Gastroparesis: Etiology, clinical manifestations, and diagnosis

INTRODUCTION — Normal gastrointestinal motor function is a complex series of events that requires coordination of the sympathetic and parasympathetic nervous systems, neurons and pacemaker cells (called interstitial cells of Cajal) within the stomach and intestine, and the smooth muscle cells of the gut. Abnormalities of this process can lead to a delay in gastric emptying (gastric stasis) [1].

This topic will review the etiology and diagnosis of gastroparesis. Our recommendations are largely consistent with guidelines by the American Gastroenterological Association (AGA) and the American College of Gastroenterology (ACG) [2,3]. The pathogenesis and treatment of gastroparesis are discussed separately. (See "Pathogenesis of delayed gastric emptying" and "Treatment of gastroparesis".)

DEFINITION — Gastroparesis is a syndrome of objectively delayed gastric emptying of solids in the absence of a mechanical obstruction and cardinal symptoms of nausea, vomiting, early satiety, belching, bloating, and/or upper abdominal pain [4].

EPIDEMIOLOGY — In one of the largest population-based studies that identified 3604 potential cases of gastroparesis, of whom 83 fulfilled diagnostic criteria for definite gastroparesis, the age-adjusted incidence of gastroparesis was 2.4 per 100,000 person-years for men, 9.8 per 100,000 person-years for women, and 6.3 per 100,000 person-years for the combined cohort of men and women [5]. The age-adjusted prevalence of definite gastroparesis (based on symptoms and delayed gastric emptying measured by scintigraphy) was 9.6 per 100,000 persons for men and 38 per 100,000 persons for women. In an epidemiologic study from Europe, the estimated overall prevalence of gastroparesis was 13.8 per 100,000 persons with an incidence of 1.9 per 100,000 person-years [6]. A systematic review of the literature concluded that the prevalence of definite gastroparesis (symptoms plus evidence of delayed gastric emptying) in the general population ranged from 13.8 to 267.7 per 100,000 adults, and the incidence ranged from 1.9 to 6.3 per 100,000 person-years [7]. Across studies, gastroparesis was more common among females. Overall survival was significantly lower in patients with diabetes and in those with gastroparesis than for the age- and sex-matched general population [5,6]. However, other estimates have been lower. In a United States cross-sectional population-based study using electronic medical records and results of upper gastrointestinal endoscopy and gastric emptying tests, the prevalence of gastroparesis in type 1 and type 2 diabetics was 4.6 and 1.3 percent, respectively [8]. Overall, there were about 70,000 people with gastroparesis out of the 44 million people based on the electronic medical records, and the diagnosis was confirmed by the tests in only about 14 percent of those with a record of gastroparesis. Overall, these data suggest a calculated prevalence of 0.16 percent.

ETIOLOGY — Although multiple conditions have been associated with gastroparesis, the majority of cases are idiopathic, diabetic, iatrogenic (eg, medication-induced), or postsurgical (figure 1).

Idiopathic — Idiopathic gastroparesis may be the most common form of gastroparesis. It is estimated that no detectable primary underlying abnormality is found in approximately one-half of patients with delayed gastric emptying [9].

Diabetes mellitus — Diabetes mellitus (DM) is the most frequently recognized systemic disease associated with gastroparesis. Population-based studies in patients with diabetes mellitus have reported upper gastrointestinal symptoms in 11 to 18 percent of patients [10-13]. The estimated 10-year cumulative incidence of gastroparesis in patients with type 1 DM and type 2 DM was estimated to be 5.2 and 1 percent, respectively [7]. In studies from referral centers and hence potentially biased to select for patients with relatively severe disease, 50 to 65 percent of patients with diabetes and upper abdominal symptoms had delayed gastric emptying [14-16]. However, in a population-based cohort study, the cumulative incidence of gastroparesis over 10 years in patients with type 1 and type 2 DM was 5 percent and 1 percent, respectively, as compared with 0.2 percent in controls [17]. Symptoms of delayed gastric emptying are more pronounced in patients with type 1 DM as compared with patients with type 2 DM [18]. (See "Diabetic autonomic neuropathy of the gastrointestinal tract".)

Gastrointestinal complications of diabetes typically occur in patients who have had the disorder for more than five years. Patients with diabetes mellitus have abnormalities at several levels in the process of gastric emptying, including abnormal postprandial proximal gastric accommodation and contraction, and reduced frequency of antral contractions. These abnormalities are primarily due to autonomic dysfunction or abnormal intrinsic nervous system (eg, nitrergic neurons, or interstitial cells of Cajal, the pacemaker system of the gut) [19-21].

An alternative theory implicates a role for oxidative stress in the pathogenesis of diabetic gastroparesis [22-24]. Observations based predominantly on animal models of diabetes suggest that oxidative stress is associated with an increased number of macrophages and up-regulation of heme-oxygenase-1 (HO1) in CD206(+) M2 macrophages. Indeed, onset of delayed gastric emptying in these models of diabetic gastroparesis was not associated with alteration in the total number of macrophages, but a selective loss of the protective CD206(+)/HO1(+) M2 macrophages [23]. The clinical relevance of this oxidative stress was explored by studying the effects of hemin in a small randomized controlled trial; unfortunately, hemin, which was previously shown to activate HO-1 in humans, failed to sustain increased HO1 levels beyond a week and did not improve gastric emptying or symptoms in diabetic gastroparesis [25]. Therefore, the clinical relevance and potential to reverse effects of oxidative stress on intrinsic neural or ICC pathways in diabetic gastroparesis is still unclear.

Hyperglycemia (blood glucose >200 mg/dL) may also contribute to delayed gastric emptying. Although acute hyperglycemia, associated with poorly controlled diabetes, typically has a reversible effect on gastric emptying, chronic hyperglycemia is associated with an increased risk of neuropathy. The pathogenesis of delayed gastric emptying in diabetes is discussed in detail, separately. (See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on 'Pathogenesis'.)

There is increased appreciation of the impact of risk factors on gastroparesis, particularly in urban centers [26], and these include prescriptions for narcotic medications and the presence of comorbid risk factors, of which the most prevalent was type 2 diabetes.

Viral — A subset of patients with gastroparesis report sudden onset of symptoms after a viral prodrome, suggesting a viral etiology. Several reports have documented the occurrence of gastric stasis in association with prior viral infections, including Norwalk virus and rotavirus [27-29].

Postviral gastroparesis often improves over one year [28,30,31]. However, a small proportion of patients with infections due to viruses such as cytomegalovirus, Epstein-Barr virus, and varicella-zoster virus may develop severe dysautonomia or even selective cholinergic dysautonomia leading to persistent symptoms due to extrinsic autonomic denervation [32,33].

Medications — Several medications can delay gastric emptying. These include [2]:

●Narcotics (affecting mu opiate receptors alone or combined with inhibition of norepinephrine reuptake [eg, oxycodone and tapentadol, respectively]) [34].

●Alpha-2-adrenergic agonists (eg, clonidine).

●Tricyclic antidepressants [35].

●Calcium channel blockers.

●Dopamine agonists.

●Muscarinic cholinergic receptor antagonists.

●Octreotide [36].

●Glucagon-like peptide (GLP)-1 agonists (eg, exenatide) or analogues (eg, liraglutide) and amylin analogues [37].

●Phenothiazines [38].

●Cyclosporine (but not tacrolimus, which is derived from macrolide molecule like erythromycin, and does not inhibit gastric emptying).

●Immune checkpoint inhibitor therapy [39].

Postsurgical — Previous gastric and thoracic surgery can result in gastric stasis due to intended or accidental injury to the vagus nerves (eg, with Billroth II gastrectomy, fundoplication, lung or heart transplantation, paraesophageal hernia repair) [40,41]. Other cases of gastroparesis have been rarely reported in patients after duodenal switch, or biliopancreatic diversion or after Roux-en-Y gastric bypass for obesity [42,43]. Extrinsic vagal denervation or loss of the antrum reduces the capacity of the stomach to empty nondigestible solids during fasting, resulting in bezoar formation, and to triturate and empty digestible food postprandially. (See "Pathogenesis of delayed gastric emptying" and "Gastric bezoars", section on 'Pathogenesis'.)

Fundoplication is one of the most common surgical procedures leading to reversible or permanent vagal injury. Other causes of vagal injury include variceal sclerotherapy and botulinum toxin injection for medical treatment of achalasia [44-46] and radiofrequency ablation for atrial fibrillation [47]. Vagal injury can be demonstrated by measurement of the plasma pancreatic polypeptide (PP) response to modified sham feeding. With normal physiology, sham feeding, which consists of chewing but not swallowing food, results in cephalic vagal stimulation and thereby a rapid increase in plasma PP of at least 25 pg/mL in the first 20 minutes followed by a return to baseline. In patients with vagal injury, sham feeding is not associated with an increase in PP over baseline. In a generalized neuropathy or injury to the vagus nerve between the brainstem and the level of the heart, evidence of vagal injury can also be appraised by the heart period response to deep breathing (six times per minute); breathing results in sinus arrhythmia through a vagally-mediated reflex. Vagal injury or denervation results in a loss of sinus arrhythmia. This can be initially appraised on a standard 12-lead electrocardiogram. Loss of sinus arrhythmia may be reversible (eg, over several months after radiofrequency ablation for atrial fibrillation) [47].

Roux stasis syndrome can occur after a Roux-en-Y anastomosis. Uncoordinated contractions in the efferent Roux limb itself causes stasis either in the gastric remnant or in the Roux limb itself.

Neurologic disease — Several common neurologic disorders are associated with dysmotility of the upper gastrointestinal tract and resultant gastroparesis (figure 1).

●Extrinsic neural control (eg, the vagus nerve and lower thoracic spinal sympathetic outflow) may be affected in disorders such as multiple sclerosis, brainstem stroke or tumor, Parkinsonism, diabetic or amyloid neuropathy, or primary dysautonomias.

●The myenteric plexus may be involved in a degenerative, diffuse neurologic disorder (eg, diabetes, AIDS, or parkinsonism). Focal loss of intrinsic inhibitory innervation of the pylorus is responsible for congenital pyloric stenosis. In Parkinson disease, enteric nervous system dysfunction has been reported to precede motor symptoms by years to decades [48]. (See "Clinical manifestations of Parkinson disease", section on 'Cardinal features'.)

●Medications used to treat neurologic disease can also contribute to gastric stasis (eg, anticholinergics, dopaminergics). (See 'Medications' above.)

●Gastroparesis may be a manifestation of autonomic dysfunction. In a study of 242 patients with chronic gastroparetic symptoms, parasympathetic dysfunction was associated with delayed gastric emptying and more severe upper gastrointestinal symptoms [49]. Conversely, sympathetic hypofunction was associated with milder symptoms.

Autoimmune — Delayed gastric emptying has been described in association with autoimmune gastrointestinal dysmotility [50,51]. Autoimmune gastrointestinal dysmotility is a dysautonomia affecting the gastrointestinal tract that occurs idiopathically or in association with an anatomically remote neoplasm, most commonly small cell lung cancer. In addition to delayed gastric emptying, affected patients may have slow intestinal transit, slow colonic transit, and pelvic floor dyssynergia. The role of the autoimmune process in cases of acquired dysautonomia manifesting with symptoms that include gastroparesis is illustrated by the response to plasmapheresis treatment [52]. In a retrospective analysis of 11 female patients with drug- and device-resistant gastroparesis who had coexisting positive autoimmune profiles, treatment for 8 to 12 weeks with diverse immunomodulatory treatment showed total symptom score improvement in 6 out of 11 patients, with maximum gastrointestinal symptom improvement with intravenous immunoglobulin (2 out of 3 patients treated) [53]. In a subsequent open-label study, which included 14 patients (3 diabetic, 1 postsurgical, and 10 idiopathic gastroparesis) with serological and/or tissue evidence of immunological abnormality, intravenous immunoglobulin (400 mg/kg infusion weekly for 12 weeks) was associated with significant improvement in nausea, vomiting, early satiety, and abdominal pain, with 9 out of 14 patients declared as responders to this open-label treatment [54]. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Autonomic neuropathy'.)

Other — Other causes of gastroparesis include mesenteric ischemia and diseases that result in infiltration or degeneration of the muscle layer of the stomach (eg, scleroderma). Patients with gastric or intestinal involvement due to scleroderma usually have clinically evident systemic disease involving the skin, lungs, and/or the esophagus [55]. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

CLINICAL MANIFESTATIONS

Clinical features — Patients with gastroparesis can present with nausea (93 percent), vomiting (68 to 84 percent), abdominal pain (46 to 90 percent), early satiety (60 to 86 percent), postprandial fullness, bloating, and, in severe cases, weight loss [9,56]. The vomitus may contain food ingested several hours previously.

The predominant symptom may vary based on the underlying etiology. In a retrospective study that included 416 patients with gastroparesis, patients with idiopathic gastroparesis reported more early satiety, postprandial fullness, and abdominal pain as compared with patients with diabetic gastroparesis. In contrast, patients with diabetic gastroparesis had more severe retching and vomiting [18].

Bloating is common in gastroparesis and is severe in many individuals. In one study of 335 individuals with gastroparesis, bloating was at least mild in 76 percent and severe in 41 percent of individuals [57].

While abdominal pain is a frequent symptom in patients with gastroparesis, it is rarely the predominant symptom (18 percent). In patients whose predominant symptom is abdominal pain, other causes should be sought [58]. The pain is usually localized to the upper abdomen and is often described as burning, vague, or crampy. Approximately 60 percent report exacerbation of pain after eating. In one case series, pain interfered with sleep in 80 percent of patients. However, the severity of abdominal pain did not correlate with a delay in gastric emptying, suggesting that the cause of pain in this tertiary referral cohort may not have been gastroparesis [59]. (See 'Differential diagnosis' below.)

In the cohort of 506 patients assessed in the National Institute of Health gastroparesis consortium, abdominal pain was reported to be common in patients with gastroparesis, both idiopathic and diabetic. Severe or very severe upper abdominal pain occurred in 34 percent of the patients with gastroparesis and was associated with other symptoms of gastroparesis, somatization, anxiety, impaired quality of life, and opiate medication use [60], as well as cannabis use [61]. It is unclear whether this prominent and severe pain component reflects the tertiary nature of the cohort.

Early satiety and postprandial fullness are commonly severe symptoms in both diabetic and idiopathic gastroparesis [62,63].

Physical examination — Abdominal examination may reveal epigastric distention or tenderness, but not guarding or rigidity. There may be a succussion splash. (See "Gastric outlet obstruction in adults", section on 'Physical examination'.)

Patients may have signs of the underlying disorder resulting in gastroparesis. As an example, patients with systemic sclerosis and Raynaud phenomenon may have taut skin in the hands and chest, telangiectasia, small joint arthropathy, and crackles over the lower lung fields from interstitial lung disease. In diabetic patients, gastrointestinal complications are often associated with other signs of autonomic dysfunction [64,65]. These may include orthostatic hypotension and absence of the pupillary reaction to light with persistence of the accommodation response (the pseudo-Argyll-Robertson pupil or tonic pupil). (See "Tonic pupil" and "Diagnosis of and screening for hypothyroidism in nonpregnant adults", section on 'Clinical features' and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

EVALUATION — Gastroparesis should be suspected in patients with nausea, vomiting, early satiety, postprandial fullness, abdominal pain, or bloating. The goal of evaluation is to exclude a mechanical obstruction and establish the diagnosis of gastroparesis by an assessment of gastric motility. Evaluation should begin with a history and physical examination.

Exclude mechanical obstruction — All patients with suspected delayed gastric emptying and, in particular, patients with colicky abdominal pain should undergo a careful upper gastrointestinal endoscopy. We also perform computed tomographic (CT) enterography or magnetic resonance (MR) enterography to exclude mechanical obstruction (eg, from a small bowel mass or superior mesenteric artery syndrome). A barium follow-through examination is performed if CT/MR enterography are unavailable. The presence of retained food after an overnight period of fasting, although supportive of a diagnosis of gastroparesis, is not diagnostic.

Assess gastric motility — In patients with suspected gastroparesis and no evidence of a mechanical obstruction on imaging or upper endoscopy, an assessment of gastric motility is necessary to establish the diagnosis of gastroparesis.

Scintigraphic gastric emptying — The most cost-effective, simple, and widely available technique to confirm the presence of delayed gastric emptying of solids is scintigraphy (figure 2). Documenting the presence of delayed gastric emptying and assessing the severity is best achieved by evaluating the gastric emptying of solids. Since liquids often empty from the stomach normally even when solids are abnormally retained, assessment of liquid emptying is generally unnecessary unless dumping syndrome is suspected [66,67]. If patients are too sick to tolerate a solid meal, a liquid nutrient meal containing radioisotope may be used to permit scintigraphic measurement of gastric emptying [68]. However, it is important to establish normal values for comparison as the physical characteristics and fat content of the meal impact the rate of emptying and hence the normal values for gastric emptying [69]. Other centers [70] utilize real eggs or omelettes with higher fat content (~300 kcal with 30 percent fat) to test for gastroparesis arguing that the higher fat content provides an improved test for gastric motor function; the emptying profiles of different meal substrates are reviewed elsewhere [71]. Importantly, when an optimal gastric emptying test is conducted (solid meal, sufficient calories, assessed over at least three hours), there is a good correlation between the delayed gastric emptying and symptoms [72].

●Pretest instructions – Medications that affect gastric emptying should be stopped at least 48 hours before diagnostic testing [4]. Based on the pharmacokinetics of the medication, the medication may need to be stopped more than 48 hours before testing. Patients with diabetes should have blood glucose measured before starting the gastric emptying test, and hyperglycemia should be treated. The test should be performed only once blood glucose levels are <180 mg/dL.

●Test protocol – The suggested protocol involves a low fat egg-white meal with imaging immediately after meal ingestion and again at one, two, and four hours following ingestion. The meal composition may need to be altered depending upon the patient's specific symptoms. Updated normal values for (99m)Tc egg or egg substitute and consensus standards for performing and reporting gastric emptying scintigraphy have been published [73-75].

Studies suggest that scans obtained immediately after meal ingestion and two and four hours later are sufficient for most clinical indications [73,76,77]. Several centers limit scans to two hours; this is suboptimal. However, it is important to note that for delayed gastric emptying, gastric residual at four hours has a higher sensitivity for delayed gastric emptying as compared with the two-hour measurement [76-78]. Evaluation should be extended to four hours in patients with normal two-hour results. As an example, in one study in which scintigraphy was performed on 129 consecutive patients with suspected gastroparesis, the percentage of patients with delayed gastric emptying increased from 33 percent at two hours to 58 percent using the results of the two-, three-, and four-hour scans [78].

●Interpretation of test results – Delayed gastric emptying is defined as gastric retention of >10 percent at four hours and/or >60 percent at two hours when using the standard low fat, scrambled egg protein meal described above [73]. Although the severity of symptoms do not always correlate with the rate of gastric emptying, delayed gastric emptying has been classified based on the extent of gastric retention on scintigraphy at four hours into the following:

•Mild – 10 to 15 percent

•Moderate – 15 to 35 percent

•Severe – >35 percent

Normal values for the percent remaining in the stomach at the key time points are 37 to 90 percent at one hour, 30 to 60 percent at two hours, and 0 to 10 percent at four hours. It should be noted that each institution's nuclear medicine department may have different normal values, which vary with the nature of the meal and isotope used.

Normal data have also been reported for a higher (30 percent) fat-containing "real egg" test meal with higher caloric content (298 kcl). With such a meal, gastroparesis is diagnosed when there is >75 percent retained in the stomach at two hours and >25 percent retained in the stomach at four hours [70].

Alternatives to scintigraphy — Alternative approaches for assessment of gastric emptying include wireless motility capsule testing and ¹³C breath testing using octanoate or spirulina incorporated into a solid meal [3].

Wireless motility capsule – A wireless motility capsule (WMC) can simultaneously measure phasic pressure amplitudes, temperature, and pH as it traverses different segments of the gastrointestinal tract [79]. The characteristic change in pH between stomach and small intestine provides an indication of the gastric emptying time for a nondigestible solid >1 cm long [80]. A systematic review that included seven studies found that for the diagnosis of gastroparesis, as compared with gastric scintigraphy, WMC had a sensitivity of 59 to 86 percent and specificity of 64 to 81 percent [81].

When the WMC is given with a meal, it often emptied after five hours as it requires fasting migrating motor complex (MMC) to be emptied. In about 30 percent of occasions in healthy adults, it emptied with coordinated postprandial antral contractions; in the other healthy adults, the WMC emptied when there was a return of fasting MMCs [82]. The amplitude of contractions immediately before emptying from the stomach can provide useful information to exclude a myopathic disorder (eg, scleroderma, amyloidosis) which are associated with low amplitude distal antral contractions (<40 mmHg) [83].

●¹³C breath testing – C¹³-labeled acetate, octanoic acid breath tests, or spirulina (a plant-based protein source) have been used to assess gastric emptying [84-86]. After ingestion of the stable isotope labeled test meal, the expiratory 13-CO₂ concentration is measured (eg, by mass spectrometry or infrared spectroscopy). The test is noninvasive and, unlike scintigraphy, avoids radiation exposure. Most studies suggest that the accuracy of these breath tests in normal and pathologic conditions is less than that of scintigraphic measurements of gastric emptying [85,87,88]. The spirulina ¹³C breath test was approved by the US Food and Drug Administration to diagnose gastroparesis in April 2015 [89]. Approval was based on the observation in a study of 115 patients who underwent simultaneous scintigraphy and spirulina ¹³C breath test. At 80 percent specificity, the ¹³C-spirulina breath test samples at 150 and 180 minutes had a combined sensitivity of 89 percent for delayed gastric emptying [88]. (See "Diabetic autonomic neuropathy of the gastrointestinal tract".)

DIAGNOSIS — Gastroparesis is suspected in patients with nausea, vomiting, early satiety, postprandial fullness, abdominal pain, or bloating. A mechanical obstruction is excluded with imaging (eg, computed tomography or magnetic resonance enterography) or upper endoscopy as discussed in the evaluation approach above (see 'Evaluation' above). The presence of delayed gastric emptying on scintigraphy establishes the diagnosis of gastroparesis.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of gastroparesis includes other causes of chronic nausea and vomiting. This is discussed in detail, separately. (See "Approach to the adult with nausea and vomiting", section on 'Chronic disorders'.)

●Psychiatric disease – Vomiting, anorexia, and other clinical symptoms of gastroparesis may be the presentation of psychiatric diseases (eg, depression or anxiety neurosis), classical eating disorders (eg, anorexia nervosa, bulimia), psychogenic vomiting, or a side effect of a psychotropic medication.

The differentiation between an intrinsic gastric stasis syndrome and an eating disorder that includes vomiting can be very difficult. A thorough history may help (eg, in bulimia); however, physiologic abnormalities of the stomach such as gastric emptying delays or dysrhythmias have been documented in anorexic patients, rendering the distinction difficult. A high index of suspicion of an eating disorder is essential, particularly in young women with significant weight loss and an altered body perception or indifference towards weight loss. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Gastroparesis'.)

●Rumination syndrome – Rumination syndrome is a behavioral disorder that is most commonly identified among mentally disadvantaged children, although it is increasingly recognized among adolescents and adults of normal mental capacity, particularly among those who are highly stressed, high achievers, or perfectionists [90-92]. The behavior consists of daily, effortless regurgitation of undigested food within minutes of starting or completing ingestion of a meal. Regurgitation is not preceded by nausea or retching. Unlike patients with gastroparesis, patients with rumination syndrome have normal gastric emptying. (See "Rumination syndrome", section on 'Clinical manifestations'.)

●Functional dyspepsia – Symptoms of gastroparesis overlap with those of functional dyspepsia. However, early satiety, postprandial fullness, and epigastric pain or burning are the predominant symptoms in patients with functional dyspepsia and, in contrast, nausea, vomiting, and weight loss are the predominant symptoms in patients with gastroparesis. In contrast to patients with gastroparesis, gastric emptying is normal in patients with functional dyspepsia, but one-third of patients with functional dyspepsia have slow emptying. The National Institutes of Health (NIH) gastroparesis consortium data also identified overlap of diagnosis during follow-up, as patients originally diagnosed as gastroparesis subsequently fulfilled criteria for functional dyspepsia and vice-versa [63]. Therefore, a gastric emptying test with definite cut-off criteria for diagnosing gastroparesis (eg, 300 kcal, 30 percent fat egg meal and >25 percent retained in the stomach at four hours, and/or >75 percent retained at two hours) is recommended based on normal value data acquired in 319 healthy adults [70]. It is unclear whether "chronic unexplained nausea and vomiting" included as a subcategory in Rome IV criteria is an entity distinct from gastroparesis or functional dyspepsia. (See "Functional dyspepsia in adults".)

●Cyclic vomiting syndrome – Cyclic vomiting syndrome (CVS) refers to recurrent episodes of intense nausea and vomiting lasting hours to days separated by symptom-free periods of variable lengths. CVS is mimicked by cannabinoid hyperemesis [93]. Gastric emptying is rapid in some patients with CVS during symptom-free periods. (See "Cyclic vomiting syndrome", section on 'Clinical manifestations' and "Cyclic vomiting syndrome", section on 'Diagnosis'.)

ESTABLISHING THE ETIOLOGY — Once the diagnosis of gastroparesis is established, the underlying etiology should be determined. In patients with gastroparesis in whom there is a known underlying disease, no further investigation is necessary. In patients with gastroparesis and no known underlying disease, we perform laboratory testing. We perform gastroduodenal manometry in patients without an identifiable etiology despite laboratory testing. Autonomic testing is useful in patients with evidence of neuropathic dysmotility on manometry, but without a known underlying neurologic disorder (algorithm 1).

Laboratory studies — Laboratory testing may help to identify diseases associated with delayed gastric emptying. We obtain the following tests: hemoglobin, fasting plasma glucose, serum total protein, albumin, thyrotropin (TSH), and an antinuclear antibody (ANA) titer. In patients with diabetes, we obtain an HbA1c to assess their glycemic control. In patients with a long-standing history of smoking, we test for ANNA-1 or anti-Hu antibody in search for paraneoplastic gastroparesis. In patients with multiple symptoms suggesting other neurological or autonomic (including bladder, sweating, postural dizziness), we perform additional laboratory tests for evidence of viral infection or autoimmune process directed to nicotinic acetyl choline receptors. (See 'Viral' above.)

Gastroduodenal manometry — Manometry can help differentiate a myopathic process (eg, amyloid and scleroderma) from a neuropathic process (eg, diabetes mellitus, amyloid neuropathy, and idiopathic autonomic neuropathy), if this distinction cannot be achieved by other tests (eg, gastric emptying, blood tests or tissue diagnosis). Myopathic disorders are typically associated with low amplitude contractions (mean <40 mmHg in antrum), whereas in neuropathic disorders the amplitude of contractions is typically normal, but the organization of the contractile response is abnormal and there is a persistence of fasting motor patterns after meal ingestion [94]. High resolution water-perfused antropyloroduodenal and jejunal manometry may identify antral, pyloric, or small intestinal dysmotility that may aid in selection of therapy (eg, pharmacologic stimulation or pyloromyotomy) [95,96].

Identification of pylorospasm or reduced pyloric compliance — Multilumen manometry or Endoflip can identify pylorospasm [97] or reduced diameter or compliance or distensibility of the pylorus [98]. Evaluation for pylorospasm or reduced compliance is increasingly relevant as gastric per-oral endoscopic myotomy or laparoscopic pyloroplasty is being offered as a treatment for gastroparesis. It is important to note that opioid stimulation results in pylorospasm as well as gastroparesis with antral hypomotility [99]. (See "Treatment of gastroparesis".)

Autonomic testing — Autonomic testing may be useful in patients with a neuropathic pattern on manometry to further define the etiology of gastric stasis (table 1). These tests permit differentiation of a preganglionic or central lesion from a peripheral neuropathy associated with autonomic dysfunction. In patients in whom a central lesion is suspected, brain and spinal cord magnetic resonance imaging (MRI) should be performed. In patients with a peripheral dysautonomia, further screening for a toxic (eg, lead poisoning), metabolic (eg, porphyria), or paraneoplastic process (eg, lung cancer) should be performed (algorithm 1).

Other tests — Several other tests have been used in patients with gastroparesis but are predominantly research tools. Their role in clinical practice has not been defined.

●Electrogastrogram – Cutaneous electrogastrogram (EGG), involves placement of surface electrodes to record the electrical control activity or "pacemaker" of the stomach (figure 3) [100,101]. Alterations in frequency (bradygastria, tachygastria, or mixed) and reduction in the amplitude ("power") of the postprandial electrical signal are seen in patients with idiopathic and diabetic gastroparesis, anorexia nervosa, vector/motor sickness, and nausea of pregnancy. Dysrhythmias have also been described in patients with nonulcer dyspepsia, with or without evidence of gastric stasis. The precise role of EGG in the clinical evaluation and management of patients with gastroparesis is the subject of ongoing research [100,101].

●Single photon emission computed tomography (SPECT) – The accommodation response is related to early satiety and bloating postprandially. SPECT has been used to characterize postprandial accommodation in a variety of upper gut dysmotilities [102-104]. SPECT may help to identify subgroups of patients with gastroparesis that are candidates for more selective pharmacotherapy. MRI measurements have also been used to measure gastric accommodation [105]. In a cohort of approximately 100 patients with diabetes and upper gastrointestinal symptoms (16.7 percent with a history of opioid use), there were almost equal numbers with abnormal gastric emptying, abnormal gastric accommodation, both abnormal or neither abnormal [106]. Increased gastric accommodation volume is associated with slower gastric emptying rate [107], and this may explain the potential benefit of sleeve gastrectomy in patients with significant gastro-esophageal reflux reported in an uncontrolled study [108]. It is important to note that the results of sleeve gastrectomy require confirmation with sham-controlled trials in patients with gastroparesis, including documentation of the gastric fasting and post-meal or accommodation volume.

●Full thickness gastric and small intestinal biopsy – Pathological examination of full thickness gastric and small intestinal biopsies may provide confirmation of the organic nature of the gastric stasis and may provide prognostic information [109]. Full thickness biopsy should not be performed outside of research studies [3]. In the largest series of 101 patients in a referral practice with refractory and unexplained nausea and vomiting, a high incidence of small bowel morphologic abnormalities (primarily neuropathies) was reported [110]. The histologic abnormalities in gastroparesis are heterogeneous and include myenteric inflammation, decreased innervation, reduced number of interstitial cells of Cajal (ICC), and rarely muscle fibrosis [111,112]. Absence of ICCs was associated with abnormalities of gastric slow waves, worse symptoms of gastroparesis, and less improvement with gastric electrical stimulation [20].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastroparesis".)

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SUMMARY AND RECOMMENDATIONS

●Definition – Gastroparesis is a syndrome of objectively delayed gastric emptying in the absence of a mechanical obstruction and cardinal symptoms of nausea, vomiting, early satiety, bloating, and/or upper abdominal pain. (See 'Definition' above.)

●Etiology – Although multiple conditions have been associated with gastroparesis, the majority of cases are idiopathic, diabetic, or postsurgical. (See 'Etiology' above.)

●Clinical manifestations – Patients with gastric stasis present with nausea, vomiting, abdominal pain, early satiety, postprandial fullness, bloating, and, in severe cases, weight loss. While abdominal pain is a frequent symptom in patients with gastroparesis, it is rarely the predominant symptom. (See 'Clinical manifestations' above.)

●Diagnosis – Gastroparesis should be suspected in patients with nausea, vomiting, early satiety, abdominal pain or bloating. We perform upper endoscopy followed if clinically indicated by computed tomography/magnetic resonance enterography to exclude mechanical obstruction or mucosal disease as a cause of impaired gastric emptying. Delayed gastric emptying on scintigraphy is required to establish the diagnosis of gastroparesis (algorithm 1).

On scintigraphy, delayed gastric emptying is defined as gastric retention of >10 percent at four hours and/or >60 percent at two hours when using the 250 kcal, 2 percent fat egg protein meal. Alternatively, the cut-offs are >75 percent at two hours and >25 percent at four hours when using the 300 kcal, 30 percent fat "real egg" meal. (See 'Evaluation' above and 'Diagnosis' above.)

●Routine evaluation to determine the underlying etiology – Once the diagnosis of gastroparesis is established, the underlying etiology should be determined. In patients with gastroparesis and no known underlying disease, we obtain the following laboratory tests: hemoglobin, fasting plasma glucose, serum total protein, albumin, thyrotropin (TSH) concentrations, and antinuclear antibody titer. (See 'Laboratory studies' above.)

●Additional evaluation in patients without a clear etiology – In patients with gastroparesis without an identifiable cause despite laboratory testing, we perform gastroduodenal manometry provided that the expertise is available. Manometry can help differentiate a myopathic process from a neuropathic process. We perform autonomic testing in patients with a neuropathic pattern on manometry to further define the etiology of gastric stasis (algorithm 1). (See 'Gastroduodenal manometry' above and 'Autonomic testing' above.)