2434 PART 10 Disorders of the Gastrointestinal System

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 emptying.

■ 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

Furuta GT, Katzka DA: Eosinophilic esophagitis. N Engl J Med

373:1640, 2015.

Hirano I et al: American Gastroenterological Institute and the joint

task force on allergy-immunology practice parameters clinical guidelines for the management of eosinophilic esophagitis. Gastroenterology 158:1776, 2020.

Kahrilas PJ, Boeckxstaens G: The spectrum of achalasia: Lessons

from studies of pathophysiology and high-resolution manometry.

Gastroenterology 145:954, 2013.

Kahrilas PJ et al: American Gastroenterological Association Institute

technical review on the management of gastroesophageal reflux disease. Gastroenterology 135:1392, 2008.

Katzka DA et al: Phenotypes of gastroesophageal reflux disease:

where Rome, Lyon, and Montreal meet. Clin Gastroenterol Hepatol

18:767, 2020.

Pandolfino JE, Gawron AJ: Achalasia: A systematic review. JAMA

313:1841, 2015.

Shaheen NJ et al: Diagnosis and management of Barrett’s esophagus.

Am J Gastroenterol 111:30, 2016.

Spechler SJ, Souza RF: Barrett’s esophagus. N Engl J Med 371:836,

2014.

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 contributing

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 billion per year in the United States, with $3 billion spent on

hospitalizations, $2 billion on physician office visits, and $1 billion in

decreased productivity and days lost from work.

324 Peptic Ulcer Disease

and Related Disorders

John Del Valle

Gastric pit

 (foveolus)

Isthmus

Neck

Oxyntic Gland

Base

 (fundus)

Surface mucous cells

Mucous neck cells

Parietal cells

Endocrine cell

Chief cells

FIGURE 324-1 Diagrammatic representation of the oxyntic gastric gland.

(Reproduced with permission from S Ito, RJ Winchester: The Fine Structure of the

Gastric Mucosa in the Bat. J Cell Biol 16:541, 1963.)

■ 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. 324-1). 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 unstimulated,

parietal cell has prominent cytoplasmic tubulovesicles and intracellular

canaliculi containing short microvilli along its apical surface (Fig. 324-2).

H+

,K+

-adenosine triphosphatase (ATPase) is expressed in the tubulovesicle

membrane; upon cell stimulation, this membrane, along with apical membranes, transforms into a dense network of apical intracellular canaliculi

containing long microvilli. Acid secretion, a process requiring high energy,

occurs at the apical canalicular surface. Numerous mitochondria (30–40%

of total cell volume) generate the energy required for secretion.

Gastroduodenal Mucosal Defense The gastric epithelium is

under constant assault by a series of endogenous noxious factors,

including hydrochloric acid (HCl), pepsinogen/pepsin, and bile salts.

In addition, a steady flow of exogenous substances such as medications,

alcohol, and bacteria encounter the gastric mucosa. A highly intricate

biologic system is in place to provide defense from mucosal injury and

to repair any injury that may occur.

The mucosal defense system can be envisioned as a three-level barrier,

composed of preepithelial, epithelial, and subepithelial elements

2435Peptic Ulcer Disease and Related Disorders CHAPTER 324

(Fig. 324-3). The first line of defense is a mucus-bicarbonate-phospholipid

layer, which serves as a physicochemical barrier to multiple molecules,

including hydrogen ions. Mucus is secreted in a regulated fashion by

gastroduodenal surface epithelial cells. It consists primarily of water

(95%) and a mixture of phospholipids and glycoproteins (mucin). The

mucous gel functions as a nonstirred water layer impeding diffusion of

ions and molecules such as pepsin. Bicarbonate, secreted in a regulated

manner by surface epithelial cells of the gastroduodenal mucosa into

the mucous gel, forms a pH gradient ranging from 1 to 2 at the gastric

luminal surface and reaching 6–7 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 intracellular tight junctions. Surface epithelial cells generate heat

shock proteins that prevent protein denaturation and protect cells from

certain factors such as increased temperature, cytotoxic agents, or oxidative stress. Epithelial cells also generate trefoil factor family peptides

and cathelicidins, which also play a role in surface cell protection and

regeneration. If the preepithelial barrier 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), transforming growth factor (TGF) α, and basic

fibroblast growth factor (FGF), modulate the process of restitution.

Larger defects that are not effectively repaired by restitution require cell

proliferation. Epithelial cell regeneration is regulated by prostaglandins

and growth factors such as EGF and TGF-α. In tandem with epithelial

cell renewal, formation of new vessels (angiogenesis) within the injured

microvascular bed occurs. Both FGF and vascular endothelial growth

factor (VEGF) are important in regulating angiogenesis in the gastric

mucosa. In addition, the gastric peptide gastrin (see below) has been

recently found to stimulate cell proliferation, migration, 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.

An elaborate microvascular system within the gastric submucosal layer is the key component of the subepithelial defense/repair

system, providing HCO3

−, which neutralizes the acid generated by

the parietal cell. Moreover, this microcirculatory bed provides an

adequate supply of micronutrients and oxygen while removing toxic

metabolic by-products. Several locally produced factors including

nitric oxide (NO) (see below), hydrogen sulfide, and prostacyclin contribute to the vascular protective pathway through vasodilation of the

microcirculation.

Prostaglandins play a central role in gastric epithelial defense/

repair (Fig. 324-4). 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

Resting Stimulated

Canaliculus HCl

H3O+

Ca

– cAMP

KCl

KCl

H+,K+–ATPase

Gastrin

Active

pump

Tubulovesicles

ACh Histamine

Active

pump

FIGURE 324-2 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.)

mucosal blood flow and epithelial cell restitution. Prostaglandins are

derived from esterified arachidonic acid, which is formed from phospholipids (cell membrane) by the action of phospholipase A2

. A key

enzyme that controls the rate-limiting step in prostaglandin synthesis

is cyclooxygenase (COX), which is present in two isoforms (COX-1,

COX-2), each having distinct characteristics regarding structure, tissue

distribution, and expression. COX-1 is expressed in a host of tissues,

including the stomach, platelets, kidneys, and endothelial cells. This

isoform is expressed in a constitutive manner and plays an important

role in maintaining the integrity of renal function, platelet aggregation,

and gastrointestinal (GI) mucosal integrity. In contrast, the expression

of COX-2 is inducible by inflammatory stimuli, and it is expressed in

macrophages, leukocytes, fibroblasts, and synovial cells. The beneficial

effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on tissue

inflammation are due to inhibition of COX-2; the toxicity of these

drugs (e.g., GI mucosal ulceration and renal dysfunction) is related to

inhibition of the COX-1 isoform. The highly COX-2–selective NSAIDs

have the potential to provide the beneficial effect of decreasing tissue

inflammation while minimizing toxicity in the GI tract. Selective

COX-2 inhibitors have had adverse effects on the cardiovascular (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. 324-3).

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) components. 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 microbiome 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 HCl and pepsinogen are the

two principal gastric secretory products capable of inducing mucosal

injury. Gastric acid and pepsinogen play a physiologic role in protein

digestion; absorption of iron, calcium, 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 histaminergic input from local gastric

sources are the principal contributors to basal acid secretion. Stimulated gastric acid secretion occurs primarily in three phases based on

the site where the signal originates (cephalic, gastric, and intestinal).

Sight, smell, and taste of food are the components of the cephalic phase,

which stimulates gastric secretion via the vagus nerve. The gastric

phase is activated once food enters the stomach. This component of

2436 PART 10 Disorders of the Gastrointestinal System

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 (parietal 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 secretion through stimulation of histamine

release from ECL cells, but this remains to be confirmed.

The acid-secreting parietal cell is located in the oxyntic gland,

adjacent to other cellular elements (ECL cell, D cell) important in the

gastric secretory process (Fig. 324-5). 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,

FIGURE 324-3 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.)

2437Peptic Ulcer Disease and Related Disorders CHAPTER 324

M3

). Binding of histamine to the H2

 receptor leads to activation of

adenylate cyclase and the phosphoinositol pathways, in turn resulting

in an increase in cyclic adenosine monophosphate (AMP) and intracellular calcium, respectively. Activation of the gastrin and muscarinic

receptors results in activation of the protein kinase C/phosphoinositide

signaling pathway. Each of these signaling pathways in turn regulates

a series of downstream kinase cascades that control the acid-secreting

pump, H+,K+-ATPase. The discovery that different ligands and their

corresponding receptors lead to activation of different signaling pathways explains the potentiation of acid secretion that occurs when histamine and gastrin or acetylcholine are combined. More importantly, this

observation explains why blocking one receptor type (H2

) decreases

acid secretion stimulated by agents that activate a different pathway

(gastrin, acetylcholine). Parietal cells also express receptors for ligands

that inhibit acid production (glucagon-like peptide-1, prostaglandins,

somatostatin, EGF, neurotensin, and urocortin). Histamine also stimulates gastric acid secretion indirectly by activating the histamine H3

receptor on D cells, which inhibits somatostatin release.

The enzyme H+,K+-ATPase is responsible for generating the large

concentration of H+. It is a membrane-bound protein that consists of

two subunits, α and β. The active catalytic site is found within the α

subunit; the function of the β subunit is unclear. This enzyme uses the

chemical energy of adenosine triphosphate (ATP) to transfer H+ ions

from parietal cell cytoplasm to the secretory canaliculi in exchange

for K+. The H+,K+-ATPase is located within the secretory canaliculus

and in nonsecretory cytoplasmic tubulovesicles. The tubulovesicles are

impermeable to K+, which leads to an inactive pump in this location.

The distribution of pumps between the nonsecretory vesicles and the

secretory canaliculus varies according to parietal cell activity (Fig. 324-2).

Proton pumps are recycled back to the inactive state in cytoplasmic

vesicles once parietal cell activation ceases. Ezrin (an actin binding protein), actin, myosin, soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), small G proteins of the Rab family,

and secretory carrier membrane proteins (SCAMPS) are postulated

to participate in parietal cell membrane translocation. 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),

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 idiopathic 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. Eradication 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

Membrane phospholipids

Arachidonic acid

Phospholipase A2

Stomach

Kidney

Platelets

Endothelium

TXA2, PGI2, PGE2 Gastrointestinal mucosal integrity

 Platelet aggregation

 Renal function

PGI2, PGE2 Inflammation

 Mitogenesis

 Bone formation

 Other functions?

Macrophages

Leukocytes

Fibroblasts

Endothelium

COX-1

housekeeping

COX-2

inflammation

FIGURE 324-4 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

.

Vagus

CGRP

EC Cell

(ANP)

D Cell

(SST)

G Cell

(Gastrin)

D Cell

(SST)

H2 H3

Parietal

Cell

ECL Cell

(Histamine)

Antrum Fundus

HP

(Chronic Antrum)

Acid

HP (Acute)

–

–

– +

+

+ +

+

+ +

+

+

+

+

+ – –

–

–

–

–

PACAP ACh VIP ACh ACh GRP ACh ACh

FIGURE 324-5 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, gastrinreleasing peptide; PACAP, pituitary adenylate-cyclase activating peptide; SST, somatostatin; VIP, vasoactive intestinal

peptide.

2438 PART 10 Disorders of the Gastrointestinal System

in males and are less common than DUs, perhaps due to the higher

likelihood of GUs being silent and presenting only after a complication

develops. Autopsy studies suggest a similar incidence of DUs and GUs.

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 secretory

mucosa. Benign GUs are quite rare in the gastric fundus and are histologically similar to DUs. Benign GUs associated with H. pylori are also

associated with antral gastritis. In contrast, NSAID-related GUs are not

accompanied by chronic active gastritis but may instead have evidence

of a chemical gastropathy, typified by foveolar hyperplasia, edema of

the lamina propria, and epithelial regeneration in the absence of H.

pylori. Extension of smooth-muscle fibers into the upper portions of

the mucosa, where they are not typically found, may also occur.

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 duodenal

bulb of patients with an active DU as compared to control subjects.

H. pylori infection may also play a role in this process (see below).

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. GUs have been classified based on their location: type I occur in the gastric body and tend to be associated with low

gastric acid production; type II occur in the antrum, and gastric acid

can vary from low to normal; type III occur within 3 cm of the pylorus

and are commonly accompanied by DUs and normal or high gastric

acid production; and type IV are found in the cardia and are associated

with low gastric acid production.

H. PYLORI AND ACID PEPTIC DISORDERS Gastric infection with the

bacterium H. pylori accounts for the majority of PUD (Chap. 163). 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 populations, particularly

in individuals who have not developed chronic atrophic gastritis and

gastric metaplasia.

The Bacterium The bacterium, initially named Campylobacter pyloridis,

is a gram-negative microaerophilic rod found most commonly in

the deeper portions of the mucous gel coating the gastric mucosa or

between the mucous layer and the gastric epithelium. It may attach to

gastric epithelium but under normal circumstances does not appear

to invade cells. It is strategically designed to live within the aggressive

environment of the stomach. It is S-shaped (~0.5–3 μm in size) and

contains multiple sheathed flagella. Initially, H. pylori resides in the

antrum but, over time, migrates toward the more proximal segments

of the stomach. The organism is capable of transforming into a coccoid

form, which represents a dormant state that may facilitate survival in

adverse conditions. The genome of H. pylori (1.65 million base pairs)

encodes ~1500 proteins. Among this multitude of proteins there are

factors that are essential determinants of H. pylori–mediated pathogenesis and colonization such as the outer membrane protein (Hop

proteins), urease, and the vacuolating cytotoxin (Vac A). Moreover,

the majority of H. pylori strains contain a genomic fragment that

encodes the cag pathogenicity island (cag-PAI). Several of the genes

that make up cag-PAI encode components of a type IV secretion island

that translocates Cag A into host cells. Once in the cell, Cag A activates a series of cellular events important in cell growth and cytokine

production. H. pylori also has extensive genetic diversity that in turn

enhances its ability to promote disease. The first step in infection by

H. pylori is dependent on the bacteria’s motility and its ability to produce urease. Urease produces ammonia from urea, an essential step in

alkalinizing the surrounding pH. Additional bacterial factors include

catalase, lipase, adhesins, platelet-activating factor, and pic B (induces

cytokines). Multiple strains of H. pylori exist and are characterized by

their ability to express several of these factors (Cag A, Vac A, etc.). It is

possible that the different diseases related to H. pylori infection can be

attributed to different strains of the organism with distinct pathogenic

features.

Epidemiology The prevalence of H. pylori varies throughout the world

and depends largely on the overall standard of living in the region. In

developing parts of the world, 80% of the population may be infected

by the age of 20, whereas the prevalence is 20–50% in industrialized

countries. In contrast, in the United States, this organism is rare in

childhood. The overall prevalence of H. pylori in the United States is

~30%, with individuals born before 1950 having a higher rate of infection than those born later. About 10% of Americans <30 years of age

are colonized with the bacteria. The rate of infection with H. pylori in

industrialized countries has decreased substantially in recent decades.

The steady increase in the prevalence of H. pylori noted with increasing

age is due primarily to a cohort effect, reflecting higher transmission

during a period in which the earlier cohorts were children. It has been

calculated through mathematical models that improved sanitation

during the latter half of the nineteenth century dramatically decreased

transmission of H. pylori. Moreover, with the present rate of intervention, the organism will be ultimately eliminated from the United States.

Two factors that predispose to higher colonization rates include poor

socioeconomic status and less education. These factors, not race, are

responsible for the rate of H. pylori infection in blacks and Hispanic

Americans being double the rate seen in whites of comparable age.

Other risk factors for H. pylori infection are (1) birth or residence in a

developing country, (2) domestic crowding, (3) unsanitary living conditions, (4) unclean food or water, and (5) exposure to gastric contents

of an infected individual.

Transmission of H. pylori occurs from person to person, following

an oral-oral or fecal-oral route. The risk of H. pylori infection is declining in developing countries. The rate of infection in the United States

has fallen by >50% when compared to 30 years ago.

Pathophysiology H. pylori infection is virtually always associated with

a chronic active gastritis, but only 10–15% of infected individuals develop frank peptic ulceration. The basis for this difference is

unknown but is likely due to a combination of host and bacterial factors, some of which are outlined below. Initial studies suggested that

>90% of all DUs were associated with H. pylori, but H. pylori is present

in only 30–60% of individuals with GUs and 50–70% of patients with

DUs. The pathophysiology of ulcers not associated with H. pylori or

NSAID ingestion (or the rare Zollinger-Ellison syndrome [ZES]) is

becoming more relevant as the incidence of H. pylori is dropping, particularly in the Western world (see below).

The particular end result of H. pylori infection (gastritis, PUD,

gastric MALT lymphoma, gastric cancer) is determined by a complex

interplay between bacterial and host factors (Fig. 324-6).

Bacterial factors: H. pylori is able to facilitate gastric residence,

induce mucosal injury, and avoid host defense. Different strains of

H. pylori produce different virulence factors including γ-glutamyl

transpeptidase (GGT), cytotoxin-associated gene A (Cag A) product,

and virulence components vacuolating toxin (Vac A), in addition to

2439Peptic Ulcer Disease and Related Disorders CHAPTER 324

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 mucosal

damage, in part through their ability to target the host immune cells.

For example, Vac A targets human CD4 T cells, inhibiting their proliferation, and in addition can disrupt normal function of B cells, CD8

T cells, macrophages, and mast cells. Multiple studies have demonstrated that H. pylori strains that are cag-PAI positive are associated

with a higher risk of 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 compared to that of other organisms. It may promote a smoldering chronic

inflammation.

Host factors: Studies in twins suggest that there may be genetic

predisposition to acquire H. pylori. The inflammatory response to H.

pylori includes recruitment of neutrophils, lymphocytes (T and B),

macrophages, and plasma cells. The pathogen leads to local injury by

binding to class II major 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 factor

(TNF) α, and interferon (IFN) γ. H. pylori infection also leads to both

a mucosal and a systemic humoral response, which does not lead to

eradication of the bacteria but further compounds epithelial cell injury.

Additional mechanisms by which H. pylori may cause epithelial cell

injury include (1) activated neutrophil-mediated production of reactive oxygen or nitrogen species and enhanced epithelial cell turnover

and (2) apoptosis related to interaction with T cells (T helper 1 [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, colonization of

the stomach with H. pylori likely alters the composition of the gastric

microbiota. The impact of the latter on gastric pathophysiology remains

unknown. 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 reason for H. pylori–mediated duodenal ulceration remains

unclear. Studies suggest that H. pylori associated with duodenal ulceration may be more virulent. In addition, certain specific bacterial

factors such as the 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 somatostatinsecreting 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. 324-7). 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 contradicting each of these interesting theories have been

demonstrated. Thus, the mechanism by which H. pylori infection of

the stomach leads to duodenal ulceration remains to be established.

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 invitro system. Moreover,

the development of advanced microscopic optical imaging techniques

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 324-6 Outline of the bacterial and host factors important in determining

H. pylori–induced gastrointestinal disease. MALT, mucosal-associated lymphoid tissue.

Parietal cell FUNDUS

Vagus

Acetylcholine

Histamine

Histamine

H, K ATPase

Tubulovesicles

Somatostatin

Somatostatin

ECL cell

Gastrin

ECL cell

D cell

Canaliculus

Blood vessel

Gastrin

D cell

G cell

ANTRUM

Somatostatin

+ +

–

–

+

+

+

–

FIGURE 324-7 Summary of potential mechanisms by which H. pylori may lead to

gastric secretory abnormalities. D, somatostatin cell; ECL, enterochromaffin-like 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.)

2440 PART 10 Disorders of the Gastrointestinal System

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 distribution of gastritis correlate with the ultimate gastric and duodenal

pathology observed. Specifically, the presence of antral-predominant

gastritis is associated with DU formation; gastritis involving primarily

the corpus predisposes to the development of GUs, gastric atrophy, and

ultimately gastric carcinoma (Fig. 324-8).

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 billion over-the-counter tablets sold. More than 30 million individuals

take NSAIDs, with >100 million prescriptions sold yearly in the

United States alone. In fact, after the introduction of COX-2 inhibitors

in the year 2000, the number of prescriptions written for NSAIDs was

>111 million at a cost of $4.8 billion. Side effects and complications due

to NSAIDs are considered the most common drug-related toxicities in

the United States. The spectrum of NSAID-induced morbidity ranges

from nausea and dyspepsia (prevalence reported as high as 50–60%)

to a serious GI complication such as endoscopy-documented peptic

ulceration (15–30% of individuals taking NSAIDs regularly), 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. 324-9. 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 (AGT), and an organic ion transporting polypeptide (SLCO1B1),

but these findings need confirmation in larger-scale studies.

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.

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

High level of acid production

Low level of acid production

Childhood Advanced age

Normal gastric

mucosa

Acute

H. pylori

infection

Chronic

H. pylori

infection

Antralpredominant

gastritis

Nonatrophic

pangastritis

Corpuspredominant

atrophic

gastritis Gastric ulcer

Gastric

cancer

Intestinal metaplasia

Dysplasia

Duodenal ulcer

MALT

lymphoma

Asymptomatic

H. pylori

infection

FIGURE 324-8 Natural history of H. pylori infection. MALT, mucosal-associated

lymphoid tissue. (From S Suerbaum, P Michetti: Helicobacter pylori infection. N Engl J

Med 347:1175, 2002. Copyright © 2002 Massachusetts Medical Society. Reprinted with

permission from Massachusetts Medical Society.)

Gastrointestinal mucosal injury

Mitochondrial uncoupling

Reactive prooxidants

MOS

ATP

M itochondrial fission

Mucosal PGHS-1

PGE2

Mucosal defense

Intestinal mucosal barrier function

Mucosal inflammation

Apoptosis

FIGURE 324-9 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.)