In gastroparesis, there is abnormal function of extrinsic vagal innervation, smooth muscle, enteric nervous system, or pacemakers in the stomach wall, specifically, the interstitial cells of Cajal (ICCs) or fibroblast-like cells that have receptors for platelet-derived growth factor α. The delay of gastric emptying in gastroparesis is associated with distal antral hypomotility, pylorospasm, or intestinal dysmotility. In general, antral hypomotility is usually present when there is pylorospasm . In patients with diabetes, delayed gastric emptying is associated with retinopathy and a number of complications of diabetes and, as shown originally by Kassander, with triopathy (retinopathy, neuropathy, nephropathy) . Nevertheless, in the modern era, with so many patients having type 2 diabetes rather than insulin-dependent and ketosis-prone type 1 diabetes, 39% of diabetic patients with gastroparesis in the NIH gastroparesis consortium database did not have any diabetic complications .
Another confounding factor in discussion of gastroparesis is the increased use of opioid medications for abdominal pain. Among 583 patients in the NIH gastroparesis consortium database, 41% were taking opioids which included 33% on potent morphine-like agents and the indication was abdominal pain for 61% of patients taking opioids. These patients have higher symptoms scores, greater levels of gastric retention, worse quality of life, increased hospitalization, and increased use of antiemetic and pain modulator medications compared with nonusers or those using weaker opioids (e.g., tramadol, tapentadol, codeine, or propoxyphene) . It has been proposed that such patients should be excluded from studies of pathophysiology, clinical characteristics, and outcomes of gastroparesis, and that such patients receive a therapeutic trial with a peripherally-active mu-opioid receptor antagonist to differentiate the relative contributions of the opioid and underlying disease to the gastroparesis . Given this controversy, opioid-induced gastroparesis will not be specifically addressed in this chapter.
There have been significant recent advances in understanding and treatment options for gastroparesis; however, many controversies exist and the field is rapidly changing. One of the inevitable challenges in the current and future management of gastroparesis is the broadening of the “definition” which includes symptomatically overlapping conditions that result from different pathophysiological mechanisms which are not always those associated with delayed gastric emptying. The other main pathophysiological mechanisms resulting in upper gastrointestinal symptoms mimicking those of gastroparesis are reduced gastric accommodation and increased gastroduodenal sensitivity; among almost 1300 patients (including 108 patients with diabetes) who underwent tests to evaluate both gastric emptying of solids and gastric accommodation using SPECT imaging, there were roughly equal proportions of patients with abnormal gastric emptying, abnormal gastric accommodation, both abnormal or neither abnormal ; the latter presumably reflecting gastroduodenal hypersensitivity.
New drugs targeting receptors with 5-HT 4 agonists, dopamine D 2/3 and NK 1 antagonists
Disorders of gastric emptying can be identified with an optimal gastric emptying test, typically 4-hour measurement by scintigraphy, and can be targeted by drugs acting on traditional receptors including 5-HT 4 , dopamine D 2/3 , and NK 1 . Normal values and performance characteristics of the scintigraphic test have been published . Delayed gastric emptying is associated with nausea, vomiting, and bloating, but not with pain; moreover, there is a significant relationship between the acceleration of gastric emptying and the improvement in symptoms based on a meta-regression analysis which demonstrated that a change in gastric emptying t 1/2 of 20.4 minutes was associated with a 1 unit change in symptoms severity (based on standardized mean difference) .
There are several methods used to measure gastric accommodation, although most of the reports in the literature have used one of three methods: SPECT imaging , which unfortunately is not widely available; or an intragastric, infinitely compliant polyethylene balloon with tone measured by the intra-balloon volume as a barostat maintains constant pressure within the balloon; or intraluminal high resolution manometry . The latter two methods are predominantly used as research tests. In contrast, a nutrient drink test [with ingestion at constant rate until the maximum tolerated volume (MTV) is reached] may assess the overall functions of gastric accommodation and sensation . When the MTV of a nutrient drink is less than ~750 kilocalories, the MTV is linearly correlated with gastric accommodation measured by a barostat . Recent attempts to use two-dimensional imaging to estimate gastric accommodation require further validation .
Current state of evidence
Although it had not been approved or marketed for the indication of gastroparesis, there was evidence that the 5-HT 4 agonist, cisapride, accelerated gastric emptying and improved symptoms in patients with gastroparesis in short-term, placebo-controlled trials , as well as in long-term, open-label studies . Cisapride is a potent human ether-à-go-go-related gene (hERG) potassium channel inhibitor; it was taken off the market due to cardiovascular concerns (cardiac arrhythmias).
Since symptoms may result from diverse mechanisms, future treatment of gastroparesis symptoms should be based on identified pathophysiology. Potentially, effective pharmacological approaches are directed to the “traditional” pathways, specifically 5-HT 4 , dopamine D 2 and D 3 , and NK 1 receptors, or novel mechanisms (discussed in the next section).
5-HT 4 receptor agonists
In a randomized, placebo-controlled, cross-over study of 4 weeks duration with a 2-week washout, prucalopride improved symptom control as well as gastric emptying in 28 patients with idiopathic and 6 patients with diabetic gastroparesis . Similarly, velusetrag, was efficacious in the treatment of diabetic and idiopathic gastroparesis . Among “new generation” 5-HT 4 agonists, prucalopride, velusetrag, and naronapride are selective for 5-HT 4 receptors without hERG effects .
Results of the pharmacodynamics effects of a new specific 5-HT 4 receptor agonist, TAK-954 (TD-8954), are keenly awaited (NCT03281577). Velusetrag and TAK-954 had no significant effects on canine, porcine, and human coronary artery tone, human platelet aggregation, hERG potassium channel conductance, or off-target actions . TAK-954 had high affinity (pK(i)=9.4) for human recombinant 5-HT 4(c) receptors and selectivity (>2000-fold) over all other 5-HT and non-5-HT receptors, ion channels, enzymes, and transporters (n=78 tested) .
Targeting sensations with D 2 /D 3 and NK 1 antagonists
For increased gastric sensation, the dopamine D 2 / 3 antagonist, TAK-506, significantly increased the volume to fullness compared to baseline with 1 week of treatment . The NK 1 receptor antagonist, aprepitant, improved multiple symptoms of gastroparesis including nausea , and it has been shown to enhance gastric accommodation rather than affect gastric emptying in healthy controls . Similarly, tradipitant, a novel NK 1 receptor antagonist, improved nausea and other symptoms of gastroparesis in a 4-week, randomized, controlled trial .
What is needed for evidence-based clinical application?
Completion of phase III, pivotal, randomized, controlled trials in gastroparesis is required for all three classes of medications.
New drugs targeting a new mechanism: ghrelin receptor agonist
Ghrelin is a 28-amino acid orexigenic hormone found mainly in the stomach. Administration of a pharmacological dose of ghrelin induced premature phase III of the migrating motor complex, increased proximal gastric tone through central and peripheral sites of action , and accelerated gastric emptying in some studies of patients with gastroparesis (reviewed in ref. ).
Relamorelin, a pentapeptide ghrelin receptor agonist, has potent prokinetic effects estimated to be 15- to 130-fold more potent than natural ghrelin . Relamorelin, 100 mg subcutaneous (s.c.), accelerated gastric emptying of solids in patients with prior documentation of delayed gastric emptying and either type 1 or type 2 diabetes mellitus , and it increased the frequency of distal antral contractions without inhibiting gastric accommodation or inducing satiation in healthy volunteers .
Current state of evidence
Relamorelin has proven clinical efficacy and safety in phase 2 A and 2B, randomized, controlled trials in patients with diabetic gastroparesis .
What is needed for evidence-based clinical application?
Completion of phase III, pivotal, randomized, controlled trials is required.
Modulation of M2 macrophages and oxidative stress
There is evidence that enteric mechanisms may play a role in the development of gastroparesis, and the dysfunction of intrinsic mechanisms involved in stomach motility may be at least in part mediated by immune dysregulation. Macrophage-based immune dysregulation is associated with delayed gastric emptying in diabetic mice . Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages have been reported in full-thickness gastric biopsies from patients with gastroparesis. Specifically, it has been demonstrated that abnormalities in the enteric neural control including disorders of the pacemaker cells (interstitial cells of Cajal, and PDGFRα fibroblast-like cells), and alterations in numbers of nitrergic neurons and CD206 positive macrophages are associated with idiopathic or diabetic gastroparesis manifesting as delayed gastric emptying ( Table 40.1 ) .
|Cellular marker||Diabetic gastroparesis (n=11)||Idiopathic gastroparesis (n=6)||Controls (n=5)||ANOVA/KW test P value|
|PDGFRα staining FLC (CM)||11.03±0.96 (n=10)||11.72±0.96 (n=10)||10.75±10.87||>.05|
|n NOS neurons (MP)||1.85±0.12||2.00±0.34||2.07±0.30||.82|
|n NOS neurons (CM)||27.15±2.95||35.43±4.75||26.57±3.90||.27|
|Tyrosine hydroxylase (MP)||32.50±4.01||41.57±4.69||38.32±4.67||.30|
Significant differences in circular muscle were observed [e.g., c-Kit (ICCs) in the circular muscle and CD206 macrophages or M2 macrophages] between both groups of gastroparesis and controls (generally bariatric surgery patients). The current evidence is available from morphological or proteomic or mRNA expression studies of gastric biopsies from patients with gastroparesis, as well as clinical trials, and some, but not all, of the evidence is congruent.
A summary of quantitative morphological data based on full-thickness biopsies from patients with gastroparesis, published from studies by the NIH Gastroparesis Consortium , is provided in Table 40.1 . However, there may be differences in the morphological abnormalities in diabetic and idiopathic gastroparesis in other studies. Thus, PDGFRα fibroblast-like cells in the electrical syncytium that controls gastric contractility are reduced in idiopathic gastroparesis in association with increased CD68 (not decreased CD206) immunocytes (M1 macrophages); in addition, numbers of ICCs were not altered, in contrast to the report from the NIH Gastroparesis Consortium . The biochemical mechanism leading to loss of these different pacemaker cells is considered to be oxidative stress, and the depletion of anti-inflammatory resident M2 macrophages expressing heme oxygenase-1 (HO 1 ) is believed to be the underlying pathobiology.
Proteomics and RNA expression
Based on full-thickness gastric body biopsies and deep RNA sequencing , granulocyte adhesion and diapedesis, as well as a macrophage-based immune dysregulation pathway were shown to be the most significantly affected pathway in both diabetic and idiopathic gastroparesis. In addition, proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis. A subset of differentially expressed genes ( SGK1 , APOLD1 , CXCR4 , CXCL2 , and FOS ) was also validated in a separate cohort in diabetic gastroparesis using QT-PCR. It is relevant to note that many of the differentially expressed genes, including many involved in immune functions such as cytokines and interleukins, were actually down-regulated on deep RNA sequencing and RT-PCR in gastric tissues from patients with gastroparesis. In the same study, immune cell analysis revealed no significant differences in enrichment of genes associated with M1 or M2 macrophages in the diabetic gastroparesis and diabetic control samples, although genes associated with M1 (pro-inflammatory) macrophages were increased in idiopathic gastroparesis samples compared to their controls. .
In addition, full-thickness gastric antrum biopsies obtained from patients with diabetic gastroparesis (n=9) and idiopathic gastroparesis (n=7), and from nondiabetic controls (n=5) were subjected to an aptamer-based tissue scan that quantitatively identifies 1305 human proteins. Based on this method, 73 and 132 proteins, respectively, are differentially expressed in diabetic and idiopathic gastroparesis gastric tissue, with 40 proteins common to both conditions. In both conditions, the “role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis” was the most significantly altered pathway; in idiopathic gastroparesis, another significantly altered pathway was “role of cytokines in mediating communication between immune cells” . The authors concluded that these data suggest that innate immune signaling and macrophage-driven immune dysregulation likely play a role in the pathogenesis of human gastroparesis .
Thus, human observations on immune dysregulation in gastroparesis suggest upregulated M1 pro-inflammatory mechanisms in idiopathic gastroparesis. There is a need for further studies to characterize innate immune mechanisms in diabetic gastroparesis, which seem to be associated with reduced expression of inflammatory markers on transcriptomics and M2 macrophage deficiency, which would be expected to be pro-inflammatory in diabetic gastroparesis.
Based on basic science studies showing that a deficiency of M2 (CD206) macrophages is associated with oxidative injury to the enteric nervous system or ICCs in animal models of gastroparesis , a randomized, controlled trial of hemin, a HO 1 inhibitor, was performed. However, hemin failed to reverse delayed gastric emptying, although the pharmacokinetics of the drug proved insufficient to adequately test the hypothesis .
What is needed for evidence-based clinical application?
It is still unclear whether diabetic gastroparesis is primarily a disorder of extrinsic vagal control, or a disorder of enteric neural mechanisms, or both. Even if one were to accept the primary importance of the enteric neural control and “immune modulation”, it is relevant that vagal innervation and 5-HT 4 stimulation of intrinsic cholinergic neurons are known to have important anti-inflammatory actions, including regulation of both innate and adaptive immune responses. Thus, both vagal stimulation and the 5-HT 4 agonist, prucalopride, modify T helper 2 cell responses that may even shorten post-operative ileus . Ultimately, the proof of the relevance of the M2 macrophage deficiency as a pivotal etiopathogenic mechanism would be supported by reversing gastroparesis, either by restoring M2 macrophages or by reversing effects of HO 1 by pharmacological approaches, as was attempted with hemin . There are no studies in humans showing restoration of M2 macrophages in the enteric nervous system. Several fundamental questions remain to be resolved regarding the role of macrophages and oxidative stress in the development of gastroparesis, and additional advances are required to restore normal innate immunity and recover pacemaker and enteric neural dysfunction. A few of these fundamental pitfalls in the current data and requisites for future clinical application are detailed here.
The observations of altered pathways related to macrophages and innate immunity have been observed in small numbers of tissue biopsies and require replication, just as there is still controversy as to whether ICC or PDGFRα cells are abnormal in idiopathic and diabetic gastroparesis . In addition, the replication studies should include assessment of abdominal vagal function, since vagal neuropathy is a potential confounder in the interpretation of the immune mechanisms and the potential for immune restoration by alternative electrical (vagal stimulation) or pharmacological approaches .
Gut-resident macrophages that are self-maintained and not derived from circulating monocytes can impact enteric nervous system function; these are a different lineage of macrophages from the M2 or CD206-positive macrophages . Further studies are, therefore, indicated to identify the macrophage lineage of greatest relevance to restore enteric nervous system function and to determine whether the same approach is required for diabetic versus idiopathic gastroparesis, given the commonalities and diversities in the protein expression abnormalities in the two disease states.
There are still no known treatments to effectively inhibit oxidative stress in the gut neuromuscular apparatus. In the next section, advances in neurogenesis are discussed, and there are experimental approaches using neurotrophic factors to stimulate the production or function of the pacemaker cells or enteric neurons.
After the characterization of the treatments to achieve the inhibition of oxidative stress or restoration of pacemaker cells, there will be a need for safety, dose-response pharmacodynamics studies and phase 2B and phase III trials in patients with idiopathic and diabetic gastroparesis, which will require separate efficacy and safety trials in accordance with FDA guidance.
The enteric nervous system exists in a dynamic balance between cell loss by apoptosis, resident macrophage phagocytosis to remove dead neurons, and neurogenesis from precursor cells (nestin-positive) that behave like stem cells, are not glia, and are prominent in the submucosal zone and in the muscular layers . The enteric nervous system is vulnerable to exogenous influences, even in adults, and loss of the precursor cells in an animal model results in a phenotype that mimics chronic intestinal pseudo-obstruction.
Studies with a selective estrogen receptor β (ERβ) agonist have demonstrated that LY3201 was able to stimulate glial-to-neuron cell differentiation in vitro and promoted neurogenesis in the damaged myenteric plexus in vivo in two murine models of enteric neuronal damage and loss, namely, high-fat diet and topical application of the cationic detergent, benzalkonium chloride, on the intestinal serosa, respectively. In both models, treatment with LY3201 significantly increased the recovery of neurons after damage .
The potential for neurogenesis and nerve growth factors in restoring normal propulsive function is illustrated in animal and human studies centered mostly in the intestine and colon. First, in a clinical trial of brain-derived neurotrophic factor (BDNF) in patients with amyotrophic lateral sclerosis, an increased stool frequency occurred in patients treated with a higher dose of BDNF . Second, in patients with slow transit constipation, BDNF expression and nerve fiber density were decreased . Third, exogenous BDNF and neurotrophin-3 accelerated gastrointestinal and colonic transit in healthy human volunteers and in patients with constipation . In rats, exogenous BDNF increased myoelectric activity and peristalsis in the gastrointestinal tract and colon . Therefore, there are approaches that can stimulate neurogenesis even among neurogenic precursors in the adult enteric nervous system and this may be relevant to patients with gastroparesis.
What Is needed for evidence-based clinical application?
It has been recommended that there should be thorough investigation of the role of neurotrophic factors in enteric physiology and pathophysiology before therapeutic approaches can be administered . It is also essential to have further understanding of the rate of neuronal turnover in mature bowel to further advance this field .
Transcutaneous vagal nerve stimulation in the neck
While much recent research has been conducted on the enteric neural control, it is important to emphasize other important pathophysiological processes including vagal neuropathy in gastroparesis, with or without impaired fundic accommodation and pyloric dysfunction .
Given that the gastrointestinal tract has extensive, surgically accessible nerve connections with the central nervous system, there is opportunity to exploit rapidly advancing methods of nerve stimulation to treat gastrointestinal disorders . The benefit of vagal nerve stimulation may reflect anti-inflammatory effects (as seen in some patients with Crohn’s disease in a single trial), direct stimulation of the efferent vagal fibers to activate the antral muscles through the nerve of Latarjet, or acting centrally via afferent vagus nerve stimulation.
An open-label, proof-of-concept study has assessed the effects of neck vagus nerve stimulation in patients with severe drug-refractory gastroparesis with self-administered use of a device (gammaCore, electroCore) which provides 120 second stimulations to the neck vagus nerve three times daily. Response was defined as a ≥1 point decrease from baseline in the Gastroparesis Cardinal Symptom Index (GCSI) score. Response rates were 35% at 3 weeks and 43% for the duration of therapy (3–6 weeks). For the entire cohort and the 10 responders, improvements from baseline were noted for mean total GCSI and GCSI subscale scores (nausea/vomiting, postprandial fullness/early satiety, bloating). No serious adverse events were reported .
What is needed for evidence-based clinical application?
The preliminary results provide a signal that neck vagus nerve stimulation may be useful for treating refractory gastroparesis. Larger controlled studies are warranted.
Gastric electrical stimulation: novel insights
The electrical control activity provides the underpinning for contractility of the stomach. High frequency muscle stimulation through electrical stimulation is thought to reduce gastroparesis symptoms, probably through afferent modulation . Nevertheless, prior studies were predominantly open-label experiences in relatively small numbers, and it was shown that benefit may result from regression of symptoms to the mean or “placebo” effect of the intervention .
Important novel insights include the importance of the numbers of remaining interstitial cells of Cajal to responsiveness to gastric electrical stimulation and the discrepancies in the patients undergoing this treatment in Europe (more diabetics, 100% with gastric emptying at baseline) compared to the United States (more idiopathic, more females, and 75% with baseline measurement of gastric emptying). Thus, although it is difficult to draw definite conclusions about efficacy of gastric electrical stimulation, the recent data from Europe suggest there may still be responders in carefully selected patients.
Two recent studies argue in favor of beneficial effects of gastric electrical stimulation. First, in a comparison of 319 patients from the Gastroparesis Clinical Research Consortium (GpCRC), 238 patients without gastric electrical stimulation and 81 with gastric electrical stimulation were assessed. Improvements in 48-week GCSI total scores for gastric electrical stimulation vs. non-gastric electrical stimulation showed improvement by ≥1 point [RR=1.63; 95% CI (1.14, 2.33); P =.01] and change from enrollment [difference=−0.5 (−0.8, −0.3); P <.001]. However, when adjusting for patient characteristics, symptom scores were smaller and not statistically significant, and only the symptom of nausea remained significant .
Second, in a large, multicenter, randomized, double-blind trial with cross-over to study the efficacy of gastric electrical stimulation in patients with refractory vomiting, with or without gastroparesis, Ducrotte et al. assessed symptoms in 172 patients (66% women; mean age 45±12 years; 133 with gastroparesis) with chronic (more than 12 months) refractory vomiting (idiopathic, associated with type 1 or 2 diabetes, or post-surgical) . The primary end-points were the vomiting score, ranging from 0 (daily vomiting) to 4 (no vomiting), and the quality of life, assessed by the Gastrointestinal Quality of Life Index (GIQLI) scoring system. During both phases of the cross-over study, vomiting scores were improved (with higher score being a positive response) in the group with the device on (median score, 2) than in the control group (median score, 1), in diabetic and non-diabetic patients. Vomiting scores increased significantly when the device was on in patients with delayed or normal gastric emptying. Gastric emptying and quality of life were not different.
What is needed for evidence-based clinical application?
While recent studies add to the body of work suggesting benefit, it is disappointing that only individual symptoms (nausea or vomiting) seem to improve, rather than the spectrum of symptoms and quality of life, and, as shown repeatedly in the past, there was no effect on gastric emptying. Of the surgical treatments, pyloromyotomy, gastric electrical stimulation, or combined pyloromyotomy with gastric electrical stimulation, we need to determine what type of patients will respond best to these therapies.
Endoscopic interventions directed at the pylorus including gastric per oral endoscopic myotomy (G-POEM)
When pyloric dysfunction was first described in diabetic gastroparesis in 1986 , the pathophysiology of the disease was unclear and unusually prolonged, and intense tonic pyloric contractions, or “pylorospasms,” were described in 24 diabetic patients with symptoms of gastroparesis. The rationale for interventions on the pylorus is based on those observations as well as reduced expression of neuronal nitric oxide synthase in the pylorus of non-obese diabetic mice when they develop diabetes; the reduced expression is reversed by insulin treatment and with the phosphodiesterase-5 inhibitor, sildenafil [which increases intracellular cyclic guanosine monophosphate (cGMP) and mimics the effect of nitric oxide]. Unfortunately, sildenafil had no significant effect on gastric emptying in gastroparesis associated with uremia . The advent of procedures directed at the pylorus (botulinum toxin injection, surgical or endoscopic pyloromyotomy) has renewed interest in the role of this region in the pathophysiology of gastroparesis.
There have been multiple, open-label trials of intra-pyloric botulinum toxin injections attesting to the efficacy of this approach , but there have been only two randomized, controlled trials , both of which failed to show any improvement in symptoms. It has been argued that one reason for the failure of these studies to demonstrate a positive treatment effect was the incorrect selection of patients who would be most likely to benefit, that is, those with pyloric dysfunction at baseline. In addition, neither of the two randomized, control trials measured pyloric function after botulinum neurotoxin injection; therefore, it is unclear if botulinum neurotoxin truly had the anticipated functional effect, aside from the hypothesized clinical effect. However, at least in the trial performed by Friedenberg and colleagues , botulinum neurotoxin improved gastric emptying compared to placebo, suggesting that the intervention can result in the desired physiological effect, but not the clinical outcome. It is also conceivable that, even in patients with documented pyloric dysfunction who receive adequate botulinum neurotoxin injections, dysmotility in other critical regions of the stomach (e.g., antral hypomotility or impaired gastric accommodation) precluded a functional and clinical response to treatment with botulinum toxin.
Nevertheless, more robust interventions such as surgical pyloroplasty have been advocated, with retrospective reports providing evidence of meaningful short-term improvements in clinical outcomes such as symptom severity scores for nausea, vomiting, bloating, abdominal pain, and early satiety 3 months post-procedure, and accelerated gastric emptying . However, 19/177 patients (10.7%) required subsequent surgeries. Other clinical experience with surgical pyloroplasty also documented improvements, and set the stage for further technological advancements in the form of G-POEM . Overall, there is also evidence of improved gastric emptying with G-POEM ( Fig. 40.1 ).