Clinical manifestations of peptic ulcer disease

Author Section Editor Deputy Editor

Andrew H Soll, MD Mark Feldman, MD Carla H Ginsburg, MD,
MPH, AGAF

Last literature review version 17.3: septiembre 2009 | This topic last
updated: septiembre 11, 2008 (More)

INTRODUCTION — Peptic ulcers may present with a wide variety of symptoms,

or may be completely asymptomatic, sometimes until complications such as
hemorrhage or perforation occur. Many patients complain of upper abdominal
discomfort, but these symptoms are not specific and the differential diagnosis is
broad. (See "Approach to the patient with dyspepsia".)

This topic review will discuss the clinical manifestations of peptic ulcer disease
and the differential diagnosis that should be considered. The methods used to
establish the diagnosis, association with H. pylori infection, and an approach to
therapy are presented separately. (See appropriate topic reviews.)

EPIDEMIOLOGY — The epidemiology of peptic ulcer disease is discussed

separately. (See "Overview of peptic ulcer: Epidemiology and major causes" and
"Helicobacter pylori-negative peptic ulcer disease".)

CLINICAL MANIFESTATIONS — A pragmatic definition of "dyspepsia" is when

the clinician suspects that symptoms are coming from the upper GI tract [1].
Dyspepsia occurs in three common patterns: ulcer-like or acid dyspepsia (eg,
burning, epigastric hunger pain with food, antacid, and antisecretory agent
relief); indigestion (also called functional dyspepsia or dysmotility-like dyspepsia,
with postprandial belching, bloating, epigastric fullness, anorexia, early satiety,
nausea, and occasional vomiting); and reflux-like dyspepsia. These patterns
overlap considerably. Although the clinical assessment is critical for overall
management, it has poor predictive value for the specific diagnosis found upon
the endoscopy [2,3]. (See "Approach to the patient with dyspepsia".)

The "classic" symptoms of duodenal ulcer (DU) occur when acid is secreted in
the absence of a food buffer. Food is usually well emptied by two to three hours
after meals, but food-stimulated acid secretion persists for three to five hours;
thus, classic ulcer symptoms occur two to five hours after meals or on an empty
stomach. Symptoms also occur at night, between 11 PM and 2 AM, when the
circadian stimulation of acid secretion is maximal. The ability of alkali, food, and
antisecretory agents to produce relief suggests the role of acid in this process.
Thus, "acid dyspepsia" is a fitting term. Gastric ulcer (GU) has classically been
associated with more severe pain occurring soon after meals, with less frequent
relief by antacids or food.

Discomfort occurs in the epigastrium in about two-thirds of symptomatic

patients, but may occasionally localize to the right or left upper quadrants or the
hypochondrium [4]. Radiation of pain to the back may occur, but primary back
pain is atypical. Although ulcer pain is often burning, gnawing, or hunger-like in
quality, the discomfort can be vague or cramping. Symptomatic periods lasting a
few weeks followed by symptom-free periods of weeks or months is a pattern
characteristic of classic DU.

However, dyspeptic symptoms are neither sensitive nor specific. Thus, reliance
upon the presence of these symptoms alone to make the diagnosis of peptic
ulcer will result in overdiagnosis of patients who have nonulcer dyspepsia and
will miss the diagnosis in some patients who have peptic ulcers [4-6]. In one
study, for example, a self-report questionnaire examined the three common
dyspeptic symptom patterns [7]. Ulcer-like dyspepsia was most common, but 43
percent of the subjects with dyspepsia could be classified into more than one
subgroup, suggesting that the history alone had a poor discriminant value for
determining the etiology. Several other studies have indicated that only 15 to 25
percent of patients presenting with typical acid dyspepsia have underlying peptic
ulcer disease [8,9].

The classic symptoms of acid dyspepsia with food relief, described above, occur
in only about 50 percent of patients with a DU. Approximately 20 percent report
an increase in appetite or weight gain, while many others have a stomach that is
"irritable" to food, other chemicals, or mechanical distention, resulting in
indigestion, anorexia, weight loss, and fatty food intolerance. Heartburn occurs
in 20 to 60 percent of patients with DU, and symptoms typical of irritable bowel
syndrome (eg, crampy, periumbilical abdominal pain related to altered bowel
function and often relieved by decompressing the colon) are also common [6].
(See "Clinical manifestations and diagnosis of irritable bowel syndrome".)

Silent ulcers — In a study from Taiwan, 11 percent of 6457 subjects

undergoing screening endoscopy had a peptic ulcer of whom 70 percent were
asymptomatic [10]. In addition, 20 to 50 percent of complicated ulcers present
without heralding symptoms; this "silent" presentation is more frequent in
elderly patients and individuals consuming nonsteroidal antiinflammatory drugs
(NSAIDs) [11,12].

Pathogenesis of ulcer pain — The mechanism by which peptic ulcers cause

symptoms is unclear. At least a portion of patients with DU develop symptoms
when acid bathes the ulcer crater. This was demonstrated in a randomized,
double-blind study of 40 patients with DU which found that 16 (40 percent)
developed typical acid pain upon bathing the ulcer through the endoscope with
0.1 N hydrochloric acid, while only 4 (10 percent) complained of pain with saline
[13]. In comparison, hydrochloric acid infusion into the duodenum did not
produce pain in patients without DU.

However, the pain experienced by patients with peptic ulcers reflects factors
more complex than acid bathing an ulcer crater. The secretory rates and
concentration of acid in symptomatic patients overlaps with that found in
asymptomatic patients and in controls. In addition, there is often no correlation
between the presence of an active ulcer (as shown by endoscopy) and
symptoms. As many as 40 percent of patients with healed ulcers (as shown by
endoscopy) have persistent symptoms, while 15 to 44 percent of those who
become symptom-free still have an ulcer crater at endoscopy [14,15].

Thus, the disappearance of symptoms does not guarantee ulcer healing, nor
does the persistence of symptoms consistently predict the presence of an ulcer
crater. For reasons that are not explicable, some patients perceive acid bathing
their gastroduodenal mucosa, while others do not. In some cases this
sensitization to acid is related to the presence of an ulcer crater or to the
secretion of excess acid, but it may occur in the face of grossly normal mucosa
and with physiologic levels of acid secretion.

Ulcer complications — The majority of complications, especially in the absence

of NSAID use, are associated with chronic peptic ulcers, which are surrounded by
fibrosis and have been presumably smoldering for months or longer. NSAID
ulcers sometimes lack surrounding fibrosis and are presumably acute,
developing and complicating over the first days or weeks of NSAID use.
Similarly, stress ulcers developing in the ICU setting can be acute, without
surrounding fibrosis. Complications may be heralded by new ulcer symptoms or
a change in symptoms or may occur in the absence of typical symptoms ("silent"
ulcers). (See "Complications of peptic ulcer disease".)

• Penetrating ulcers classically present with a shift from the typical vague
visceral discomfort to a more localized and intense pain that radiates to the back
and is not relieved by food or antacids.
• The sudden development of severe, diffuse abdominal pain may indicate
perforation.
• Vomiting is the cardinal feature present in most cases of pyloric outlet
obstruction.
• Hemorrhage may be heralded by nausea, hematemesis, melena, or
dizziness.
• Gastrocolic fistula, a very rare complication, can present with halitosis,
feculent vomiting, postprandial diarrhea, dyspepsia, and sometimes weight loss
[16].

Many patients underestimate the significance of their symptoms and fail to

present in a timely fashion.

NSAID-induced ulcers — Although NSAIDs can cause dyspepsia and peptic

ulcers, there is frequently a dissociation between symptoms and pathology [17].
As an example, one study evaluated the appearance of the gastroduodenal
mucosa in 65 patients treated with a variety of NSAIDs for at least six
consecutive weeks to treat osteoarthritis or rheumatoid arthritis [18]. Dyspeptic
symptoms were more common in patients with a completely normal endoscopy
(19 versus 9 percent in those with an abnormal endoscopy). In addition, only 3
of the 10 patients with ulcers had dyspeptic symptoms. In contrast, dyspepsia
appearing during a controlled trial of NSAID treatment in high risk patients has
been observed to predict ulcer recurrence [19]. Thus, although one can expect
frequent dissociation between symptoms and ulcers, the development of
gastrointestinal symptoms in a patient taking NSAIDs is an important clue to an
underlying ulcer and should prompt evaluation. (See "NSAIDs (including
aspirin): Pathogenesis of gastroduodenal toxicity".)

Atypical ulcers — A number of atypical presentations of peptic ulcer may

occur.

Giant ulcers — Most peptic ulcers are less than 1 to 2 cm in diameter; ulcers
more than 2 cm in diameter are termed giant ulcers. Giant DUs are usually
located on the posterior wall. They may present with a prolonged typical history,
pain radiating to the back, or few, if any, symptoms. Reversible anorexia and
weight loss can be observed in the absence of malignancy [20].

Giant ulcers are frequently complicated by bleeding and posterior penetration

and, depending on location, by pyloric obstruction [20-23]. One study,
comparing 62 patients with giant gastric ulcers (defined as ≥3 cm) to 476
patients with smaller gastric ulcers [21], found that the giant ulcers were more
prone to severe hemorrhage (44 versus 27 percent) and penetration into
contiguous organs (45 versus 10 percent). In addition, the risk of microscopic
malignancy in the macroscopically benign giant ulcer was significantly higher (13
versus 3 percent). Other studies have also confirmed that malignancy is more
frequent in giant compared to smaller ulcers [24]. In one report, the presence of
a visible vessel in the ulcer crater predicted the clinical course of giant duodenal
ulcers; 7 of 15 patients with a visible vessel required eventual operation,
compared to only 1 of 13 patients without a visible vessel [23].

There are some conflicting data regarding demographics and risk factors
associated with giant ulcers, which probably reflect the time frame and
population under investigation. In one study, giant ulcers occurred more
frequently in older subjects [20] and in association with NSAID consumption
[22]. However, in another study methamphetamine or cocaine use, as well as
NSAIDs, were major risk factors (the odds ratio for stimulant use was 9.7) [24].
This latter study also found that giant ulcers were inversely related to patient
age, possibly indicating that demographics of drug users may have influenced
the outcomes.

Comorbidities appear to be an important contributing factor in the development

of giant ulcers [20]. Giant duodenal or prepyloric ulcers have been reported in
association with end-stage renal failure [25], orthotopic lung transplantation
[26], and Crohn's disease. The ulcer symptoms may be the presenting complaint
in patients with Crohn's disease [27]. Mechanisms were not defined, but are
probably include poor nutrition, decreased mucosal blood flow, and poor healing.

H. pylori is certainly an important factor in some giant ulcers, but no

prospective, controlled studies have examined its prevalence. Of the 23 patients
who underwent antral biopsy in one study, only 9 were positive for H. pylori
[23], suggesting the importance of other factors, such as NSAID use and
comorbid conditions that predispose to ulceration.

Giant ulcers also heal more slowly and relapse more frequently than smaller
ulcers, especially in patients with comorbid conditions [20]. Medical
management should include three elements: detection and treatment of H.
pylori, if present; aggressive investigation to detect NSAID use and their
discontinuation since healing is very difficult with continued use; and use of
PPIs. (See "Overview of the natural history and treatment of peptic ulcer
disease", Giant ulcers.)

Pyloric channel ulcers — Ulcers located in the pyloric channel may be

associated with pain occurring shortly after eating, poor relief by antacids, and
vomiting, the latter sometimes reflecting pyloric obstruction or dysfunction.
Juxtapyloric ulcers, which occur at or within 2 cm of the pylorus, often present
with complications. In one series, for example, patients with pyloric channel
ulcers were more likely to undergo surgery than those with ulcers in the
duodenal bulb [28].

Postbulbar ulcers — Duodenal ulcers are generally located in the duodenal

bulb within 2 to 3 cm of the pylorus. Ulcers distal to the duodenal bulb
(postbulbar ulcers) were found in 10 percent of cases in a necropsy series, but in
only 15 of 4016 radiographic examinations [29]. Ulcers beyond the second
portion of the duodenum and into the proximal jejunum are characteristic of a
gastrinoma and possibly other hypersecretory states. In one report of patients
with gastrinoma, 75 percent of ulcers were in the first portion of the duodenum,
14 percent in the distal duodenum, and 11 percent in the jejunum [30]. (See
"Clinical manifestations and diagnosis of Zollinger-Ellison syndrome
(gastrinoma)".)

No clinical features clearly distinguish postbulbar ulcers, although a higher rate

of complications has been reported [29]. The differential diagnosis includes
diverticulae, adhesive bands, annular pancreas, and neoplasia of the pancreas
and duodenum.

Multiple ulcers — Multiple simultaneous ulcers occur in 2 to 20 of patients with

peptic ulcer (picture 1) [31,32]. In one series, multiple DUs were associated with
a higher male to female ratio, more patients with a late-onset (ulcer symptoms
starting after age 30 years), chronic cigarette smoking, and moderate to severe
deformity of the duodenal bulb [33]. Multiple ulcers are often clustered together,
suggesting that local pathogenic mechanisms, which involve compromised
mucosal resistance to injury or impaired healing, are important for the
development of this entity [32]. NSAID use and gastrinoma should also be
considered when multiple ulcers are encountered.

DIFFERENTIAL DIAGNOSIS — Peptic ulcer must be differentiated from other

disorders that cause symptoms in the upper abdomen and ulcerative lesions of
the stomach and duodenum that are secondary to diseases involving the
gastroduodenal mucosal itself (table 1). The specific causes of ulcerative lesions
of the stomach and duodenum must be identified whenever possible, since
effective therapy is available for many cases secondary to other specific causes.
Some of these conditions can be diagnosed by gross and histologic assessment
of the gastric mucosa and are described below. In addition, a variety of other
conditions are associated with PUD, which may or may not be detectable by
biopsy or visual inspection (see "Unusual causes of peptic ulcer disease".

Functional dyspepsia — The most common type of dyspepsia encountered in

primary care and gastroenterology practice is functional (idiopathic) dyspepsia,
also referred to as nonulcer dyspepsia [34,35]. Although developed by an
international committee for research purposes, the following definition of
functional dyspepsia (Rome criteria) has clinical utility [34]:
 "Chronic or recurrent abdominal pain or discomfort centered in the upper
abdomen; a duration of ≥one month with symptoms 25 percent of the time (ie,
on seven days or more). No clinical, biochemical, endoscopic or ultrasonographic
evidence of any known organic disease that is likely to explain the symptoms (ie,
acid-peptic or neoplastic disease of the stomach, esophagus or duodenum, or
disease of the pancreas or hepatobiliary system), and no history of major gastric
or intestinal surgery. Patients with a past history of documented chronic peptic
ulcer disease should not be classified as having functional dyspepsia at least
until the relationship between these entities is clarified."

There are no diagnostic tests for functional dyspepsia, and it is difficult to

distinguish ulcer from nonulcer dyspepsia on the basis of the clinical
examination. As a result, the diagnosis is made upon the exclusion of other
causes of dyspepsia. (See "Approach to the patient with dyspepsia".)

Gastric carcinoma — It is important to differentiate between gastric carcinoma

and peptic ulcer at an early stage, when the cancer is operable and potentially
curable. Gastric malignancy infrequently causes chronic dyspepsia. However, the
possibility should be considered, particularly in patients over 45 to 55 years of
age and in those who have the following "alarm symptoms:"

• Unintended weight loss

• Bleeding
• Anemia
• Dysphagia
• Odynophagia
• Hematemesis
• A palpable abdominal mass or lymphadenopathy
• Persistent vomiting
• Unexplained iron deficiency anemia
• Family history of upper gastrointestinal cancer
• Previous gastric surgery
• Jaundice

(See "Clinical features, diagnosis, and staging of gastric cancer" and "Approach
to the patient with dyspepsia".)

Although early gastric cancer is usually asymptomatic, it can present with

dyspepsia that is indistinguishable from peptic ulcer. A new onset of symptoms
or a recent change in pattern are the usual flags that raise concern over possible
neoplasia. In general, compared to advanced disease, early gastric cancer has
fewer associated symptoms and a much better prognosis. (See "Early gastric
cancer".)

A review of published studies noted the following incidence of symptoms in

European patients with early gastric cancer [36]:

• Epigastric pain and/or dyspepsia, similar to peptic ulcer disease — 65 to

90 percent
• Nausea and/or vomiting — 6 to 40 percent
• Anorexia — 12 to 40 percent.

Warning (or alarm) signs or symptoms suggestive of invasive disease, such as

anemia or weight loss, occurred less frequently (5 to 15 percent and 4 to 40
percent, respectively).

Other neoplastic lesions — Other neoplastic processes can mimic peptic

ulcers, presenting with dyspepsia or ulcers, such as gastric lymphoma (see
"Clinical presentation and diagnosis of primary gastrointestinal lymphomas";
leiomyosarcoma; primary gastric [37] and metastatic [38], malignant
melanoma; and metastatic renal cell carcinoma [39].

Drug-induced dyspepsia — Numerous drugs can cause dyspepsia, epigastric

distress, nausea, or vomiting. These include NSAIDs, with or without ulceration,
theophylline, and digitalis. Caffeine, coffee, alcohol, and smoking can also
contribute to symptoms.

Infiltrative or granulomatous diseases — Infiltrative or granulomatous

diseases can present with dyspepsia and occasionally ulceration. Involvement of
the stomach is the most common site of sarcoidosis in the gastrointestinal tract,
almost always occurring in association with pulmonary disease [40-42].
Ulceration resembling peptic ulcer disease can occur with or without
enlargement of mucosal folds. (See "Gastrointestinal sarcoidosis".) Eosinophilic
granuloma and Wegener's granulomatosis [43] can also present in this fashion.
(See "Clinical manifestations and diagnosis of Wegener's granulomatosis and
microscopic polyangiitis" and "Langerhans cell histiocytosis (histiocytosis X,
eosinophilic granuloma)".)

Hypertrophic gastritis (including Menetrier's disease) may present with dyspeptic

symptoms. (See "Hyperplastic gastropathies and other causes of enlarged
gastric folds".)

Crohn's disease — Crohn's disease may involve the stomach or duodenum and
produce symptoms and a radiographic appearance which mimics peptic ulcer
(picture 2). Isolated gastroduodenal Crohn's is uncommon; radiographic
abnormalities are usually present in more distal portions of the duodenum and
the small intestine. (See "Clinical manifestations, diagnosis and prognosis of
Crohn's disease in adults".)

Infections — Gastric and duodenal tuberculosis involving the mucosa can

present with ulceration [44-46]. The diagnosis is generally difficult to make since
superficial biopsies do not detect caseating granulomata, which are often
submucosal, and the acid-fast stain may be negative. Thus, a high level of
suspicion is necessary.

Other infections have also been associated with chronic ulcer:

• Mycobacterium avium intracellulare [47] (see "Overview of

nontuberculous mycobacterial infections in HIV-negative patients")

• Strongyloidiasis can produce upper abdominal pain and nausea; in

addition, gastric ulcer with bleeding has been reported with infiltration in the
ulcerated mucosa [48]. (See "Strongyloidiasis".)

• Giardiasis may produce upper abdominal discomfort, nausea, and

anorexia; these symptoms are often associated with diarrhea and occasionally
evidence of malabsorption (picture 3). Dyspeptic symptoms may persist over
months, interspersed with periods of diarrhea lasting a few days.

Duodenal neoplasia — Duodenal carcinoma is very uncommon, but can

occasionally present with gastrointestinal bleeding or as an apparently benign
ulcer [49,50]. However, most cases present as a mass lesion rather an ulcer.
Localized duodenal lymphoma can also mimic duodenal ulcer and respond to
therapy for a period of time [51].

Miscellaneous — A large number of disorders have been associated with peptic

ulcer disease. (See "Unusual causes of peptic ulcer disease".)

INFORMATION FOR PATIENTS — Educational materials on this topic are

available for patients. (See "Patient information: Peptic ulcer disease" and
"Patient information: Helicobacter pylori infection and treatment".) We
encourage you to print or e-mail these topic reviews, or to refer patients to our
public web site, www.uptodate.com/patients, which includes these and other
topics.

SUMMARY
 • Peptic ulcers may present with a wide variety of symptoms, or may be
completely asymptomatic, sometimes until complications such as hemorrhage or
perforation occur. Many patients complain of upper abdominal discomfort, but
these symptoms are not specific and the differential diagnosis is broad.
• The "classic" symptoms of duodenal ulcer (DU) occur when acid is
secreted in the absence of a food buffer. Food is usually well emptied by two to
three hours after meals, but food-stimulated acid secretion persists for three to
five hours; thus, classic ulcer symptoms occur two to five hours after meals or
on an empty stomach. Symptoms also occur at night, between 11 PM and 2 AM,
when the circadian stimulation of acid secretion is maximal. The ability of alkali,
food, and antisecretory agents to produce relief suggests the role of acid in this
process. Thus, "acid dyspepsia" is a fitting term. Gastric ulcer (GU) has
classically been associated with more severe pain occurring soon after meals,
with less frequent relief by antacids or food.
• Discomfort occurs in the epigastrium in about two-thirds of symptomatic
patients, but may occasionally localize to the right or left upper quadrants or the
hypochondrium [4]. Radiation of pain to the back may occur, but primary back
pain is atypical. Although ulcer pain is often burning, gnawing, or hunger-like in
quality, the discomfort can be vague or cramping. Symptomatic periods lasting a
few weeks followed by symptom-free periods of weeks or months is a pattern
characteristic of classic DU.

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