Functional Dyspepsia

Pilin  Francis; Stacey Zavala

Functional Dyspepsia

Author: Pilin Francis Editor: Stacey R. Zavala Updated: 6/8/2024 6:32:37 PM

Introduction

Functional dyspepsia is one of the most prevalent functional gastrointestinal disorders, affecting over 20% of the population. The condition has 3 subtypes—epigastric pain syndrome, postprandial distress syndrome (PDS), and a combination of both—each thought to result from different mechanisms. Diagnosis is based on the Rome IV criteria, which define functional dyspepsia as the presence of one or more symptoms, such as epigastric pain, burning, early satiety, and postprandial fullness, and in the absence of structural disease detectable by imaging or endoscopy. These symptoms may be severe enough to interfere with daily activities. While some patients may also experience nausea, vomiting, or heartburn, these symptoms are typically infrequent.[1][2][3]

Patients should be tested and treated for Helicobacter pylori if applicable.[4] Further treatment involves symptom management with proton pump inhibitors (PPIs), H2-receptor antagonists (H2RAs), prokinetic agents, and antidepressants.[1][4] Alarming symptoms such as weight loss, dysphagia, or vomiting warrant an endoscopic evaluation.[5]

Etiology

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Etiology

Various factors can cause symptoms of functional dyspepsia, including disturbed gastric motility, such as inadequate fundic accommodation or delayed gastric emptying, and disordered gastric sensation, such as hypersensitivity to gas and bloating. Additionally, gastric and duodenal inflammation can contribute to these symptoms. A genetic predisposition for functional dyspepsia is likely but less evident than in other functional gastrointestinal disorders such as irritable bowel syndrome (IBS). Psychiatric comorbidity and psychopathological states may also contribute to functional dyspepsia, although they are not specific to the condition and are less pronounced than in IBS.[1]

Epidemiology

Functional gastrointestinal disorders affect almost 40% of people worldwide.[6] The prevalence of functional dyspepsia—a type of functional gastrointestinal disorder—varies worldwide, with higher rates of 10 to 40% in Western countries, including the United States. The global prevalence ranges from 5% to 11%.[7][8] In Asian countries, the prevalence of uninvestigated dyspepsia and functional dyspepsia is 5% to 30%.[9] Functional dyspepsia is more common in women than in men.[10] This difference is due to inherent sex-specific differences in gastrointestinal function. For example, sex-specific variation exists in hormone mechanisms, pain signaling, and healthcare maintenance.

Pathophysiology

Although the exact mechanism is poorly understood, the pathophysiology of functional dyspepsia is complex, involving several different mechanisms thought to contribute to each subtype. Traditionally, disturbances in gastric physiologic factors, including both macroscopic and microscopic mechanisms, have been attributed to functional dyspepsia.

Macroscopic physiological mechanisms include:

Gastroesophageal reflux disease (GERD).
Delayed gastric emptying, rapid gastric emptying, gastric dysrhythmias, and antral hypomotility.[11]
Visceral hypersensitivity alterations in the nervous system, including a lower threshold for pain in the presence of normal gastric compliance, abnormal processing of afferent input in the spinal cord or brain, and dysfunction of mechanoreceptors.[12][13]

Microscopic physiologic mechanisms include:

Impaired barrier function due to altered sensitivity to duodenal acid or lipids that impair mucosal integrity.
Gastroduodenal inflammation characterized by altered lymphocytes, including "gut-homing" lymphocytes, increased eosinophils, and mast cells.[14][15]
Altered gut microbiome and H pylori infection [16][17]

Additional proof of the connection between intestinal inflammation and functional dyspepsia includes the discovery of increased small-bowel homing T lymphocytes in patients suffering from functional dyspepsia. These lymphocytes are positive for both α4β7-integrin and chemokine receptor 9. This finding is particularly significant because it has been strongly associated with cytokine release, including tumor necrosis factor-α (TNF-α).[18][19] Furthermore, it has been linked to an increase in the severity of symptoms and a delay in gastric emptying, thereby suggesting a crucial involvement of the duodenum in the development and progression of gastric disorders.[20] In addition, it can also result from allergen exposure, which can lead to eosinophil recruitment in genetically predisposed patients.

Psychological factors such as anxiety and depression can lead to increased activation of the amygdala and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, indicating central processing of visceral stimuli from the gastrointestinal tract. Stress activates the HPA axis, leading to the release of specific hormones from the hypothalamus and pituitary, culminating in the synthesis of cortisol. This process has been linked to increased cortisol levels and heightened HPA responses in patients with IBS.[21] Acute stress also increases salivary cortisol levels and intestinal permeability in healthy individuals.[22] Furthermore, a higher prevalence of functional gastrointestinal disorders is observed in patients with a history of childhood abuse.[23][24]

History and Physical

Typical symptoms of functional dyspepsia can be divided into 3 subtypes—epigastric pain syndrome, PDS, and an overlap between the 2 syndromes. Symptoms can be acute or chronic. Patients should be asked about the severity and duration of symptoms. Symptom-based criteria are used to confirm the diagnosis. Any abnormal or progressive symptoms should be considered in the differential diagnoses.[25]

Rome IV Criteria for Functional Dyspepsia

In adults, functional dyspepsia with no evidence of structural disease is diagnosed with at least 1 of the following symptoms present for 3 or more months, with onset at least 6 months before diagnosis and affecting quality of life:

Postprandial fullness
Epigastric pain
Epigastric burning
Early satiety

Subclassifications of Functional Dyspepsia

Functional dyspepsia is further classified into epigastric pain syndrome and PDS. Epigastric pain syndrome is characterized by epigastric pain or burning, while PDS is usually meal-induced and presents with postprandial fullness and early satiety.[26]

Epigastric pain syndrome: This condition, with no evidence of systemic, organic, or metabolic disease, is diagnosed when at least 1 of the following symptoms is present, severe enough to impact usual activities, occurring at least once per week for 3 or more months, with onset at least 6 months before diagnosis—epigastric burning, epigastric pain, or both.

Supportive criteria include the following:

Postprandial epigastric bloating, nausea, and belching
Pain that does not meet biliary pain criteria
Pain that may be provoked or relieved by ingesting meals and can also occur while fasting
Heartburn

Postprandial distress syndrome: This condition, with no evidence of systemic, organic, or metabolic disease, is diagnosed when at least 1 of the following symptoms is present, severe enough to impact usual activities, occurring at least 3 days per week for 3 or more months, with onset at least 6 months before diagnosis—postprandial fullness (that impacts the quality of life) or early satiety that prevents finishing a regular-size meal.

Supportive symptoms include the following:

Loss of appetite
Nausea
Retching
Vomiting (persistent vomiting suggests another condition)
Postprandial epigastric pain or burning as with reflux
Epigastric bloating
Excessive belching
Heartburn
Symptoms of IBS may also be present

Notably, symptoms relieved by flatus or defecation are typically not considered part of dyspepsia. Persistent vomiting could suggest a coexisting condition.

Evaluation

Evaluation begins with laboratory tests, including blood count, complete metabolic panel, thyroid function, celiac disease serology, and inflammatory markers. As H pylori infection is prevalent in at least 10% of the population, testing for this bacterium is recommended.[27]

Instrumental examinations include esophagogastroduodenoscopy with biopsy and abdominal ultrasonography. The American College of Gastroenterology (ACG) recommends routine use of upper endoscopy in patients aged 60 or older, irrespective of alarm symptoms, and for patients aged 60 or younger if alarm symptoms are present.

Alarm symptoms include:

Unintentional weight loss
Difficulty swallowing (dysphagia)
Painful swallowing (odynophagia)
Unexplained iron deficiency anemia
Persistent vomiting
Detectable mass or lymphadenopathy
Family history of upper gastrointestinal cancer [28]

If patients do not respond to treatment, pursuing more specialized testing specific to the symptoms is reasonable.[29] The diagnosis of functional dyspepsia is confirmed based on the patient’s history and the exclusion of other diseases with similar presentations.

Treatment / Management

Treating functional dyspepsia can be challenging, with the primary goal being symptom control. Initial management involves educating the patient about the diagnosis and discussing treatment expectations.

Eradication of H pylori Infections

The global prevalence of H pylori infection exceeds 50% and is recognized as a significant risk factor for conditions such as chronic gastritis, peptic ulcers, gastric adenocarcinoma, GERD, and functional dyspepsia.[30] Therefore, eradicating H pylori is recommended as the first-line treatment for all patients with functional dyspepsia. Compared to no therapy, H pylori eradication therapy has a statistically significant, albeit small, benefit for relieving symptoms. This therapy can also help reduce the development of peptic ulcer disease and gastric cancer.[4][31] Testing for the presence of H pylori is usually performed during upper endoscopy to investigate dyspepsia. However, if upper endoscopy is not indicated or the testing was not performed during the upper endoscopy, the diagnosis of H pylori can be confirmed with a stool antigen assay or urea breath test. To ensure the accurate diagnosis of the patient with H pylori, they must refrain from antibiotics for 4 weeks and PPIs for 1 to 2 weeks before the stool antigen test. Symptoms may be reduced when acid secretion changes or intestinal microbiota is modified.[30][32] (A1)

Various treatment regimes used for H pylori eradication include:

Bismuth quadruple therapy includes the coadministration of bismuth subsalicylate, metronidazole, tetracycline, and a PPI such as omeprazole for 14 days. A combination capsule containing bismuth subcitrate, metronidazole, and tetracycline is approved by the United States Food and Drug Administration (FDA). North American trials reported a mean eradication rate of 91% with 10-day bismuth quadruple therapy.[33]

(A1)

Clarithromycin-based therapy includes triple, concurrent, and sequential therapies.[34] Triple therapy involves administering clarithromycin, amoxicillin, and a PPI twice daily for 14 days. With this regimen, eradication rates in the United States are typically below 80%. Concomitant therapy combines clarithromycin, amoxicillin, metronidazole, and a PPI for 10 to 14 days. Sequential therapy consists of a 10-day regimen with clarithromycin, where patients take amoxicillin and a PPI for 5 days initially, followed by clarithromycin, metronidazole, and a PPI for the remaining 5 days.

(A1)

Hybrid therapy consists of 7 days of amoxicillin and a PPI, followed by another 7 days of amoxicillin, clarithromycin, metronidazole, and a PPI. Despite its complexity, this regimen has been suggested as an alternative to clarithromycin triple therapy.

Levofloxacin-based therapy is only recommended for H pylori infection when sensitivity is confirmed or resistance rates are below 15%. This therapy can be part of triple, quadruple, or sequential therapy.

Vonoprazan-based regimens have high eradication rates in triple therapy with amoxicillin and clarithromycin or as dual therapy with high-dose amoxicillin. However, their effectiveness is dependent on clarithromycin resistance.[35]

In case of treatment failure, some salvage therapies may also be used. A study found rifabutin triple therapy similar to bismuth quadruple therapy for eradicating H pylori.[36] However, patients on rifabutin had better compliance and fewer adverse effects. This supports using rifabutin triple therapy as a salvage treatment for H pylori.(A1)

After the successful eradication of H pylori, treatment is a 2-step process. The first-line treatment involves a PPI or H2RA for at least 4 weeks. Then, if symptoms persist, subsequent treatment with tricyclic antidepressants (TCAs) or prokinetic agents such as metoclopramide and acotiamide (not available in the United States) is pursued.[37][38][39][40](B3)

Proton Pump Inhibitors

PPIs are recommended for 4 to 8 weeks for patients who initially test negative for H pylori and those with persistent symptoms 4 weeks after the eradication of H pylori confirmed by stool antigen testing, urea breath test, or upper endoscopy-based testing. PPIs are believed to reduce mast cells, duodenal eosinophils, and mucosal permeability.[41] In patients showing improvement with PPIs, therapy should be discontinued every 6 to 12 months to mitigate long-term risks.

The standard dosages of orally administered PPIs are mentioned below.

Lansoprazole: 30 mg daily
Omeprazole: 20 mg daily
Pantoprazole: 40 mg daily
Rabeprazole: 20 mg daily
Esomeprazole: 20 mg daily

H2-Receptor Antagonists

Further studies are required to validate the efficacy of H2RA treatment compared to PPI therapy. Several studies have demonstrated their effectiveness over placebo, showing a 23% reduction in symptoms.[42](A1)

Antidepressants

Patients whose symptoms remain refractory after the initial 8 weeks of PPI therapy should discontinue PPIs, with consideration for initiating a TCA.[43] For those who respond partially to PPIs, TCAs may be administered in combination with PPI therapy. The recommended approaches are mentioned below.

The treatment can be initiated with either of the following low-dose TCAs at night:
- Amitriptyline: 10 mg [44]
- Nortriptyline: 10 mg
- Desipramine: 25 mg

(A1)

TCA doses may be cautiously titrated based on symptom responses; higher doses may induce sedation without enhancing efficacy.

TCAs are initially administered for 8 to 12 weeks and then continued for 6 months if the patient responds appropriately.

Doses must be gradually tapered to discontinue TCA use.

TCAs may be resumed if symptoms recur.

Mirtazapine has shown effectiveness in improving early satiation, nutrient tolerance, and gastrointestinal-specific anxiety, and in addressing unintentional weight loss.[45][46][45] Initial therapy typically begins with 7.5 mg, administered 1 hour before bedtime. Similar to other TCAs, starting with a low dose initially is advisable, which can be gradually increased up to 45 mg daily.(A1)

Prokinetic Agents

A 4- to 8-week course of a prokinetic agent is recommended when the aforementioned therapies fail or when symptoms recur. However, in some patients, adverse effects may lead to discontinuation of therapy. Therefore, treatment with minimal doses is advised (eg, domperidone 10 mg 3 times daily and metoclopramide use for less than 12 weeks). Domperidone is linked to a slight increase in the risk of serious ventricular arrhythmias or sudden cardiac death, particularly in patients aged 60 or older, those taking daily doses over 30 mg, or those with factors predisposing them to QT prolongation. Notably, it is contraindicated in patients with cardiac conduction prolongation, significant electrolyte disturbances, heart disease, moderate or severe liver impairment, and those taking QT-prolonging drugs and potent CYP3A4 inhibitors.[5]

Metoclopramide 5 to 10 mg is usually administered 30 minutes before meals and at night. Metoclopramide can cause tardive dyskinesia, a severe, often irreversible movement disorder. The risk increases with treatment duration and total dose; it should be discontinued if adverse effects develop. Some patients may see a reduction or resolution of the adverse effects after stopping metoclopramide. Metoclopramide can also increase the risk of psychosis and death in patients with dementia.[45]

Optional Therapies

Some patients may find the therapies below effective, although insufficient data exist to support their validation.

Psychotherapy: Although insufficient data on its efficacy exist, it is usually reserved for patients with associated stressors and those who fail to respond to medical therapy.[46]
Buspirone: This drug may relax the gastric fundus when used 10 mg, 3 times daily for 4 weeks. Patients treated with buspirone have shown improvement with early satiation.[47]
Dietary modification.[48]
Lifestyle modification.

(A1)

Differential Diagnosis

The conditions below should be considered in the differential diagnosis.

GERD
H pylori infection [49]
Gastritis
Peptic ulcer disease
Celiac disease
IBS [50]
Small intestinal bacterial overgrowth
Chronic pancreatitis
Gastroparesis [29]
Acute cholecystitis
Gastric carcinoma
Chronic abdominal pain
Biliary pain
Hepatocellular carcinoma [51]
Mesenteric ischemia
Giardiasis
Strongyloidiasis
Sarcoidosis [52]

Treatment Planning

Table. First-Line Therapies for H pylori Infection

Regimens	Drugs and Dosages	Dosing duration
Clarithromycin triple [53]	PPI regular dose twice a day Clarithromycin 500 mg twice a day Amoxicillin 1 g twice a day or metronidazole 500 mg thrice a day	14 days
Bismuth quadruple [54]	PPI regular dose twice a day Bismuth subcitrate 120-300 mg or 420 mg 4 times a day Tetracycline 500 mg 4 times a day Metronidazole 250 mg (4 times a day) or 500 mg (3-4 times a day)	10 to 14 days
Clarithromycin-based concomitant [55]	PPI regular dose twice a day Clarithromycin 500 mg twice a day Amoxicillin 1 g twice a day Metronidazole or tinidazole 500 mg twice a day	10 to 14 days
Clarithromycin-based hybrid [56]	PPI standard dose Amoxicillin 1 g twice a day for 7 days followed by PPI, amoxicillin, clarithromycin 500 mg, plus either tinidazole 500 mg or metronidazole for an additional 7 days	Total 14 days
Clarithromycin-based sequential [57]	PPI standard dose Amoxicillin 1 g twice a day for 5 days followed by PPI, clarithromycin 500 mg plus either tinidazole 500 mg or metronidazole for an additional 5 days	Total 10 days

Prognosis

Functional dyspepsia is characterized by a relapsing and remitting course, with periods of symptom relief interspersed with flare-ups. While lifestyle changes, medications, and sometimes psychotherapy can provide significant relief for some patients, others may experience persistent symptoms over an extended period. Studies indicate that approximately half of individuals diagnosed with functional dyspepsia continue to experience symptoms up to a year after diagnosis.

A study found that patients with functional dyspepsia had a similar quality of life compared to those with peptic ulcer disease, and their quality of life was significantly worse than healthy individuals.[58]

Complications

Although functional dyspepsia is not associated with increased mortality, it does cause significant physical and mental distress, impacting the patient’s quality of life. Patients with functional dyspepsia often score higher on psychometric tests for symptoms of anxiety, depression, and somatization. Approximately 10% to 25% of patients report that the social impact of their symptoms is significant enough to seek medical attention, resulting in increased healthcare visits, significant health impairment, and a decline in overall quality of life.

Consultations

Patients usually present to family practitioners, internists, or nurse practitioners for their initial symptoms. Based on the severity and nature of the symptoms, a consultation with a gastroenterologist may be necessary for an endoscopy. Depending on the patient's symptoms, a consultation with a dietitian could be beneficial to address dietary concerns. Additionally, a mental health professional may be involved if stress or mental health issues are contributing to the condition.

Deterrence and Patient Education

Educating patients on the benign course of this disorder and establishing long-term care and expectations for treatment is essential.[3] Patients should be informed to promptly report red flag signs such as unintentional weight loss, persistent vomiting, or dysphagia and understand that further evaluation may be necessary.

Enhancing Healthcare Team Outcomes

Functional dyspepsia is a relatively common condition that prompts patients to seek medical attention. Patients have symptoms that may mimic other conditions. More invasive testing is also essential to rule out any potential organic causes of the symptoms, especially if red flag signs are present. Diagnosis can be challenging, relying on clinical assessment aligned with patient history and symptoms meeting the Rome IV criteria.

Treatment can be equally challenging because symptoms are frequently refractory to first-line therapies. An interprofessional healthcare team of primary care physicians, advanced practice clinicians, gastroenterologists, nurses, psychiatrists, and pharmacists is critical in recognizing and effectively managing this condition for patients.

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