DOI:10.3760/cma.j.cn311367-20201027-00633

Functional dyspepsia (FD) and gastroparesis are the most common disorders involving the upper gastrointestinal tract. The prevalence of FD ranges from 10% to 40% in western countries and 5% to 30% in Asia^［1］. Although the exact epidemiology of gastroparesis is unclear, it is estimated that gastroparesis occurs in 1.3% to 1.4% of the general population^［2］. FD and gastroparesis have common symptoms, including postprandial fullness, early satiation, epigastric pain or burning, upper abdominal bloating, bothersome belching, nausea, vomiting, etc. Besides, FD pathophysiologically and therapeutically overlaps with gastroparesis. Herein, we summarize our understanding of definitions, etiology, pathophysiology, and treatment in FD and gastroparesis.

Definition

1. FD: FD is a chronic digestive disorder defined by upper abdominal symptoms considered to originate from the gastroduodenal region with no organic diseases by clinical investigations, including upper gastrointestinal endoscopy. According to the Rome Ⅳ criteria published in 2016, FD patients must display one or more of the following symptoms for more than three of the past six months: postprandial fullness, early satiation, epigastric pain, and epigastric burning, which are unexplained by other structural or organic causes. FD is divided into two subgroups: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) ^［3］. These two groups may overlap.

2.Gastroparesis: Gastroparesis is a clinical syndrome characterized by delayed gastric emptying in the absence of mechanical obstruction. Major symptoms include early satiety after eating, postprandial fullness, nausea, vomiting, belching, and bloating.

Etiology

1. FD: The etiology of FD is diverse, including dietary factors, infections, stress, duodenal inflammation, surgery, trauma, psychological distress, etc. Although no exact relationship has been established, genetic factors and hormonal influences may also be involved in some patients with FD^［4-5］.

2.Gastroparesis: Gastroparesis is caused by several clinical disorders, such as diabetes mellitus, upper gastrointestinal surgery (fundoplication and vagotomy), neurological disease (Parkinson disease, amyloidosis, and dysautonomia), viral infections (norovirus, Epstein-Barr virus, cytomegalovirus, and herpesvirus), drugs (opioids, antibiotics, antiarrhythmics, and anticonvulsants), connective tissue disorders (scleroderma and systemic lupus erythematosus), renal insufficiency, etc^［6］. Although traditionally, diabetes has been considered as the main cause of gastroparesis, idiopathic gastroparesis (IG) constitutes the most common etiology.

Pathophysiology

1. FD: FD is considered a multifactorial disorder that involves different pathophysiological mechanisms, including impaired gastric accommodation, delayed gastric emptying, visceral hypersensitivity, gastric dysrhythmia, duodenal mucosal alterations, etc. (Fig.1). Impaired gastric accommodation has been reported in 30%-40% of patients with FD^［7］, and it is associated with early satiation and weight loss^［8］. Delayed emptying is found in approximately 35% of FD patients^［9］, and this was associated with more nausea, vomiting, and postprandial fullness symptoms, and a lower quality of life^［10］. About 37% of FD patients have hypersensitivity to gastric distention (visceral hypersensitivity) assessed by barostat^［11］. The degree of visceral hypersensitivity correlates with symptom severity^［12］. It was found that 36% to 60% of FD patients had abnormal gastric pace-making activity assessed by non-invasive electrogastrography (EGG) ^［13］, characterized by a lower percentage of normal slow waves in either fasting or postprandial state or both ^［14］. Duodenal mucosal hyperpermeability and low-grade duodenal inflammation have also been regarded as pathophysiological mechanisms in FD^［15］. An increased duodenal mucosal permeability assessed by using chamber and low-grade inflammation, as demonstrated by increased infiltration of mucosal mast cells and eosinophils were found in FD^［16］. Duodenal hyperpermeability and markers of inflammation were correlated with gastric emptying to solids^［17］. Some FD patients have none of these abnormalities, and these abnormalities correlate poorly or not at all with specific symptoms^［11］.

Fig.1 Major pathophysiologies of functional dyspepsia

2.Gastroparesis: Although the pathophysiology of gastroparesis has not been fully understood, several abnormalities are involved. Meanwhile, there are potential differences in these pathophysiologic abnormalities among different etiological groups (for example, diabetic and idiopathic). Delayed gastric emptying is a prerequisite for the diagnosis of gastroparesis. However, the pathophysiological mechanisms underlying delayed gastric emptying in gastroparesis are not clear. Similar to FD, abnormalities such as impaired gastric accommodation, visceral hypersensitivity, and gastric dysrhythmias also contribute to gastroparesis. Tack et al. found that 43% of refractory IG patients had impaired gastric accommodation^［18］. In refractory IG, 29% of the study subjects displayed visceral hypersensitivity and this was associated with early satiety, abdominal pain, and anorexia^［18］. Gastric dysrhythmias, such as bradygastria and bradyarrhythmia, have been found to be associated with gastroparesis^［19］. In particular, successful treatment for IG was associated with normalization of EGG parameters, which suggests a central pathophysiological role of gastric dysrhythmias in IG^［20］. Small intestinal dysmotility can lead to impaired gastric emptying and clinical manifestations of gastroparesis^［2］.

There are several cellular pathological alterations in gastroparesis, including loss of interstitial cells of Cajal (ICC), fibrosis of the muscular layers, inflammatory cell infiltration around myenteric neurons, neuronal abnormalities, etc (Fig.2). Using full-thickness gastric body biopsies, a loss of ICC has been reported in patients with diabetic and IG^［21］. The decrease in the ICC found in patients with diabetic and IG may cause delayed gastric emptying, which impairs gastric pace-making activity and motor coordination^［22］. However, it is unclear whether the loss of ICC could predict the severity of symptoms. Fibrosis, especially around the nerves is another prominent ultrastructural feature of IG^［23］. It is estimated that these fibrillary sheets may impair smooth muscle metabolism and cause cell damage^［23］. Abnormal infiltration of eosinophils or macrophages in the muscular layer has been reported in some cases^［24-25］. A reduction in the numbers of CD206⁺ cells (anti-inflammatory M2 macrophages) has been reported in the gastric tissues of diabetic and IG patients, which is associated with the loss of ICC^［26］. An increase in gene expression of proinflammatory macrophages (M1 macrophages) has also been found in gastroparesis tissues^［27］. Macrophage-caused immune dysregulation and oxidative stress damage are central to driving injury to the ICC and subsequent delayed gastric emptying^［2］. Neuronal abnormalities in gastroparesis include decreased nerve fibers, dysfunction of the vagus nerve, enteric nervous system changes, and decreased numbers of inhibitory neurons expressing neuronal nitric oxide synthase (nNOS) ^［28］.

【Summary of updates】 Traditionally, FD and gastroparesis are considered as gastric motility disorders. However, recent studies have clearly demonstrated that in addition to motility disorders, pathophysiologies of both FD and gastroparesis include substantially impaired accommodation and visceral hypersensitivity. Moreover, mechanistic studies have suggested the involvement of duodenal components, such as duodenal mucosal alterations in FD and molecular mechanisms of macrophages in gastroparesis.

Diagnostic tests

An organic disease or mechanical obstruction should be suspected first and excluded mainly via upper endoscopy, if patients have digestive alarm symptoms, such as bleeding, anemia, unexplained weight loss, progressive dysphagia, recurrent vomiting, and family history of gastrointestinal cancer. In the case of negative findings, especially refractory patients are recommended to take more tests to evaluate underlying pathophysiological mechanisms, including gastric emptying, gastric accommodation, visceral sensitivity and gastric slow waves.

Abbreviations: ICC: interstitial cells of Cajal; nNOS: neuronal nitric oxide synthase

Fig.2 Cellular and neuronal alterations in gastroparesis

1.Assessment of gastric emptying

Various methods are available to measure gastric emptying, including scintigraphy of solids, stable isotope breath test, the wireless motility capsule (WMC), ultrasonography and magnetic resonance imaging (MRI).

① Scintigraphy: Currently, scintigraphy is the most widely accepted method and represents the gold standard. In general, an anteroposterior γ-camera is used to record the gastric area after ingestion of a ^99mTc-labelled solid meal at hourly intervals of 0,1, 2, and 4 h^［29］. Generally, gastric retention of >90% at 1 h, >60% at 2 h, > 10% at 4 h is considered delayed gastric emptying of solids^［30］. Gastric retention of > 10% at 4 h has been found to have a sensitivity of 100% and specificity of 70% for delayed gastric emptying. Gastric emptying scintigraphy is reproducible, with a good concordance correlation coefficient (CCC) between two repeated studies. It has been discovered that the mean CCC between two studies was 0.79 (0.67, 0.87) at 1 h, 0.83 (0.75, 0.9) at 2 h, and 0.54 (0.34, 0.70) at 4 h^［31］. Several factors can affect the results of scintigraphy, such as test meal, the timing of imaging, glycemia, and quantitative method. The content of the meal used for measuring gastric emptying is the most important variable when applying normal values. Current meals used in the test include ground beef and chicken liver, egg white, whole egg, oatmeal, and pancakes, with or without liquid elements. The American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine recommend a low-fat, egg-white meal: a ^99mTc labeled solid meal containing two large eggs (30 g), two slices of bread (120 kcal), and strawberry jam (30 g, 74 kcal), with water (120 mL)^［30］. Considering eating habits, some Asian hospitals have modified the components of the meal, for example using rice-based meals. The timing of imaging after ingestion of the meal is also of importance, with emphasis on the 4 h value. Pathikonda et al. found gastric retention at 4 h correlates well with gastric retention at 3 h, good at 2 h, but only fair at 1 h. Gastric retention at 1 h may miss 36% of patients with delayed gastric emptying at 4 h^［32］. There is an increasing understanding that glycemia has an impact on gastric emptying. The clinical guideline of the American College of Gastroenterology suggests that the test meal should be given when the blood glucose is < 15.3 mmol/L^［33］. Other factors, including medications, smoking, gender, the region of interest placement, etc. also need to be considered. This method, however, has several limitations: first, the solid meal is not tolerable in some patients; second, it has mild radiation exposure; third, nuclear medicine departments are rare globally and not widely available; moreover, gastric emptying scintigraphy is expensive.

② Breath test: The breath test is an alternative approach, particularly when scintigraphy is not available. During the test, ¹³C-labeled substrate, usually octanoic acid or Spirulina platensis, is incorporated into a solid meal. The underlying principle of this test is that the rate of gastric emptying of the ¹³C-labeled substrate incorporated in the solid meal is reflected by breath excretion of ¹³CO₂. The test is performed over 4 h after 8-hour fasting and provides reproducible results that are comparable with gastric emptying scintigraphy^［34］. The sensitivity and specificity of the breath test are between 75%—86% and 80%—86%, respectively^［35］. It is non-invasive, easy to perform, and without radiation exposure. Thus, this test has advantages especially suitable for repeated testing, pregnant or breastfeeding women, and children. Besides, the breath test is cheaper than scintigraphy. Its limitation is that many factors may affect the test results, for example, changes in endogenous CO₂ excretion caused by physical activity such as walking and malabsorption, small intestinal bacterial overgrowth, pancreatic exocrine insufficiency and significant hepatic, cardiac or pulmonary diseases. Furthermore, ¹³C-labeled substrate is not available in some countries and samples have to be sent to a commercial company for assay. 

③ SmartPill: The wireless motor capsule has also been approved by the U.S. Food and Drug Administration (FDA) for measuring gastric emptying. The capsule is ingested following a test meal and transmits information of pH, pressure and temperature to an external recorder. It evaluates gastric emptying by the acidic gastric residence time of the capsule^［33］. Gastric emptying time measured by wireless motor capsule correlated moderately with gastric emptying at 4 h by scintigraphy, with an overall correlation 0.73^［36］. The 300 min cut-off time for gastric emptying time provides a sensitivity of 0.65 and specificity of 0.87 for diagnosis of gastroparesis, compared with a sensitivity of 0.44 and specificity of 0.93 for 4 h standard scintigraphy. This method has no radiation exposure, is relatively safe, and can measure whole gut transit time; however, it does not directly measure physiological gastric emptying of a meal since the capsule is typically emptied during phase Ⅲ of migrating motor complex in the fasting state when the stomach is completely emptied. Further validation is needed in larger populations to confirm these findings.

④ Other methods: Other techniques for assessing gastric emptying include radiopaque markers, ultrasonography and MRI. Gastric emptying of radiopaque markers is conducted by the ingestion of several radiopaque markers together with a standardized meal. Then a supine abdominal radiograph or fluoroscopy is taken. It is easy to perform, not expensive, and highly available; however, the method has low diagnostic reliability^［37］. Ultrasonography^［38］ and MRI^［39］ are non-invasive tests, which avoid radiation exposure. They are mainly used for research purposes because of the expertise requirement, expensive equipment, or slow image capture and interpretation. The advantage of using MRI for assessing gastric emptying is that it may also provide information on antral contractions and pyloric opening^［40］.

2.Gastric accommodation

①Gastric barostat: Currently, the gold standard for measuring fundic accommodation is the gastric barostat. The barostat consists of a double-lumen polyvinyl tube with a polyethylene balloon with a maximum capacity of 1.0 to 1.2 L, which is placed in the proximal stomach to detect changes in the volume of the fundus. Gastric barostat shows excellent reproducibility both in dyspeptic patients and in healthy subjects. However, the technique is invasive, time-consuming, uncomfortable for most subjects, and requiring special expertise, which limits its availability in clinical practice. Besides, the gastric balloon has been shown to interfere with normal gastric physiology; the direct stimulus imposed by the balloon on the stomach wall may result in exaggeration of antral relaxation and alter the intragastric distribution of the meal^［41］.

② Ultrasonography: Both two- and three-dimensional ultrasonography has also been used to estimate gastric accommodation. They are non-invasive and well-tolerated. However, gas interposition brings technical difficulties to operation, and it is labor-intensive. Its reliability and accuracy of evaluating gastric accommodation need further evaluation.

③ MRI: Similar to ultra sonography, MRI is a non-invasive means of measuring gastric volumes. However, it is time-consuming. It remains a research tool and has not been well validated for assessing gastric accommodation.

④ Single-photon emission computed tomography (SPECT): SPECT was first proposed to quantify gastric accommodation by Mayo Clinic. This technique acquires images of the gastric wall utilizing intravenously administered ^99mTc pertechnetate (taken up by gastric parietal and mucin-secreting cells) with a non-invasive SPECT γ-camera. As a non-invasive method, it has demonstrated reliability and reproducibility compared to barostat measurements^［42］. However, it requires expensive equipment and specific software, involves radiation exposure, needs to perform in a supine position, and is only available at very few specialized centers. SPECT could be a promising tool for diagnostic use when further validation results are obtained.

⑤ Nutrient drinking test: The nutrient drinking test is a simple and non-invasive surrogate approach to quantify gastric accommodation. Subjects are requested to drink a liquid nutrient meal, for example, Nutridrink^©and Ensure^©, at a slow constant rate until maximum satiety had been reached. The principle of this test is based on the hypothesis that impaired accommodation causes a decreased gastric volume capacity and this is reflected in the maximum tolerated drinking volume. It has been found that the drinking test is highly reproducible and correlates well with the barostat measurement of gastric accommodation^［43］. Also, this inexpensive test is easy to perform, does not need special devices, is well tolerated by subjects, and is widely available.

3.Visceral sensitivity

At present, visceral sensitivity tests include barostat, nutrient drink test or water load test, chemical stimulation test, e.g. acid provocation or capsaicin ingestion, electrical, or thermal stimulation test. The gastric barostat test is the traditional “gold standard” for evaluating mechanical hypersensitivity. The evaluation uses balloon distension of the fundus and subjective scoring of discomfort. It provides information on sensory thresholds in response to mechanical distension. As stated earlier, barostat is complicated and invasive, so it is available in very few specialized centers.

In contrast, the nutrient drink test or water load test is a simple, widely available test to determine gastric sensitivity by ingestion of liquid nutrients or water^［44-45］. This approach does not affect the physiology of the stomach. During the test, the subject is asked to report levels of discomfort or pain corresponding to different amounts of nutrient drink ingested. 

Chemical stimulation tests, thermal stimulation tests, and electrical stimulation tests are often used for scientific research purposes^［46］.

4.Gastric pace-making activity

In humans, gastric slow waves (pace-making activity) initiate at the upper or mid-corpus region of the stomach and propagate down the antrum at a frequency of approximately three cycles per minute (cpm). The first recording of the gastric slow wave was reported by Alvarez in 1922^［47］. Cutaneous EGG is a simple non-invasive approach to record gastric myoelectrical activity utilizing multiple electrodes placed on the skin of the abdomen. Usually, a 1-channel or 4-channel EGG is recorded^［48］. To be reliable in interpretation, the EGG has to be recorded for 30 min (a minimum of 15 min) under each condition in a quiet room, and patients are required to lie down quietly and motionlessly in the supine position during recording. A standard meal, a minimum of 250 kcal (better > 400 kcal) with no more than 35% of fat, is used to compare fasting and postprandial EGG measurements. The EGG provides the following main information: percentage of normal gastric slow waves, dominant frequency (DF), dominant power (DP), the ratio of power before and after a meal, and percentage of gastric dysrhythmias. It has been validated that EGG findings correlate with internal serosal recording, gastric motility, and gastric emptying^［49-51］. The EGG provides meaningful information on gastric myoelectrical activity when it is recorded, analyzed, and interpreted appropriately.

High-resolution (HR) electrical mapping has recently been developed as a new technique for evaluating gastric slow-wave activity. HR mapping places spatially-dense arrays of electrodes on gastric serosa to permit the recording and reconstruction of patterns of electrical activation. Several studies on HR mapping revealed abnormal gastric slow wave activity in gastroparesis and FD^［52］. However, this method is invasive, and the recording is directly from the serosa layer of a subject undergoing abdominal surgery. In addition, it causes discomfort, risk of infection, and cannot be used for long-term studies. Recently, HR EGG has also been developed via densely positioned abdominal surface electrodes and used to study the correlation between spatial patterns of the HR EGG and symptoms in patients with FD and gastroparesis^［53］. The major advantage of the HR EGG is its ability to reveal spatial abnormalities of gastric slow waves.

5.Antroduodenal manometry

Similar to esophageal and anorectal manometry, antroduodenal manometry was used to assess antral and duodenal contraction in patients with FD and gastroparesis^［54］. Unlike esophageal and anorectal manometry which are used as routine clinical assessment of impaired motility in the esophagus and anoretum, antroduodenal manometry is rarely used as a clinical tool for the assessment of antroduodenal motility. This is attributed to following factors: ① there is a poor correlation between antroduodenal motility and symptoms of FD and gastroparesis; ② the procedure is invasive and not well tolerated by patients; ③ the procedure is long: it requires at least 4 h to cover an entire period of fasting state and postprandial period; ④ the accuracy of manometry is questionable due to unpredictable contacts between manometric sensors and gastric mucosa. Accordingly, the technique is available at very few tertiary centers, and not every patient has access to the test.

【Summary of updates】 Unlike for functional disorders of the esophagus and anorectum, the progress in the diagnosis of FD and gastroparesis has been slow largely attributed to the fact that the intraluminal methods are invasive whereas the noninvasive methods are not entirely reliable. In addition, the lack of treatment options for FD and gastroparesis may have also contributed to the slow progress in the diagnostic arena. For our readers in China, the noninvasive nutrient test may be an excellent surrogate test for assessing both gastric accommodation and visceral hypersensitivity. On the other hand, the noninvasive assessment of gastric emptying and antral contractions using MRI is an attractive tool for clinical research. There is a great opportunity for research as well.

Treatments

Due to multi-factorial pathophysiologies and etiologies of FD and gastroparesis, there are various treatment options targeting different pathophysiologies as shown in Fig.3. When a patient suffers from multiple symptoms attributed to different pathophysiologies, the treatment is difficult and special attention should be paid. For example, if a patient is suffering from both reduced fundic accommodation (such as a symptom of early satiety) and impaired antral contractions (such as symptoms of postprandial fullness and bloating), the treatment one selects could be controversial as the selection of muscle relaxant may improve gastric accommodation but could worsen symptoms attributed to impaired antral motility and vice versa. Another common example is the co-existence of visceral pain and symptoms of antral dysmotility as most of pain medications, such as opioids would worsen dysmotility. Under these conditions, an integrative method of treatment should be considered and it is not uncommon that Traditional Chinese Medicine may provide a better solution.

Fig.3 Treatments and targeted pathophysiology in functional dyspepsia and gastroparesis

1.Current and emerging therapeutic approaches for FD

①Dietary adjustments：Dietary factors are increasingly considered to play an important part in the induction of symptoms in FD. Many FD (particularly PDS) patients report that their symptoms are associated with meal ingestion. It is reported that wheat-containing foods, high fat, and high fermentable oligosaccharide, disaccharide, monosaccharide, and polyols (FODMAP) may play key roles in the generation of FD symptoms^［55］. Unfortunately, there have been few studies investigating the benefit of dietary adjustments in improving FD symptoms. Currently, dietary adjustments are mainly based on doctors′ or patients′ experience. Further systematical studies are required to design dietary intervention.

② Helicobacter pylori（H.pylori） eradication：H.pylori eradication is recommended by most of the guidelines for FD patients who are infected, as it could improve symptoms and decrease the risk of developing peptic ulcers and gastric cancers. The therapeutic effect is more evident in patients with EPS than in patients with PDS^［56］.

③ Acid-suppressive therapy：Traditionally, acid-suppressive therapy is the first-line treatment for FD patients, who have no response to H.pylori eradication or are H.pylori negative. A systematic review shows that PPIs are effective for the treatment of FD^［57］. Besides, proton pump inhibitors (PPIs) may have little or no advantage of effect compared with histamine-2 receptor antagonists (H2RA) and may be slightly more effective than prokinetics. It was confirmed that there were no differences in efficacy among different doses or types of PPIs. Patients with EPS are more likely to respond than patients with PDS. Other agents, including antacids, bismuth, and sucralfate, do not seem to be effective in FD^［58］.

④ Prokinetics：Prokinetic drugs are widely used for the treatment of FD, especially in PDS. Prokinetics include 5-hydroxytryptamine (5-HT)₄ receptor agonists, dopamine D₂ receptor antagonists, and motilin receptor agonists, such as erythromycin. The quality of evidence investigating symptomatic benefit is always low, possibly attributed to a disassociation between antral motility and dyspeptic symptoms^［59］. 

⑤ Centrally acting neuromodulators：Centrally acting neuromodulators have been suggested as a therapeutic option for FD, considering the potential role of the brain-gut axis and abnormal central pain processing in FD. They may relieve symptoms of FD through the treatment of comorbid depression, enhancing gastric accommodation, and manipulating pain perception. These medications include antipsychotics, tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI), tetracyclic antidepressants, etc. Systematic review and meta-analysis discovered that beneficial effects of psychotropic drugs were limited to antipsychotics (such as sulpiride and levosulpiride) and TCA (such as amitriptyline and imipramine) ^［60］. We should pay much attention to the side effects of these drugs since adverse events and adverse events leading to withdrawal is common.

⑥ Fundus-relaxing drugs：Impaired fundic accommodation is one of the major pathophysiological mechanisms of FD.  5-HT_1A receptor agonist relaxes the proximal stomach through inhibition of cholinergic activity. Studies have shown symptomatic improvements in FD of the 5-HT_1A receptor agonists buspirone^［61］ and tandospirone^［62］, compared with placebo. Acotiamide, a mixed presynaptic muscarinic type 1 and type 2 (M1/M2) autoreceptor inhibitor and a cholinesterase inhibitor, can enhance both gastric accommodation and motility. Several studies have reported that acotiamide is associated with the improvement of clinical symptoms in FD patients^［63］. However, these drugs have not been approved for FD treatment in China.

⑦ Chinese herbal medicine：Traditional Chinese medicine plays an essential role in FD treatments^［64］. FD is divided into multiple subtypes, which need corresponding herbs. Traditional herbal therapies have shown beneficial effects in clinical studies^［65-66］; however, they often lack an identified mechanism of action and standard methodology. Thus, high-quality clinical trials are required to obtain convincing evidence supporting the use of herbal therapies as treatment for FD.

⑧ Psychological and behavioral therapies：FD patients have a higher prevalence of psychosocial comorbidity compared with healthy subjects, although the role in symptom generation remains unclear. Psychological and behavioral therapies, including psychotherapy, cognitive therapy, and hypnotherapy, may be useful for FD patients whose symptoms are severe and not responding to pharmacotherapy, or symptoms correlate with life stressors or comorbid psychiatric disorders. Overall, these therapies lack convincing evidence of clinical benefit because of small sample sizes and poor study quality^［67］. Most of medical psychological therapies affect gastric motility, either enhancement or inhibition of motility and therefore careful attention should be made when treatment is provided or a patient is referred to other healthcare providers for treating psychological abnormalities. Although difficult to sort out, it is important to figure out whether anxiety and depression a patient is experiencing are attributed to FD or contribute to the severity of FD symptoms. 

⑨ Acupuncture and electroacupuncture：Acupuncture is a traditional, non-pharmacologic therapeutic option for the management of FD. A meta-analysis reported an improvement of FD symptoms and quality of life after acupuncture compared with sham acupuncture^［68］. However, the majority of the trials included were of low quality or small sample size. Randomized controlled trials of high methodological quality are needed. A recent multi-center randomized clinical trial with the use of acupuncture for treating PDS has revealed promising findings: acupuncture resulted in an increased response rate and elimination rate of all three cardinal symptoms compared with sham acupuncture, with sustained efficacy over 12 weeks in patients who received thrice-weekly acupuncture for four weeks^［69］.

While manual acupuncture is commonly used in clinical practice, electroacupuncture seems more commonly used in clinical and basic research due to its distinct advantages: ① it can be performed uniformly; ② it adds effects of neuromodulation if the stimulation parameters are appropriately chosen only not to mimic the manual manipulation of the needle but also to improve autonomic functions^［70］. A number of studies have been published with the use of electroacupuncture for FD^［71］. A recent multi-center randomized controlled trial study has shown improvement in dyspeptic symptoms in patients with refractory FD^［72］. 

When acupuncture or electroacupuncture is applied for treating FD, a few important issues should be considered: ① the choice of stimulation points and stimulation parameters. While numerous studies have been performed in comparing different acupoints, not much has been done in the optimization of stimulation parameters as most of electrical current is applied to mimic manual manipulation of acupuncture rather to alter autonomic functions. ② The treatment frequency is critically important. Whenever possible, frequent administration of acupuncture or electroacupuncture, such as once daily as the effect of one-time electroacupuncture cannot last more than 24 h. A large portion of controversial results reported in the literature might have been attributed to different weekly treatment regimens. ③ For clinical research, a placebo control, such as sham stimulation at different points, is still needed to show the effectiveness of the therapy as placebo is common in FD patients as well as with acupuncture/electroacupuncture treatment. 

⑩ Electrical neuromodulation： Electrical neuromodulation, a new treatment approach of bioelectronic medicine, has been studied to treat several gastrointestinal diseases, including FD and gastroparesis. The methods include gastric electrical stimulation (GES), transcutaneous electrical acustimulation (TEA), vagus nerve stimulation (VNS), spinal cord stimulation (SCS), sacral nerve stimulation (SNS), etc.

GES means direct electrical stimulation to the stomach or vagal branches on the gastric surface using a laparoscopically implanted device. Considering this method is invasive, it is seldomly used for the treatment of FD. Only two related studies were performed in children and adolescents, discovering significant improvements in upper gastrointestinal symptoms and quality of life^［73-74］.

TEA is a non-invasive method that applies electrodes instead of needles. Our studies discovered that TEA at acupuncture points ST36 and PC6 improved dyspeptic symptoms, quality of life, gastric emptying, and gastric accommodation in FD patients^［75-76］. The advantages of TEA in comparison with acupuncture and electroacupuncture are as follows: ① without the insertion of needles, the treatment can be performed by the patient and therefore the treatment can be administrated at home; ② the stimulation parameters are designed to enhance vagal activity and thus improve gastric motility or improve symptoms of dyspepsia; ③ to enhance its efficacy, the TEA therapy can be applied once or even multiple times daily instead of a few times weekly^［70］.  

2.Current and emerging therapeutic approaches for gastroparesis

① Dietary modifications and nutrition support：Solid meals with high fat increase the severity and frequency of symptoms in patients with gastroparesis. Dietary modifications are the first-line of treatment for gastroparesis and are suitable for all patients. Gastroparesis patients are suggested to eat small meals and to avoid foods high in fat and indigestible fibers, since they delay gastric emptying^［33］. Meal frequency is at least four to six meals. Supplementation with high caloric liquids or homogenized solids helps to provide adequate nutrition without causing symptoms.

For patients who are unable to maintain nutrition with oral intake, enteral nutrition via a jejunostomy feeding tube, which bypasses the stomach, can improve symptoms and reduce hospitalizations^［77］. Naso-jejunal feeding should be tried first to see whether the patients tolerate jejunal feeding.

② Prokinetics：Prokinetics have long been used for the treatment of gastroparesis. A systematic analysis confirmed the efficacy of prokinetics on gastric emptying and clinical symptoms, though the majority of trials included had methodological limitations^［78］. Medications commonly prescribed include metoclopramide, domperidone, and macrolide antibiotics. Metoclopramide (a 5-HT₃ and dopamine D₂ antagonist and 5-HT₄ agonist) is the only FDA-approved medication for the treatment of gastroparesis in the USA. It relieves symptoms through the promotion of gastric motility as well as inhibition of emesis. Much attention should be paid to its side effects, such as tardive dyskinesia. 

Domperidone is another dopamine D₂ receptor antagonist with similar efficacy as metoclopramide and was one of the most commonly used medications in China for treating gastrointestinal motility disorders^［79］. It has less central side effects since domperidone does not readily cross the blood-brain barrier. However, recently, domperidone has been associated with prolongation of the cardiac QT interval, due to inhibition of human ether-à-go-go-related gene (hERG) channel activity^［80］.

Macrolide antibiotics are motilin receptors agonists. Although not approved for gastroparesis, erythromycin and azithromycin are also used in clinical practice based on their efficacies in the improvement of symptoms and gastric emptying in the short term. However, their use is limited by the loss of the long-term efficacy due to tachyphylaxis and by side effects. They are typically used for a short period. In addition, these medications impair gastric accommodation and therefore overall symptom improvement is not impressive for gastroparesis. 

New prokinetic drugs, such as novel motilin agonist (GSK962040), ghrelin receptor agonist (relamorelin), new 5-HT₄ receptor agonists (prucalopride, velusetrag, and YKP10811), are promising in the treatment of gastroparesis but requiring further investigation^［81］.

③Antiemetics：Considering the high prevalence and severity of nausea and vomiting in gastroparesis, antiemetic agents are commonly prescribed in practice, but they do not improve gastric emptying. The most commonly used drugs are phenothiazines (prochlorperazine), histamine H1 antagonists (promethazine), 5-HT₃ receptor antagonists (ondansetron), and neurokinin NK₁ antagonist (aprepitant). The evidence of the utility of antiemetic agents for treating gastroparesis is always based on case reports or lacking data^［82］. These medications all have side effects such as QT prolongation and therefore should be considered only after the failure of prokinetic agents in gastroparesis.

④ Pyloric interventions：Pyloric sphincter dysfunction, namely pylorospasm, has been observed in some gastroparesis patients, providing the rationale for interventions on the pylorus.

Botulinum toxin injections block the exocytosis of acetylcholine in cholinergic nerve endings, thereby inhibiting the spasm of the pyloric sphincter. Unfortunately, there is no evidence to support widespread use of botulinum toxin injections, based on the current results of the randomized, controlled trials^［83-84］. 

Transpyloric stent placement via endoscopy has been tested in small sample size studies, especially in patients with refractory gastroparesis^［85-86］. In one study, 75% of the total 30 patients displayed improvements in gastric emptying and clinical symptoms^［86］. However, transpyloric stent placement may not be a permanent solution due to the high probability of stent migration (52%). It can be considered as a temporary salvage treatment for intractable symptoms. 

Pyloroplasty via laparoscopy or surgery, widening the pylorus and preventing spasm, has demonstrated improvement in symptom severity and gastric emptying for the treatment of gastroparesis^［87］. However, it should be performed rarely and in carefully selected refractory patients, considering the lack of high-quality randomized controlled studies and a long follow-up. 

Gastric peroral endoscopic myotomy (G-POEM) has been developed as a novel and minimally invasive treatment approach for refractory gastroparesis^［88］. It is an extension of peroral endoscopic myotomy, a well-studied treatment option for achalasia. The procedure involves an injection and submucosal incision, submucosal tunnel creation, myotomy of antral muscular layers, followed by mucosal entry closure. A systematic review and meta-analysis discovered that G-POEM improved gastroparesis symptoms and gastric emptying significantly with a low incidence rate of adverse events, although the majority of included studies had a small sample size and lacked control groups^［89］. Large controlled trials evaluating G-POEM in gastroparesis are required.

The major issue in the pyloric intervention is the selection of appropriate patients. Currently, there is a lack of effective screening method to identify patients who are suitable for pyloric intervention. Overall, pyloric spasm is not common in gastroparesis. Moreover, loosening of pylorus could result in reflux of bile into the stomach. 

⑤Alternative approaches：Acupuncture has shown to improve gastroparesis symptoms, reduce gastric retention, and accelerate solid gastric emptying in patients with diabetic gastroparesis^［90-91］. It can be considered as an alternative therapy, but further studies are needed to assess the long-term effect on gastroparesis.

GES (the enterra therapy) exerts high-frequency, low energy electrical stimulation to the stomach. The exact mechanisms of GES are unclear, but it appears to interfere with sensory transduction to the brain through vagus afferent fibers. GES has been found to enhance symptom control (mainly nausea and vomiting), quality of life, and improves oral tolerance of feeding^［92］, thus providing compassionate treatment for refractory gastroparesis. It seems that the response in patients with diabetic gastroparesis was better than in patients with other etiologies, such as IG or postsurgical gastroparesis. It should be noted, however, the Enterra GES therapy does not improve gastric emptying^［93］. Complications related to the implanted stimulation device include local infection, lead migration, bowel obstruction, and perforation, etc. which occurred in approximately 20% of patients.

The vagus nerve plays an important role in the regulation of nausea and vomiting. VNS was first used to treat epilepsy in the late 19th century. Considering that implanted GES act centrally through vagus afferents, VNS might have a similar therapeutic effect on gastroparesis. Non-invasive vagus nerve stimulation (nVNS) does not require surgical implantation of the electrode or pulse generator, avoiding surgical complications. To date, there have been only two studies evaluating nVNS for the treatment of gastroparesis patients^［94-95］. The results showed symptoms and gastric emptying were both improved in a subset of patients. Larger randomized controlled trials are needed to verify the findings.

As to other electrical stimulation methods, we found that SCS was able to improve gastric emptying via enhancing vagal activity in rats and dogs^［96-97］. Most recently, SNS was found to improve gastric accommodation and gastric dysmotility through a novel spinal afferent and vagal efferent pathway in rats^［98-99］. These findings suggest a potential therapeutic role of SCS and SNS for gastroparesis. Further clinical studies are required.

【Summary of updates】 Overall, treatment options are rather limited as there are none or  few medications approved specifically for FD or gastroparesis. The situation in China is slightly better as there are a few prokinetics approved for use in China and the traditional Chinese medicine therapies are more readily available. However, the major challenges are the multifactorial factors involved in the pathophysiology of FD and gastroparesis. Accordingly, it is critically important to determine as accurately as possible the exact pathophysiology of the disease for a particular patient before the treatment is provided.

Conclusions

FD and gastroparesis patients share similar symptoms. Multiple diagnostic tests are needed to identify the underlying pathophysiology, which helps to direct therapy. Although there are various treatment options for FD and gastroparesis, their efficacies are limited. However, progress is being made in new treatment approaches, including new medications, endoscopic interventions and electrical neuromodulation.