2428 PART 10 Disorders of the Gastrointestinal System

randomized controlled trial demonstrated an equivalent response rate

of ~90% for both pneumatic dilation and laparoscopic Heller myotomy

at 5-year follow-up. Occasionally, patients with advanced disease fail

to respond to pneumatic dilation or Heller myotomy or relapse years

after response to primary therapy. In such refractory cases, esophageal

resection with gastric pull-up or interposition of a segment of transverse colon may be the only option other than gastrostomy feeding.

An endoscopic approach to LES myotomy is increasingly available,

referred to as peroral esophageal myotomy (POEM). This technique

involves the creation of a tunnel in the submucosa of the esophageal

wall through which the circular muscle of the LES and distal esophagus are transected with electrocautery. As expected, GERD is common

after POEM but managed effectively with medications. Potential

advantages over the conventional laparoscopic approach include avoidance of surgical disruption of the diaphragmatic hiatus and more rapid

recovery. An international, multicenter, randomized trial of POEM and

pneumatic dilation demonstrated greater symptom relief with POEM

compared to dilation at 2 years. A European, multicenter, randomized

trial of POEM and Heller myotomy reported similar efficacy for symptom relief, with exceeded 80% with either modality.

In untreated or inadequately treated achalasia, esophageal dilatation

predisposes to stasis esophagitis. Prolonged stasis esophagitis is the

likely explanation for the association between achalasia and esophageal

squamous cell cancer. Tumors develop after years of achalasia, usually

in the setting of extreme esophageal dilatation, with the overall squamous cell cancer risk increased 17-fold compared to controls.

■ DIFFUSE ESOPHAGEAL SPASM

DES is manifested by episodes of dysphagia and chest pain attributable

to abnormal esophageal contractions with normal deglutitive LES

relaxation. The pathophysiology and natural history of DES are poorly

defined. Radiographically, DES has been characterized by tertiary

contractions or a “corkscrew esophagus” (Fig. 323-7), but in many

instances, these abnormalities are indicative of achalasia. Manometrically, a variety of defining features have been proposed including

uncoordinated (“spastic”) activity in the distal esophagus, spontaneous

and repetitive contractions, or high-amplitude and prolonged contractions. High-resolution manometry has defined DES by the occurrence

of contractions in the distal esophagus with short latency relative to

the time of the pharyngeal contraction, a dysfunction indicative of

impairment of inhibitory myenteric plexus neurons. When defined

with this restrictive criterion (Fig. 323-8), DES is substantially less

common than achalasia.

Esophageal chest pain closely mimics angina pectoris. Features suggesting esophageal pain include pain that is nonexertional, prolonged,

meal-related, relieved with antacids, and accompanied by heartburn,

dysphagia, or regurgitation and interrupts sleep. However, all of these

features exhibit overlap with cardiac pain, which still must be the

primary consideration. Furthermore, even within the spectrum of

esophageal diseases, both chest pain and dysphagia are also characteristic of peptic or infectious esophagitis. Only after these more common

entities have been excluded by evaluation and/or treatment should a

diagnosis of DES be pursued.

Although DES is diagnosed by manometry, endoscopy is useful to

identify alternative structural and inflammatory lesions that may cause

chest pain. Radiographically, a “corkscrew esophagus,” “rosary bead

esophagus,” pseudodiverticula, or curling can be indicative of DES,

but these are also found with spastic achalasia. Given these vagaries of

defining DES and the resultant heterogeneity of patients identified for

A. Classic achalasia

B. Achalasia with compression

C. Spastic achalasia

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FIGURE 323-6 Three subtypes of achalasia: classic (A), with esophageal

compression (B), and spastic achalasia (C) imaged with pressure topography. All

are characterized by impaired lower esophageal sphincter (LES) relaxation and

absent peristalsis. However, classic achalasia has minimal pressurization of the

esophageal body, whereas substantial fluid pressurization is observed in achalasia

with esophageal compression, and spastic esophageal contractions are observed

with spastic achalasia.

FIGURE 323-7 Diffuse esophageal spasm. The characteristic “corkscrew”

esophagus results from spastic contraction of the circular muscle in the esophageal

wall; more precisely, this is actually a helical array of muscle. These findings are

also seen with spastic achalasia.

2429 Diseases of the Esophagus CHAPTER 323

inclusion in therapeutic trials, it is not surprising that trial results have

been disappointing. Only small, uncontrolled trials exist, reporting

response to nitrates, calcium channel blockers, hydralazine, botulinum

toxin, and anxiolytics. POEM with distal esophageal myotomy or surgical myotomy should be considered only with severe weight loss or

intractable pain. These indications are extremely rare.

■ NONSPECIFIC MANOMETRIC FINDINGS

Manometric studies done to evaluate chest pain and/or dysphagia

often report minor abnormalities (e.g., hypertensive or hypotensive

peristalsis, hypertensive LES) that are insufficient to diagnose either

achalasia or DES. These findings are of unclear significance. Reflux

and psychiatric diagnoses, particularly anxiety and depression, are

common among such individuals. A lower visceral pain threshold and

symptoms of irritable bowel syndrome are noted in more than half of

such patients. Consequently, therapy for these individuals should target either the most common esophageal disorder, GERD, or cognitive

disorders that may be present.

GASTROESOPHAGEAL REFLUX DISEASE

The current conception of GERD is that it encompasses a family of

conditions with the commonality that they are caused by gastroesophageal reflux resulting in either troublesome symptoms or an array

of potential esophageal and extraesophageal manifestations. It is

estimated that 10–15% of adults in the United States are affected by

GERD, although such estimates are based on population studies of

self-reported chronic heartburn. With respect to the esophagus, the

spectrum of injury includes esophagitis, stricture, Barrett’s esophagus,

and adenocarcinoma (Fig. 323-9). Of particular concern is the rising

incidence of esophageal adenocarcinoma, an epidemiologic trend that

parallels the increasing incidence of GERD. About 9200 incident cases

of esophageal adenocarcinoma were noted in the United States in 2020

(estimated as half of all esophageal cancers); this disease burden has

increased two- to sixfold in the past 20 years.

■ PATHOPHYSIOLOGY

The best-defined subset of GERD patients, albeit a minority overall,

have esophagitis. Esophagitis occurs when refluxed gastric acid and

pepsin induce inflammation of the esophageal mucosa that leads to

microscopic injury and macroscopic erosions and ulcers. Experimental evidence supports a cytokine-mediated inflammatory pathway

rather than direct caustic injury to the esophageal epithelium. Note

that some degree of gastroesophageal reflux is normal, physiologically

intertwined with the mechanism of belching (transient LES relaxation),

but esophagitis results from excessive reflux, often accompanied by

impaired clearance of the refluxed gastric juice. Restricting reflux

Jackhammer esophagus

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Diffuse esophageal spasm

Short latency, premature contraction

0 10 3 20 0

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FIGURE 323-8 Esophageal pressure topography of the two major variants of esophageal spasm: jackhammer

esophagus (left) and diffuse esophageal spasm (right). Jackhammer esophagus is defined by the extraordinarily

vigorous and repetitive contractions with normal peristaltic onset and normal latency of the contraction. Diffuse

esophageal spasm is similar but primarily defined by a short latency (premature) contraction.

to that which is physiologically intended

depends on the anatomic and physiologic

integrity of the esophagogastric junction,

a complex sphincter comprised of both

the LES and the surrounding crural diaphragm. Three dominant mechanisms of

esophagogastric junction incompetence are

recognized: (1) transient LES relaxations (a

vagovagal reflex in which LES relaxation

is elicited by gastric distention), (2) LES

hypotension, or (3) anatomic distortion

of the esophagogastric junction inclusive

of hiatal hernia. Of note, the third factor,

esophagogastric junction anatomic disruption, is significant both unto itself and also

because it interacts with the first two mechanisms. Transient LES relaxations account

for ~90% of reflux in normal subjects or

GERD patients without hiatal hernia, but

patients with hiatal hernia have a more

heterogeneous mechanistic profile. Factors

tending to exacerbate reflux regardless of

mechanism are abdominal obesity, pregnancy, gastric hypersecretory states, delayed gastric emptying, disruption of esophageal peristalsis, and gluttony.

After acid reflux, peristalsis returns the refluxed fluid to the stomach, and acid clearance is completed by titration of the residual acid by

bicarbonate contained in swallowed saliva. Consequently, two causes

of prolonged acid clearance are impaired peristalsis and reduced salivation. Impaired peristaltic emptying can be attributable to disrupted

peristalsis or superimposed reflux associated with a hiatal hernia.

With superimposed reflux, fluid retained within a sliding hiatal hernia

refluxes back into the esophagus during swallow-related LES relaxation, a phenomenon that does not normally occur.

Inherent in the pathophysiologic model of GERD is that gastric

juice is harmful to the esophageal epithelium. However, gastric acid

hypersecretion is usually not a dominant factor in the development

of esophagitis. An obvious exception is with Zollinger-Ellison syndrome, which is associated with severe esophagitis in ~50% of patients.

Another caveat is with chronic Helicobacter pylori gastritis, which may

have a protective effect by inducing atrophic gastritis with concomitant hypoacidity. Pepsin, bile, and pancreatic enzymes within gastric

secretions can also injure the esophageal epithelium, but their noxious

properties are either lessened without an acidic environment or dependent on acidity for activation. Bile warrants attention because it persists

in refluxate despite acid-suppressing medications. Bile can transverse

the cell membrane, imparting severe cellular injury in a weakly acidic

environment, and has also been invoked as a cofactor in the pathogenesis of Barrett’s metaplasia and adenocarcinoma. Hence, the causticity

of gastric refluxate extends beyond hydrochloric acid.

■ SYMPTOMS

Heartburn and regurgitation are the typical symptoms of GERD.

Somewhat less common are dysphagia and chest pain. In each case,

multiple potential mechanisms for symptom genesis operate that

extend beyond the basic concepts of mucosal erosion and activation of

afferent sensory nerves. Specifically, visceral sensitivity is increasingly

recognized as a cofactor. Nonetheless, the dominant clinical strategy is

empirical treatment with acid inhibitors, reserving further evaluation

for those who fail to respond. Important exceptions to this are patients

with chest pain or persistent dysphagia, each of which may be indicative of more morbid consequences of GERD or alternative diagnoses.

With chest pain, cardiac disease must be carefully considered. In the

case of dysphagia, chronic reflux can lead to the development of a peptic stricture, eosinophilic esophagitis (EoE), or adenocarcinoma, each

of which benefits from early detection and/or specific therapy.

Extraesophageal syndromes with an established association to

GERD include chronic cough, laryngitis, asthma, and dental erosions. A multitude of other conditions including pharyngitis, chronic

2430 PART 10 Disorders of the Gastrointestinal System

bronchitis, pulmonary fibrosis, chronic sinusitis, cardiac arrhythmias,

sleep apnea, and recurrent aspiration pneumonia have proposed

associations with GERD. However, in both cases, it is important to

emphasize the word association as opposed to causation. In many

instances, the disorders likely coexist because of shared pathogenetic

mechanisms rather than strict causality. Potential mechanisms for

extraesophageal GERD manifestations are either regurgitation with

direct contact between the refluxate and supraesophageal structures or

via a vagovagal reflex wherein reflux activation of esophageal afferent

nerves triggers efferent vagal reflexes such as bronchospasm, cough,

or arrhythmias.

■ DIFFERENTIAL DIAGNOSIS

Although generally quite characteristic, symptoms from GERD need to

be distinguished from symptoms related to infectious or pill esophagitis, EoE, peptic ulcer disease, dyspepsia, biliary colic, coronary artery

disease, and esophageal motility disorders. It is especially important

that coronary artery disease be given early consideration because of its

potentially lethal implications. The remaining elements of the differential diagnosis can be addressed by endoscopy, upper gastrointestinal

series, or esophageal manometry as appropriate. Erosive esophagitis

at the esophagogastric junction is the endoscopic hallmark of GERD

but identified in only about one-third of patients with GERD. The

distinction among etiologies of esophagitis is readily made by endoscopic appearance, but mucosal biopsies may be helpful to evaluate

for infectious or eosinophilic inflammation. In terms of endoscopic

appearance, the ulcerations seen in peptic esophagitis are usually few

and distal, whereas infectious ulcerations are numerous, punctate, and

diffuse. EoE characteristically exhibits multiple esophageal rings, linear

furrows, white punctate exudate, and strictures. Esophageal ulcerations from pill esophagitis are usually singular and deep at points of

luminal narrowing, especially near the carina, with sparing of the distal

esophagus.

Erosive esophagitis

Barrett’s esophagus Esophageal adenocarcinoma

with Barrett’s esophagus

Esophageal stricture with chronic

erosive esophagitis

A B

C D

FIGURE 323-9 Endoscopic appearance of (A) peptic esophagitis, (B) a peptic stricture, (C) Barrett’s

metaplasia, and (D) adenocarcinoma developing within an area of Barrett’s esophagus.

■ COMPLICATIONS

The complications of GERD are related to chronic

esophagitis (bleeding and stricture) and the relationship between GERD and esophageal adenocarcinoma. However, both erosive esophagitis and peptic

strictures have become increasingly rare in the era

of potent antisecretory medications. Conversely, the

most severe histologic consequence of GERD is Barrett’s metaplasia with the associated risk of esophageal

adenocarcinoma, and the incidence of these lesions

has increased, not decreased, in the era of potent

acid suppression. Barrett’s metaplasia, recognized

endoscopically by salmon-colored mucosa extending proximally from the gastroesophageal junction

(Fig. 323-9) or histopathologically by the finding of

specialized columnar metaplasia, is associated with a

significantly increased risk for development of esophageal adenocarcinoma.

Barrett’s metaplasia can progress to adenocarcinoma through the intermediate stages of low- and

high-grade dysplasia (Fig. 323-10). Owing to this

risk, areas of Barrett’s metaplasia and especially any

included areas of mucosal irregularity should be

carefully inspected and extensively biopsied. The rate

of cancer development is estimated at 0.1–0.3% per

year, but vagaries in definitional criteria and of the

extent of Barrett’s metaplasia requisite to establish

the diagnosis have contributed to variability and

inconsistency in this risk assessment. The group at

greatest risk is obese white males in their sixth decade

of life. Despite common practice, however, the utility

of endoscopic screening and surveillance programs

intended to control the adenocarcinoma risk remains

an open question. Also of note, although in a large,

randomized, controlled chemoprevention trial in

Barrett’s patients high-dose proton pump inhibitor therapy along with

aspirin did significantly better at achieving the primary composite

endpoint of delaying all-cause mortality, development of esophageal

adenocarcinoma, or progression to high-grade dysplasia, the effect was

driven mainly by improved overall survival rather than reduced Barrett’s progression or esophageal adenocarcinoma development.

Although the management of Barrett’s esophagus remains controversial, the finding of dysplasia in Barrett’s, particularly high-grade

dysplasia, mandates further intervention. In addition to the high rate

of progression to adenocarcinoma, there is also a high prevalence of

unrecognized coexisting cancer with high-grade dysplasia. Treatment

recommendations for Barrett’s esophagus with high-grade dysplasia

have evolved over the past several years. Historically, esophagectomy

was the gold standard treatment for high-grade dysplasia. However,

esophagectomy has a mortality ranging from 3 to 10%, along with

substantial morbidity. Prospective studies have demonstrated the

efficacy of endoscopic mucosal ablation therapy with substantially less

morbidity and essentially no mortality. Consequently, current societal

guidelines endorse endoscopic mucosal ablation therapies for the management of high-grade dysplasia.

TREATMENT

Gastroesophageal Reflux Disease

Lifestyle modifications are routinely advocated as GERD therapy.

Broadly speaking, these fall into three categories: (1) avoidance of

foods that reduce LES pressure, making them “refluxogenic” (these

commonly include fatty foods, alcohol, spearmint, peppermint,

and possibly coffee and tea); (2) avoidance of acidic foods that are

inherently irritating (citrus fruits, tomato-based foods); and (3)

adoption of behaviors to minimize reflux and/or heartburn. In

general, minimal evidence supports the efficacy of these measures.

2431 Diseases of the Esophagus CHAPTER 323

However, clinical experience dictates that subsets of patients benefit

from specific recommendations based on their individual history

and symptom profile. A patient with sleep disturbance from nighttime heartburn is more likely to benefit from elevation of the head

of the bed and avoidance of eating before retiring. The most broadly

applicable recommendation is for weight reduction. Even though

the benefit with respect to reflux cannot be assured, the strong epidemiologic relationship between body mass index and GERD and

the secondary health gains of weight reduction is beyond dispute.

The dominant pharmacologic approach to GERD management

is with inhibitors of gastric acid secretion, and abundant data support the effectiveness of this approach. Pharmacologically reducing

the acidity of gastric juice does not prevent reflux, but it ameliorates

reflux symptoms and allows esophagitis to heal. The hierarchy of

effectiveness among pharmaceuticals parallels their antisecretory

potency. Proton pump inhibitors (PPIs) are more efficacious than

histamine-2 receptor antagonists (H2

RAs), and both are superior to

placebo. No major differences exist among PPIs, and only modest

gain is achieved by increased dosage.

Paradoxically, the perceived frequency and severity of heartburn

correlate poorly with the presence or severity of esophagitis. When

GERD treatments are assessed in terms of resolving heartburn, both

efficacy and differences among pharmaceuticals are less clear-cut

than with the objective of healing esophagitis. Although the same

overall hierarchy of effectiveness exists, observed efficacy rates are

lower and vary widely, likely reflecting patient heterogeneity.

Reflux symptoms tend to be chronic, irrespective of esophagitis.

Thus, a common management strategy is indefinite treatment with

PPIs or H2

RAs as necessary for symptom control. The side effects of

PPI therapy are generally minimal. Rare cases of interstitial nephritis and severe, reversible hypomagnesemia have been reported.

Vitamin B12 and iron absorption may be compromised and susceptibility to enteric infections, particularly Clostridium difficile colitis,

increased with treatment. Observational data have also noted an

association between PPI exposure and renal disease, dementia,

and cardiovascular disease, but the hazard ratios reported in these

studies were small, and the potential for unrecognized residual

confounding bias was substantial. Population studies have also suggested a slight increased risk of bone fracture with chronic PPI use

suggesting an impairment of calcium absorption, but prospective

studies have failed to corroborate this. Nonetheless, as with any

medication, PPI dosage should be minimized to that necessary for

the clinical indication.

Laparoscopic Nissen fundoplication, wherein the proximal

stomach is wrapped around the distal esophagus to create an

antireflux barrier, is a surgical alternative to the management of

chronic GERD. Just as with PPI therapy, evidence on the utility of

fundoplication is strongest for treating esophagitis, and controlled

trials suggest similar efficacy to PPI therapy. However, the benefits

of fundoplication must be weighed against potential deleterious

effects, including surgical morbidity and mortality, postoperative

dysphagia, failure or breakdown requiring reoperation, an inability

to belch, and increased bloating, flatulence, and bowel symptoms

after surgery.

■ EOSINOPHILIC ESOPHAGITIS

EoE is increasingly recognized in adults and children around the

world. Current prevalence estimates in the United States identified

4–8 cases per 10,000 with a predilection for white males between 30

and 40 years of age. The increasing prevalence of EoE is attributable

to a combination of an increasing incidence and a growing recognition of the condition. There is also an incompletely understood, but

important, interaction between EoE and GERD that may confound the

diagnosis of the disease. Genome-wide analysis studied demonstrated

susceptibility elements at 5q22 (thymic stromal lymphopoietin) and

2p23 (CAPN14) in EoE.

EoE is diagnosed based on the combination of esophageal symptoms

and esophageal mucosal biopsies demonstrating eosinophil-predominant inflammation. Alternative etiologies of esophageal eosinophilia

include GERD, drug hypersensitivity, connective tissue disorders,

hypereosinophilic syndrome, Crohn’s disease, eosinophilic gastroenteritis, and infection. EoE is an immunologic disorder induced by

antigen sensitization in susceptible individuals. Food allergens are the

dominant triggers, although aeroallergens may also contribute. The

natural history of EoE is incompletely understood, but an increased

risk of esophageal stricture development paralleling the duration of

untreated disease has been noted.

EoE should be strongly considered in children and adults with

dysphagia and esophageal food impactions. In preadolescent children, symptom presentations of EoE include chest or abdominal

pain, nausea, vomiting, and food aversion. Other symptoms in adults

may include atypical chest pain and heartburn. An atopic history of

IgE-mediated food allergy, asthma, eczema, and/or allergic rhinitis is

present in the majority of patients. Peripheral blood eosinophilia is

demonstrable in 25–50% of patients, but the specificity of this finding

is problematic in the setting of concomitant atopy. The characteristic

endoscopically identified esophageal findings include loss of vascular

markings (edema), multiple esophageal rings, longitudinally oriented

furrows, and whitish exudate (Fig. 323-11). Histologic confirmation

is made with the demonstration of esophageal mucosal eosinophilia

(peak density ≥15 eosinophils per high-power field) (Fig. 323-12).

Complications of EoE include food impaction, esophageal stricture,

narrow-caliber esophagus, and rarely esophageal perforation.

The goals of EoE management are symptom control and the prevention of complications. Primary therapy often starts with PPI therapy,

which is effective at improving eosinophilic inflammation in 30–50%

of patients. Additional first-line therapies include elimination diets

or swallowed topical glucocorticoids. Elemental formula diets devoid

of allergenic protein are a highly effective therapy but are limited by

palatability. Notably, allergy testing by means of either serum IgE or

skin prick testing has demonstrated poor sensitivity and specificity in

Barrett’s metaplasia High-grade dysplasia

Alcian blue stain H&E stain

FIGURE 323-10 Histopathology of Barrett’s metaplasia and Barrett’s metaplasia with high-grade dysplasia. H&E, hematoxylin and eosin.

2432 PART 10 Disorders of the Gastrointestinal System

A B

C D

FIGURE 323-11 Endoscopic features of (A) eosinophilic esophagitis (EoE),

(B) Candida esophagitis, (C) giant ulcer associated with HIV, and (D) a Schatzki ring.

FIGURE 323-12 Histopathology of eosinophilic esophagitis (EoE) showing

infiltration of the esophageal squamous epithelium with eosinophils. Additional

features of basal cell hyperplasia and lamina propria fibrosis are present.

Eosinophilic inflammation can also be seen with gastroesophageal reflux disease.

the identification of foods responsible for EoE in an individual patient.

Empiric elimination of common food allergies (milk, wheat, egg, soy,

nuts, and seafood) followed by systematic reintroduction has been an

effective diet therapy in both children and adults with EoE. The intent

of the elimination diet approach is the identification of specific food

trigger(s). Swallowed, topical glucocorticoids (e.g., fluticasone propionate or budesonide) are effective in 50–80% of patients, but recurrence

of disease is common following the cessation of short-term therapy.

Systemic glucocorticoids are not generally recommended due to side

effects and lack of proven benefit beyond that achieved with topical

glucocorticoids. Biologic therapies targeting allergic cytokine mediators including interleukin (IL) 4, IL-5, and IL-13 have shown promise in initial clinical trials. Esophageal dilation is highly effective at

relieving dysphagia in patients with fibrostenosis but does not address

the underlying inflammatory process. Dilation should be approached

conservatively because of the risk of deep, esophageal mural laceration

or perforation in the stiff-walled esophagus that is characteristic of the

disease.

INFECTIOUS ESOPHAGITIS

As a result of the increased use of immunosuppression for organ transplantation and chronic inflammatory diseases and use of chemotherapy

agents, along with the AIDS epidemic, infections with Candida species,

herpesvirus, and cytomegalovirus (CMV) have become relatively

common. Although rare, infectious esophagitis also occurs among the

non-immunocompromised, with herpes simplex and Candida albicans

being the most common pathogens. Among AIDS patients, infectious

esophagitis becomes more common as the CD4 count declines; cases

are rare with a CD4 count >200 and common when <100. HIV itself

may also be associated with a self-limited syndrome of acute esophageal ulceration with oral ulcers and a maculopapular skin rash at the

time of seroconversion. Additionally, some patients with advanced

disease have deep, persistent esophageal ulcers treated with oral glucocorticoids or thalidomide. However, with the widespread use of highly

effective antiviral therapies, a reduction in these HIV complications

has been noted.

Regardless of the infectious agent, odynophagia is a characteristic

symptom of infectious esophagitis; dysphagia, chest pain, and hemorrhage are also common. Odynophagia is uncommon with reflux

esophagitis, so its presence should always raise suspicion of an alternative etiology.

■ CANDIDA ESOPHAGITIS

Candida is normally found in the throat but can become pathogenic

and produce esophagitis in a compromised host; C. albicans is most

common. Candida esophagitis also occurs with esophageal stasis

secondary to esophageal motor disorders and diverticula. Patients

complain of odynophagia and dysphagia. If oral thrush is present,

empirical therapy is appropriate, but co-infection is common, and persistent symptoms should lead to prompt endoscopy with biopsy, which

is the most useful diagnostic evaluation. Candida esophagitis has a

characteristic appearance of white plaques or exudate with friability.

Oral fluconazole (400 mg on the first day, followed by 200 mg daily) for

14–21 days is the preferred treatment. Patients refractory to fluconazole may respond to voriconazole or posaconazole. Alternatively,

poorly responsive patients or those who cannot swallow medications

can be treated with an intravenous echinocandin.

■ HERPETIC ESOPHAGITIS

Herpes simplex virus type 1 or 2 may cause esophagitis. Vesicles on

the nose and lips may coexist and are suggestive of a herpetic etiology. Varicella-zoster virus can also cause esophagitis in children

with chickenpox or adults with zoster. The characteristic endoscopic

findings are vesicles and small, superficial ulcerations. Because herpes

simplex infections are limited to squamous epithelium, biopsies from

the ulcer margins are most likely to reveal the characteristic groundglass nuclei, eosinophilic Cowdry’s type A inclusion bodies, and giant

cells. Culture or polymerase chain reaction (PCR) assays are helpful to

identify acyclovir-resistant strains. Acyclovir (200 mg orally five times

a day for 7–10 days) can be used for immunocompetent hosts, although

the disease is typically self-limited after a 1- to 2-week period in such

patients. Immunocompromised patients are treated with acyclovir

(400 mg orally five times a day for 14–21 days), famciclovir (500 mg

orally three times a day), or valacyclovir (1 g orally three times a day).

2433 Diseases of the Esophagus CHAPTER 323

In patients with severe odynophagia, intravenous acyclovir, 5 mg/kg

every 8 h for 7–14 days, reduces this morbidity.

■ CYTOMEGALOVIRUS

CMV esophagitis occurs primarily in immunocompromised patients,

particularly those with HIV, patients with malignancy, and recipients

of bone marrow or organ transplants. CMV is usually activated from a

latent stage. Endoscopically, CMV lesions appear as large serpiginous

ulcers in an otherwise normal mucosa, particularly in the distal esophagus. Biopsies from the ulcer bases have the greatest diagnostic yield

for finding the pathognomonic large nuclear or cytoplasmic inclusion

bodies. Immunohistology with monoclonal antibodies to CMV and in

situ hybridization tests are useful for early diagnosis. Data on therapy

for CMV esophagitis are limited. Treatment studies of CMV gastrointestinal disease have demonstrated effectiveness of both ganciclovir

(5 mg/kg every 12 h IV) and valganciclovir (900 mg orally every 12 h).

Therapy is continued until healing, which may take 3–6 weeks. Maintenance therapy may be needed for patients with relapsing disease.

MECHANICAL TRAUMA AND

IATROGENIC INJURY

ESOPHAGEAL PERFORATION

Most cases of esophageal perforation are from instrumentation of

the esophagus or trauma. Alternatively, forceful vomiting or retching

can lead to spontaneous rupture at the gastroesophageal junction

(Boerhaave’s syndrome). More rarely, corrosive esophagitis or neoplasms lead to perforation. Instrument perforation from endoscopy or

nasogastric tube placement typically occurs in the hypopharynx or at

the gastroesophageal junction. Perforation may also occur at the site of

a stricture in the setting of endoscopic food disimpaction or esophageal dilation. Esophageal perforation causes pleuritic retrosternal pain

that can be associated with pneumomediastinum and subcutaneous

emphysema. Mediastinitis is a major complication of esophageal perforation, and prompt recognition is key to optimizing outcome. CT

of the chest is most sensitive in detecting mediastinal air. Esophageal

perforation is confirmed by a contrast swallow, usually Gastrografin

followed by thin barium. Treatment includes nasogastric suction and

parenteral broad-spectrum antibiotics with prompt surgical drainage

and repair in noncontained leaks. Conservative therapy with NPO

status and antibiotics without surgery may be appropriate in cases of

contained perforation that are detected early. Endoscopic clipping or

stent placement may be indicated in nonoperated iatrogenic perforations or nonoperable cases such as perforated tumors.

■ MALLORY-WEISS TEAR

Vomiting, retching, or vigorous coughing can cause a nontransmural

tear at the gastroesophageal junction that is a common cause of upper

gastrointestinal bleeding. Most patients present with hematemesis.

Antecedent vomiting is the norm but not always evident. Bleeding

usually abates spontaneously, but protracted bleeding may respond

to local epinephrine or cauterization therapy, endoscopic clipping, or

angiographic embolization. Surgery is rarely needed.

■ RADIATION ESOPHAGITIS

Radiation esophagitis can complicate treatment for thoracic cancers,

especially breast and lung cancers, with the risk proportional to radiation dosage. Radiosensitizing drugs such as doxorubicin, bleomycin,

cyclophosphamide, and cisplatin also increase the risk. Dysphagia and

odynophagia may last weeks to months after therapy. The esophageal

mucosa becomes erythematous, edematous, and friable. Submucosal

fibrosis and degenerative tissue changes and stricturing may occur

years after the radiation exposure. Radiation exposure in excess of

5000 cGy has been associated with increased risk of esophageal stricture. Treatment for acute radiation esophagitis is supportive. Chronic

strictures are managed with esophageal dilation.

■ CORROSIVE ESOPHAGITIS

Caustic esophageal injury from ingestion of alkali or, less commonly,

acid can be accidental or from attempted suicide. Absence of oral

injury does not exclude possible esophageal involvement. Thus, early

endoscopic evaluation is recommended to assess and grade the injury

to the esophageal mucosa. Severe corrosive injury may lead to esophageal perforation, bleeding, stricture, and death. Glucocorticoids have

not been shown to improve the clinical outcome of acute corrosive

esophagitis and are not recommended. Healing of more severe grades

of caustic injury is commonly associated with severe stricture formation and often requires repeated dilation.

■ PILL ESOPHAGITIS

Pill-induced esophagitis occurs when a swallowed pill fails to traverse

the entire esophagus and lodges within the lumen. Generally, this is

attributed to poor “pill-taking habits”: inadequate liquid with the pill or

lying down immediately after taking a pill. The most common location

for the pill to lodge is in the mid-esophagus near the crossing of the

aorta or carina. Extrinsic compression from these structures halts the

movement of the pill or capsule. Since initially reported in 1970, >1000

cases of pill esophagitis have been reported, suggesting that this is not

an unusual occurrence. A wide variety of medications are implicated,

with the most common being doxycycline, tetracycline, quinidine,

phenytoin, potassium chloride, ferrous sulfate, nonsteroidal anti-inflammatory drugs (NSAIDs), and bisphosphonates.

Typical symptoms of pill esophagitis are the sudden onset of chest

pain and odynophagia. Characteristically, the pain will develop over

a period of hours or will awaken the individual from sleep. A classic

history in the setting of ingestion of recognized pill offenders obviates

the need for diagnostic testing in most patients. When endoscopy is

performed, localized ulceration or inflammation is evident. Histologically, acute inflammation is typical. Chest CT imaging will sometimes

reveal esophageal thickening consistent with transmural inflammation.

Although the condition usually resolves within days to weeks, symptoms may persist for months and stricture can develop in severe cases.

No specific therapy is known to hasten the healing process, but antisecretory medications are frequently prescribed to remove concomitant

reflux as an aggravating factor. When healing results in stricture formation, dilation is indicated.

■ FOREIGN BODIES AND FOOD IMPACTION

Food or foreign bodies may lodge in the esophagus, causing complete

obstruction, which in turn can cause an inability to handle secretions

(foaming at the mouth) and severe chest pain. Food impaction may

occur due to peptic stricture, carcinoma, Schatzki ring, EoE, or simply

inattentive eating. If it does not spontaneously resolve, impacted food

should be removed endoscopically. Use of meat tenderizer enzymes

to facilitate passage of a meat bolus is discouraged because of potential esophageal injury. Glucagon (1 mg IV) is sometimes tried before

endoscopic dislodgement. After emergent treatment, patients should

be evaluated for potential causes of the impaction with treatment rendered as indicated.

ESOPHAGEAL MANIFESTATIONS

OF SYSTEMIC DISEASE

■ SCLERODERMA AND CONNECTIVE

TISSUE DISORDERS

Scleroderma esophagus (hypotensive LES and absent esophageal contractility) was initially described as a manifestation of scleroderma or

other collagen vascular diseases and thought to be specific for these

disorders. However, this nomenclature subsequently has been discarded because an estimated half of qualifying patients do not have

an identifiable rheumatologic disease, and reflux disease is often the

only identifiable association. When scleroderma esophagus occurs as

a manifestation of a connective tissue disorder, the histopathologic

findings are of infiltration and destruction of the esophageal muscularis propria with collagen deposition and fibrosis and reduction in

the number of interstitial cells of Cajal. The pathogenesis of absent

peristalsis and LES hypotension in the absence of a connective tissue

disorder is unknown. Regardless of the underlying cause, the manometric abnormalities predispose patients to severe GERD due to inadequate LES barrier function combined with poor esophageal clearance