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376 SECTION VI Gastrointestinal Disease
starting a PPI trial. Surgery is not generally considered in PPI nonresponders because the available data show no benefit in patients who have surgery.
Barrett Esophagus
Barrett esophagus (BE) is defined as the presence of at least 1 cm of
metaplastic columnar epithelium in the tubular esophagus and can
be described as either long-segment BE (>3 cm) or short-segment BE
(<3 cm). It can further be described using the Prague classification system, which uses the circumferential extent of BE and the extent of the
longest visualized segment.
BE can develop from long-standing GERD. The diagnosis of GERD is
associated with a 10% to 15% risk of developing Barrett esophagus. The
risk factors for developing BE are chronic GERD (>5 years), age greater
than 50, male gender, tobacco use, central obesity, and Caucasian race.
BE can progress to dysplasia and esophageal adenocarcinoma. The risk
factors for progression include advancing age, central obesity, tobacco
use, and lack of NSAID, PPI, or statin use. The majority (>90%) of
patients diagnosed with BE do not die of esophageal adenocarcinoma.
The risk of progression from BE to cancer is determined by the amount
of dysplasia (nondysplastic is 0.2% to 0.5% risk per year, low-grade dysplasia is 0.7% risk per year, high-grade dysplasia is 7% per year).
Screening for BE should be considered in men with chronic GERD
(>5 years) and/or weekly symptoms of reflux who have two additional
risk factors: age greater than 50 years, Caucasian, central obesity, history of smoking, or first-degree relative with BE or adenocarcinoma.
Although the progression of BE to adenocarcinoma is rare in females,
they should still be screened based on the presence of the aforementioned
risk factors. The endoscopist should take at least eight random biopsies
to maximize yield on histology to look for intestinal metaplasia. The
pathology from the biopsies is confirmed by two pathologists making
the diagnosis. Alternative screening modalities include balloon cytology.
BE is treated with chemoprevention, endoscopic therapy, or surgery.
All patients with BE should receive once-daily PPI for chemoprevention.
Endoscopic treatment is not required in the absence of dysplasia. At initial
diagnosis, if nodularity is observed in the suspected segment, the patient
should undergo endoscopic mucosal resection as a diagnostic and therapeutic procedure. Endoscopic ablative therapy is used in patients with
low-grade and high-grade dysplasia. Ablative techniques include radiofrequency ablation and the lesser used cryotherapy. Recurrence rates appear
to be similar across different ablative modalities. Endoscopic ultrasound
can also be used to evaluate the depth of invasion of nodules and adenocarcinoma, guiding definitive therapy. Antireflux surgery can be used in
patients with poor control of reflux symptoms on PPI.
Endoscopic surveillance is continued to monitor for stability or progression of BE. The surveillance intervals are determined by the level of
dysplasia from 3 to 5 years for patients without dysplasia, to as often as
every 3 months for patients with high-grade dysplasia treated endoscopically. Surveillance endoscopy will collect four-quadrant biopsies at 2-cm
intervals in patients without dysplasia and 1-cm interval in patients with
prior dysplasia. Any visible abnormalities are also sampled. Virtual or
chemical chromoendoscopy may enhance the yield of surveillance.
MOTILITY DISORDERS
Achalasia
Achalasia is a primary esophageal motor disorder defined as aperistalsis in the esophageal body and relaxation failure of the LES resulting in
increased tone in the LES. The pathophysiology of achalasia is related
to the loss of inhibitory innervation in the esophagus. Primary achalasia is caused by the failure of distal inhibitory neurons (ganglion cells)
in the esophageal myenteric plexus. Denervation can also occur within
the extraesophageal vagus nerve or dorsal motor nucleus of the vagus.
Cholinergic innervation has also been found to remain intact and
Fig. 36.5 Barium contrast radiography demonstrating narrowing at the
esophagogastric junction with a bird-beak appearance and a dilated distal esophagus with retained contrast and an air-fluid level.
could possibly contribute to the increase in LES pressure. The denervation is thought to be an autoimmune process with increasing evidence,
suggesting that genetic susceptibility and latent human herpes simplex
virus 1 may also play a role. This is considered primary achalasia and is
idiopathic by definition.
Dysphagia to solids and liquids is the classic presentation, but patients
may also suffer from regurgitation, heartburn, and chest pain. Initial
work-up of achalasia includes a barium swallow and/or endoscopy. A
barium swallow can show esophageal dilation with a bird-beak narrowing
around the gastroesophageal junction (Fig. 36.5). An endoscopy allows
observation of esophageal dilation, a high-pressure LES, and the possibility
of retained food in the esophagus and helps to exclude causes of secondary
achalasia. The “gold standard” for the diagnosis of achalasia is high-resolution esophageal manometry. Manometry can record aperistalsis in the distal esophagus and absent LES relaxation. High-resolution manometry has
defined subsets of patients with achalasia, using the Chicago Classification,
who have different responses to treatment and prognoses. Type I, or classic achalasia, shows aperistalsis, incomplete or absent LES relaxation, and
high resting LES pressure. Type II shows panesophageal pressurization
with swallows and type III shows spastic lumen obliterating contractions
of the distal esophagus with 20% or more of swallows.
The goal of treating achalasia is to promote esophageal emptying and
decrease LES pressure. The initial (and most effective) treatment options
include pneumatic dilation or laparoscopic surgical (Heller) myotomy.
Pneumatic dilation is an endoscopic approach used to treat achalasia,
involving the use of balloons to dilate the LES, theoretically breaking the
fibers within. The number and the degree of dilations are determined by
progression of symptom relief. Surgical (Heller) myotomy can provide
a permanent solution by cutting the LES, allowing for food and liquid
to pass through freely. In patients who are poor candidates for definitive therapy, endoscopy can be used to inject botulinum toxin into the
gastroesophageal junction, which inhibits acetylcholine release from
nerves. Acetylcholine is responsible for increased LES tone, especially
when there is denervation of the inhibitory nerves. Botulinum toxin will
thereby reduce the tone of the LES. If botulinum toxin therapy fails,
pharmacologic therapy with nitrates and calcium-channel blockers may
be considered, but the effects do not provide long-term treatment. The
CHAPTER 36 Esophageal Disorders
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377
newest approach to treatment, POEM (Per Oral Endoscopic Myotomy),
uses an endoscope to tunnel below the esophageal mucosa to perform a
myotomy from within, without the need for surgical incisions.
Diffuse Esophageal Spasm
Diffuse esophageal spasm (DES) is defined by uncoordinated contractions in the esophagus. Esophageal manometry provides the most specific description of the spasms. Specifically, the Chicago Classification
defines DES as 20% or greater premature contractions (<4.5 seconds)
with normal LES relaxation. Patients often present with dysphagia and
chest pain. Similar to achalasia, DES is likely related to a decrease in
inhibitory innervation. This is often observed on barium swallow.
Pharmacologic therapy has been ineffective in reliably treating DES.
Pneumatic dilation of the LES or the esophageal body may alleviate
some of the symptoms, but botulinum toxin is used to a better effect.
VARIANT FORMS OF ESOPHAGITIS
Eosinophilic Esophagitis
Eosinophilic esophagitis (EoE) is (likely) an allergen-mediated eosinophilic-dominant inflammation of the esophageal mucosa and is diagnosed when esophageal biopsies in symptomatic patients show 15 or
greater eosinophils per high-power microscopic field. When assessing
for EoE, two to four esophageal biopsies should be taken from the
proximal and distal esophagus. Endoscopy can visualize fixed esophageal rings in the lumen, which are characteristic, but not diagnostic, of
EoE. These rings are often referred to as trachealization of the esophagus. Other features include white eosinophilic exudates, longitudinal
furrows, edema, diffuse esophageal narrowing, strictures, and lacerations secondary to the endoscope.
When EoE is diagnosed, a PPI response should be tested. Following
an 8-week PPI trial, a repeat endoscopy and biopsy should be performed. If symptoms and eosinophilia have resolved then PPIresponsive esophageal eosinophilia (PPI-REE) is diagnosed. PPI-REE
may be associated with GERD. If symptoms and eosinophilia persist,
then EoE is diagnosed.
The goal of treatment for EoE is improvement in symptoms and
decrease in esophageal inflammation. The first-line pharmacologic
therapy is 8 weeks of swallowed topical corticosteroids (fluticasone or
budesonide). If symptoms do not improve or rapid improvement is
needed, then systemic corticosteroids (i.e., prednisone) can be used.
Conversely, a specific elimination diet can also be used as initial therapy prior to the administration of topical corticosteroids. When medical and dietary therapy fail, then esophageal dilation is considered in
patients with strictures.
Pill-Induced Esophagitis
Pill-induced esophagitis results in direct esophageal mucosal injury
due to a pill. Patients will complain of heartburn, chest pain, odynophagia, and dysphagia. Common medications that can cause this
include: tetracycline, doxycycline, clindamycin, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, potassium
chloride, quinidine preparations, iron compounds, emepronium,
alprenolol, and pinaverium.
Complications include stricture, esophageal hemorrhage, and perforation. Cessation of the offending agent is often enough to treat the
condition with eventual mucosal healing.
ESOPHAGEAL INFECTIONS
Infections of the esophagus are rare in immunocompetent patients.
Immunocompromised individuals are typically affected, including
patients on immunosuppressive medications, chemotherapy, and
patients suffering from AIDS. In patients with AIDS, infectious esophagitis is more prevalent as the CD4 count declines, especially with
counts below 100. The most common symptom of infectious esophagitis is odynophagia often associated with dysphagia, chest pain, and
gastrointestinal bleeding. Coinfection is common and treatment is targeted by etiology. Maintenance suppressive therapy with antifungal or
antiviral agents may need to be initiated in patients with AIDS.
The most common cause of infectious esophagitis is Candida. It
typically presents with dysphagia and odynophagia, but oral thrush in
patients has a high positive predictive value for esophageal candidiasis.
On endoscopy, friable white patches overlying the mucosa are visualized and fungal hyphal forms are seen on histology. Patients are typically treated successfully with oral fluconazole whereas intravenous
fluconazole or an echinocandin is used in patients unable to tolerate
oral therapy.
Cytomegalovirus (CMV) esophagitis occurs in severely immunocompromised patients. These patients present almost identically
to patients with candida esophagitis except without oropharyngeal
thrush. Endoscopy reveals large (>10 cm), shallow ulcers in the middle
to distal parts of the esophagus. The margins are distinct and the ulcers
are often described as “punched-out.” Histopathologic examination
of mucosal and submucosal biopsies from the ulcer edges and bases
can accurately diagnose CMV esophagitis. Histology will reveal large
endothelial cells or fibroblasts with large, dense inclusion bodies. CMV
esophagitis is treated with intravenous ganciclovir, foscarnet (intravenous) or valganciclovir (intravenous or oral).
Another cause of infectious esophagitis is herpes simplex virus
(HSV). HSV-1 is typically the offending strain, but HSV-2 can also be
a cause. HSV esophagitis is often seen in immunosuppressed individuals but can affect healthy adults. The endoscopic appearance of HSV
esophagitis is multiple, small, superficial ulcers in the distal esophagus. More advanced or aggressive infections can reveal large confluent
ulcers, pseudomembranous or denuded epithelium. Viral cultures can
grow HSV-1 and occasionally HSV-2. The quantitative polymerase
chain reaction for HSV-1 has a high sensitivity when tested in biopsy
samples. Histopathologic examination reveals large intranuclear
Cowdry type-A inclusion bodies along with ballooning degeneration
and multinucleated giant cells. HSV esophagitis is treated with acyclovir (oral or intravenous) or valacyclovir (oral).
ESOPHAGEAL TRAUMA AND EMERGENCIES
Perforation of the Esophagus
Perforation of the esophagus can be due to numerous etiologies. The
most common cause is iatrogenic but can occur due to trauma, caustic
injury, malignancy, or severe vomiting. Iatrogenic perforation is often
related to instrumentation from endoscopy, nasogastric tube insertion,
intubation, or dilation. Boerhaave syndrome describes the spontaneous rupture of the esophagus following severe vomiting.
The most common presenting symptom is pain, which can vary
depending on location of the perforation. Patients may also present
with symptoms of shock or systemic infection. A physical exam can
reveal palpable crepitus in the neck or chest related to subcutaneous
emphysema.
Esophageal perforation should be diagnosed and treated promptly.
A chest radiograph can suggest perforation by revealing mediastinal
air, pleural effusion, pneumothorax, and subdiaphragmatic air. The
diagnosis can be confirmed with computed tomography, Gastrografin
imaging or emergency endoscopy.
The treatment of esophageal perforation starts with adequate
resuscitation and early antibiotics, if needed. The perforation can be
378 SECTION VI Gastrointestinal Disease
repaired surgically or by endoscope. Surgery is indicated in unstable
patients or patients with abdominal esophageal perforations. An endoscope can be used to place stents or clips. Perforations can be treated
conservatively as well with medical management. This includes no oral
intake for at least 7 days, parenteral nutrition, empiric antibiotics (consider antifungals), and management of complications (i.e., drainage of
abscesses).
Foreign Bodies and Food Impaction
Ingestion of foreign bodies can be accidental or intentional. Symptoms
depends on the object’s size, shape, consistency, and location, but some
patients will remain asymptomatic. Food can also become lodged in
the esophagus and present with similar symptoms to foreign bodies.
Food impaction is normally the result of an underlying disease process
including peptic stricture, Schatzki ring, EoE, or malignancy.
Foreign bodies and food can result in complete obstruction of the
esophagus. Patients will present with inability to handle secretions and
severe chest pain. If the obstruction does not resolve spontaneously,
emergent endoscopy is often required to resolve the obstruction.
Occasionally, glucagon can be administered intravenously when food
impaction is suspected prior to endoscopic intervention. Glucagon
relaxes the LES and esophageal smooth muscle allowing for spontaneous passage of the bolus.
Mallory-Weiss Tear
A Mallory-Weiss tear is a mucosal or submucosal tear near the gastroesophageal junction. It results from anything that may cause a rapid
increase in intra-abdominal pressure and gastric herniation. It is most
often described in the setting of retching or vomiting but can also
occur as a result of increased strain or forceful coughing.
Patients present with hematemesis and/or melena. They will often
report excessive retching or vomiting, but the tear can also occur without this history. Endoscopy is used to diagnose a tear and rule out
other causes of an upper gastrointestinal bleed.
Supportive therapy involves treating the underlying disorder and
reducing instances of vomiting and retching. A Mallory-Weiss tear
can be massive but is rarely fatal. Endoscopic therapies for ongoing
bleeding include use of epinephrine, which can be injected locally
to reduce bleeding. Cauterization, clipping, and ligation can also be
used to control the site of bleeding. Patients with persistent bleeding
may undergo angiographic intervention or, in rare instances, surgical
intervention.
SYSTEMIC AND OTHER ILLNESSES
Scleroderma
Progressive systemic sclerosis can affect any part of the gastrointestinal tract, but more often involves the esophagus. The progressive loss
of smooth muscle, collagen deposition, and fibrosis in the esophageal
wall can cause reduced or absent peristalsis, GERD, and a patulous
LES. Manometry is used to diagnose the esophageal disease, whereas
endoscopy can be used to evaluate for complications.
Dermatologic Disorders
A wide variety of dermatologic disorders can affect the esophagus. These
disorders include pemphigus vulgaris, bullous pemphigoid, erythema
multiforme, Behçet’s syndrome, lichen planus, dermatitis herpetiformis, and toxic epidermolysis necrosis/Stevens-Johnson syndrome.
The treatment of the underlying disorder is most effective in treating
the esophageal involvement and often involves glucocorticoids.
SUGGESTED READINGS
Ajani JA, D’Amico TA, Bentrem DJ, et al: Esophageal and esophagogastric
junction cancers, version 2.2019, NCCN clinical practice guidelines in
oncology, J Natl Compr Canc Netw 17(7):855–883, 2019.
Dellon ES, Gonsalves N, Hirano I, et al: ACG clinical guideline: evidenced
based approach to the diagnosis and management of esophageal
eosinophilia and eosinophilic esophagitis (EoE), Am J Gastroenterol
108(5):679–692, 2013.
Kahrilas PJ, Bredenoord AJ, Fox M, et al: The Chicago Classification of
esophageal motility disorders, v3.0, Neurogastroenterol Motil 27(2):
160–174, 2015.
Shaheen NJ, Falk GW, Iyer PG, Gerson LB, American College of
Gastroenterology: ACG clinical guideline: diagnosis and management of
Barrett’s esophagus, Am J Gastroenterol 111(1):30–50, 2016.
Vakil N, van Zenten SV, Kahrilas P, et al: The Montreal definition and
classification of gastroesophageal reflux disease: a global evidence-based
consensus, Am J Gastroenterol 101(8):1900–1920, 2006; quiz 1943.
37
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Diseases of the Stomach and
Duodenum
Alma M. Guerrero Bready, Akwi W. Asombang, Steven F. Moss
INTRODUCTION
The process of digestion begins in the mouth, with mastication. The
ingested food bolus is then propelled into the esophagus, passes
through the lower esophageal sphincter (LES), and enters the stomach. The stomach can hold between 1.5 and 2 L of food, which allows
for intermittent feeding. While in the stomach, food is further broken down through a series of chemical and mechanical reactions into
smaller particles (chyme) that travel through the pyloric channel
into the beginning of the small intestine, the duodenum. This chapter reviews the normal anatomy and physiology of the stomach and
duodenum and discusses the most common disease processes affecting
these two organs.
ANATOMY
Anatomy of the Stomach
The stomach is a hollow organ with a superior dome-like structure
on the lateral aspect (the fundus) (Fig. 37.1). The outer edge along
the dome and down to the end of the stomach is called the greater
curvature. On the other side is the lesser curvature. The stomach is
made up of four parts: the cardia, fundus, corpus, and the pylorus. The
stomach is connected proximally to the distal esophagus by the LES, a
circular smooth muscle structure under parasympathetic and sympathetic control. The LES acts as a valve to prevent gastric contents from
traveling in a retrograde fashion into the esophagus, thus preventing
gastroesophageal reflux. The most proximal region of the stomach is
the cardia, which is the area between the LES and the fundus. Below
the fundus is the gastric body (also known as the corpus), which has
characteristic longitudinal folds or ridges (rugae). This gastric body is
where food is mainly mixed and broken down. Below a prominent circular fold (the angulus incisura), is the antrum, which leads into the
pyloric channel. The antrum holds food until it is ready to be released
through the pylorus (a circular structure made up of smooth muscle)
into the duodenum. A hiatal hernia occurs when part of the stomach
is pushed upward through a weakness in the diaphragm into the chest.
The stomach is innervated and controlled by both the sympathetic
nervous system, via the celiac plexus, and by the parasympathetic nervous system, which is supplied by the anterior and posterior trunks of
the vagus nerve. The arterial supply for the stomach originates from
the celiac trunk (Video 37.1).
Anatomy of the Duodenum
Immediately past the pylorus, the duodenum bends posteriorly to
become a retroperitoneal structure and curves around the head of
the pancreas in a C-shape and then re-emerges into the peritoneal
cavity to join the second portion of the small intestine, the jejunum
(see Fig. 37.1). The duodenum can be divided into four parts: superior (first part, or bulb), descending (second part), horizontal (third
part), and ascending (fourth part). Within the descending duodenum
is the ampulla of Vater, where the biliary system and the pancreatic
duct unite to drain their secretions into the duodenum via the major
duodenal papilla.
Similar to the stomach and the rest of the digestive tract, the duodenum is innervated by both the parasympathetic and sympathetic
nervous system. The blood supply to the first half of the duodenum
is from projections of the celiac trunk and to the second half of the
duodenum by the superior mesenteric artery. It is this transition point
that demarcates the progression from foregut to midgut.
HISTOLOGY
Histology of the Stomach
The walls of the stomach and duodenum, like the rest of the digestive
system, are composed of four layers: the mucosa, submucosa, muscularis externa, and serosa. In the stomach, the mucosa is formed by a
layer of simple columnar epithelial cells that invaginate to create gastric pits. These extend into millions of gastric glands that secrete gastric
acid and other products. The depth and function of the gastric pits and
glands differ between the various regions of the stomach. Below the
mucosa is the submucosa, which houses dense connective tissue and
lymphocytes, plasma cells, arterioles, venules, lymphatics, and the submucosal plexus (Meissner plexus). Deeper to this layer is the muscularis externa, which provides the contractions needed for the stomach
to churn chyme. This muscle layer contains the inner oblique, middle
circular, and outer longitudinal smooth muscle layers. In addition, it
contains the myenteric neural plexus (Auerbach plexus). The outermost layer of the stomach is a continuation of the visceral peritoneum
called the serosa.
Histology of the Duodenum
The duodenal wall is also comprised of the mucosa, submucosa, muscularis externa, and serosa. However, in the case of the duodenum, the
epithelial cells contain microvilli and are arranged such that the surface of the duodenum has projections of epithelial cells called villi that
are flanked by intestinal glands, called crypts of Lieberkühn. Villi and
microvilli serve to increase the absorptive surface of the duodenum.
In addition to its primarily absorptive function, the submucosa of the
duodenum contains Brunner glands, which secrete an acid-neutralizing solution that protects the rest of the digestive tract from the effects
of the acidic gastric juices.
379
380 SECTION VI Gastrointestinal Disease
2nd part
of duodenum
H
+
Mast cells
Esophagus
Lower
esophageal
sphincter
Pylorus
Duodenal
bulb
Ampulla
of Vater
Fig. 37.1 Normal gastroduodenal anatomy.
Incisura
Antrum
Fundus
Body
GASTRODUODENAL SECRETIONS
Gastric secretions are responsible for breaking down food macromolecules into nutrients that can be absorbed in the gut. Gastric secretions
are finely coordinated in a sophisticated system of feedback loops that
ensure the balance between an acidic environment to break down food
(created by parietal cells secreting hydrochloric acid) and a protective
environment that defends the integrity of the gastric lumen. The latter
is achieved by secretion of a bicarbonate-rich water/electrolyte/mucus
solution from surface mucosal cells that buffers the gastric acid, to
prevent autodigestion of the gastric epithelial cells and glands. Gastric
secretions also function to protect the digestive tract from pathogenic
microorganisms and aid in the absorption of calcium, iron, and vitamin B12.
Parietal Cells
Acid Secretion
Gastric juice is primarily made up of hydrochloric acid (HCl), which
is secreted by parietal cells at a concentration of 160 mmol/L. Parietal
cells are mostly located in the gastric fundus and body, and they are
stimulated to release HCl through three major pathways.
Histamine is released by specialized neuroendocrine cells called
enterochromaffin-like (ECL) cells, and it is the major stimulant of H+
ion secretion. Histamine acts on H2 receptors, to activate adenylate
cyclase leading to increased level of intracellular cAMP. This results
in activation of the proton pumps (H+, K+-ATPases), located on the
apical surface of the cell, to promote the release of HCl into the gastric
lumen (Fig. 37.2).
Acetylcholine (Ach), which is released from nerve endings following vagal stimulation, also promotes acid secretion by acting on the M3
receptor on the basal aspect of parietal cells This increases intracellular
Ca++, which also stimulates acid release into the stomach lumen via
the apical proton pump (see Fig. 37.2).
Gastrin promotes acid release in two distinct ways (see Fig. 37.2).
Gastrin is released from G cells in the antrum in response to food
(especially protein) and also in response to the neural release of gastrin-related peptide, stimulated by gastric distension. Gastrin circulates in the bloodstream and may directly bind CCK2/gastrin receptors
in parietal cells, stimulating the release of H+. Of greater functional
consequence during feeding, gastrin also stimulates acid secretion
indirectly by binding similar CCK2/gastrin receptors in ECL cells to
Proton
pump
inhibitors
+
K
2+
Ca
+
Acetylcholine
+
Fig. 37.2 Stimuli and mechanisms of gastric acid secretion by the pari-
etal cell.
+
Gastrin
+
ECL cells
–
Adenylate
Histamine
+
H
K
AT Pase
Protein
kinases
cAMP
cyclase
G
s
+
+
AT P
G
i
–
–
–
Prostaglandins
Somatostatin
H2 blockers
promote the release of histamine, which in turn acts on H2 receptors
on parietal cells, as previously mentioned.
Acid secretion is inhibited by somatostatin, which is released by D
cells in the gastric antrum and fundus. D cells are stimulated to secrete
somatostatin when there is a high concentration of H+ ions in the gastric lumen, and they are inhibited by ACh. Somatostatin inhibits acid
secretion by decreasing cAMP levels in parietal cells and by inhibiting
gastrin release from G cells (see Fig. 37.2).
Intrinsic Factor
In addition to being the key cell for acid secretion, parietal cells also
secrete intrinsic factor, a glycoprotein that plays a critical role in vitamin B12 absorption. Intrinsic factor is released from parietal cells under
the same stimuli as H+ ions and binds vitamin B12 in the alkaline environment of the duodenum. This binding ultimately enables vitamin
B12 absorption via specific receptors in the terminal ileum.
Chief Cells
Chief cells are zymogenic cells located deep in the gastric pits that
secrete the pro-enzyme pepsinogen. Pepsinogen is converted into the
active form, pepsin, under the acidic conditions created by gastric
juices. Pepsin aids in digestion by breaking down proteins into peptides and amino acids, which, as mentioned above, aid in the release of
gastrin as well as CCK.
Protective Factors
Gastroduodenal cells are at a high risk for damage given the very
low pH of gastric juices, but these cells are well protected by several
mechanisms that prevent autodigestion. The first line of defense is a
mucosal barrier that consists of a thick, alkaline, aqueous mucus and
−
HCO
-rich fluid that serves to lubricate the mucosa and neutralize
3
acid at the epithelial level. This mucus is secreted in the stomach by
mucus-producing cells located at the neck of gastric pits and in the
CHAPTER 37 Diseases of the Stomach and Duodenum
Chronic H. pylori infection
•
•
• High g
• Impair
•
o
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381
Duodenal ulcer phenotype
Around 10–15% of infected subjects
Antral predominant gastritis
astrin and acid secretion
ed inhibitory control of acid secretion
Protection from gastric cancer
Fig. 37.3 Diverse pathologic and clinical consequences of H. pylori. Acid secretory status and ultimately
clinical outcome are dependent upon the extent and degree of gastric inflammation in response to H. pylori
infection. (From Amieva MR, El-Omar EM. Host-bacterial interactions in Helicobacter pylori infection. Gastroenterology. 2008;134:306-23.)
Simple gastritis phenotype Gastric cancer phenotype
• Majority of infected subjects
• Mild mixed gastritis
• High gastrin but normal acid secretion
• No gastric atrophy
• No significant clinical outcome
duodenum by mucus-producing goblet cells. Additionally, the lipid
bilayer and tight junctions of the apical epithelial cell membranes
serve to protect the mucosa from H+ ions diffusing into the stomach wall, thus preserving mucosal integrity. A rich submucosal blood
supply enables rapid drainage of H+ ions from the mucosa and neutralizes H+ ions intravascularly with HCO
−
and proteins. Of note,
3
prostaglandins promote blood flow, mucus secretion, and stimulation of HCO
−
secretion, thus prostaglandins play an important role
3
in gastric mucosal defense.
GASTRODUODENAL MOTILITY
The physiology of gastric motility and emptying can be understood
via two major gastric geographic regions. As food enters the stomach, it increases gastric intraluminal pressure, causing the fundus and
proximal body to relax reflexively (a process called accommodation)
in order to allow space to store recently ingested food. The proximal
stomach, however, also has characteristic tonic contractions, which aid
in downstream gastric emptying.
Distally in the stomach, high-pressure peristaltic contractions by
the lower gastric body and the antrum grind food and liquefy it into
chyme. Once food particles reach a small enough size, they are propelled through the pylorus and into the duodenum.
Gastroduodenal motility is coordinated through intrinsic and
extrinsic neural and hormonal signals. Neuronal control originates
from the enteric nervous system and the sympathetic and parasympathetic nervous system via gastric mechanoreceptors, whereas
certain hormones, such as gastrin and cholecystokinin, serve to
relax the proximal stomach and create contractions in the distal
stomach.
A series of negative feedback loops initiated by the presence of
chyme within the duodenum inhibit further gastric emptying into the
duodenum.
• Around 1% of infected subjects
• Corpus predominant gastritis
• Multi-focal atrophic gastritis
• High gastrin
• Hypo/achlorhydria
• Low pepsinogen I and pepsinogen I/II rati
• Increased risk of gastric cancer
PEPTIC ULCER DISEASE
Definition and Epidemiology
A peptic ulcer is a defect or defects in the mucosal layer of the stomach or duodenum measuring at least 5 mm in diameter that penetrates
into the muscularis mucosa. Lesions that are smaller than 5 mm or
more superficial to the muscularis mucosa are classified as erosions.
Men and women are at equal risk for developing peptic ulcer disease
(PUD), and in the United States the lifetime risk of suffering from
PUD is about 5% to 10%.
Gastric acid plays an important role in the digestion of food. PUD
development is the result of an imbalance of gastric acid and other
noxious substances in the gastric lumen relative to gastric protective
functions. Some persons with PUD do secrete excessive amounts of
gastric acid, particularly in duodenal ulcer disease, where depletion of
antral somatostatin by Helicobacter pylori leads predictably to gastrin
and acid hypersecretion (Fig. 37.3). However, most people with PUD
have normal-to-low acid secretion, suggesting that a defect in mucosal
defense is the major pathophysiologic culprit.
The two most common causes of PUD are H. pylori infection and
the use of nonsteroidal anti-inflammatory drugs (NSAIDs). These
two factors compromise mucosal defense mechanisms and predispose patients to peptic ulcers. They work synergistically to increase
the risk of PUD when both factors are present. The risk of developing
PUD increases with age, and, given that the prevalence of H. pylori
has been decreasing in the general population and the use of NSAIDs
has been increasing among older persons, the incidence of PUD has
been decreasing in younger age groups (who tend to have low rates of
NSAID use and H. pylori infection), and increasing in persons 65 years
of age and older.
Other factors also modulate the risk of developing PUD. For example, smoking impairs ulcer healing, increases the risk of recurrence,
and is associated with a higher PUD-related mortality. Similarly, there
382 SECTION VI Gastrointestinal Disease
is an association between PUD development and concomitant use of
high-dose corticosteroids with NSAIDs, though there is no evidence
that corticosteroids alone cause PUD.
Less common causes of PUD include hypersecretory states such as
Zollinger-Ellison syndrome, Crohn’s disease, vascular insufficiency,
viral infection, radiation therapy, and cancer therapy. Development of
PUD may also be influenced by other factors such as stress, personality
type, alcohol consumption, occupation, and diet, though these play a
relatively minor role compared with the effects of H. pylori infection
and NSAID usage.
Additionally, certain chronic diseases are positively correlated with
PUD. These include chronic obstructive pulmonary disease, systemic
mastocytosis, cirrhosis, and uremia.
Given that PUD is a complex disease resulting from diverse pathophysiologic processes, this chapter focuses on the different etiologic
agents and mechanisms individually, after considering the shared clinical features.
A
Clinical Presentation
The clinical presentation of PUD varies depending on the location and
severity of the ulcer. Uncomplicated PUD typically presents as sharp,
burning, nonradiating epigastric abdominal pain. In duodenal ulcers
the pain tends to occur 2 to 3 hours after the ingestion of food or at
night, when the stomach is empty. The opposite is often true of gastric
ulcers. Patients with duodenal ulcers tend to present with weight gain
because the ingestion of food relieves symptoms, whereas patients with
gastric ulcers tend to be food averse and are more likely to present
with weight loss. Older patients (>60 years) may report no pain at all
at the time of presentation and may instead present with nonspecific
complaints, such as confusion, restlessness, abdominal distention, and
falls. In pregnant patients, symptoms are often fairly mild and might
even improve as the pregnancy progresses. They may also present as
abnormal patterns of nausea and vomiting of pregnancy, such as nocturnal vomiting or worsening of vomiting in the third trimester. Most
patients with PUD present after several weeks or months of symptoms,
unless there is a complication that necessitates urgent medical care.
Diagnosis
The diagnosis of PUD requires clinical suspicion in patients with the
appropriate clinical presentations. Physical exam may determine focal
epigastric tenderness.
Contrast imaging with a barium upper GI series used to be the primary method of diagnosis but is now supplanted by the widespread
availability of upper gastrointestinal endoscopy, now considered the
“gold standard” for diagnosis because it permits direct visualization of
the ulcer or ulcers.
In addition to providing a diagnosis of PUD, endoscopy also
enables tissue sampling by biopsy to evaluate for malignancy and H.
pylori infection. Furthermore, endoscopy can be therapeutic, providing curative hemostasis in patients with acute life-threatening GI
bleeding secondary to PUD.
Causes of Peptic Ulcer Disease
There are several conditions associated with the development of ulcer
disease; these may be present in isolation or coexist with each other.
Identifying specific causes is important to prevent recurrences.
Helicobacter pylori
H. pylori is a flagellated gram-negative bacillus that colonizes the gastric
epithelium of half of the world’s population. This bacterium is responsible for over 80% of duodenal ulcers and at least half of all cases of gastric ulcers. However, only a fraction of patients with H. pylori infection
B
Fig. 37.4 (A) Gastric biopsy (hematoxylin and eosin stain) showing gas-
tric mucosa with intense inflammatory infiltrate including clusters of
neutrophils infiltrating gastric pit and surface epithelium and lymphocytes
and plasma cells in the lamina propria. At high power (B) H. pylori organisms can be seen faintly (arrows) adjacent to surface epithelial cells.
(Courtesy of Murray Resnick, MD, PhD, Adjunct Professor of Pathology
and Laboratory Medicine, Warren Alpert Medical School, Providence, RI.)
develop PUD. H. pylori infection is also a strong risk factor for PUD
and malignancy (adenocarcinoma and mucosa-associated lymphoid
tissue [MALT] lymphoma), as well as a cause of iron deficiency anemia
and immune thrombocytopenic purpura (ITP). Infection is transmitted via the fecal-oral route and typically occurs during childhood. H.
pylori infection tends to persist throughout the lifetime of the host if
left untreated, despite a strong gastric inflammatory response and both
cell-mediated and humoral immune system recognition.
Rates of H. pylori infection differ globally, with highest prevalence
in the developing world. In the United States, infection rates are 10%
to 15% in persons under 12 years old and 50% to 60% in persons older
than 60 years. There is increased prevalence in persons with lower
socioeconomic status, increased household crowding and, in the United
States, higher prevalence in immigrants from the developing world.
H. pylori has several unique characteristics enabling gastric colonization. H. pylori can survive in gastric acid by producing urease, which
catalyzes the conversion of urea (which is present in gastric juice) into
ammonia, thus neutralizing H. pylori’s microenvironment. H. pylo-
ri’s flagella allow the organism to move fluidly through the stomach’s
viscous mucous layer toward gastric epithelial cells, where H. pylori
uses a series of adhesins and receptors to attach and chronically infect
its host. At the gastric epithelium, H. pylori induces an inflammatory
response consisting of neutrophils, leukocytes, plasma cells, and macrophages. Neutrophilic infiltration of the gastric epithelium causing
chronic gastritis is a hallmark of H. pylori infection, easily recognizable
in gastric biopsies (Fig. 37.4).
Determinants of pathogenicity include the location of infection
within the stomach, H. pylori genomic heterogeneity, and differences
in host response. For example, infections that are most predominant
in the antrum are more strongly associated with duodenal ulcers and
increased acidity due to depletion of antral somatostatin-producing
cells leading to uninhibited gastrin secretion. In contrast, H. pylori
colonization of the corpus is correlated with gastric ulcers, gastric
adenomas, and decreased acid production due to inflammation-mediated inhibition of parietal cell secretion and subsequent parietal cell
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383
loss resulting in atrophic gastritis (see Fig. 37.3). This latter pattern of
gastric inflammation is most common in persons residing in Southeast
Asia, South America, and certain regions of Central, Eastern, and
Southern Europe.
Additionally, H. pylori’s ability to produce lipopolysaccharide, leukocyte-activating factors, specific adhesins and vacuolating toxins, and
a type IV bacterial secretory system contribute to its virulence. Strains
with more of these pathogenic factors have been associated with more
severe disease states. The most important of those pathogenic markers
is cytotoxin-associated gene (cagA), a marker of the presence of the
type IV secretory system, which is associated with acute gastritis, peptic ulcers, and gastric cancer. This multigene H. pylori system serves
as a “molecular syringe” functioning to insert certain H. pylori proteins directly into host epithelial cells to activate pro-inflammatory and
pro-oncogenic signaling pathways.
Diagnosis of H. pylori
In persons with clinical manifestations of H. pylori, eradication of the
infection leads to improved outcomes. Because eradication of H. pylori
from asymptomatic patients has not yet been shown to significantly
prevent disease, H. pylori diagnostic testing is generally reserved for
those patients with certain H. pylori–associated diseases or conditions
such as PUD, uninvestigated dyspepsia without alarm symptoms,
unexplained iron deficiency anemia, idiopathic thrombocytopenic
purpura, early gastric cancer, and low-grade MALT lymphoma. It is
remarkable that 80% of patients with low-grade MALT lymphoma and
H. pylori infection will be cured by H. pylori eradication.
There are two categories of diagnostic tests for H. pylori: invasive
and noninvasive. Noninvasive tests include urea breath test and stool
antigen test, and the invasive tests are performed on endoscopic biopsies by histology, rapid urease test, and culture. The sensitivity of these
tests, however, is decreased by proton pump inhibitors (PPIs), antibiotics, and bismuth compounds. Blood tests for the presence of H. pylori
antibodies are relatively inaccurate and no longer recommended. They
are particularly poor at monitoring the outcome of treatment because
they may remain positive months to years after successful eradication.
For the urea breath test, patients must stop taking PPIs 2 weeks prior
to the test. They ingest urea in which the carbon atoms are labeled with
either radioactive carbon-14 or nonradioactive carbon-13. If present,
H. pylori hydrolyzes the urea into ammonia. The presence of a labeled
carbon atom in exhaled CO2 indicates active H. pylori infection, and
with a 95% specificity and sensitivity, it is the best choice for test
of cure.
The stool antigen test detects fecal antigens by immunoassay.
Proton pump inhibitors must be stopped 2 weeks prior to the test, but
it is a good test for both detection and eradication, though their sensitivity and specificity are slightly lower than the urea breath test.
Invasive tests all require endoscopic biopsies. The H. pylori can be
visualized histologically (especially if immunohistochemistry or other
special stains are used) and the presence of chronic active gastritis, a
hallmark of H. pylori infection, noted. Additionally, the biopsy can
be tested with a rapid urease test, which detects pH changes in the
urea-rich test matrix when the H. pylori derived urease converts urea
to ammonia. Biopsies may also be used to culture H. pylori; however,
this is a relatively costly and time-consuming process that is currently
rarely used. The major advantage of this method is that it allows testing for antibiotic resistance of individual strains. This is an increasingly important focus of research and likely to be important in clinical
practice, too, due to the emergence of multiply antibiotic-resistant H.
pylori.
Given the increasing incidence of antibiotic resistance in H. pylori,
a test of cure 4 weeks after the end of treatment and 2 weeks after
cessation of PPI treatment with a stool antigen or breath tests is recommended to confirm eradication of H. pylori.
Treatment of H. pylori
Treatment consists of combination therapy with antibiotics and acid
inhibitors to guarantee adequate antibiotic coverage and to ensure
penetration of the antibiotics into the gastric mucosa (Fig. 37.5).
Additionally, the duration of therapy must be long enough to ensure
eradication.
The increasing rates of antibiotic resistance, especially to clarithromycin and levofloxacin, make it imperative that providers ask patients
about any prior macrolide antibiotic exposures, because prior exposure is associated with likely resistance. They have also spurred efforts
to measure local antibiotic resistance rates.
The treatment options are bismuth quadruple therapy, which consists of a PPI, bismuth, tetracycline, and metronidazole for 14 days, and
clarithromycin triple therapy, which consists of a PPI, clarithromycin,
and amoxicillin or metronidazole for 14 days. Given the increasing
rates of clarithromycin resistance, however, clarithromycin triple therapy is falling out of favor and should only be used in regions where it
is known that H. pylori clarithromycin resistance rates are less than
15% and in patients with no history of macrolide exposure. Otherwise,
bismuth quadruple therapy is the current therapy of choice with an
expected cure rate of 80% to 90%.
If a patient fails initial treatment, then second-line therapy for that
patient should avoid any antibiotics that were previously taken by the
patient. If the patient failed first-line bismuth quadruple therapy, salvage
therapy should contain either clarithromycin or levofloxacin depending
on local antimicrobial resistance patterns and the patient’s prior antibiotic exposures. If the patient failed clarithromycin triple therapy, bismuth quadruple therapy should be tried next. Other “salvage” options in
cases of recurrent failure include regimens containing rifabutin and dual
regimens of high-dose amoxicillin and high-dose PPIs.
H. pylori infection treatment is complete only after eradication has
been confirmed with a test of cure, as outlined above.
NSAID-Induced PUD
NSAIDs are a class of drugs that are very useful in the treatment of
pain, arthritis, and inflammatory diseases; however, their use can
be limited by their side effect profile. Upper GI side effects are dose
dependent and include PUD and GI bleeds. Side effects are also more
common in patients with certain risk factors, such as age older than
65 years, past history of PUD, heart disease, and concomitant therapy
with antiplatelet agents, corticosteroids, and anticoagulants. There is
synergism between H. pylori infection and chronic NSAID use in terms
of PUD risk.
NSAID-induced PUD accounts for approximately 100,000 hospital admissions annually, and about 25% of persons on chronic
NSAID therapy will develop PUD. Chronic NSAID users who have
the above-mentioned risk factors have a 9% risk of having a serious
adverse event, while those who do not have risk factors only have a
0.4% risk. Thus, before starting a patient on chronic NSAIDs, it is
important to evaluate their risk factors and consider alternative therapies, if appropriate.
Mechanism of Injury
Half of people taking NSAIDs will develop NSAID-induced gastropathy consisting of superficial mucosal hemorrhages and erosions. These
asymptomatic erosions are usually found incidentally during upper
endoscopies performed for other reasons and are mainly concentrated
in the gastric antrum. Most cases of NSAID gastropathy will not progress to PUD.
384 SECTION VI Gastrointestinal Disease
s
s
H pylori
PAL
If fails
+
If fails
Penicillin allergic
No
Previous macrolide
exposure
No
PBMT*PAMC*
If fails
PAL
If fails
No
PBMT
SALVAGE
PBMT (PMC if low
clarithromycin resistance)
PBMT
Known clarithromycin sensitive or
clarithromycin resistance <15% or
local proven eradication >85%
with PPI triple therapy
Yes
PAC PMC
If fails
PAL PAL
If fails
If fails
If fail
If fail
PBMT
HDDT
PAR
Fig. 37.5 H. pylori eradication therapy algorithm. PAC, Clarithromycin-based PPI triple therapy with amoxi-
cillin; PAL, levofloxacin-based therapy; PAMC, concomitant non-bismuth quadruple therapy; PAR, rifabutin
containing therapy; PBMT, PPI/bismuth/metronidazole/tetracycline quadruple therapy; PMC, clarithromycin-based PPI triple therapy with metronidazole; HDDT, high-dose dual therapy. (From Fallone CA, Moss
SF, Malfertheiner P. Reconciliation of recent Helicobacter pylori treatment guidelines in a time of increasing
resistance to antibiotics. Gastroenterology 2019;157:44-53.)
HDDT
PAR
Once ingested and exposed to gastric acid, NSAIDs become weak
acids and are able to cross the lipid bilayer membranes of gastric epithelial cells. There, they lose a hydrogen atom and become trapped intracellularly, disrupting normal cell function. This leads to decreased cellular
integrity and increased cellular permeability leaving gastric epithelial
cells vulnerable to topical injury, hemorrhages, erosions, and cell death.
Additionally, NSAIDs also inhibit the arachidonic acid pathway, which
is crucial for the synthesis of prostaglandins (PGs) that protect gastric epithelial cells, and for mucosal integrity. The synthesis of PGs is catalyzed by
cyclooxygenases (COX). The COX-1 isoform is constitutively expressed in
the GI tract independent of external factors. In contrast, COX-2 is largely
inducible, promoting PG synthesis under the influence of inflammatory
mediators that are present in pro-inflammatory states. PGs play a very
important role in gastric mucosal protection by increasing mucus and
bicarbonate production, increasing blood flow to the gastric mucosa, and
promoting epithelial cell repair and turnover after injury. Inhibition of PG
synthesis by NSAIDs leaves epithelial cells vulnerable to unopposed injury
from gastric acid and pepsin. Aspirin exposes patients to PUD in a similar
way. It acetylates COX-1, thus irreversibly inhibiting it.
PAL
HDDT
PAR
If fails
PBMT
If fails
HDDT
PAR
PBMT
HDDT
PAR
The more common NSAIDs, such as ibuprofen, naproxen,
diclofenac, and aspirin, are nonselective COX inhibitors. Selective
COX-2 inhibitors, such as celecoxib and valdecoxib, were developed
with the aim of reducing gastric toxicity by primarily acting at sites
of inflammation, thus leaving COX-1 function intact. Though the
COX-2 inhibitors have fewer GI side effects, they have been associated
with increased cardiovascular events such as myocardial infarctions
and strokes. The COX-2 inhibitors that are still on the market now
carry a black box warning.
Prevention and Therapy of NSAID-Induced PUD
Prevention and treatment of NSAID-induced PUD can be divided
into three categories: primary prevention, treatment, and secondary
prevention.
Prior to prescribing chronic NSAIDs, providers should assess a
patient’s risk for NSAID-induced adverse side effects, such as history of
ulcers and GI bleeding, age older than 65 years, concomitant H. pylori
infection, and co-prescription with antiplatelet agents, steroids, and
anticoagulants.
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Those patients with risk factors for developing NSAID-induced
PUD should receive co-therapy with a gastroprotective agent.
Currently there are several treatment options, including H2 receptor
antagonists (H2RAs), synthetic prostaglandins, and PPIs. PPIs remain
the co-treatment of choice because they are most efficacious in this
regard and generally very well tolerated.
H2RAs work by blocking histamine 2 receptors in parietal cells,
thus decreasing acid production. However, in clinical trials their effects
on NSAID ulcer prevention have been very limited.
Prostaglandins such as misoprostol work similarly to endogenous
prostaglandins in the protection of the stomach and duodenal lining.
Unfortunately, prostaglandins are poorly tolerated due to their side
effect profile, which includes diarrhea and abdominal pain.
PPIs inhibit the H+/K+-ATPase in parietal cells, hence reducing
acid secretion into the gastric lumen. Prescription of PPIs together with
NSAIDs significantly reduces GI-related NSAID complications with a
10% to 15% absolute risk reduction in ulcer formation and ulcer-related bleeding in high-risk patients taking nonselective NSAIDs. It
must be noted, though, that recent studies have shown that selective
COX-2 inhibitors plus a PPI provide better GI protection compared to
a nonselective NSAID plus PPI.
With the widespread overuse of chronic PPIs in recent years (principally
for GERD and dyspepsia), several likely adverse side effects of PPIs have
come to light. These include increased risk of micronutrient deficiencies
such as hypomagnesemia, iron and vitamin B12 deficiency, and GI-related
infections, such as Clostridioides difficile infection (CDI) and small intestinal
bacterial overgrowth (SIBO). Additionally, PPI use has been associated with
increased incidence of osteoporosis and bone fractures and acute interstitial nephritis. More controversially, associations of chronic PPI usage with
chronic kidney disease, cerebrovascular disease, upper GI cancers, and
dementia have been reported in some studies, though almost entirely from
observational cohorts. Better controlled prospective studies are needed to
clarify any causal link between PPIs and these side effects. However, given
these potential side effects, patients should be evaluated individually for PPI
co-prescription with NSAIDs, and the lowest effective doses should be used
when prescribing long-term in primary prophylaxis.
H. pylori infection in the setting of chronic NSAID has been shown
to increase the risk of PUD, more specifically for duodenal ulceration.
The risk for developing ulcers in H. pylori positive patients starting
chronic NSAID therapy is higher during the first few months after
starting therapy. Therefore, H. pylori testing, and treatment is recommended prior to starting chronic NSAID use.
Treatment of NSAID-related ulcers is more straightforward. First
and foremost, the offending NSAID or aspirin should be discontinued if medically possible in order to allow endogenous protective
prostaglandins to be formed. Subsequently, acid secretion should be
suppressed with standard doses of PPIs (or H2RAs or misoprostol).
In patients who require NSAID therapy but have a history of PUD,
risk factors should be assessed, and COX-2 inhibitors should be used
preferentially, along with co-therapy with a PPI if there are no cardiovascular contraindications to COX-2 inhibitor therapy.
Patients with cardiovascular risk factors for whom aspirin is
required for secondary prevention of myocardial infarction cannot
stop aspirin therapy. In this case, cardiovascular protection outweighs
the benefit of aspirin cessation for PUD treatment. These patients must
be tested for H. pylori, if they have not been previously tested, and they
should be treated if they test positive. Additionally, these patients must
remain on PUD prophylaxis with either a PPI or misoprostol.
Zollinger-Ellison Syndrome
PUD generally occurs in patients with normal or near normal rates of
acid secretion. However, a rare cause of PUD is the Zollinger-Ellison
syndrome (ZES), in which PUD is the direct result of severe acid hypersecretion due to gastrin-producing G-cell tumors, called gastrinomas.
These tumors are generally located in the pancreas or the duodenum,
and patients with ZES typically present with recurrent, multiple,
refractory ulcers as well as PUD-related complications, esophagitis,
and diarrhea. Individuals with ZES generally do not have concomitant
H. pylori infection or use NSAIDs therapy. This condition will be discussed in further detail later in the chapter.
Stress-Induced Ulcers
Critically ill ICU patients are at increased risk of developing stress
ulcers that lead to increased risk of clinically significant GI bleeding.
The risk is higher in burn victims, those with significant injury, cranial
trauma, shock, and mechanical ventilation. Endoscopically, stress-related mucosal damage is found in 60% to 100% of patients recently
admitted to the ICU. Stress ulcers are typically multiple and shallow.
They usually present with hematemesis or melena in the ICU patient.
ICU patients are predisposed to stress ulcers due to decreased
splanchnic vascular perfusion and impaired microcirculation due to
hypovolemia, shock, and low cardiac output leading to gut ischemia
and injury. Additionally, they are often subject to pro-inflammatory
states, associated with decreased innate mucosal defenses.
Prevention of stress ulcers with acid suppression through prophylactic treatment with PPIs or H2RAs has been common practice for
the past four decades. Recently, the side effect profile of these agents
has been evaluated against the risk of stress ulcer bleeds. Serious side
effects of PPIs and H2RAs in the ICU setting include increased rate of
nosocomial infections, such as ventilator-associated pneumonia and
CDI. Consequently, stress ulcer prophylaxis should be reserved only
for those patients at high risk for life-threatening GI bleeding such
as patients with a history of GI bleeding within the past 12 months,
greater than 48 hours of mechanical ventilation, spinal or traumatic
brain injuries, and patients with coagulopathies.
Idiopathic Ulcers
Ulcers that appear to arise spontaneously with no known cause are
called idiopathic ulcers. Idiopathic PUD (IPUD) prevalence varies by
geographic location and has a prevalence of about 15% in developed
countries as compared to around 80% in developing countries. With
the advent of increased H. pylori treatment, the incidence of non–H.
pylori idiopathic ulcers has increased dramatically, mainly in Asian
countries. Idiopathic ulcers, similar to H. pylori ulcers, have a slightly
higher likelihood of being located in the duodenum.
Diagnosis of idiopathic ulcers requires exclusion of all known
causes of PUD such as missed H. pylori infection, surreptitious use
of ulcerogenic medications, certain systemic diseases such as Crohn’s
disease, eosinophilic gastroenteritis, vasculitis, ZES, and other infections besides H. pylori that may lead to ulcers such as cytomegalovirus
(CMV), herpes simplex virus (HSV), tuberculosis (TB), and syphilis.
IPUD carries an increased risk of ulcer recurrence when compared
with other etiologies. One study concluded that recurrence rates for
H. pylori–positive, NSAID-induced, and IPUD-related ulcers were
4.1%, 11.7%, and 23.2%, respectively.
Treatment consists of PPI administration for 4 to 8 weeks, or longer in the case of complicated disease. After PPI administration, it is
important to monitor patients clinically. If there is recurrence, maintenance therapy is reasonable.
General PUD Treatment
As highlighted above, the single most important treatment option for
PUD is to tailor therapy based on ulcer etiology. Generally, ulcers will
heal with antisecretory treatment with a PPI. Uncomplicated duodenal
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