The Diagnosis and Treatment of Peptic Ulcer Disease and Its Complications: A Review

Author:
Claire Wunker, MD

Citation:
Wunker C. The diagnosis and treatment of peptic ulcer disease and its complications: a review. Consultant. 2018;58(1):10-16.

ABSTRACT: Peptic ulcer disease (PUD) is a common condition with a significant impact on patients’ quality of life. Although many patients present with characteristic gnawing epigastric pain, many others—particularly elderly patients—are asymptomatic and present with gastrointestinal (GI) tract bleeding, perforation, and malignancy. The most common risk factors are Helicobacter pylori infection and nonsteroidal anti-inflammatory drug use, both of which lead to a breakdown of the mucosal barriers that protect GI tract tissues from acidic gastric contents. Although acid suppression is the most common treatment for most cases of PUD, accurate determination of the need for antibiotic therapy is essential. This review discusses the pathophysiology, epidemiology, clinical manifestations, diagnosis, treatment, and complications associated with PUD.

Abdominal pain is the most common gastrointestinal (GI) tract concern among US outpatients, accounting for more than 11 million annual visits.¹ Approximately 500,000 people develop peptic ulcers each year in the United States.² Peptic ulcer disease (PUD) accounts for significant morbidity and mortality, with patients’ quality of life being adversely affected. It is important for primary care providers to recognize the need for further evaluation and treatment, especially with antibiotics, for patients who are at risk for Helicobacter pylori infection to prevent further complications. These patients can present with symptoms of dyspepsia, including epigastric pain, nausea, and nighttime awakening from pain; however, none of these symptoms are pathognomonic for PUD. Further questioning about risk factors and, possibly, H pylori testing should be conducted with appropriate follow-up treatment.

This review aims to identify the pathophysiology, epidemiology, clinical manifestations, diagnosis, treatment recommendations, and possible complications associated with PUD.

NEXT: Pathophysiology

PATHOPHYSIOLOGY

PUD can affect multiple areas of the GI tract, including the esophagus, stomach, and duodenum. Ulcers generally result from a disruption of the mucosal lining of the GI tract or overproduction of hydrochloric acid. The disruption most commonly results from H pylori infection and the use of nonsteroidal anti-inflammatory drug (NSAIDs), which also act synergistically.³ This decreases the protection of the stomach and the first portion of the duodenum from the acidic contents, which are then able to erode into the muscularis mucosae.^4,5 Erosion into the muscularis mucosae differentiates ulcers from the more superficial damage seen in gastritis or erosions.

Alternatively, peptic ulcers can form in hypersecretory states such as a gastrinoma, carcinoid, and mastocytosis. Other damage or abnormal cell replication that can cause ulceration includes that associated with malignancy, radiation therapy, chemotherapy, and bisphosphonate therapy.⁶ Furthermore, erosions and ulcerations can occur in cases of severe stress with hypoperfusion.⁷

Although the general mechanism for ulcer formation in normosecretory states is the same as in hypersecretory states, the underlying insults are different. H pylori bacteria are pH-sensitive and rely on mucosal infiltration to survive. The bacteria produce urease, which creates an ammonia-rich environment that is cytotoxic to the epithelium. Additionally, local inflammation causes further damage and weakens the protective factors.⁸ NSAIDs act by inhibiting cyclooxygenase, which leads to decreased levels of prostaglandins, which in turn stimulates mucus formation, bicarbonate production, and epithelialization.^2,8,9 The acidity of the drugs can also adversely affect the hydrophobic properties of the mucosal gel layer.⁹

H pylori infection occurs in up to 80% of duodenal ulcers and up to 60% of gastric ulcers, while NSAID use accounts for more than 50% of peptic ulcers.^8,10 With better treatment and eradication of H pylori, more idiopathic peptic ulcers are being diagnosed. PUD that is not related to either H pylori infection or NSAID use is increasing, with up to 39% of cases being idiopathic.^11-16 Risk factors other than H pylori and NSAIDs for developing peptic ulcers include smoking (proportional to the number of cigarettes smoked) and obesity.^10,17,18 Smoking also increases the risk of recurrence.¹⁰ Protective factors are more controversial; one study found that moderate wine use was protective,¹⁷ but no definitive data exist on the relationship between alcohol consumption and ulcer formation.¹⁰ Another study found that physical exercise in combination with H pylori was protective.¹⁸

NEXT: Epidemiology, Clinical presentation, Differential Diagnosis

EPIDEMIOLOGY

Approximately 500,000 people across all ages develop peptic ulcers annually in the United States, with the highest prevalence in middle-aged adults.^2,10 PUD is a leading cause of morbidity nationally and internationally.¹⁹ It leads to decreased quality of life and affects 1 in 25 people worldwide, with a lifetime prevalence of 10%.^8,17,20 The growing use of NSAIDs has increased the risk for developing drug-induced ulcers.

A greater risk of H pylori-related ulcers occurs internationally, which is likely related to poor sanitation and crowded living conditions.^19,21 However, the prevalence of H pylori-related ulcers is also increasing nationally, with 80% of duodenal ulcers and 60% of gastric ulcers in the United States related to these bacteria.⁸ Although 50% of the population is colonized with H pylori, only 5% to 10% will develop ulcers.⁸

PUD accounts for a low disease burden nationally, but this still equates to $6.7 billion in annual expenditures based on the most recent estimates for treatment of this disease.²² This amount increased annually from 1996 to 2013.²² The financial implications can also be seen in the market for antacid medications, which account for 3 of the top 11 drugs by branded US retail sales,¹ accounting for $10 billion in annual sales.²³

CLINICAL PRESENTATION

The presentation of peptic ulcers can vary broadly. Abdominal pain, specifically in the epigastric region, and heartburn are the most common findings in patients with PUD.^10,20 The pain is usually described as gnawing or burning. 

Many patients, especially elderly patients, may have very limited symptoms, with up to 30% of patients older than 60 years having no pain.^10,24,25 Symptoms that are significant predictors of PUD include heartburn or acid reflux and nausea.¹⁷ However, even with symptoms of heartburn, most patients do not have erosive esophagitis.²⁶ The pain is often relieved with food and antacids in duodenal ulcers but worsened with food in gastric ulcers.⁶ Duodenal ulcers are more typically associated with pain at night.¹⁰ More concerning symptoms include loss of appetite and weight loss.²

The location of an ulcer can also affect the presentation. Ulcers located in the region of the pylorus can cause obstructive symptoms such as bloating, nausea, and vomiting due to progressive scarring or edema.¹⁰ Physical examination findings are nonspecific.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of epigastric pain is broad, especially since the pain can present as nonlocalized. Commonly mistaken for PUD are esophagitis, gastroesophageal reflux, gastritis, and gastroenteritis. Less commonly, it can be mistaken for pancreatitis, cholelithiasis, inflammatory bowel disease, irritable bowel syndrome, and, rarely, abdominal aortic aneurysm, acute coronary syndrome, or hepatitis.²⁷ For the most part, imaging and laboratory testing are able to distinguish these causes from PUD. In cases of gastritis, esophagitis, or gastroesophageal reflux, more-specific diagnostic testing may be required.

NEXT: Diagnosis

DIAGNOSIS

The diagnosis of ulcers is generally divided into 2 categories: patients younger than 55 years with no alarming symptoms, and patients 55 years or older and/or patients with alarming symptoms. Older patients and patients with concerning symptoms require esophagogastroduodenoscopy (EGD).² This endoscopic technique allows visualization of the first part of the duodenum and is highly sensitive and specific for PUD. While computed tomography and ultrasonography are useful in diagnosing other causes of abdominal pain, they have little usefulness in visualizing PUD. The most useful imaging study would be fluoroscopy, but it is less sensitive and less specific than EGD. EGD is more than 90% sensitive and specific, while diatrizoate contrast radiography has 80% to 90% sensitivity for duodenal ulcers.² Radiography should be used when EGD is not possible or when obstruction is suspected.

Younger patients generally undergo testing for H pylori with a urea breath test or a stool antigen test, since either is as effective at detecting H pylori infection as EGD but without the need for an invasive procedure.^28-30 In addition, patients with a previous history of PUD, gastric mucosa-associated lymphoid tissue lymphoma, or endoscopically resected gastric cancer should undergo testing for H pylori.³¹ In patients who begin taking long-term NSAIDs, testing for H pylori is recommended. For patients who have been on long-term aspirin therapy, the use of testing could decrease the risk of bleeding.³¹ Patients should also be counseled on NSAID use, to smoking cessation, alcohol consumption, and illicit drug use.

H pylori infection can be detected in several ways (Table 1).^32-37 Active testing, including urea breath tests and stool antigen tests, decreases the unnecessary treatment of patients who previously had been infected but are now healthy but who still would have positive serology test results.²⁸

If diagnosed by EGD, ulcers can be staged using the 6-category Sakita staging system.^38,39

In ulcers that are in the distal duodenum or that are refractory to treatment, further investigation is warranted to look for gastrinoma or malignancy.¹⁰

NEXT: Treatments

TREATMENT

With any ulcer type, a patient’s modifiable risk factors should be addressed, including smoking and alcohol consumption.¹⁰ Acid suppression is included in all ulcer treatment approaches.

H pylori-related ulcers. The first-line treatment is a triple-drug therapy of clarithromycin, a proton-pump inhibitor (PPI), and amoxicillin for 14 days. In patients with penicillin allergy, metronidazole may be substituted for amoxicillin, unless the patient has had previous macrolide exposure, in which case bismuth quadruple therapy should be instituted. Bismuth quadruple therapy is also recommended in areas where resistance to clarithromycin is known to be less than 15%. Bismuth quadruple therapy consists of a PPI, bismuth, tetracycline, and a nitroimidazole for 10 to 14 days.³¹ Concomitant therapy for 10 to 14 days with a PPI, clarithromycin, amoxicillin, and a nitroimidazole is also a recommended first-line approach. These treatments are summarized in Table 2.³¹ Alternative first-line treatments are listed in Table 3.³¹

Predictors of successful eradication include the choice of regimen, patient adherence, and sensitivity of the H pylori strain.³¹ Previously, active ulcers and younger age were independent predictors of eradication.^40,41 Eradication rates rarely reach 90%, and more than 1 course may be needed for eradication.³¹

H pylori eradication therapy is superior at healing duodenal ulcers to no therapy and to ulcer-healing drugs. However, eradication therapy was not found to be superior in gastric ulcers.⁴⁰ Additionally, gastric ulcers differed in eradication rates based on their initial staging, while duodenal ulcers had statistically similar levels of eradication regardless of ulcer stage.⁴¹

Recently, a new type of acid-suppression medication, a potassium-competitive acid blocker, has been tested and has yielded promising results, with significantly higher eradication rates than PPIs with the same antibiotics.⁴² This novel drug could change treatment regimens, but for now it has not been approved by the Food and Drug Administration (FDA) for H pylori eradication. The current FDA-approved treatments include clarithromycin triple therapy combinations and Pylera, a combination of bismuth subcitrate, tetracycline, and metronidazole, plus a PPI.

Probiotics have been used as an adjunct to triple or quadruple therapy and have been shown to decrease antibiotic-associated adverse effects, specifically diarrhea.^43,44

NSAID-related ulcers. In patients on long-term NSAID treatment who develop ulcers, the first step is to stop the offending agent if possible. If not, the mainstay of treatment is with acid suppression, primarily with PPIs, which are superior to other forms of acid suppression.⁴⁵ If a patient will be starting long-term therapy with NSAIDs, PPI prophylaxis can be started simultaneously.^5,46 This approach leads to reduced GI tract adverse events, but there is no difference in symptomatic ulcers.⁴⁷ Overall ulcer rates are significantly decreased with a combination of famotidine and ibuprofen, but this regimen does not reduce the risk of adverse events except for dyspepsia.⁴⁸

Other options include the use of protective agents such as misoprostol, histamine H₂-receptor antagonists, and selective cyclooxygenase-2 (COX-2) inhibitors. However, the use of COX-2 inhibitors has been associated with an increased rate of cardiovascular events, and as such a cost-benefit analysis is necessary before starting or changing medications. Per the American College of Gastroenterology, patients who are at a low cardiovascular risk level may use any of the treatments mentioned above for moderate or high GI risk levels. For high cardiovascular risk, PPI prophylaxis should be used unless the GI risk is also high, in which case an alternative therapy should be chosen.⁴⁹ Table 4 lists the recommended acid-suppression drugs for the treatment of ulcers.⁵⁰

Non-H pylori– and non-NSAID–related ulcers. This category has yet to be heavily researched; however, prevalence studies indicate that it covers a growing number of ulcers in the United States. It is a diagnosis of exclusion after H pylori, NSAIDs, and gastrinoma or other malignancy have been ruled out as causative factors by EGD and negative biopsy findings.⁸ These patients are managed primarily with PPIs on a continuous basis.⁴⁶

NEXT: Surgery, Follow-up care

SURGERY

The rate of surgical procedures for PUD has been declining, but highly selective or parietal cell vagotomy is still used in rare cases resistant ulcers.^10,51 Duodenal ulcers are more likely to be operated on.⁵² In one study, most ulcers requiring operations were duodenal ulcers.⁵³

The reasons for surgery included perforation (35% of cases), obstruction (30%), chronic disease (28%), and bleeding (7%).⁵³ In cases that require resection of part of the stomach, drainage is via gastroduodenostomy (Billroth I procedure) or gastrojejunostomy (Billroth II procedure).¹⁰

FOLLOW-UP CARE

Follow-up for PUD varies with ulcer location, response to treatment, H pylori infection status, and ulcer complications.⁵⁴ Patients who have gastric ulcers that were biopsied at the time of diagnosis or who have duodenal ulcers, who have responded well to treatment, and who have had no complications generally require no monitoring.⁵⁴ Patients with gastric ulcers that were not biopsied generally should have an EGD 6 to 8 weeks after starting treatment to rule out cancer.⁵⁴ Any ulcer that presented with complications also should be monitored with EGD 6 to 8 weeks after starting treatment.⁵⁴ 

Patients who are diagnosed with H pylori-induced ulcers should have eradication testing performed 4 weeks after treatment with a urea breath test or a stool antigen test. Blood test results will remain positive for H pylori and cannot be used to confirm eradication.⁵⁴

NEXT: Complications

COMPLICATIONS

Because many patients, especially elderly patients, can be completely asymptomatic, complications from ulcers (eg, hemorrhage, perforation, obstruction, malignancy, ulcer recurrence, postoperative problems) can be the first presenting symptom. Risk factors include NSAID use (including aspirin), H pylori infection, and ulcer size of 1 cm or greater.⁵⁵ Duodenal location of the ulcer, shock, and delayed treatment are associated with increased mortality.^52,55 Readmission after diagnosis has been increasing and is more likely in rural locations, with duodenal ulcers, and in elderly patients.⁵²

Elderly patients. Because they often are symptomatic and often have comorbidities, elderly patients can present with ulcer complications and have a significant mortality risk.⁵⁵ They are also more likely to have dementia, which has not been shown to increase mortality but does increase length of stay and cost to treat.⁵⁶ One concern in elderly patients with PUD is their increased risk for osteoporosis.⁵⁷ PPIs have been shown to be related to the occurrence of fractures, but one recent study found that long-term PPI use is not associated with changes in bone mineral density.⁵⁸

Hemorrhage. Hemorrhage is the most common complication of PUD.¹⁰ It affects from 50 to 170 per 100,000 people each year in the United States, with the elderly at highest risk.⁵⁹ Approximately 50% of all upper GI bleeds are due to PUD.⁶ Since many patients are otherwise asymptomatic, bleeding is the initial manifestation in almost one-third of patients.²⁰ As with all upper GI bleeds, symptoms include hematemesis, melena, hematochezia, weakness, palpitations, and syncope.¹⁰

Risk factors for bleeding include H pylori infection and the use of NSAIDs, including aspirin. In addition, H pylori infection and concurrent use of NSAIDs is synergistic in increasing bleeding risk. This synergistic effect is not seen with H pylori and aspirin.⁶⁰ 

In patients who have H pylori-related ulcers, eradication of the organism is more efficient the earlier that appropriate antibiotic treatment is started following the bleed.⁴¹ Additionally, bleeding duodenal ulcers are at a higher risk of mortality and reintervention compared with gastric ulcers.⁶¹

Perforation. Although perforation is less common than hemorrhage, it carries a poor prognosis, with a mortality rate of 6% to 14%.⁶² It has a worldwide incidence of 7 to 10 per 100,000 population.⁸ No difference in mortality has been reported between duodenal and gastric ulcers,⁶¹ but elderly patients and patients with comorbidities are at higher risk for perforation.⁶²

Patients with ulcer perforations present with severe abdominal pain, guarding, and rebound tenderness and can progress to shock. Treatment is with emergency surgery. Occasionally, confined perforation occurs, and medical treatment may be tried before surgery.¹⁰

Obstruction. Chronic ulcers can lead to scarring that, depending on location, can cause blockage. Obstruction can occur with ulcers in the pyloric channel and is also possible with ulcers in the duodenum. In acute ulcers, edema of the surrounding tissue can also cause obstructive symptoms. Obstructive symptoms can include bloating, nausea, and vomiting. The treatment approach is endoscopy to identify the cause of obstruction, and acid suppression for active ulcers or balloon dilation if chronic scarring is found to be the cause.

Malignancy. PUD increases the risk of gastric cancer.⁶³ Other risk factors for developing gastric malignancy in persons with PUD include age, sex, ulcer location, ulcer-associated complications, H pylori infection, and the NSAID use.⁶³ If malignancy is suspected, biopsy of the ulcer should be performed.

Recurrent disease. Recurrence is related to continuation of H pylori infection, NSAID use, and smoking, and thus these risk factors should eradicated if possible.^10,46 Eradicating the H pylori infection reduces the ulcer recurrence rate from 50% to less than 10%.^10,40 Patients who have continued ulceration after treatment for H pylori should undergo bacterial resistance testing, especially if treatment was with clarithromycin triple therapy, since some areas of the United States have resistance rates greater than 15%.^31,46 A newer quadruple therapy consisting of a PPI, bismuth, metronidazole, and amoxicillin (instead of traditional bismuth quadruple therapy, which contains tetracycline) showed noninferiority in patients with 2 or more previous treatment failures, with fewer adverse events.⁶⁴ 

In patients on long-term NSAIDs who develop peptic ulcers, long-term PPI therapy should be continued.⁴⁶ Ulcers that are not related to H pylori infection or NSAID use have a higher risk of recurrence.⁶⁵

The ulcer recurrence rate is 2% to 5% after gastric resection and 5% to 12% after highly selective vagotomy.¹⁰ In these patients, treatment is generally with PPIs or histamine H₂-receptor antagonists. Patients who continue to have PUD despite treatment should be reassessed for gastrinoma and H pylori infection and should undergo testing to confirm that vagotomy has resulted in sufficient gastric destimulation.

Postsurgical complications. After surgical procedures, patients may experience symptoms such as weight loss, anemia, malnutrition, dumping syndrome, gastroparesis, and ulcer recurrence.¹⁰ Depending on the procedure, associated symptoms can be very similar to those of bariatric procedures that decrease the size of the stomach and cause early satiety. Additionally, gastrojejunostomy can lead to malabsorption and malnutrition. And, the unwell feeling caused by dumping syndrome (eg, postprandial sweating, weakness, nausea, vomiting, palpitations) can lead patients to avoid food, leading to weight loss. To prevent postsurgical weight loss, patients should be encouraged to eat small, frequent meals.

Vagotomy can affect gastric motility, leading to gastroparesis and its associated signs and symptoms. Anemia caused by deficient intake of iron or vitamin B₁₂ can be prevented with iron supplementation and intramuscular B₁₂ injections in patients who have undergone total gastrectomy.¹⁰ 

Claire Wunker, MD, is a general surgery resident at Saint Louis University Hospital in Saint Louis, Missouri.

NEXT: References

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