Dyspepsia
Clinical Practice Guideline: Diagnosis and Management of Dyspepsia and Peptic Ulcer Disease
1.0 Introduction and Scope
Dyspepsia represents one of the most common and complex symptom presentations encountered in both primary care and gastroenterology. Its management requires a nuanced understanding of a broad differential diagnosis, ranging from benign functional disorders to life-threatening malignancies. This clinical practice guideline is designed to provide healthcare professionals with a clear, evidence-based, and systematic framework for the evaluation and management of patients presenting with dyspeptic symptoms.
The term "dyspepsia" is derived from its Greek etymology: dys- (meaning 'bad' or 'difficult') and pepsis (meaning 'digestion'). It is a symptom complex, not a final diagnosis, characterized by chronic or recurrent discomfort centered in the epigastrium. The core symptoms include bothersome postprandial fullness, early satiation, epigastric pain, and epigastric burning.
The primary objectives of this guideline are threefold: to standardize the diagnostic approach to uninvestigated dyspepsia, to provide clear criteria for differentiating between functional and organic etiologies, and to outline rational, stepwise treatment algorithms for both functional dyspepsia and confirmed peptic ulcer disease. By adhering to this structured pathway, clinicians can enhance diagnostic accuracy, optimize resource utilization, and improve patient outcomes.
Therefore, a formal classification system is the essential foundation for subsequent diagnostic and therapeutic decisions.
2.0 Defining and Classifying Dyspepsia
The strategic importance of classifying dyspepsia cannot be overstated. A proper initial classification into either functional or organic etiologies serves as the cornerstone of effective and efficient patient management, directing the clinician toward appropriate testing, targeted therapies, and realistic prognostic counseling.
2.2 Functional Dyspepsia (FD)
Functional Dyspepsia (FD) is diagnosed in patients who meet specific symptom criteria in the absence of an identifiable structural cause. It is the most common cause of chronic dyspepsia, accounting for approximately two-thirds of cases.
The formal Rome IV diagnostic criteria for Functional Dyspepsia require the presence of one or more of the following symptoms for the last three months, with symptom onset at least six months prior to diagnosis:
- Bothersome postprandial fullness
- Early satiation
- Epigastric pain
- Epigastric burning
Crucially, a definitive diagnosis of FD requires that there be no evidence of organic, systemic, or metabolic disease that is likely to explain the symptoms, typically confirmed by a normal upper endoscopy.
FD is further categorized into two primary subtypes based on the predominant symptom pattern:
- Postprandial Distress Syndrome (PDS): Characterized by meal-induced symptoms, specifically bothersome postprandial fullness and/or early satiation.
- Epigastric Pain Syndrome (EPS): Characterized by epigastric pain or burning that is not exclusively related to meals and may occur during fasting.
2.3 Organic Dyspepsia
Organic dyspepsia is defined as dyspeptic symptoms that are caused by an identifiable structural, metabolic, or pathological condition. The diagnostic investigation is focused on identifying and treating this underlying cause.
Common causes of organic dyspepsia include:
- Peptic Ulcer Disease (PUD), including both gastric and duodenal ulcers
- Gastric or esophageal cancer
- Erosive gastritis or duodenitis
- Gastroesophageal Reflux Disease (GERD)
- Pancreatobiliary diseases (e.g., chronic pancreatitis, cholelithiasis)
Medication-Induced Dyspepsia
A significant subset of organic dyspepsia is directly attributable to medications that injure the upper gastrointestinal mucosa or alter its function. Common offending agents include:
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Aspirin
- Bisphosphonates
- Iron supplements
Moving from this classification framework, the next step involves the practical diagnostic evaluation of the patient.
3.0 Diagnostic Evaluation of Dyspepsia: A Stepwise Approach
A systematic, stepwise diagnostic approach is critical to avoid unnecessary procedures while ensuring the timely identification of serious pathology. The following clinical pathway is recommended for the evaluation of a patient presenting with dyspepsia.
3.2 Initial Assessment and Identification of Alarm Features
The first step in the clinical encounter is to confirm the symptom profile and screen for features suggestive of serious underlying disease. It is essential to differentiate true dyspepsia from other conditions. Specifically, clinicians must note that isolated heartburn and regurgitation are the cardinal symptoms of GERD, not dyspepsia.
The following "Alarm Features" are critical indicators that mandate prompt and direct endoscopic evaluation:
- Age ≥60 with new-onset symptoms
- Unintentional weight loss
- Progressive dysphagia or odynophagia
- Anemia or signs of gastrointestinal bleeding (e.g., melena)
- Persistent vomiting
- A palpable abdominal mass or lymphadenopathy
- A family history of upper gastrointestinal cancer
3.3 Diagnostic Pathway for Patients with Alarm Features (or Age ≥60)
The first and most appropriate diagnostic step is an Esophagogastroduodenoscopy (EGD) with biopsies for any patient with one or more alarm features, or for any patient aged 60 or older presenting with new-onset dyspepsia, even in the absence of other alarm features. Empiric therapy in this population is inappropriate and may delay the diagnosis of a malignancy.
3.4 Diagnostic Pathway for Patients without Alarm Features (and Age <60)
In younger patients without alarm features, a more conservative initial approach is recommended to balance efficacy with cost and procedural risk. The preferred strategy involves noninvasive testing and empiric therapy in a sequential manner:
- H. pylori Testing: The initial step should be noninvasive testing for Helicobacter pylori using either a urea breath test or a stool antigen assay. If the test is positive, the patient should receive a course of eradication therapy.
- Empiric PPI Trial: If H. pylori testing is negative, or if symptoms persist following successful eradication, the next step is a 4- to 8-week trial of a once-daily Proton Pump Inhibitor (PPI).
- Referral for EGD: An EGD is warranted only if symptoms remain refractory to both H. pylori eradication (if applicable) and an empiric PPI trial.
In a patient with persistent symptoms meeting Rome IV criteria, a normal EGD confirms the diagnosis of Functional Dyspepsia, reinforcing the clinical axiom: Dyspepsia + Normal Endoscopy = Functional Dyspepsia.
This structured diagnostic process allows for the confident identification of Functional Dyspepsia, a condition that requires a distinct management approach.
4.0 Management of Functional Dyspepsia (FD)
Managing Functional Dyspepsia is often challenging and requires a multimodal, stepwise approach that prioritizes patient education and reassurance. The goal is symptom control and improved quality of life, as there is no curative therapy. A strong therapeutic alliance is essential.
The following management ladder details the recommended sequence of interventions for FD:
- Step 1: Foundational Therapies Initial management should focus on patient education about the benign, chronic nature of FD. Reassurance can significantly reduce health-related anxiety. Lifestyle and dietary modifications, including consuming smaller, more frequent, low-fat meals and avoiding patient-specific triggers (e.g., NSAIDs, alcohol, caffeine), form the foundation of care.
- Step 2: H. pylori Eradication Even in the absence of peptic ulcers, evidence shows that eradicating H. pylori infection can provide durable symptom relief in a subset of patients with FD. The Number Needed to Treat (NNT) to achieve symptom improvement in one patient is approximately 14. Therefore, all patients with FD should be tested for and, if positive, treated for H. pylori.
- Step 3: Acid Suppression A 4- to 8-week therapeutic trial of a PPI is a reasonable next step for patients who remain symptomatic. While effective for some, particularly those with Epigastric Pain Syndrome, it is important to note that twice-daily dosing has not been shown to be more effective than standard once-daily dosing for FD.
- Step 4: Neuromodulators and Prokinetics (for Refractory FD) For patients with symptoms refractory to the above measures, therapy should be tailored to the FD subtype:
- For Epigastric Pain Syndrome (EPS): Low-dose Tricyclic Antidepressants (TCAs), such as nortriptyline or amitriptyline, are the recommended first-line neuromodulators due to their proven efficacy in visceral pain syndromes. Tricyclic antidepressants have demonstrated superior efficacy compared to Selective Serotonin Reuptake Inhibitors (SSRIs) for visceral pain in FD; therefore, SSRIs are not recommended as first-line neuromodulators for this condition.
- For Postprandial Distress Syndrome (PDS): A trial of a prokinetic agent is appropriate. In the United States, buspirone is used off-label for its ability to enhance gastric accommodation; the recommended regimen is 10 mg three times daily for a 4-week trial.
- Mirtazapine can be a useful agent, particularly in patients who have associated weight loss or nausea.
- Step 5: Adjunctive and Complementary Therapies For patients with persistent symptoms, adjunctive therapies can be considered. Psychological therapies, such as Cognitive Behavioral Therapy (CBT), have shown benefit. Certain herbal preparations (e.g., Iberogast/STW-5 and combination peppermint-caraway oils) have demonstrated modest efficacy and can be considered as complementary options.
While FD is common, it is crucial to manage organic causes of dyspepsia, such as Peptic Ulcer Disease, with distinct and definitive protocols.
5.0 Diagnosis and Management of Peptic Ulcer Disease (PUD)
Peptic Ulcer Disease is a major cause of organic dyspepsia characterized by mucosal ulceration in the stomach or duodenum. Its management hinges on an accurate diagnosis, eradication or removal of the underlying cause, and effective strategies to promote healing and prevent recurrence.
5.2 Definition and Etiology
A peptic ulcer is formally defined as a mucosal break of 5 mm or greater in diameter that penetrates the muscularis mucosae, occurring in a region of the gastrointestinal tract exposed to gastric acid.
The vast majority of PUD is caused by one of two primary etiologies:
- Helicobacter pylori infection
- Use of NSAIDs or aspirin
A rare but important cause of refractory or multiple ulcers is Zollinger-Ellison Syndrome (ZES), a condition of profound acid hypersecretion caused by a gastrin-producing tumor.
5.3 Distinguishing Gastric vs. Duodenal Ulcers
Although both are forms of PUD, gastric ulcers (GU) and duodenal ulcers (DU) have distinct clinical features, risks, and management requirements.
Feature | Gastric Ulcer (GU) | Duodenal Ulcer (DU)
Typical Pain Pattern | Epigastric pain that is typically worse with meals. | Epigastric pain that is often relieved by meals, recurring 2-5 hours later.
Malignancy Risk | Malignancy must always be considered; gastric cancer can present as an ulcer. | Almost never malignant.
Biopsy Requirement | Mandatory biopsy of the ulcer edge is required at diagnosis. | Not routinely needed if the appearance is classic.
Key Complication Risks | Bleeding (commonly from the left gastric artery). | Perforation (anterior ulcers) or bleeding (posterior ulcers, from the gastroduodenal artery).
5.4 Management Protocol for PUD
The management of PUD follows a clear, cause-directed protocol.
5.4.1 Initial Steps
All patients with a diagnosis of PUD must be tested for H. pylori infection.
5.4.2 H. pylori Eradication
If the test is positive, the patient must undergo a 14-day course of eradication therapy (e.g., Bismuth quadruple therapy or Concomitant therapy).
- Confirmation of eradication is mandatory. This must be performed with a urea breath test or stool antigen test no sooner than four weeks after completion of therapy and after PPIs have been held for at least two weeks.
5.4.3 NSAID-Induced Ulcers
If H. pylori is negative and the patient has a history of NSAID use, the offending agent should be discontinued if clinically possible. The clinician should initiate therapy with a proton pump inhibitor for a duration of 8 weeks for duodenal ulcers or 8 to 12 weeks for gastric ulcers. If NSAIDs must be continued, long-term co-therapy with a PPI is required.
5.4.4 Follow-Up Endoscopy
The need for follow-up endoscopy differs significantly by ulcer location:
- Gastric Ulcers: A repeat EGD after 8-12 weeks of therapy is mandatory for all gastric ulcers to document complete healing and definitively rule out an underlying malignancy.
- Duodenal Ulcers: A repeat EGD is not routinely required for uncomplicated duodenal ulcers if symptoms have resolved with therapy.
While most cases of PUD respond well to standard therapy, clinicians must be prepared to manage special and refractory clinical scenarios.
6.0 Management of Special and Refractory Cases
While most cases of dyspepsia and PUD follow the standard diagnostic and therapeutic pathways, clinicians must remain vigilant for atypical presentations or refractory disease, as these often signal a different or more complex underlying pathology.
6.2 The Non-Healing Gastric Ulcer
A non-healing, or refractory, gastric ulcer is defined as an ulcer that persists after 8 to 12 weeks of appropriate, high-dose PPI therapy. This clinical scenario should be approached with a high index of suspicion for malignancy.
The stepwise management approach is as follows:
- First, verify patient compliance with PPI therapy and confirm the cessation of all potential risk factors, including NSAIDs, aspirin, and smoking.
- Perform a repeat EGD with multiple, large-volume biopsies taken from both the ulcer edge and the ulcer base to aggressively rule out malignancy.
- If the ulcer remains unhealed despite these measures, even with repeat negative biopsies, it must be treated as malignant until proven otherwise. The next best step is referral for surgical evaluation and possible resection.
6.3 Zollinger-Ellison Syndrome (ZES)
Zollinger-Ellison Syndrome is a rare cause of PUD that should be suspected in specific clinical contexts. The key indicators that should raise suspicion for ZES include:
- Multiple peptic ulcers
- Ulcers located in atypical locations (e.g., the jejunum)
- Peptic ulcer disease that is refractory to standard therapy
- Concurrent severe diarrhea
The diagnosis of ZES is confirmed by the concurrent findings of a significantly elevated fasting serum gastrin level and a low gastric pH (e.g., <4.0).
7.0 Key Clinical Pearls and Practice Pitfalls
This final section synthesizes the most critical, high-yield points from the guideline to reinforce best practices and help clinicians avoid common diagnostic and management errors.
- Always perform an EGD in patients with new-onset dyspepsia who are age ≥60 or have any alarm features.
- Distinguish GERD from Dyspepsia: Do not misclassify patients with primary heartburn/regurgitation.
- All Gastric Ulcers require biopsy and follow-up endoscopy to confirm healing and rule out malignancy, regardless of initial appearance or size.
- Duodenal Ulcers are almost always benign and do not require routine biopsy or follow-up endoscopy if symptoms resolve.
- Recognize PUD complication patterns: Anterior DU perforation; Posterior DU bleeding.
- Functional Dyspepsia is a diagnosis of exclusion: It can only be diagnosed after a normal EGD in a patient with persistent symptoms.
- Select neuromodulators based on FD subtype: TCAs are superior to SSRIs for epigastric pain (EPS).
- A non-healing Gastric Ulcer mandates surgical referral, even with negative biopsies.
- Suspect ZES with refractory/multiple/distal ulcers and diarrhea.
