Clinical Manifestation of Peptic Ulcer Disease

CLINICAL MANIFESTATION OF

PEPTIC ULCER DISEASE

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.

CLINICAL MANIFESTATIONS

A pragmatic definition of "dyspepsia" is when the clinician suspects that symptoms are coming from the upper GI tract. 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.

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. 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. In one study, for example, a self-report questionnaire examined the three common dyspeptic symptom patterns. 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.

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.

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. 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).

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. 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.

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).

• 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.

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. 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. 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. 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.

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.

Giant ulcers are frequently complicated by bleeding and posterior penetration and, depending on location, by pyloric obstruction. One study, comparing 62 patients with giant gastric ulcers (defined as ≥3 cm) to 476 patients with smaller gastric ulcers, 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. 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.

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 and in association with NSAID consumption. 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). 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. Giant duodenal or prepyloric ulcers have been reported in association with end-stage renal failure, orthotopic lung transplantation, and Crohn's disease. The ulcer symptoms may be the presenting complaint in patients with Crohn's disease. 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, 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. 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.

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.

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. 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.

No clinical features clearly distinguish postbulbar ulcers, although a higher rate of complications has been reported. 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. 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. 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. 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. 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.

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. Although developed by an international committee for research purposes, the following definition of functional dyspepsia (Rome criteria) has clinical utility :

"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.

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

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.

A review of published studies noted the following incidence of symptoms in European patients with early gastric cancer :

• 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; leiomyosarcoma; primary gastric and metastatic, malignant melanoma; and metastatic renal cell carcinoma.

Drug-induced dyspepsia — Numerous drugs can cause dyspepsia, epigastric distress, nausea, or vomiting. These include NSAIDs, with or without ulceration, Theophylline, and Digitalis. Caffein, 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. Ulceration resembling peptic ulcer disease can occur with or without enlargement of mucosal folds. Eosinophilic granuloma and Wegener's granulomatosis can also present in this fashion.

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

Crohn's disease — Crohn's disease may involve the stomach or duodenum and produce symptoms and a radiographic appearance which mimics peptic ulcer. Isolated gastroduodenal Crohn's is uncommon; radiographic abnormalities are usually present in more distal portions of the duodenum and the small intestine.

Infections — Gastric and duodenal tuberculosis involving the mucosa can present with ulceration. 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.

• Strongyloidiasis can produce upper abdominal pain and nausea; in addition, gastric ulcer with bleeding has been reported with infiltration in the ulcerated mucosa.

• Giardiasis may produce upper abdominal discomfort, nausea, and anorexia; these symptoms are often associated with diarrhea and occasionally evidence of malabsorption. 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. 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.

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

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. 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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