upon surgical exploration. Poor outcome is 
seen in patients with shorter disease duration; female sex; older age 
at diagnosis; higher gastrin levels (>10,000 pg/mL); poor histologic 
differentiation; high proliferative index; certain tumor molecular 
changes including chromosome 1qLOH and chromosome XLOH; 
large pancreatic primary tumors (>2–3 cm); metastatic disease 
to lymph nodes, liver, and bone; and Cushing’s syndrome. Rapid 
growth of hepatic metastases is also predictive of poor outcome.
■
■STRESS-RELATED MUCOSAL INJURY
Patients suffering from shock, sepsis, massive burns, severe trauma, or 
head injury can develop acute erosive gastric mucosal changes or frank 
ulceration with bleeding. Classified as stress-induced gastritis or ulcers, 
injury is most commonly observed in the acid-producing (fundus 
and body) portions of the stomach. The most common presentation 
is GI bleeding, which is usually minimal but can occasionally be lifethreatening. Respiratory failure requiring mechanical ventilation and 
underlying coagulopathy are risk factors for bleeding, which tends to 
occur 48–72 h after the acute injury or insult.
Histologically, stress injury does not contain inflammation or H. 
pylori; thus, “gastritis” is a misnomer. Although elevated gastric acid 

secretion may be noted in patients with stress ulceration after head 
trauma (Cushing’s ulcer) and severe burns (Curling’s ulcer), mucosal 
ischemia, breakdown of the normal protective barriers of the stomach, 
systemic release of cytokines, poor GI motility, and oxidative stress 
also play an important role in the pathogenesis. Acid must contribute 
to injury in view of the significant drop in bleeding noted when acid 
inhibitors are used as prophylaxis for stress gastritis.

Improvement in the general management of intensive care unit 
patients has led to a significant decrease in the incidence of GI bleed­
ing due to stress ulceration. The estimated decrease in bleeding is from 
20–30% to <5%. This improvement has led to some debate regarding 
the need for prophylactic therapy. The high mortality associated with 
stress-induced clinically important GI bleeding (>40%) and the limited 
benefit of medical (endoscopic, angiographic) and surgical therapy in a 
patient with hemodynamically compromising bleeding associated with 
stress ulcer/gastritis support the use of preventive measures in high-risk 
patients (mechanically ventilated, coagulopathy, multiorgan failure, or 
severe burns). Meta-analysis comparing H2 blockers with PPIs for the 
prevention of stress-associated clinically important and overt GI bleed­
ing demonstrates superiority of the latter without increasing the risk 
of nosocomial infections, increasing mortality, or prolonging intensive 
care unit length of stay. Therefore, PPIs are the treatment of choice for 
stress prophylaxis. Oral PPI is the best option if the patient can toler­
ate enteral administration. Pantoprazole is available as an intravenous 
formulation for individuals in whom enteral administration is not 
possible. If bleeding occurs despite these measures, endoscopy, intra­
arterial vasopressin, and embolization are options. If all else fails, then 
surgery should be considered. Although vagotomy and antrectomy 
may be used, the better approach would be a total gastrectomy, which 
has an exceedingly high mortality rate in this setting. Concerns with 
the effect of PPIs on the immune system coupled with the high cost of 
this agent have led to several comparative studies of PPIs and H2 recep­
tor antagonists for stress prophylaxis in patients requiring mechanical 
ventilation. Although the PEPTIC trial demonstrated comparative effi­
cacy between the two agents regarding mortality, technical aspects of 
the study led to some limitation in the final interpretation of the results. 
A meta-analysis performed in neurocritical patients did not reach 
strong clinical recommendations about the utility of ulcer prophylaxis. 
Reasons for this conclusion included the overall high or unclear risk of 
bias of individual trials, the low event rates, and the modest sample size 
examined. Currently, a trial to determine safety and efficacy of panto­
prazole compared to placebo for preventing stress-induced erosions is 
ongoing in mechanically ventilated patients.
CHAPTER 335
Peptic Ulcer Disease and Related Disorders 
■
■GASTRITIS
The term gastritis should be reserved for histologically documented 
inflammation of the gastric mucosa. Gastritis is not the mucosal 
erythema seen during endoscopy and is not interchangeable with 
“dyspepsia.” The etiologic factors leading to gastritis are broad and het­
erogeneous. Gastritis has been classified based on time course (acute 
vs chronic), histologic features, and anatomic distribution or proposed 
pathogenic mechanism (Table 335-10).
The correlation between the histologic findings of gastritis, the clini­
cal picture of abdominal pain or dyspepsia, and endoscopic findings 
noted on gross inspection of the gastric mucosa is poor. Therefore, 
there is no typical clinical manifestation of gastritis.
Acute Gastritis 
The most common causes of acute gastritis are 
infectious. Acute infection with H. pylori induces gastritis. However, H. 
pylori acute gastritis has not been extensively studied. It is reported as 
presenting with sudden onset of epigastric pain, nausea, and vomiting, 
and limited mucosal histologic studies demonstrate a marked infiltrate 
of neutrophils with edema and hyperemia. If not treated, this picture 
will evolve into one of chronic gastritis. Hypochlorhydria lasting for up 
to 1 year may follow acute H. pylori infection.
Bacterial infection of the stomach or phlegmonous gastritis is a rare, 
potentially life-threatening disorder characterized by marked and dif­
fuse acute inflammatory infiltrates of the entire gastric wall, at times 
accompanied by necrosis. Elderly individuals, alcoholics, and AIDS

TABLE 335-10  Classification of Gastritis
I.	 Acute gastritis
A.	 Acute Helicobacter pylori infection
B.	 Other acute infectious gastritides
1.	 Bacterial (other than H. pylori)
2.	 Helicobacter heilmannii
3.	 Phlegmonous
4.	 Mycobacterial
5.	 Syphilitic
6.	 Viral
7.	 Parasitic
8.	 Fungal
II.	 Chronic atrophic gastritis
A.	 Type A: Autoimmune, body-predominant
B.	 Type B: H. pylori–related, antral-predominant
C.	 Indeterminate
III.	 Uncommon forms of gastritis
A.	 Lymphocytic
B.	 Eosinophilic
C.	 Crohn’s disease
D.	 Sarcoidosis
E.	 Isolated granulomatous gastritis
F.	 Russell body gastritis
patients may be affected. Potential iatrogenic causes include polypec­
tomy and mucosal injection with India ink. Organisms associated with 
this entity include streptococci, staphylococci, Escherichia coli, Proteus, 
and Haemophilus species. Failure of supportive measures and antibiot­
ics may result in gastrectomy.
PART 10
Disorders of the Gastrointestinal System
Other types of infectious gastritis may occur in immunocompro­
mised individuals such as AIDS patients. Examples include herpetic 
(herpes simplex) or CMV gastritis. The histologic finding of intra­
nuclear inclusions would be observed in the latter.
Chronic Gastritis 
Chronic gastritis is identified histologically by 
an inflammatory cell infiltrate consisting primarily of lymphocytes 
and plasma cells, with very scant neutrophil involvement. Distribution 
of the inflammation may be patchy, initially involving superficial and 
glandular portions of the gastric mucosa. This picture may progress 
to more severe glandular destruction, with atrophy and metaplasia. 
Chronic gastritis has been classified according to histologic character­
istics. These include superficial atrophic changes and gastric atrophy. 
The association of atrophic gastritis with the development of gastric 
cancer has led to the development of endoscopic and serologic markers 
of severity. Some of these include gross inspection and classification 
of mucosal abnormalities during standard endoscopy, magnification 
endoscopy, endoscopy with narrow band imaging and/or autofluores­
cence imaging, and measurement of several serum biomarkers includ­
ing pepsinogen I and II levels, gastrin-17, and anti–H. pylori serologies. 
The clinical utility of these tools is currently being explored.
The early phase of chronic gastritis is superficial gastritis. The 
inflammatory changes are limited to the lamina propria of the surface 
mucosa, with edema and cellular infiltrates separating intact gastric 
glands. The next stage is atrophic gastritis. The inflammatory infil­
trate extends deeper into the mucosa, with progressive distortion and 
destruction of the glands. The final stage of chronic gastritis is gastric 
atrophy. Glandular structures are lost, and there is a paucity of inflam­
matory infiltrates. Endoscopically, the mucosa may be substantially 
thin, permitting clear visualization of the underlying blood vessels.
Gastric glands may undergo morphologic transformation in chronic 
gastritis. Intestinal metaplasia denotes the conversion of gastric glands 
to a small intestinal phenotype with small-bowel mucosal glands con­
taining goblet cells. The metaplastic changes may vary in distribution 
from patchy to fairly extensive gastric involvement. Intestinal metapla­
sia is an important predisposing factor for gastric cancer (Chap. 85).

Chronic gastritis has also been classified according to the predomi­
nant site of involvement. Type A refers to the body-predominant form 
(autoimmune), and type B is the antral-predominant form (H. pylori–
related). This classification is artificial in view of the difficulty in dis­
tinguishing between these two entities. The term AB gastritis has been 
used to refer to a mixed antral/body picture. Histologic classification is 
the most accurate way to approach chronic gastritis.
TYPE A GASTRITIS  The less common of the two forms involves pri­
marily the fundus and body, with antral sparing. Traditionally, this 
form of gastritis has been associated with pernicious anemia (Chap. 
104) in the presence of circulating antibodies against parietal cells and 
IF; thus, it is also called autoimmune gastritis. H. pylori infection can 
lead to a similar distribution of gastritis.
Antibodies to parietal cells have been detected in >90% of patients 
with pernicious anemia and in up to 50% of patients with type A 
gastritis. The parietal cell antibody is directed against H+,K+-ATPase. 

T cells are also implicated in the injury pattern of this form of gastritis. 
A subset of patients infected with H. pylori develop antibodies against 
H+,K+-ATPase, potentially leading to the atrophic gastritis pattern 
seen in some patients infected with this organism. The mechanism 
is thought to involve molecular mimicry between H. pylori LPS and 
H+,K+-ATPase.
Parietal cell antibodies and atrophic gastritis are observed in fam­
ily members of patients with pernicious anemia. These antibodies 
are observed in up to 20% of individuals aged >60 and in ~20% of 
patients with vitiligo and Addison’s disease. About one-half of patients 
with pernicious anemia have antibodies to thyroid antigens, and 
~30% of patients with thyroid disease have circulating anti–parietal 
cell antibodies. Anti-IF antibodies are more specific than parietal cell 
antibodies for type A gastritis, being present in ~40% of patients with 
pernicious anemia. Another parameter consistent with this form of 
gastritis being autoimmune in origin is the higher incidence of specific 
familial histocompatibility haplotypes such as HLA-B8 and HLA-DR3. 
Low pepsinogen levels have also been observed; thus, this marker has 
been used as an additional diagnostic tool in autoimmune gastritis.
The parietal cell–containing gastric gland is preferentially targeted 
in this form of gastritis, and achlorhydria results. Parietal cells are the 
source of IF, the lack of which will lead to vitamin B12 deficiency and its 
sequelae (megaloblastic anemia, neurologic dysfunction).
Gastric acid plays an important role in feedback inhibition of gastrin 
release from G cells. Achlorhydria, coupled with relative sparing of the 
antral mucosa (site of G cells), leads to hypergastrinemia. Gastrin levels 
can be markedly elevated (>500 pg/mL) in patients with pernicious 
anemia. ECL cell hyperplasia with frank development of gastric carci­
noid tumors may result from gastrin trophic effects. Hypergastrinemia 
and achlorhydria may also be seen in nonpernicious anemia–associated 
type A gastritis.
TYPE B GASTRITIS  Type B, or antral-predominant, gastritis is the 
more common form of chronic gastritis. H. pylori infection is the cause 
of this entity. Although described as “antral-predominant,” this is likely 
a misnomer in view of studies documenting the progression of the 
inflammatory process toward the body and fundus of infected individ­
uals. The conversion to a pangastritis is time dependent and estimated 
to require 15–20 years. This form of gastritis increases with age, being 
present in up to 100% of persons aged >70. Histology improves after 
H. pylori eradication. The number of H. pylori organisms decreases 
dramatically with progression to gastric atrophy, and the degree of 
inflammation correlates with the level of these organisms. Early on, 
with antral-predominant findings, the quantity of H. pylori is highest 
and a dense chronic inflammatory infiltrate of the lamina propria is 
noted, accompanied by epithelial cell infiltration with polymorpho­
nuclear leukocytes (Fig. 335-16).
Multifocal atrophic gastritis, gastric atrophy with subsequent 
metaplasia, has been observed in chronic H. pylori–induced gastritis. 
This may ultimately lead to development of gastric adenocarcinoma 
(Fig. 335-8; Chap. 85). H. pylori infection is now considered an 
independent risk factor for gastric cancer. Worldwide epidemiologic 
studies have documented a higher incidence of H. pylori infection in

FIGURE 335-16  Chronic gastritis and H. pylori organisms. Steiner silver stain of 
superficial gastric mucosa showing abundant darkly stained microorganisms 
layered over the apical portion of the surface epithelium. Note that there is no tissue 
invasion.
patients with adenocarcinoma of the stomach as compared to control 
subjects. Seropositivity for H. pylori is associated with a three- to 
sixfold increased risk of gastric cancer. This risk may be as high as 
ninefold after adjusting for the inaccuracy of serologic testing in the 
elderly. The mechanism by which H. pylori infection leads to cancer 
is unknown, but it appears to be related to the chronic inflamma­
tion induced by the organism. Eradication of H. pylori as a general 
preventative measure for gastric cancer is being evaluated but is not 
yet recommended.
Infection with H. pylori is also associated with development of a 
low-grade B-cell lymphoma, gastric MALT lymphoma (Chap. 113). 
The chronic T-cell stimulation caused by the infection leads to produc­
tion of cytokines that promote the B-cell tumor. The tumor should be 
initially staged with a CT scan of the abdomen and EUS. Tumor growth 
remains dependent on the presence of H. pylori, and its eradication is 
often associated with complete regression of the tumor. The tumor 
may take more than a year to regress after treating the infection. Such 
patients should be followed by EUS every 2–3 months. If the tumor is 
stable or decreasing in size, no other therapy is necessary. If the tumor 
grows, it may have become a high-grade B-cell lymphoma. When the 
tumor becomes a high-grade aggressive lymphoma histologically, it 
loses responsiveness to H. pylori eradication.
TREATMENT
Chronic Gastritis
Treatment in chronic gastritis is aimed at the sequelae and not the 
underlying inflammation. Patients with pernicious anemia will 
require parenteral vitamin B12 supplementation on a long-term 
basis. Eradication of H. pylori is often recommended even if PUD or 
a low-grade MALT lymphoma is not present. Expert opinion sug­
gests that patients with atrophic gastritis complicated by intestinal 
metaplasia without dysplasia should undergo surveillance endos­
copy every 3 years.
Miscellaneous Forms of Gastritis 
Lymphocytic gastritis is char­
acterized histologically by intense infiltration of the surface epithelium 
with lymphocytes. The infiltrative process is primarily in the body of 
the stomach and consists of mature T cells and plasmacytes. The etiol­
ogy of this form of chronic gastritis is unknown. It has been described 
in patients with celiac sprue, but whether there is a common factor 
associating these two entities is unknown. No specific symptoms sug­
gest lymphocytic gastritis. A subgroup of patients has thickened folds 
noted on endoscopy. These folds are often capped by small nodules 
that contain a central depression or erosion; this form of the disease 
is called varioliform gastritis. H. pylori probably plays no significant 

role in lymphocytic gastritis. Therapy with glucocorticoids or sodium 
cromoglycate has obtained unclear results.

Marked eosinophilic infiltration involving any layer of the stom­
ach (mucosa, muscularis propria, and serosa) is characteristic of 
eosinophilic gastritis. Affected individuals will often have circulating 
eosinophilia with clinical manifestation of systemic allergy. Involve­
ment may range from isolated gastric disease to diffuse eosinophilic 
gastroenteritis. Antral involvement predominates, with prominent 
edematous folds being observed on endoscopy. These prominent antral 
folds can lead to outlet obstruction. Patients can present with epigastric 
discomfort, nausea, and vomiting. Treatment with glucocorticoids has 
been successful.
Several systemic disorders may be associated with granulomatous 
gastritis. Gastric involvement has been observed in Crohn’s disease. 
Involvement may range from granulomatous infiltrates noted only on 
gastric biopsies to frank ulceration and stricture formation. Gastric 
Crohn’s disease usually occurs in the presence of small-intestinal dis­
ease. Several rare infectious processes can lead to granulomatous gas­
tritis, including histoplasmosis, candidiasis, syphilis, and tuberculosis. 
Other unusual causes of this form of gastritis include sarcoidosis, idio­
pathic granulomatous gastritis, and eosinophilic granulomas involving 
the stomach. Establishing the specific etiologic agent in this form of 
gastritis can be difficult, at times requiring repeat endoscopy with 
biopsy and cytology. Occasionally, a surgically obtained full-thickness 
biopsy of the stomach may be required to exclude malignancy.
Russell body gastritis (RBG) is a mucosal lesion of unknown etiol­
ogy that has a pseudotumoral endoscopic appearance. Histologically, it 
is defined by the presence of numerous plasma cells containing Russell 
bodies (RBs) that express kappa and lambda light chains. Only 10 cases 
have been reported, and 7 of these have been associated with H. pylori 
infection. The lesion can be confused with a neoplastic process, but it 
is benign in nature, and the natural history of the lesion is not known. 
There have been cases of resolution of the lesion when H. pylori was 
eradicated.
CHAPTER 335
Peptic Ulcer Disease and Related Disorders 
Immune checkpoint inhibitor–induced enterocolitis and gastritis 
are recognized sequelae of these oncologic therapies. The gastritis 
typically occurs later in the course of therapy. The diagnosis is made 
by the histologic findings on gastric mucosal biopsies obtained endo­
scopically. This is an important diagnosis to make since therapy with 
glucocorticoids and potentially IL-6 receptor blockers will be required. 
Moreover, this side effect will have an effect on the oncologic therapy 
prescribed.
■
■MÉNÉTRIER’S DISEASE
Ménétrier’s disease (MD) is a very rare gastropathy characterized 
by large, tortuous mucosal folds. MD has an average age of onset of 
40–60 years with a male predominance. The differential diagnosis of 
large gastric folds includes ZES, malignancy (lymphoma, infiltrat­
ing carcinoma), infectious etiologies (CMV, histoplasmosis, syphilis, 
tuberculosis), gastritis polyposa profunda, and infiltrative disorders 
such as sarcoidosis. MD is most commonly confused with large or 
multiple gastric polyps (prolonged PPI use) or familial polyposis syn­
dromes. The mucosal folds in MD are often most prominent in the 
body and fundus, sparing the antrum. Histologically, massive foveolar 
hyperplasia (hyperplasia of surface and glandular mucous cells) and a 
marked reduction in oxyntic glands and parietal cells and chief cells are 
noted. This hyperplasia produces the prominent folds observed. The 
pits of the gastric glands elongate and may become extremely dilated 
and tortuous. Although the lamina propria may contain a mild chronic 
inflammatory infiltrate including eosinophils and plasma cells, MD is 
not considered a form of gastritis. The etiology of this unusual clinical 
picture in children is often CMV, but the etiology in adults is unknown. 
Overexpression of the growth factor TGF-α has been demonstrated in 
patients with MD. The overexpression of TGF-α in turn results in over­
stimulation of the epidermal growth factor receptor (EGFR) pathway 
and increased proliferation of mucus cells, resulting in the observed 
foveolar hyperplasia.
The clinical presentation in adults is usually insidious and progres­
sive. Epigastric pain, nausea, vomiting, anorexia, peripheral edema,