**4. Evaluating a patient with dyspepsia**

#### **4.1. Symptom-based diagnosis**

The introduction of Rome criteria and Rome process was a milestone in the management of FGIDs. However, the high turnover of Rome criteria is a testimony to the fact that symptombased diagnosis has limitations. Symptoms may be perceived differently within different cultures and languages. It has been recommended that the current Rome III questionnaire be translated into local languages [12]. Symptoms are poor predictors of FD and significant overlaps are often seen with functional disorders including functional heartburn and irritable bowel syndrome. [13-22].

One of the difficulties encountered in evaluating a patient with dyspepsia is that symptoms are nonspecific and cannot accurately differentiate an organic process from a functional disorder. Neither clinical impression, nor computer models incorporating patient demograph‐ ics, risk factors, history items, and symptoms can distinguish between organic and functional disease in patients referred for endoscopic evaluation of dyspepsia( [23].

of alarm features makes the likelihood of finding important structural causes for dyspepsia very low. However, a meta-analysis found that negative predictive value of alarm features was poor (6%) [55]. Worse still, subjects with organic pathologies may also have FD. [56]

Is Functional Dyspepsia Idiopathic? http://dx.doi.org/10.5772/56620 17

Testing for Helicobacter pylori in dyspepsia may be used to select the subgroup of dyspeptic patients who have Helicobacter-related dyspepsia. The Asian consensus guideline posits that this is strictly not a form of FD. Proponents of this argue that gastritis can now be identified easily with advanced endoscopic techniques, and that Helicobacter pylori-dyspepsia is a form of post-infectious FD [2]. Exclusion of Helicobacter pylori infection should be an important part of diagnostic exercise in parts of the world where the burden of infection is high [2]. The effect of Helicobacter pylori eradication on the amelioration of symptoms in patients with FD has been evaluated in several large, well-designed, randomized controlled trials, but the results were conflicting [57-61]. Eradication of Helicobacter pylori in FD appears to improve dyspeptic

The accommodation reflex is a vagally mediated volume response of the upper part of the stomach after a meal. After ingestion of food, the gastric fundus spontaneously dilates and begins to store food [62]. Impairment of this accommodation reflex is known to correlate well with dyspeptic symptoms especially early satiation [63, 64]. Enhanced perception of physio‐ logical signals arising from the stomach (visceral hypersensitivity) is considered a hallmark of functional gastrointestinal disorders including FD [65]. Such hypersensitivity can be repro‐ duced acutely by different types of mechanical gastric distension [66, 67]. However, it has not been possible to conclusively identify the site and mechanisms underlying visceral hypersen‐

Gastric barostat is gold standard for investigating gastric accommodation. It is however, invasive, time-consuming and uncomfortable to patients. Newer techniques include single photon emission computed tomography (SPECT) [64], 2- and 3- dimensional gastric ultra‐ sound [68] and magnetic resonance imaging [69]. These are noninvasive but their high cost,

Drinking test is simpler [70]. It is based on the assumption that gastric volume is reduced with impaired accommodation and therefore limits the drinking volume. This test has been validated against the gastric barostat but the reproducibility is limited due to differences in types of drink and rates of drinking. In general these tests are poorly associated with dyspeptic symptoms and cannot predict a response to treatment in FD. Therefore they are not yet

Gastroparesis is a syndrome characterized by delayed gastric emptying in absence of me‐ chanical obstruction. Its causes include diabetes mellitus, post-surgical and idiopathic [71].

symptoms more in the Chinese population than in Western populations [2]

**4.5. Gastric accommodation and visceral hypersensitivity**

sophistication and radiation exposure make them less attractive.

**4.4. Helicobacter pylori testing**

sitivity in FD.

available for routine clinical use.

**4.6. Gastric emptying**

There is also a high degree of overlap between FD symptoms and those of gastroparesis [1, 24-29]. In FD, the predominant sensation of early satiety was found to be closely associated with impaired accommodation, although it was also present in more than 30% of patients with delayed gastric emptying [26]. Nausea and vomiting, thought to be cardinal symptoms of gastroparesis, are present in at least 20-50% of patients with FD [25, 30, 31]. Epigastric pain thought to be a cardinal symptom of FD is also present in up to 90% of patients with gastro‐ paresis (GP) [32, 33]. Generally, common symptoms of gastric neuromuscular dysfunction are nonspecific and cannot reliably predict the underlying pathophysiology [24-26, 34]. Further‐ more, recent research data indicate that rapid gastric emptying has been implicated in functional dyspepsia symptoms, especially in the postprandial distress syndrome [35, 36]. Enhanced antral contractility, decreased duodenal feedback inhibition and impaired accom‐ modation represent the underlying mechanisms [37, 38].

The current approach is to view functional dyspepsia and idiopathic gastroparesis, not as completely distinct disorders, but as a broad, continuous spectrum, with significant overlap. It has been proposed that these 2 entities be reclassified under the umbrella term of functional dyspepsia with or without disordered gastric emptying [39], to enable clinicians and research‐ ers to focus on predominant symptoms expressed by the majority of patients with this disorder.

#### **4.2. Age**

Older age is an important predictor for the presence of organic disease. The American Gastroenterological Association recommends proceeding directly to endoscopy in patients older than 55 years [40], however, there has been debate about a lower cut-off age of 35 to 45 years in men [41]. The optimal age threshold for endoscopy is unclear but 55 years seems a reasonable cut-off because cancer is rare in younger patients but no age threshold is absolute [42] Age specific thresholds to trigger endoscopic evaluation may differ by sex and locality [43, 44] Prompt endoscopy in patients over 50 years regardless of alarm status has been shown to increase the proportion of curable cases of upper gastrointestinal malignancies by as much as 30% [45-47], but the cost-effectiveness of initial endoscopy in this age group for improving survival of cancer patients is uncertain [47, 48]. Distinct upper gastrointestinal malignancy incidence rates and various distributions of its topographical types in different populations [49-52], as well as differences in Helicobacter pylori infection rates [53, 54] could partly explain the variable results.

#### **4.3. Alarm features**

Alarm features include unintended weight loss, family history of upper gastrointestinal cancer, gastrointestinal bleeding, progressive dysphagia, odynophagia, unexplained iron deficiency anemia, persistent vomiting, palpable mass, lymphadenopathy and jaundice. These features are useful in identifying high risk patients who need early endoscopy. The absence of alarm features makes the likelihood of finding important structural causes for dyspepsia very low. However, a meta-analysis found that negative predictive value of alarm features was poor (6%) [55]. Worse still, subjects with organic pathologies may also have FD. [56]

#### **4.4. Helicobacter pylori testing**

disorder. Neither clinical impression, nor computer models incorporating patient demograph‐ ics, risk factors, history items, and symptoms can distinguish between organic and functional

There is also a high degree of overlap between FD symptoms and those of gastroparesis [1, 24-29]. In FD, the predominant sensation of early satiety was found to be closely associated with impaired accommodation, although it was also present in more than 30% of patients with delayed gastric emptying [26]. Nausea and vomiting, thought to be cardinal symptoms of gastroparesis, are present in at least 20-50% of patients with FD [25, 30, 31]. Epigastric pain thought to be a cardinal symptom of FD is also present in up to 90% of patients with gastro‐ paresis (GP) [32, 33]. Generally, common symptoms of gastric neuromuscular dysfunction are nonspecific and cannot reliably predict the underlying pathophysiology [24-26, 34]. Further‐ more, recent research data indicate that rapid gastric emptying has been implicated in functional dyspepsia symptoms, especially in the postprandial distress syndrome [35, 36]. Enhanced antral contractility, decreased duodenal feedback inhibition and impaired accom‐

The current approach is to view functional dyspepsia and idiopathic gastroparesis, not as completely distinct disorders, but as a broad, continuous spectrum, with significant overlap. It has been proposed that these 2 entities be reclassified under the umbrella term of functional dyspepsia with or without disordered gastric emptying [39], to enable clinicians and research‐ ers to focus on predominant symptoms expressed by the majority of patients with this disorder.

Older age is an important predictor for the presence of organic disease. The American Gastroenterological Association recommends proceeding directly to endoscopy in patients older than 55 years [40], however, there has been debate about a lower cut-off age of 35 to 45 years in men [41]. The optimal age threshold for endoscopy is unclear but 55 years seems a reasonable cut-off because cancer is rare in younger patients but no age threshold is absolute [42] Age specific thresholds to trigger endoscopic evaluation may differ by sex and locality [43, 44] Prompt endoscopy in patients over 50 years regardless of alarm status has been shown to increase the proportion of curable cases of upper gastrointestinal malignancies by as much as 30% [45-47], but the cost-effectiveness of initial endoscopy in this age group for improving survival of cancer patients is uncertain [47, 48]. Distinct upper gastrointestinal malignancy incidence rates and various distributions of its topographical types in different populations [49-52], as well as differences in Helicobacter pylori infection rates [53, 54] could partly explain

Alarm features include unintended weight loss, family history of upper gastrointestinal cancer, gastrointestinal bleeding, progressive dysphagia, odynophagia, unexplained iron deficiency anemia, persistent vomiting, palpable mass, lymphadenopathy and jaundice. These features are useful in identifying high risk patients who need early endoscopy. The absence

disease in patients referred for endoscopic evaluation of dyspepsia( [23].

16 Dyspepsia - Advances in Understanding and Management

modation represent the underlying mechanisms [37, 38].

**4.2. Age**

the variable results.

**4.3. Alarm features**

Testing for Helicobacter pylori in dyspepsia may be used to select the subgroup of dyspeptic patients who have Helicobacter-related dyspepsia. The Asian consensus guideline posits that this is strictly not a form of FD. Proponents of this argue that gastritis can now be identified easily with advanced endoscopic techniques, and that Helicobacter pylori-dyspepsia is a form of post-infectious FD [2]. Exclusion of Helicobacter pylori infection should be an important part of diagnostic exercise in parts of the world where the burden of infection is high [2]. The effect of Helicobacter pylori eradication on the amelioration of symptoms in patients with FD has been evaluated in several large, well-designed, randomized controlled trials, but the results were conflicting [57-61]. Eradication of Helicobacter pylori in FD appears to improve dyspeptic symptoms more in the Chinese population than in Western populations [2]

#### **4.5. Gastric accommodation and visceral hypersensitivity**

The accommodation reflex is a vagally mediated volume response of the upper part of the stomach after a meal. After ingestion of food, the gastric fundus spontaneously dilates and begins to store food [62]. Impairment of this accommodation reflex is known to correlate well with dyspeptic symptoms especially early satiation [63, 64]. Enhanced perception of physio‐ logical signals arising from the stomach (visceral hypersensitivity) is considered a hallmark of functional gastrointestinal disorders including FD [65]. Such hypersensitivity can be repro‐ duced acutely by different types of mechanical gastric distension [66, 67]. However, it has not been possible to conclusively identify the site and mechanisms underlying visceral hypersen‐ sitivity in FD.

Gastric barostat is gold standard for investigating gastric accommodation. It is however, invasive, time-consuming and uncomfortable to patients. Newer techniques include single photon emission computed tomography (SPECT) [64], 2- and 3- dimensional gastric ultra‐ sound [68] and magnetic resonance imaging [69]. These are noninvasive but their high cost, sophistication and radiation exposure make them less attractive.

Drinking test is simpler [70]. It is based on the assumption that gastric volume is reduced with impaired accommodation and therefore limits the drinking volume. This test has been validated against the gastric barostat but the reproducibility is limited due to differences in types of drink and rates of drinking. In general these tests are poorly associated with dyspeptic symptoms and cannot predict a response to treatment in FD. Therefore they are not yet available for routine clinical use.

#### **4.6. Gastric emptying**

Gastroparesis is a syndrome characterized by delayed gastric emptying in absence of me‐ chanical obstruction. Its causes include diabetes mellitus, post-surgical and idiopathic [71]. Delayed gastric emptying occurs in 23-59% of patients with FD [72]. Research has shown that delayed gastric emptying may be related to postprandial fullness and vomiting with symp‐ toms being more frequently found in female patients than in males [73-75]. Other studies have failed to confirm any difference in the occurrence of FD symptoms between patients with normal or delayed gastric emptying [76, 77]

The new drug, Acotiamide, an acetylcholinesterase inhibitor is promising and has been shown to be efficacious and safe in the elimination of meal-related FD symptoms [86]. Though not yet approved for treatment of FD, it holds high promise as no adverse events were recorded.

Eosinophils and mast cells may be specifically recruited to the duodenum, altering sensation and motility [87]. The duodenum, which is often ignored in the search for pathophysiologic explanations for FD may be key to the symptom experience in FD. Mast cells induce eosinophil migration and eosinophils activate mast cells [88]. Degranulation from mast cells and eosino‐ phils leads to neural stimulation and smooth muscle contraction, which in turn results in gastrointestinal symptoms, such as abdominal pain and bloating [89]. While a significant increase in mast cells has not been observed in the duodenum of patients with FD, duodenal eosinophilia in FD has been described [90, 91]. This finding is exciting, because, in patients undergoing endoscopy, duodenal biopsy is safe and easy to perform. This finding also has a

Helicobacter pylori testing Useful in identifying patients who have Helicobacter pylori

Gastric accommodation test Several tests have been developed. Invasiveness, high cost,

Gastric emptying test Scintigraphy is currently available for clinical use. Empirical treatment Not a viable option because of poorly understood

Duodenal eosinophilia Initial studies promising. Larger studies needed.

Chemical hypersensitivity tests Several candidate chemicals at various stages of

**Table 2.** Summary of structural and functional abnormalities of the gastrointestinal tract in functional dyspepsia

In conclusion, dyspepsia is a very common clinical problem globally. Majority of patients with this problem have FD, defined traditionally as dyspepsia in which investigations, including upper gastrointestinal endoscopy fail to reveal a structural, biochemical or other pathophy‐ siologic reason for the symptom. The pathophysiology of FD remains poorly understood.

Recent information from research shows that there are structural and physiological changes in FD that may hold the key to further understanding of the pathogenesis of this disease. These

Duodenal lipid infusion Duodenal hypersensitivity to lipids consistently obtained

challenges

from most studies

development

– associated dyspepsia

patient discomfort and radiation exposure remain

Is Functional Dyspepsia Idiopathic? http://dx.doi.org/10.5772/56620 19

pathogenesis and lack of effective treatment

potential therapeutic implication which further research would unravel.

**Putative test/Abnormality Comments/Pitfalls**

Duodenal acid infusion Results controversial

**5.1. Duodenal eosinophilia**

Assessment of gastric emptying is commonly performed for such indications as nausea, vomiting and dyspepsia. However, there is a poor correlation of symptoms to observed abnormalities.

Techniques of gastric emptying include scintigraphy, which is the standard method in clinical practice, but is associated with radiation exposure. Newer non-invasive methods include wireless motility capsule and gastric emptying breath testing. Ultrasound, single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) are pre‐ dominantly research tools.

#### **4.7. Chemical hypersensitivity test**

The duodenum is implicated in the pathophysiology of FD. Duodenal hypersensitivity and abnormal responses to various substances have been observed in FD.

**Duodenal hypersensitivity to lipid:** Duodenal infusion of lipid in subjects with FD increased gastric distension and symptoms in a dose-dependent fashion [78]. Symptom relief is achieved with administration of Loxiglumide, a cholecystokinin A receptor antagonist and this suggests that cholecystokinin release following a lipid stimulus is the mediator of gastric hypersensi‐ tivity in FD [79] Using cholecystokinin infusion as a challenge test is appealing [80] but is not yet available for clinical use.

Buspirone challenge test [81] is another chemical hypersensitivity test. This chemical is a serotonin 1A agonist that acts at the hypothalamic level to stimulate prolactin release. The extent of prolactin release following Buspirone challenge is a reliable measure of central 5HT sensitivity which can be impaired in patients with FD [82, 83].

**Duodenal sensitivity to acid infusion:** Studies on the presence of duodenal hypersensitivity to acid in FD patients and its role in the pathophysiology of FD remain controversial. Samson et al [84] reported that duodenal acid infusion induced nausea in a subset of FD patients, but not in healthy controls, suggesting the presence of duodenal hypersensitivity to acid in FD patients. However, other studies found that dyspeptic symptoms such as nausea could be induced by duodenal acidification in healthy volunteers [85].
