Functional Dyspepsia: A Review of the Symptoms, Evaluation, and Treatment Options Kimberly N. Harer, MD, ScM, and William L. Hasler, MD Dr Harer is a clinical lecturer and Dr Abstract: The community prevalence of dyspepsia ranges from Hasler is a professor in the Division of 20% to 40%, and dyspepsia accounts for 3% to 5% of primary care Gastroenterology in the University of visits. Dyspepsia symptoms include epigastric pain, epigastric burn- Michigan Health System in Ann Arbor, ing, postprandial fullness, early satiety, epigastric bloating, nausea, Michigan. and belching. Functional dyspepsia is diagnosed when an organic etiology for the symptoms is not identified. Diagnostic symptom- Address correspondence to: based criteria are defined by Rome IV. Functional dyspepsia is Dr William L. Hasler further subclassified into postprandial distress syndrome and University of Michigan Health System epigastric pain syndrome based on the predominance of post- 3912 Taubman Center, SPC 5362 prandial bloating and fullness vs epigastric pain. Evaluation of Ann Arbor, MI 48109 Tel: 734-936-4780 functional dyspepsia is driven by patient age and the presence of Fax: 734-936-7392 red-flag symptoms, such as patients over age 60 years or those with E-mail: [email protected] anemia undergoing evaluation with esophagogastroduodenoscopy. Helicobacter pylori infection should be excluded in all patients. Treatment options include proton pump inhibitors, neuromodu- lators, and prokinetics; however, the evidence supporting these therapies is weak, and the response rate is less than robust. he diagnosis and treatment of functional dyspepsia is often clinically challenging due to factors such as the heterogene- ity of upper gastrointestinal symptoms and the generalized Tpoor response to currently available treatment options. This article defines functional dyspepsia, discusses known and proposed patho- physiologic mechanisms, and outlines a recommended approach to the evaluation and treatment of the disorder. Definition and Clinical Presentation Dyspepsia symptoms include a constellation of upper gastrointesti- Keywords nal complaints, such as belching, postprandial fullness, early satiety, Epigastric pain, epigastric burning, early satiety, epigastric pain, and epigastric burning. Functional dyspepsia is diag- postprandial fullness, nausea, Helicobacter pylori, nosed when an organic etiology for the symptoms is not identified. peptic ulcer disease The disorder is defined by Rome IV criteria and subclassified into 66 Gastroenterology & Hepatology Volume 16, Issue 2 February 2020 FUNCTIONAL DYSPEPSIA Rome IV Criteria for Functional Dyspepsia • Presence of ≥1 symptom(s) of postprandial fullness, early satiety, epigastric pain, or epigastric burning • No evidence of structural disease that could explain the symptoms PDS EPS Postprandial fullness or early satiety Epigastric pain and/or burning ≥1 day(s)/ ≥3 days/week for the past 3 months and week for the past 3 months and onset onset ≥6 months before diagnosis ≥6 months before diagnosis PDS (38%) Overlap EPS (27%) PDS/EPS (35%) Symptoms Symptoms • Early satiety • Epigastric pain • Bloating • Epigastric burning • Nausea • Vomiting/retching • Decreased appetite Figure 1. Rome IV criteria for functional dyspepsia and its subclassifications. EPS, epigastric pain syndrome; PDS, postprandial distress syndrome. postprandial distress syndrome and epigastric pain syn- the inherent heterogeneity in symptoms as well as the sig- drome (Figure 1).1 Of patients with functional dyspepsia, nificant overlap in symptoms with other disorders, such as approximately 38% are classified with postprandial dis- gastroparesis, irritable bowel syndrome, and gastroesoph- tress syndrome, 27% are classified with epigastric pain ageal reflux disease. One study demonstrated that more syndrome, and 35% meet criteria for both.2 Dyspepsia than 50% of patients with functional dyspepsia with a patients often report a range of upper gastrointestinal normal pH study reported heartburn and regurgitation.4 symptoms,3 and this complex presentation is further In a study published by the National Institutes of Health complicated by the fact that patients use terms such as Gastroparesis Clinical Research Consortium, patients heartburn or indigestion to describe epigastric pain or with functional dyspepsia and idiopathic gastroparesis burning. Despite the Rome IV definition, diagnosis of were essentially clinically indistinguishable. Other studies functional dyspepsia often remains challenging due to have demonstrated that more than 25% of patients who Gastroenterology & Hepatology Volume 16, Issue 2 February 2020 67 HARER AND HASLER were diagnosed with functional dyspepsia had delayed approximately 40% have impaired gastric accommoda- gastric emptying,5 and 86% of patients with idiopathic tion.15 Research has also demonstrated impaired gastric gastroparesis met functional dyspepsia symptom criteria.6 emptying in patients with functional dyspepsia5; however, There is growing support for the thought that functional there is significant debate regarding whether functional dyspepsia and gastroparesis share pathophysiologic dyspepsia and gastroparesis are separate entities or if mechanisms and represent a spectrum of disorders driven they are part of a spectrum of gastric neuromuscular by duodenogastric neuromuscular dysfunction. Thus, it dysfunction disorders. This debate is largely driven by is crucial to complete a thorough history and physical evidence showing that patients with symptoms suggestive examination of the patient when working to identify the of gastroparesis (eg, early satiety, nausea, vomiting, and most likely etiology of the patient’s symptoms. For exam- postprandial fullness) in the setting of a normal gastric ple, predominant nausea and vomiting symptoms point emptying study are clinically indistinguishable from toward gastroparesis, and predominant postprandial right patients with the same symptoms and impaired gastric upper quadrant pain places a pancreaticobiliary etiology emptying.16 Impaired gastric accommodation has also higher on the differential diagnosis. been associated with increased transient lower esophageal sphincter relaxations, and the increased occurrence of Epidemiology of Dyspepsia these relaxations has been proposed as an explanation of the overlap between dyspepsia and gastroesophageal The community prevalence of dyspepsia is typically reflux disease symptoms within this patient population.17 quoted in the range of 20% to 40%, and the disorder accounts for 3% to 5% of primary care visits.7-12 Of Duodenal Acid Exposure, Dysmotility, and patients with investigated dyspepsia, approximately 70% Inflammation have negative endoscopic studies and approximately There is preliminary evidence concerning the presence 50% to 60% are subsequently classified as functional of increased postprandial duodenal acid exposure in dyspepsia.12,13 Admittedly, estimating the prevalence of functional dyspepsia patients with prominent nausea functional dyspepsia is challenging due to variable diag- symptoms.18 In addition, duodenal motility and bolus nostic criteria used in prevalence studies, the overlap in clearance impairment have been induced by instilling acid symptoms with other disorders, and inconsistent inter- into the duodenum, raising concern that duodenal acid– pretation of dyspepsia symptoms. Risk factors include driven pathology may contribute to dyspepsia symptoms female sex, increasing age, Helicobacter pylori infection, in a subset of patients. high socioeconomic status, smoking, and nonsteroidal There is growing evidence regarding the role of anti-inflammatory drug use. duodenal inflammation and duodenal eosinophilia in functional dyspepsia. Duodenal inflammation, and in Etiology of Functional Dyspepsia particular duodenal eosinophilia, has been seen in up to 40% of patients with functional dyspepsia.19-21 A mean The etiology of dyspepsia has been poorly defined; how- eosinophil count of 49 eosinophils per high-power field ever, numerous pathophysiologic mechanisms, most of was associated with a diagnosis of functional dyspep- which are directed at gastroduodenal pathways, have sia in one study19; however, data are lacking regarding been proposed to explain the disorder. Many mecha- normative values. The cause of duodenal eosinophilia is nisms are currently being investigated as potential causes unknown, but increased duodenal permeability, mast cell of functional dyspepsia symptoms. Given the number of disorders, and smoking are proposed to be contributing potentially unidentified etiologies for dyspepsia symp- factors. toms and the association of the word functional with The phenomenon of postinfectious irritable bowel a lack of an organic cause for symptoms, we cautiously syndrome due to bowel inflammation has been expanded use the term functional dyspepsia to describe dyspepsia to include postinfectious dyspepsia as a potential cause symptoms without an identified organic etiology. of functional dyspepsia.22 A systematic review and meta- analysis of 19 studies demonstrated a mean prevalence Gastric Neuromuscular Dysfunction of functional dyspepsia after acute gastroenteritis at Gastric neuromuscular dysfunction, including delayed approximately 10%, with an odds ratio for development gastric emptying, impaired gastric fundus relaxation with of postinfectious functional dyspepsia of 2.54 (95% CI, blunting of postprandial accommodation, and altered gas- 1.76-3.65).22 Norovirus is the most common cause of tric mechanosensitivity,