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. Author manuscript; available in PMC: 2022 Aug 1.
Published in final edited form as: Neurogastroenterol Motil. 2021 May 17;33(8):e14174. doi: 10.1111/nmo.14174

A North American perspective on the ESNM consensus statement on gastroparesis

Michael Camilleri 1, Saam Dilmaghani 1, Kia Vosoughi 1, Ting Zheng 1
PMCID: PMC8373778  NIHMSID: NIHMS1700487  PMID: 33998746

1 |. INTRODUCTION

We congratulate the members of the European Society of Neurogastroenterology and Motility (ESNM) with expertise in gastroparesis and the United European Gastroenterology (UEG) Federation Sister Societies for developing comprehensive recommendations on gastroparesis. We noted their due diligence, conduct of a Delphi consensus processes, systematic literature reviews, and grading of the strength using accepted criteria.

The objective of our commentary is to identify and comment only on topics where additional insight or more recent literature (not only from North America) is available to continue to enhance the recommendations. To achieve this objective, we have reviewed the salient ESNM statements, and whether they were endorsed or rejected by the ESNM working group, and we have provided a commentary on each based on the published evidence base.

2 |. DEFINITIONS AND SYMPTOM DESCRIPTORS

We endorse almost all statements from the European Society for Neurogastroenterology and Motility (ESNM) Consensus on Gastroparesis in this section.

2.1 |. Dyspeptic symptoms such as postprandial fullness, early satiation, epigastric pain, and bloating in the upper abdomen and belching are often present in gastroparesis patients. STATEMENT ENDORSED

2.2 |. Symptoms in gastroparesis patients overlap mainly with postprandial distress syndrome (PDS) and less with epigastric pain syndrome (EPS) symptoms of FD. STATEMENT ENDORSED

We agree that patients with gastroparesis can present with a wide range of dyspeptic symptoms, particularly those overlapping with PDS.1 Abdominal pain is often not considered a major symptom of gastroparesis. However, despite confounding elements such as opioid use, prior studies have reported abdominal pain in up to 90% of patients with either diabetic or idiopathic gastroparesis.2 Using validated questionnaires, Jehangir et al. identified both neuropathic and nociceptive components of abdominal pain, which is typically characterized as sharp and located in the epigastrium.3

3 |. EPIDEMIOLOGY AND RISK FACTORS

3.1 |. The epidemiology of gastroparesis is not established, mainly because it requires gastric emptying testing which has not been done at the population level. STATEMENT ENDORSED

We agree that the epidemiological characteristics of gastroparesis have been difficult to elucidate, as objective testing using upper gastrointestinal endoscopy and gastric emptying scintigraphy are not widely used. For example, Syed et al.2 utilized a large cloud-based platform that surveyed electronic medical records from over 340 hospitals in the USA. They found that, despite an International Classification of Disease for diagnosis of gastroparesis, nearly 80% of patients had never undergone gastric emptying scintigraphy testing, and only 14% of patients had undergone both upper gastrointestinal endoscopy and gastric emptying scintigraphy testing.2 They reported a crude prevalence rate of 0.16% for a documented diagnosis of gastroparesis. Of the patients with type 1 or type 2 diabetes, 4.6% and 1.3% had concurrent gastroparesis, respectively. Thus, epidemiological studies have relied on clinical or medical records diagnoses of gastroparesis, including that by Ye et al.3 which used a national database that included 7% of the entire UK population with nearly complete medical records.

It is, nevertheless, relevant to include important population-based studies, also recognized by the working group, such as the study by Jung et al.4 They utilized nearly complete medical data, including optimal (4-hour) scintigraphic measurement of gastric emptying, in a sample of patients representing the Caucasian population in the USA. Over the period 1996–2006, they estimated a prevalence and incidence of “definite” (i.e., those meeting diagnostic criteria) gastroparesis of 24.2 and 6.3 per 100,000 person-years, respectively.4 They also were able to describe the demographic characteristics of gastroparesis, including female preponderance, age at diagnosis, employment status, tobacco, and alcohol use.

3.2 |. Acute gastrointestinal infection is a risk factor for development of gastroparesis. STATEMENT NOT ENDORSED

Post-viral gastroparesis may result from injury to the enteric nervous system, directly via an inoculant, indirectly via an inflammatory response to the pathogen, or as a result of both processes. Meeroff and colleagues demonstrated that acute viral gastroenteritis was associated with transient gastric motor dysfunction, particularly rates of gastric emptying of liquids,5 as well as findings on small bowel biopsies consistent with non-bacterial gastroenteritis. Even more relevant is a review of patients suffering viral gastroenteritis who subsequently developed gastroparesis, including a series from Mayo Clinic.6 In many of these cases, restoration of normal gastric emptying occurred by 12 months. The most cited pathogens were not norovirus as previously suspected, but rather parvovirus, cytomegalovirus, and Epstein-Barr virus,7 which may sometimes cause a more generalized autonomic disorder.8,9 In another series of patients with suspected idiopathic gastroparesis, gastric mucosal biopsies identified enterovirus infection, and 50% responded to anti-viral treatment.10

3.3 |. Hypothyroidism is a risk factor for development of gastroparesis. STATEMENT NOT ENDORSED

We agree with the working group that it may be too early to confidently say that hypothyroidism definitively confers an increased risk of developing gastroparesis. However, the role of thyroid function on the gastrointestinal tract—from the esophagus to the colon—has been well established in prior literature for many decades.11–15 This includes improvement in gastric emptying as measured by scintigraphy following correction of hyper- and hypothyroidism,14 and slower gastric emptying in those with hypothyroidism when withdrawing thyroid replacement and when compared to control subjects.12,13 More recently, Canpolat et al. conducted a prospective study in a cohort of patients with subclinical hypothyroidism and demonstrated a significant improvement in the Gastroparesis Cardinal Symptom Index (GCSI).15 These studies have implications for patient management, particularly those with subclinical hypothyroidism.

4 |. IMPACT OF GASTROPARESIS

4.1 |. Gastroparesis is associated with decreased life expectancy. STATEMENT NOT ENDORSED

As the working group correctly noted, there have been multiple population-based studies that have investigated the mortality associated with gastroparesis. In most of these cases, excess mortality was observed. However, the working group suggested that excess deaths were attributable to cardiovascular causes, and thus they did not support this statement. We feel this position requires elaboration.

The robust epidemiological study by Jung et al.4 estimated a 5-year survival among those with gastroparesis to be 67%, as compared to 81% in population controls (p < 0.001). Furthermore, they simply presented the distribution of the causes of death in the cohort of patients with gastroparesis rather than evaluating the causes of excess deaths. Another study found, among people with diabetes, a trend toward higher mortality in those with objective gastroparesis when compared to those with gastroparesis symptoms and negative gastric emptying scintigraphy test and also no gastroparesis symptoms.16 In the epidemiological study from the United Kingdom, Ye et al.3 found worse survival among those with diabetic versus idiopathic gastroparesis, but did not provide comparison to the control population.

The working group’s suggestion that the cause of death should be considered when validating excess mortality among patients with gastroparesis assumes that the mechanisms by which gastroparesis leads to death are known. It also does not consider the potential for gastroparesis to indirectly lead to increased mortality. The mechanism of any impact of gastroparesis on survival has not been established, and, therefore, we would recommend future investigations to consider causes of both all and excess deaths among patients with gastroparesis compared to the general population.

4.2 |. Gastroparesis is an important source of loss of work productivity. STATEMENT NOT ENDORSED

The working group cited multiple studies that have demonstrated the negative societal impact from gastroparesis, yet they chose not to endorse the statement that gastroparesis is a source of loss of work productivity. Other studies have demonstrated the burden of gastroparesis on the individual, caregivers, and healthcare system. Over the period 1995–2004, Wang and colleagues found a 150% increase in hospitalizations, for which gastroparesis was the primary diagnosis, while all hospitalizations increased by only 13%, and hospitalizations due to other upper gastrointestinal causes changed from −3% to 76%. Additionally, hospitalizations for gastroparesis had the longest length of stay. Hyett et al.16 found patients with diabetes with and without objective gastroparesis had more frequent hospitalizations, and more hospital days, office visits, and emergency department visits.17 Although these studies did not specifically measure loss of work productivity as considered by the working group, it would be reasonable to infer that the patients with gastroparesis would suffer greater loss of productivity as a result of greater healthcare utilization.

A more direct impact on productivity is provided by Jehangir et al.18 who investigated the burden on patients with gastroparesis and their caregivers. They demonstrated that upper gastrointestinal symptoms prevented patients with gastroparesis from completing professional and personal responsibilities to a greater extent than those with gastroesophageal reflux disease and healthy controls. Similarly, caregivers of patients with gastroparesis reported a greater number of work hours missed, impact on professional responsibilities, and personal activities due to the patients’ symptoms.

Overall, these data support the relevance of the societal impact of gastroparesis on patients with gastroparesis and their caregivers.

4.3 |. Weight loss can be a consequence of gastroparesis. STATEMENT NOT ENDORSED

The working group decided not to endorse the statement that gastroparesis can lead to weight loss, which we think is a reasonable decision, based on the cited study by Sarnelli et al.19 and an additional U.S. report. Parkman et al.20 utilized a cross-sectional design to evaluate associations between symptom severity of gastroparesis, delayed gastric emptying, and other demographic variables. They found that body mass index was lower in those with more severe symptoms of early satiety, but that there was no association with self-reported weight changes since diagnosis of gastroparesis. However, such cross-sectional studies that rely on self-reporting are suboptimal for assessing a time-dependent variable such as weight loss and are too imprecise to evaluate any related associations. Again, this demonstrates many of the same limitations discussed in the publication by Sarnelli et al.19

Overall, there exists a paucity of data regarding the relationship between gastroparesis and subsequent weight loss, and we suggest the need for prospective follow-up of patients from the time of diagnosis of gastroparesis with repeated objective weight measurements, or use of electronic medical records and databases to retrospectively analyze trends in weight and body mass indices in the years leading up to or following the diagnosis of gastroparesis.

5 |. PATHOPHYSIOLOGY OF GASTROPARESIS

5.1 |. Delay in gastric emptying underlies symptom generation in gastroparesis. STATEMENT NOT ENDORSED

While the etiology of symptom generation in gastroparesis is likely multifactorial, delay in gastric emptying plays an essential role and is considered mandatory for the diagnosis of gastroparesis. Early studies showed inconsistent correlation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis.21 However, those studies did not assess the potential role of altered gastric accommodation and visceral hypersensitivity. Thus, among patients with upper gastrointestinal symptoms and delayed gastric emptying, 37% also had reduced gastric accommodation.22 Moreover, in a separate systematic review and meta-analysis, there was a significant association between optimally measured gastric emptying and nausea in patients with gastroparesis,23 as well as a positive association between improvement in gastric emptying and upper gastrointestinal symptoms.24 These studies underscore the critical importance of utilizing optimal gastric emptying test methodology for future research and clinical practice.

5.2 |. Duodenal mucosal alterations (low-grade inflammation, impaired permeability) are not implicated as pathophysiological mechanisms in gastroparesis. STATEMENT NOT ENDORSED

There is a paucity of studies investigating duodenal mucosal alterations in the pathogenesis of gastroparesis. Nevertheless, a recent study discovered alteration in duodenal mucosal mitochondrial gene expression and resultant reduced mitochondrial density in association with neuropathy and delayed gastric emptying in patients with diabetic gastroenteropathy compared to controls.25

5.3 |. Loss of interstitial cells of Cajal is a pathophysiological mechanism in gastroparesis. STATEMENT NOT ENDORSED

In addition to the evidence provided by the working group, we also noted that, in a study from the large cohort of the NIDDK Gastroparesis Clinical Research Consortium (GpCRC) using full-thickness gastric body biopsies, Grover et al. described loss of interstitial cells of Cajal (ICC) as the most common histological defect in gastroparesis, with remaining ICCs showing injury,26 characterized by abnormal morphology with intracytoplasmic vacuoles, mitochondria with clear matrix, and prominent rough endoplasmic reticulum encased in a stroma rich in collagen fibrils. Compared to controls, ICCs were not in contact with nerve endings and rarely in contact with smooth muscle cells and other ICCs. It was also found that ICC injury was more severe in idiopathic than diabetic gastroparesis.27

5.4 |. Loss of enteric nerves is a pathophysiological mechanism in gastroparesis. STATEMENT NOT ENDORSED

The enteric nervous system integrates the extrinsic excitatory innervation from the vagus nerve, but functions independently to stimulate the smooth muscle cells through ICCs and fibroblast-like cells that express PDGFRα. The studies by Grover et al. did not show systematic loss of intrinsic neurons expressing specific neurotransmitters.26 However, full-thickness gastric biopsies from patients with diabetic gastroparesis showed decreased nerve fibers and large, empty nerve endings surrounded by a thick basal lamina. Nerve structures were also altered in those with idiopathic gastroparesis, marked by abnormally shaped and oriented mitochondria and cristae, and chaotically arranged neurofilaments. The cytoplasm of glial cells was filled with lysosomes and vacuoles.26,27

5.5 |. Primary changes in gastric smooth muscle are a pathophysiological mechanism in gastroparesis. STATEMENT NOT ENDORSED

Smooth muscle cells from transmural gastric biopsies from patients with gastroparesis were graded as normal with H&E staining.26 However, despite normal morphology, transmission electron microscopy showed markedly thickened basal lamina, with stroma rich in collagen fibrils and smooth muscle cells distanced from each other in patients with diabetic gastroparesis compared to those with idiopathic gastroparesis and controls.27

5.6 |. Loss of vagus nerve function is a pathophysiological mechanism in gastroparesis. STATEMENT NOT ENDORSED

It is clearly demonstrable that patients with surgical trauma to the vagus nerve may suffer from delayed gastric emptying and symptoms of gastroparesis.28–30 Based on test of cardiovagal function, vagal cholinergic fibers are affected to a greater degree in patients with diabetic gastroparesis compared to those with idiopathic gastroparesis.31 A recent study from the NIDDK Gastroparesis Clinical Research Consortium (GpCRC) with 242 patients showed that both sympathetic and parasympathetic dysfunctions were observed in patients with gastroparesis-like symptoms. Parasympathetic hypo-function was associated with more severe symptoms and greater delay in gastric emptying.32 Based on these findings, noninvasive devices such as the gammaCore vagal nerve stimulator have also been shown to improve symptom scores and gastric emptying.33

6 |. DIAGNOSIS

We agree with the endorsements by the ESNM working group regarding the diagnosis of gastroparesis, specifically, exclusion of gastric or small intestinal obstruction, upper gastrointestinal endoscopy, and gastric emptying testing (by scintigraphy or breath test, but not by wireless motility capsule or ultrasound) being mandatory for establishing a diagnosis of gastroparesis, although the presence of food in the fasting state during endoscopy is not sufficient for diagnosis.

7 |. TREATMENT

7.1 |. Dietary adjustments are useful for managing gastroparesis patients. STATEMENT ENDORSED

As endorsed by the ESNM working group, dietary modification reduces gastroparesis cardinal symptoms and should be the first step in the management of patients with gastroparesis. Gastroparesis diet focuses on minimizing symptoms, maintaining adequate nutritional intake, and optimizing glycemic control in diabetic gastroparesis.34,35

Studies about optimized diets in patients with gastroparesis are scarce and, in summary, high fiber (especially nondigestible) content food causes gastric emptying delay, aggravates upper GI symptoms,36 and increases the risk of phytobezoar formation37 and abdominal distention34 as a result of fiber fermentation.

Similarly, solid, high-fat food, but not liquid, high-fat food aggravates symptoms38 and delays gastric emptying.39 Conversely, food with high carbohydrate content tends to be well tolerated,40 although it requires attention in patients with diabetic gastroparesis.

Gastric emptying of small particles is faster than large particles,41 and a randomized, controlled trial demonstrated that patients benefit from mechanically reduced or homogenized meals with small particle size.42

7.2 |. In case of severe weight loss or intractable vomiting, nutritional support may be needed in the form of enteral or parenteral nutrition. STATEMENT ENDORSED

As endorsed by the ESNM, the American College of Gastroenterology guideline35 had recommended that, in case of severe weight loss or intractable vomiting, stepwise nutritional support in the form of enteral or parenteral nutrition is required. Enteral feeding is well tolerated with an acceptable complication rate and, therefore, is recommended for long-term nutritional support in patients who do not tolerate oral intake.35 Parenteral nutrition support is rarely necessary, and it is associated with a high risk of complications.43

7.3 |. Proton pump inhibitor therapy is only effective for associated reflux symptoms in gastroparesis. STATEMENT NOT ENDORSED

Given the high prevalence of co-existing gastroesophageal reflux disease (58%) in patients with gastroparesis, proton-pump inhibitors are used extensively for anti-reflux effects (with 80% of diabetic patients in the NIDDK Gastroparesis Clinical Research Consortium taking proton pump inhibitors).44

7.4 |. Prokinetic therapy is the most appropriate first-line therapy/ies effective for gastroparesis. STATEMENT NOT ENDORSED

Prokinetics, as a whole group, are recommended as the first line of pharmacological treatment in patients who continue to have symptoms despite dietary modification, according to the American College of Gastroenterology Guideline on Gastroparesis.35 Prokinetics have been shown to improve both symptoms and gastric emptying.

7.5 |. The efficacy of prokinetics is not related to their enhancement of gastric emptying rate. STATEMENT NOT ENDORSED

A systematic review on the use of prokinetics declared a lack of correlation between improvement of symptoms and gastric emptying results based on pooled effects of botulinum toxin injection and prokinetics.21 However, when studies with optimal and sub-optimal gastric emptying test methods were analyzed separately in a more recent meta-analysis, improvement in upper gastrointestinal symptoms correlated with improvement of optimally measured gastric emptying,24 with a clinically significant effect on symptoms based on an acceleration of gastric emptying T1/2 of 20.4 min.

7.6 |. Dopamine-2 antagonists are effective for gastroparesis. STATEMENT ENDORSED

Metoclopramide is the most commonly used and is the first-line prokinetic therapy for gastroparesis.35 The problem for practitioners in the United States is a black box warning issued by the FDA in 2009 regarding long-term or high-dose metoclopramide side effects, including tardive dyskinesia. Despite evidence that the risk of irreversible tardive dyskinesia is much lower than the claim in the FDA warning, estimated to be 1–10 per 100045 or 0.1% per 1000 patient-years,46 the black box warning remains a deterrent to the use of metoclopramide.

7.7 |. Motilin-receptor agonists are effective for gastroparesis. STATEMENT NOT ENDORSED

The ESNM working group did not reach a consensus on the effectiveness of motilin-receptor agonists. Motilin-receptor agonists showed an acceleration of gastric emptying rate in small placebo-controlled studies47; they are widely used in clinical practice, typically for no longer than 4 weeks at a time due to the high risk of tachyphylaxis.48 Intravenous erythromycin has also been recommended for acute gastroparesis in hospitalized patients.35 Azithromycin appears comparable to erythromycin in gastric emptying improvement, with a better side effect profile.47

7.8 |. Pyloric botulinum toxin injection or myotomy is effective for gastroparesis. STATEMENT NOT ENDORSED

As articulated by ESNM guidance, pyloric botulinum toxin injection (PBTi) is generally not recommended for the treatment of gastroparesis49,50 in clinical practice, based on large, open-label experience.51

As a result of advances in endoscopic techniques, studies using gastric peroral endoscopic pyloromyotomy (G-POEM) performed predominantly in tertiary centers with expert endoscopists have reported promising short- to mid-term efficacy and safety profile.52 Long-term results and randomized, controlled trials are required to assess the outcomes of G-POEM.

Assessment of physiologic characteristics of the antrum and pylorus using an endoscopic functional luminal imaging probe (EndoFLIP) or antroduodenal manometry might help find a subset of patients with gastroparesis who benefits from pyloric-directed interventions including G-POEM and PBTi.53,54

7.9 |. NK1 antagonists are effective for gastroparesis. STATEMENT NOT ENDORSED

NK1 antagonists (e.g., aprepitant and tradipitant) have been shown to be effective for at least some of the cardinal symptoms of gastroparesis. Aprepitant, in comparison with placebo, was associated with increased maximum volume of a nutrient drink ingested as well as fasting and postprandial gastric volumes in healthy volunteers.55 In a placebo-controlled, randomized trial in patients with gastroparesis, several secondary endpoints [e.g., nausea, vomiting, and retching severity scores measured by the Patient Assessment of Upper Gastrointestinal Disorders - Symptom Severity (PAGI-SYM)] as well as overall symptom severity (using the GCSI) showed improvement with aprepitant compared to placebo.56 More recently, tradipitant improved nausea/vomiting and overall GCSI score during 4 weeks of treatment in a placebo-controlled study in patients with gastroparesis, with greater efficacy in patients with idiopathic compared to diabetic gastroparesis.57

7.10 |. Gastric electrical stimulation is effective for gastroparesis. STATEMENT NOT ENDORSED

The ESNM working group did not reach a consensus on the effectiveness of gastric electrical stimulation (GES) for management of gastroparesis. However, placebo-controlled trials had suggested that GES improved vomiting in patients with gastroparesis.58–60 More convincing data on potential efficacy were provided by a recent large, crossover, randomized, controlled study on GES which showed that, although gastric emptying did not improve, the frequency of nausea and vomiting decreased in diabetic and non-diabetic patients with gastroparesis.61 Thus, GES might be effective for nausea and vomiting in patients with gastroparesis who failed standard treatments.

7.11 |. Partial or subtotal gastrectomy is effective for gastroparesis. STATEMENT NOT ENDORSED

Whereas complete or subtotal gastrectomy is considered as the last resort for refractory gastroparesis and are associated with a high rate of morbidity (>40%), two recent series on sleeve laparoscopic gastrectomy for management of gastroparesis showed a significant improvement of gastric emptying62 and symptoms63 and with a lower rate of complications (10%–30%).

8 |. OVER ALL CONCLUSION

We commend the working group on their extensive review of the literature regarding gastroparesis and note that limitations in understanding mechanisms, objective testing, and prospective studies often led the working group to not endorse several statements, with which we concur. Our additional comments are intended to enhance and supplement the discussion points and recommendations from the ESNM working group.

We perceive that there are 5 high priority areas that require the attention of researchers in gastroparesis to advance the field.

First, there needs to be consensus endorsement of delayed gastric emptying measured optimally (at least 3 h after ingestion of a solid meal) in the diagnosis, to distinguish gastroparesis from functional dyspepsia. Consistent diagnosis is essential to advance the field.

Second, epidemiological study (ESNM statement 2.1) of gastroparesis should be performed with the diagnosis based on optimal gastric emptying measurement, which would be feasible using validated stable isotope breath test using a solid meal; this is essential to perform natural history studies (ESNM statement 3.2) of gastroparesis.

Third, morphological and expression studies of enteric nervous system and muscle from multiple full-thickness gastric biopsies to avoid sampling error in well-phenotyped patients are required to address intrinsic etiopathologic mechanisms of gastroparesis (ESNM 4.5–4.7).

Fourth, discovery of effective and safe prokinetics as well as optimized placebo-controlled trials using validated endpoints such as the GCSI daily diary are essential to define the role of prokinetics and other treatments (ESNM 6.10–11).

Fifth, predictors of success with pyloric interventions, particularly myotomy (ESNM 6.27/28), should be investigated including clinical features, and pathophysiological measurements of antropyloroduodenal motility, as well as pyloric cross-sectional area and distensibility index.

Funding information

Michael Camilleri is supported by grant R01-DK122280 from National Institutes of Health for studies on gastroparesis.

CONFLICTS OF INTEREST

Michael Camilleri has received research funding for studies of felcisetrag in patients with gastroparesis (Takeda) and is currently receiving research funds for studies on tradipitant (Vanda Pharmaceuticals). The other authors have no conflicts of interest.

Footnotes

DATA AVAILABILITY STATEMENT

As this is a review article, there are no original data from the authors of this review.

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