Gut and Liver, Vol. 11, No. 3, May 2017, pp. 349-357 Review Functional Dyspepsia: Advances in Diagnosis and Therapy Nicholas J. Talley Faculty of Health and Medicine, University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW, Australia Functional dyspepsia (FD) is a common but under-recognized troduodenal region.1 According to the Rome criteria, based on syndrome comprising bothersome recurrent postprandial expert consensus, the prototypical symptoms are bothersome fullness, early satiety, or epigastric pain/burning. Epidemio- recurrent postprandial fullness, inability to finish a normal sized logically, there are two clinically distinct FD syndromes (al- meal (early satiety), epigastric pain or epigastric burning in the though these often overlap clinically): postprandial distress setting of a normal upper endoscopy.2 However, many patients syndrome (PDS; comprising early satiety or meal-related with FD also experience other troublesome symptoms including fullness) and epigastric pain syndrome. Symptoms of gastro- nausea, bloating, belching, and heartburn. esophageal reflux disease overlap with FD more than expect- FD comprises two clinical syndromes which in clinical prac- ed by chance; a subset has pathological acid reflux. The pre- tice can overlap. Postprandial distress syndrome (PDS) is always test probability of FD in a patient who presents with classical meal related and refers to bothersome and frequent early satiety FD symptoms and no alarm features is high, approximately or postprandial fullness. These meal related symptoms are more 0.7. Coexistent heartburn should not lead to the exclusion of common than heartburn and are reported by over 40% of the U.S. FD as a diagnosis. One of the most exciting observations in general population.3 A less common FD syndrome is epigastric FD has been the consistent finding of increased duodenal pain syndrome (EPS) where patients present with recurrent and eosinophilia, notably in PDS. Small bowel homing T cells, bothersome epigastric pain or less commonly epigastric burn- signaling intestinal inflammation, and increased cytokines ing.1 have been detected in the circulation, and elevated tumor necrosis factor-α levels have been significantly correlated EPIDEMIOLOGY with increased anxiety. Postinfectious gastroenteritis is a risk factor for FD. Therapeutic options remain limited and provide In 100 population-based studies comprising over 312,000 only symptomatic benefit in most cases. Only one therapy is subjects, the pooled prevalence of uninvestigated dyspepsia known to change the natural history of FD–Helicobacter py- was 21% (95% confidence interval, 18% to 24%); the risk of lori eradication. Treatment of duodenal eosinophilia is under dyspepsia was increased in females and those with Helicobacter investigation. (Gut Liver 2017;11:349-357) pylori infection, smokers, and nonsteroidal anti-inflammatory drug users.4 Over 75% with dyspepsia postinvestigation includ- Key Words: Functional dyspepsia; Epidemiology ing esophagogastroduodenoscopy (EGD) will have no obvious structural explanation and based on current consensus are ap- INTRODUCTION propriately labelled as having FD. The most frequent finding of sometimes questionable significance is esophagitis (13%) Functional gastrointestinal disorders (FGIDs) are common followed by peptic ulcer (8%); in a meta-analysis of over 5,000 unexplained gastrointestinal (GI) symptom complexes that subjects endoscoped, only peptic ulcer was significantly associ- are thought to arise from different regions of the GI tract, and ated with dyspepsia with a 2-fold increased risk.5 the two most recognized disorders are functional dyspepsia In Olmsted County in the United States, evidence has emerged (FD) and the irritable bowel syndrome (IBS). FD is a clinical that FD is underdiagnosed in clinical practice; only 12.5% with syndrome comprising chronic symptoms arising from the gas- FD symptoms received an FD diagnosis.6 The data suggest pa- Correspondence to: Nicholas J. Talley The Hunter Medical Research Institute, University of Newcastle, Kookaburra Circuit, Newcastle, NSW 2258, Australia Tel: +61-249215855, Fax: +61-240420034, E-mail: [email protected] Received on January 28, 2016. Accepted on May 19, 2016. Published online February 21, 2017 pISSN 1976-2283 eISSN 2005-1212 https://doi.org/10.5009/gnl16055 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 350 Gut and Liver, Vol. 11, No. 3, May 2017 tients with FD symptoms are more likely to be given the label they had meal induced symptoms generally developed symp- gastroesophageal reflux disease (GERD) even if acid suppression toms early (within 15 minutes) after ingestion and fullness and therapy is unsuccessful.6 bloating predominated, while those who self-reported no meal In FD, an increased risk of atopic diseases most notably relationship usually had delayed postprandial symptom induc- asthma has been observed in a general practice database in the tion and pain or burning predominated.20 United Kingdom.7 Atopy may explain the finding of increased An objective test in FD that assesses meal related symptoms upper intestinal eosinophilia in FD, first reported in adults by is the nutrient test meal. A standard approach is after an 8-hour Talley et al.8 Further, an increased risk of autoimmune disease fast, provide 200 mL of a standardized enteral feeding solu- has now been observed based on an extensive analysis of over tion (e.g., Ensure) every 5 minutes up to a cumulative volume 23,000 patients and controls from the U.K. general practice da- of 800 mL; following each 200 mL drink, five key symptoms tabase; rheumatological disease in particular was increased.9 are assessed (fullness, abdominal pain, retrosternal/abdominal FD impacts on quality of life and impaired quality of life is burning, nausea, and regurgitation) using a standardized instru- associated with symptom severity and comorbid depression.10,11 ment on visual analogue scales (0 to 100), and the cumulative The direct and indirect costs of FD because it is a highly preva- symptom score across all symptoms calculated.21,22 The findings lent and chronic condition are enormous. Extrapolating data correlate with gastric motor and sensory dysfunction and are an on FD patients to the U.S. population, it has been calculated in indirect measure of gastric accommodation, but are decreased 2009 the costs of FD were $18.4 billion,12 and other indepen- in old age.21,22 However, the diagnostic utility of a nutrient test dent data support these high cost figures.13,14 However, there is meal has not been investigated in the clinical setting and it no mortality associated with dyspepsia symptoms in the general remains an investigational tool. Irregular meal ingestion and population indicating FD once diagnosed is a benign disorder rapid eating behavior are risk factors for FD perhaps because and repeat EGD usually unhelpful.15 gastroduodenal dysfunction limits normal eating and may even promote weight loss.23,24 DIAGNOSIS 2. Differentiating FD from gastroparesis The diagnosis of FD remains one of exclusion as EGD is A particularly confusing issue yet to be resolved is how to required to exclude peptic ulceration, esophagitis and malig- distinguish gastroparesis from FD. The fundamental problem is nancy.16 The Rome III criteria in terms of distinguishing FD slow gastric emptying occurs in 25% with FD but there is no from structural diseases such as peptic ulceration remain no clear-cut symptom complex associated.25 The U.S. gastroparesis better than previous Rome definitions, with a diagnostic sensi- consortium definition that has been widely applied, namely tivity of 61% and a specificity of 69%, both suboptimal.17 The that gastroparesis refers to upper GI symptoms and slow gastric pretest probability of FD in the patient who presents with classi- emptying is arguably unhelpful, as symptom correlation with cal dyspepsia (fullness, satiety, or epigastric pain) and no alarm slow emptying in this broader patient cohort is modest to poor, features however is high, around 0.7 and therefore a provisional slow gastric emptying on repeat testing is not a very consistent diagnosis in clinical practice can be considered in selected cases. finding, and accelerating gastric emptying with prokinetics fails Arguably the complaint that is the strongest indicator of FD is to accurately parallel symptom response.26 If gastroparesis is early satiety, a very distinctive symptom now linked to a spe- more strictly defined as very slow gastric emptying (3 or more cific duodenal pathology as discussed below.8 Many patients standard deviations from normal), then vomiting and weight with FD present with overlapping symptoms of PDS and EPS loss may be more predictably associated and the true albeit rare although in population-based studies PDS and EPS separate out syndrome apparent.27 more clearly.18,19 3. Confusion with GERD 1. Meal testing Symptoms of GERD overlap with FD as otherwise defined by Meal induced symptoms are an important and increasingly Rome III more than expected by chance; a subset of these over- recognized feature of FD. In a landmark study, a solid test meal lap cases have pathological acid reflux.28 Recent data suggest was ingested by patients with FD who either