Dyspepsia: literature review and evidence for management in primary care

Dyspepsia is a common reason for the clinical encounters in primary care. Two common causes of dyspepsia are gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD). These diseases clinically overlap and may present diagnostic and management challenges in primary care, especially in low resource settings. Proton pump inhibitors, eradication of H. pylori infection and endoscopy form the backbone of management of both diseases. This article reviews current considerations in the diagnosis and management of GERD and PUD in primary care.


Introduction
2][3] It accounts for 5% of visits to family physicians in the US but data is not available for most African countries. 4ere is no universally accepted definition for dyspepsia.Rather, dyspepsia refers to recurrent symptoms that alert the physician to a problem within the upper gastrointestinal tract.These symptoms include upper abdominal pain or discomfort, heartburn, and acid reflux.These symptoms are however non-specific, and alone should not be considered to identify dyspepsia. 5The commonest causes of dyspepsia are: gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD).This article reviews important diagnostic and management considerations in these two common causes of dyspepsia and provides evidence-based management approaches for primary care physicians.

Gastroesophageal reflux disease (GERD)
GERD is a common diagnosis in primary care and most people at one time of their life will suffer from it.Up to 10% of Americans experience daily heartburn and a third report periodic symptoms. 6The American College of Physicians describe GERD as symptoms or complications resulting from the perceived reflux of gastric contents into the esophagus or hypopharynx. 71] The male to female ratio is roughly 1:1 but this can vary widely in clinical subsets of GERD. 9,11,13] Although it utilised a small sample size, a South African study has also found an association between non-acid GERD and squamous cell carcinoma of the esophagus. 16GERD results from three mechanisms 17,18 : • Incompetent lower esophageal sphincter that allows backward movement of acidic gastric content into the esophagus and hypopharynx.
• Poor clearance of refluxed content from the esophagus.Though most people reflux, most do not develop GERD.The persistence of refluxed content is what results in chemical injury to the esophagus.
• Poor gastric emptying resulting in backward spilling of gastric content into the esophagus.
Risk factors for GERD are shown in Table 1. 6However, the literature is not consistent in demonstrating associations with these risk factors.

Clinical presentation
Patients with GERD may present with or without symptoms of esophagitis and may have or not have endoscopic evidence of reflux disease (erosive vs non-erosive).Clinical presentation may also overlap that of other gastrointestinal and pulmonary disorders, that are grouped into esophageal and extraesophageal symptoms -Table 2.
0] Less frequently, there may be non-cardiac chest pain and dysphagia. 19,21A key diagnostic task is to exclude differential diagnoses like angina pectoris, peptic ulcer disease, other causes of esophagitis, asthma and chronic obstructive airway disease. 20,22,23Patients may also present with complications such as ulceration, stricture, dental erosion, Barrett's esophagus and adenocarcinoma of the esophagus -Table 3. [24][25][26][27] These conditions, though uncommon, confer appreciable morbidity and decrease in quality of life. 10,19However, GERD carries minimal risk for mortality (estimated at 1 death per 100,000 patients per year) and most deaths arise from GERD-induced esophageal adenocarcinoma. 10,28he page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd27 Making a diagnosis 17 GERD is a clinical diagnosis.A history of heartburn and/or regurgitation, with or without other symptoms or complications, are the key diagnostic features. 170] However, failure to get relief does not exclude GERD.Heartburn is a perceived burning sensation under the sternum that is associated with meals, recumbency, nocturnal occurrence and is relieved by antacids. 2,6egurgitation is characterised by acid taste in the mouth and results from spontaneous return of gastric contents back into the esophagus or hypopharynx. 9,190][31][32] Red flag symptoms such as anaemia, dysphagia, haematemesis, melaena, persistent vomiting, or unintentional weight loss raise the possibility of esophagitis, stricture or cancer and should prompt immediate further investigation.
Physical examination is usually normal but may reveal extraesophageal signs -Table 2. Confirmatory tests for GERD are usually not required in patients with both heartburn and regurgitation.However, useful investigations include 18,33 : 1. Endoscopy: may assist with diagnosis but is not routine.It is highly recommended for the diagnosis and surveillance of Barrett's esophagus (white males more at risk), excluding complications and other diagnoses -hiatus hernia, stricture, ulcers and cancer.In patients with longstanding symptoms suggestive of Barrett's esophagus, it may be better to perform endoscopy while on treatment.
2. Barium imaging: is rarely used, as endoscopy is of superior diagnostic value and provides direct visualisation and the opportunity for biopsy.However, barium swallow may be useful in patients with dysphagia, as a complement to endoscopy.
If endoscopy is unrevealing and symptoms persist despite twice daily PPIs, further testing may be required, but guidelines differ as to the sequence.Further testing may include: 3. Manometry: to evaluate esophageal contractions and lower esophageal sphincter function.

Ambulatory reflux pH or impedance-pH monitoring:
where symptoms correlate with esophageal acid, and pH or impedance-pH testing to detect both acid and non-acid reflux events.

5.
Esophageal capsule endoscopy: is a potential screening and diagnostic tool.It is less invasive and has moderate sensitivity and specificity.
Patients with GERD who have longstanding or relapsing symptoms, who are unresponsive to PPIs, who have red flag symptoms that suggest complicated disease (Table 2) require further investigations because up to 60% of GERD patients may have minimal changes on white light endoscopy, narrow band imaging. 34utine testing for H. pylori is not recommended by GERD guidelines, although eradicating H. pylori infection has been found to improve quality of life of patients with GERD, regardless of treatment outcome. 35

Management
A management approach is summarised in the Figure 1.Lifestyle modification and acid suppression form the basis of treatment with most patients requiring prolonged therapy.
• Lifestyle modification: Advice should focus on healthy eating (avoiding coffee, chocolate and fatty foods), weight reduction, smoking cessation, avoiding alcohol, avoiding meals 3-4 hours before sleep and raising the head of the bed when sleeping. • Acid suppression: Response to antacids or PPIs is often diagnostic of GERD. 18Some evidence exists that on-demand PPI may not be inferior to continuous maintenance regimen. 38etails of drug treatment and important considerations are shown in Figure 1.When drug treatment fails, or patient is unable to adhere to PPI treatment, surgical management may be considered.PPI treatment on a long term may be a risk for bone fractures, hypomagnesemia, community-acquired pneumonia and decrease efficacy of clopidogrel.Except for the last, robust data is lacking. 39 • Medication review: For drugs that may aggravate dyspepsia, e.g.calcium antagonists, nitrates, theophyllines, bisphosphonates, corticosteroids and NSAIDS.
• Surgical interventions 39 : GERD patients who respond to PPIs are most likely to benefit from anti-reflux surgery.Patients who have non-acid reflux symptoms are less likely to respond to PPIs and may also benefit from anti-reflux surgery.Patients with Barrett's esophagus with low grade dysplasia may be amenable to fundoplication while those with high grade dysplasia may need ablation, mucosal resection or even esophagectomy.Patients with stricture may require repeated esophageal dilatation.Referral to a gastroenterology unit should also be considered if symptoms are unresponsive to treatment, in those who are young and require PPIs life-long, those non-adherent to PPIs and those with large or rolling hiatus hernia with obstructive symptoms.
• Psychosocial support: GERD is associated with various psychosocial factors which could decrease the quality of life.Chronic stress, anxiety and depression are common associations and are often considered risk factors for GERD.
Persons living with GERD may experience relational stress and even impairment at the workplace, and certain working conditions, such as night shift work and other life style factors, may also be risk factors for erosive esophagitis. 40ne of the big challenges marriage counsellors face when dealing with couples where one lives with GERD is the patient's self-awareness of halitosis or potential halitosis, as well as the partner's perception which can be accepting or not of the condition, especially with regard to its effects on intimate interactions.Halitosis in a patient with GERD is both a stomatological and psychological problem. 41It is important that a biopsychosocial assessment is done to offer specialised psychosocial support to the patients who may need additional help.

Peptic ulcer disease (PUD)
PUD is a common cause of dyspepsia and has a lifetime prevalence between 8 and 14%. 5 While most PUD patients are their active and productive years, most patients requiring admission for complications are older than 65 years.Table 3 shows the risk factors associated with PUD; the two commonest are H. pylori infection which is highly prevalent in South Africa (77.6%) 42,43 and the widespread use of NSAID. 24,44

Clinical presentation
PUD most commonly presents with chronic or recurrent upper abdominal pain that may be related to meals and is often nocturnal. 45The absence of pain, however, does not exclude the diagnosis, especially in the elderly and those on NSAIDS.Often, the only feature on physical examination is central epigastric tenderness, which is uncommonly experienced as 'pointing tenderness' .Less frequent presentations include severe pain radiating to the back in duodenal ulcers that penetrate posteriorly into the pancreas, or associated diarrhea in Zollinger-Ellison syndrome. 45A minority present with complications such as upper gastrointestinal bleeding, intestinal perforation and gastric outlet obstruction (up to 15%, 7% and 3% of patients respectively). 5Complications may occur without previous symptoms, especially in patients taking NSAIDS.Vomiting and early satiety should raise the suspicion of pyloric stenosis.Red-flag symptoms such as weight loss, anemia, vomiting, early satiety, dysphagia and age > 50 years should raise the possibility of upper gastrointestinal cancer and require referral for endoscopy and biopsy. 24,46

Making a diagnosis
Apart from obtaining a positive history of NSAID use, PUD can be made in a person with upper abdominal pain by: 1. Endoscopy: This is the gold standard test, being more sensitive and specific for PUD than barium radiography. 45t will show an ulcer in the stomach or proximal duodenum, confirm perforation and enable histology and biopsy for H. pylori test and cancer.However, tests may give false-negative results in patients taking proton-pump inhibitors, bismuth, or other medications.Switching to an H2RA for 2 weeks prior to endoscopy is an alternative, especially in patients without redflag features.In the absence of red flags or failure of patient to respond, endoscopy is often unnecessary in primary care and is only indicated if symptoms persist.However, in patients with red-flags or who are > 50 years of age, have family history of gastric carcinoma or previous stomach surgery, an endoscopy should be ordered immediately. 24,46 A positive test for H. pylori: South Africa has high prevalence of H. pylori infection (> 10-15%) and in the absence of redflags, the test and treat approach is recommended.42,43 Validated, non-invasive tests such as breath and stool antigen tests are more accurate than antibody tests and are recommended.If tests are not easily available in a high prevalence area, H. pylori infection should be assumed, and empiric eradication treatment given.False positive results are high in low prevalence populations and routine H. pylori testing is not recommended, except when the patient fails to respond to empiric treatment or relapses rapidly on stopping acid suppression treatment.

Other investigations 45 :
• Stool haem test for occult blood • Full blood count in the case of anemia or bleeding  The page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd29

Differential diagnosis
Table 5 lists differential diagnoses that need to be considered, especially cardiac and biliary diseases.

Management
Management approaches are summarised in Figure 1.The goals of therapy are to relieve symptoms, heal ulcers, eliminate the underlying cause if possible and treat complications. 42,47,48: Generally, leads to ulcer healing with less than 20% of patient experiencing recurrence.Success of treatment is mainly limited by antibiotic resistance and patient adherence.Fourteen days of triple therapy (a PPI plus 2 antibiotics) is recommended as this duration significantly increases H. pylori eradication.However, 7 days of quadruple therapy (PPI plus bismuth plus 2 antibiotics) and 10 days of sequential therapy (i.e., 5 days of a PPI plus amoxicillin, Un-investigated dyspepsia -defined broadly as recurrent epigastric pain, heartburn, acid regurgitation, with or without bloating, nausea and vomiting.

H. pylori eradication
In people < 55 years old with no alarm symptoms or signs, empirical full-dose PPI for 4-8 weeks.(Time to heal: 4 weeks in H. pylori negative duodenal ulcers, 8 weeks in H. pylori negative gastric ulcers, and 4-8 weeks in GERD).
Long term use of PPIs increases the risk of community acquired pneumonia and C. difficile in hospitalised patients, osteoporosis, reduced efficacy of clopidogrel and absorption of iron.Therefore, those who need long term treatment of dyspepsia symptoms should be advised to reduce their use of PPIs in a stepwise fashion (avoid reflex gastritis), down to the lowest effective dose, and to try 'as-needed' use to manage their own symptoms.Self-treatment with antacids and alginate therapy should be reattempted.Surgery (open or laparoscopic fundoplication) generally reserved for those with good response to PPIs but not wanting to take long-term therapy or poor tolerance of therapy.*Post-surgical complications in up to 20% of patients.Patients with GERD who are obese may benefit from a bariatric procedure rather than from an anti-reflux procedure.
Figure 1: Algorithm for the management of dyspepsia in primary care 8,39,45,52 followed by 5 days of a PPI plus clarithromycin and tinidazole) may address the problem of antibiotic resistance and provide improved eradication rates.There are no trials that have confirmed the superiority of the modified sequential therapy over standard triple therapy. 49 populations with low prevalence, H. pylori eradication may be omitted and an empiric trial of acid suppression with a PPI for 4-8 weeks is an acceptable initial management.In patients that respond, treatment is stopped after 4-8 weeks, and if symptoms reoccur, another course of treatment is justified.
However, if initial acid suppression fails after 2-4 weeks, the class of medications or dosing should be changed, H. pylori tested and treated before sending for endoscopy.

Acid suppression:
Many drug classes of gastroprotectants are effective. 50PPIs have simple dosing regimen, inhibit gastric acid secretion to a greater extent and heal peptic ulcers more rapidly than Histamine 2 receptor antagonists (H2RA).They are the drug of choice.

Conclusion
GERD and PUD impose significant negative effects on the quality of life of patients with these diseases.While empiric treatment with PPIs suffices for most patients with GERD, patients with PUD in developing countries, including South Africa, need H. pylori eradication treatment and acid suppression therapy.Endoscopy is not routinely done in primary care for GERD and PUD but patients with poor response or recurrence after treatment, those who present with complications or red-flags, Barrett's esophagus and those who meet other criteria for endoscopy, should be referred for one.• Endoscopy should not be routinely done for uncomplicated GERD.However, patients with Barrett's esophagus and those with complications of GERD need endoscopy.
• Lifestyle modification and acid suppression with PPI are cornerstone of GERD management.
• Surgical interventions are only indicated in patients with complications and those unresponsive to management.
• In primary care, endoscopy is not routinely performed for uncomplicated PUD.However, patients aged > 50 years, those with recurrence, complications, gastric ulcer, family history of gastric cancer, history of gastric surgery and red-flag symptoms should have endoscopy.• Empiric eradication of H. pylori infection and acid suppression with PPIs are the key strategies in the management of uncomplicated PUD.
• In high prevalence settings such as South Africa, test (using non-invasive tests) and treat approach should be employed for H. pylori eradication.
If resources are limited, H. pylori infection should be assumed to be present and empiric triple therapy treatment given.
• Routine testing and eradication of H. pylori is not recommended in low prevalence settings.

Table 1 :
39sk factors associated with GERD39 Obesity NSAIDS (not shown to cause GERD, but may contribute to esophagitis/ strictures) Pregnancy (progesterone relaxes lower esophageal sphincter) Alcohol (evidence mixed, > 7 drinks per week may increase risk) Smoking Dietary factors (inconclusive and limited evidence regarding portion size and food types including fatty foods, caffeine, carbonated drinks, citrus, chocolate, spicy foods)

Table 3 :
The differential diagnosis of GERD and PUD

Table 4 :
43,45factors associated with PUD43,45 NSAID use (More commonly cause gastric ulcers.Relief with antacids may support diagnosis, but not sensitive or specific.Increased risk associated with age > 60, previous history PUD, dose and duration, concurrent H. pylori or corticosteroid use.Low dose aspirin may increase risk.Alcohol (lack of good evidence) Smoking (associated with 23% of all ulcers) Psychological stress (lack of good evidence) Incidence and complications increase with age.Previous history/family history of PUD (related to persistent H pylori infection) Admission to Intensive Care Unit (stress ulcers) May be indicated for patients with chronic ulcer unresponsive to 2nd line drug treatment, intestinal perforation, upper gastrointestinal bleeding and outlet obstruction.The last three are life threatening and require immediate resuscitation and referral to a gastroenterology unit.

Table 5 :
Key messages• Co-existing heartburn and regurgitation have high diagnostic accuracy for GERD.Response to an empiric treatment with PPI is confirmatory.