Clinical Characteristics and Therapeutic Advances inFunctional Dyspepsia Combined withGastroesophageal Reflux Disease (Part 2)

Functional dyspepsia (FD) and gastroesophageal refluxdisease (GERD), which are among the most prevalentupper gastrointestinal (GI) disorders, respectivelyrepresents the most common type of functionalgastrointestinal disorders (FGIDs) and acid-relatedmotility disorders. These two conditions often coexist,forming an "overlap syndrome".1Epidemiologicaldata indicate that the co-occurrence of these twoconditions far exceeds random probability, suggestinga shared pathophysiological basis, such as thegeneralization of visceral hypersensitivity, gastric andduodenal dysmotility, and the dysregulated brain-gutaxis. 1-31 This overlap is not merely a simple addition ofsymptoms but may form a unique "overlap syndrome"with distinct characteristics, leading to more complexsymptoms in patients (such as the coexistence ofepigastric pain, postprandial fullness, and reflux andheartburn), more severe impairment of quality of life,and poor response to traditional monotherapy strategiestargeting either FD or GERD. At present, although theRome IV diagnostic criteria provide a framework forthe diagnosis of comorbidity of these two conditions,4l there is still a lack of systematic consensus ontheir intrinsic connections and optimal managementpathways in clinical practice. Therefore, based on ourprevious review addressing the classification of FDoverlapping with GERD, 15 this review summarizes thesymptomatic characteristics and pathophysiologicalmechanisms of FD-GERD overlap, and elaborates onevidence-based integrative therapeutic principles, withthe aim of providing clear diagnostic and therapeuticstrategies for clinical practice and improving patientoutcomes.

Epidemiological evidence shows that the symptomaticoverlap between FD and GERD is common, with aco-occurrence rate exceeding 30%, suggesting theexistence of shared pathophysiological processes [6,7]

4.1 Clinical characteristics of overlap syndromes

The clinical characteristics of overlapping FD andGERD symptoms include: 1) Mixed and intertwinedsymptoms. Patients often report the coexistence ofepigastric pain/fullness (characteristic symptoms of FD)and retrosternal heartburn/regurgitation (characteristicsymptoms of GERD). These symptoms frequentlyinteract with each other and are difficult to distinguish.For example, postprandial fullness may exacerbateregurgitation symptom, while frequent reflux can alsotrigger or worsen upper abdominal discomfort. 2)Overlapping symptom triggers. meals, psychologicalstress, and specific foods (such as high-fat or spicydiets) can simultaneously trigger or aggravate bothFD and GERD symptoms. 3) Expanded symptomspectrum. Patients with overlapping conditions areusually more prone to atypical symptoms, suchas belching, nausea, chronic cough, and globuspharyngeus (the sensation of a lump in the throat).They are also more likely to have other FGIDs, suchas irritable bowel syndrome (IBS), which furthercomplicates their clinical presentation [6-7]

4.2 Diagnosis of overlap syndromes

The diagnostic approaches for overlap syndromeinclude: 1) Symptom diagnostic scales. Commonlyused symptom questionnaires (e.g., the GerdQquestionnaire) are inadequate to precisely differentiatewhether symptoms originate from the gastroduodenalregion or the esophagus, nor can they distinguishGERD from functional esophageal disorders. 2)Endoscopy. Gastroscopy is an essential step to ruleout organic lesions (such as esophagitis and ulcers).However, negative endoscopic findings (i.e., non-erosive changes) do not exclude GERD (non-erosivereflux disease, NERD) or functional esophagealdisorders. In such cases, the value of symptomassessment and functional testing becomes particularlyprominent. 3) Functional testing. Functional evaluationis recommended for overlap patients with refractorysymptoms, unclear diagnoses, or failure of empiricaltherapy. For instance, gastric emptying scintigraphycan help to identify FD patients with concurrent delayed gastric emptying, thereby providing a rationalefor the use of prokinetic agents. High-resolutionmanometry (HRM) can be applied for assessmentof esophageal motility. 4) 24-hour multichannelintraluminal impedance-pH monitoring (MII-pH).It has been considered as the "gold standard" fordifferentiating GERD, reflux hypersensitivity, andfunctional heartburn. It can objectively record thefrequency and duration of acid, weakly acidic, andnon-acidic reflux events, and calculate the symptomassociation probability (SAP) between symptoms andreflux episodes [6].

4.3 Shared pathophysiological mechanisms of FDand GERD
The high comorbidity rate between FD and GERDsuggests the existence of shared pathophysiologicalmechanisms, which may include: 1) Generalizationof visceral hypersensitivity. Visceral hypersensitivitymay concurrently involve the stomach, duodenum, andesophagus, leading to aberrant perception of variousstimuli in patients. 2) Continuity of motor dysfunction.Delayed gastric emptying and elevated intragastricpressure may facilitate the occurrence of transientlower esophageal sphincter relaxations (TLESRs),thereby increasing the frequency of gastroesophagealreflux events. 3) Central sensitization and psychiatriccomorbidities. Alterations in the functions of the centralnervous system, such as anxiety and depression, canlower the sensory thresholds in both the stomach andesophagus and simultaneously leading to dysmotility.These central factors serve as critical drivers for theoverlap of these disorders and the chronicity of theirsymptoms.

The management of patients with concurrent FD andGERD should follow a comprehensive strategy that isstepwise, individualized, and pathophysiology-oriented[8-10]

5.1 Basic management.

1) Helicobacter pylori testing and eradication. AllFD patients should be tested for H. pylori (HP), anderadication therapy is recommended for the HP-positive patients. This is an etiological treatmentsupported by evidence-based medicine that mayimprove symptoms in a subset of FD patients.

2) Dietary modifications. It is recommended toadopt a small, frequent meal pattern and avoideating too rapidly. Intake of high-fat, spicy, andoverly sweet foods, as well as caffeine, carbonatedbeverages, and alcohol, should be reduced, as thesemay simultaneously exacerbate both FD and GERDsymptoms. For patients with postprandial distresssyndrome (PDS), a low-FODMAP diet may bebeneficial.

3) Lifestyle adjustments. Smoking cessation andweight control are advised. To specifically relievereflux symptoms, it is recommended to avoid lying flatwithin 2-3 hours after meals and to elevate the head ofthe bed during nighttime sleep.

4) Patient education and psychological support.Educating patients about the brain-gut interactions,helping them to establish realistic treatmentexpectations and alleviating their illness-related anxietyare essential. These measures are the cornerstone of alltherapeutic interventions.

5.2 First-line empirical therapy: According to current guideline recommendations, initial treatmentmay be selected based on the predominant symptoms.

1) For patients with predominant symptoms of reflux/heartburn or epigastric pain (EPS), proton pumpinhibitors (PPIs) are preferred, administered once daily30 min before breakfast, with a duration of 4-8 weeks.

2) For patients with predominant symptoms ofpostprandial fullness or early satiety (PDS), prokineticagents are preferred, such as domperidone, mosapride,or itopride.

3) For patients displaying overlapping symptomswithout an obviously predominant symptom, initialcombination therapy with PPIs and prokinetic agentscan be employed.

5.3 Second-line and optimization therapy. For pa-tients with inadequate response to first-line treat-ment after 4-8 weeks, diagnostic reassessmentshould be performed, with adjustment of the treat-ment regimen considered.

1) Neuromodulators/centrally acting agents. Theyconstitute the cornerstone of second-line therapy.Low-dose tricyclic antidepressants (e.g., amitriptyline10-25 mg) are the most evidence-based option foralleviating visceral hypersensitivity and improvingrefractory epigastric pain as well as functional chestpain/heartburn. Selective serotonin reuptake inhibitors(e.g., escitalopram) may also be considered. Agentswith combined dopamine antagonist and prokineticproperties, such as levo-sulpiride, represent anadditional therapeutic option.

2) Switching to or combining with alternative agents.Prokinetic drugs with different mechanisms of actionmay be trialed, or combination therapy with evidence-based herbal medicine, such as compound preparationscontaining peppermint oil, may be employed.

5.4 Mechanism-based precision interventions.

1) For patients with functional testing indicatingreflux hypersensitivity, PPI dosage should bereduced or discontinued. In addition, application ofneuromodulators is recommended.

2) For patients with extremely poor treatment response,re-evaluation for overlooked organic or motilitydisorders (e.g., gastroparesis, achalasia) is warranted.5.5 Multidisciplinary integrated management forrefractory cases. For refractory FD overlappingwith GERD, psychobehavioral interventions maybe employed. Cognitive behavioral therapy and gut-directed hypnotherapy have demonstrated efficacy inimproving FD and functional esophageal symptoms,particularly in patients with significant psychologicaldistress or suboptimal response to pharmacotherapy[1, Additionally, emphasis should be placed onmultidisciplinary team collaboration, whereingastroenterologists work jointly with psychiatrists/psychologists, nutritionists, and pain managementspecialists to develop comprehensive treatment plans integrating biological, psychological, and social factorsfor complex, refractory patients.

The overlap syndrome of FD and GERD reflects thecomplexity and continuum of symptoms in FGIDs.The Rome IV diagnostic framework provides tools forprecise clinical identification. Modern management hasevolved beyond simple acid suppression or prokineticmonotherapy toward an integrated treatment modelbased on predominant symptoms and underlyingpathophysiological mechanisms, with heightenedemphasis on the roles of neuromodulation andpsychological intervention. Future novel therapiestargeting duodenal low-grade inflammation, intestinalmicroecology, and specific neurotransmitter pathwayshold promise for delivering fundamental relief to thesepatients. At present, clinicians should strive to performmeticulous symptom profiling and mechanisticassessment, implementing individualized stepwisetreatment to maximize improvement in patients' qualityof life.

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