Pathophysiology Of Gastroparesis Research Articles

Ten controversies in gastroparesis and a look to the future.

Gastroparesis is a complex, challenging gastrointestinal disorder presenting with upper gastrointestinal symptoms, especially nausea and vomiting, with significant impact on patients' quality of life. After ruling out mechanical obstruction, it is essential to identify delay in gastric emptying for definitive diagnosis. The most common causes are idiopathic (no identified etiology), diabetes mellitus, and postsurgical status. Management of gastroparesis focuses on dietary modifications and treatment directed to symptom relief. Unfortunately, approximately one-third of patients are refractory to pharmacological therapy, and the effectiveness of the few nonpharmacological options has been questioned. Extensive review of the literature identifies several uncertainties or controversies regarding the differential diagnosis based on the spectrum of symptoms, the lack of availability of reliable diagnostic test, and questions regarding effective therapeutic options. In this review, we discuss ten controversies regarding gastroparesis: clinical presentation, diagnosis, overlap syndromes, pathophysiology, etiology, as well as pharmacological and nonpharmacological therapeutic options. In addition, we briefly review studies exploring pathological, inflammatory, and molecular disturbances affecting the intrinsic neuromuscular elements that may be involved in the pathophysiology of gastroparesis and may constitute possible therapeutic targets in the future. Finally, we tabulate future research opportunities to resolve these controversies in the management of patients with gastroparesis.

S1585 Combining Surgical Pyloroplasty and Gastric Electrical Stimulation in Gastroparetic Patients Is Superior to Pyloroplasty Alone: A Randomized Double Blind Placebo Control Trial

Introduction: Pathophysiology of gastroparesis (GP) is related to the depletion of interstitial cells of Cajal in the stomach and suspected pathology of the pyloric smooth muscle. Pyloroplasty (PP) accelerates gastric emptying (GE), while gastric electrical stimulation (GES) improves GP symptoms. Our double-blind randomized clinical trial investigated if combining surgical PP and GES is more effective than PP alone. Methods: Drug refractory GP patients underwent simultaneous surgical implantation of the GES system with PP. Scintigraphic GE was performed at baseline (all participants were delayed at 4 h with >10 % retention), and 3 months after surgery. Patients were randomized to 3 months of active GES stimulation (ON group with default setting of GES parameters), or no stimulation (OFF group). All patients then had GES turned ON for another 3 months. GP Cardinal Symptom Index (GCSI) with 6-points scale (0- none; 5-very severe) was recorded at baseline, 3 and 6 months after the surgery. Delta changes of GCSI and individual GP symptoms in ON and OFF groups at 3 and 6 months versus their baseline were calculated and compared using 2-way ANOVA followed by Tukey’s post-hoc analysis. Results: 30 GP patients (18F; mean age 46 (21-72); 6 idiopathics; 24 diabetics with mean duration of DM 24 years (3-50); mean duration of GP 5.6 (1-18) years met criteria for the trial. The mean baseline 4 h GE retention was not different in GES-OFF and -ON group. GE was significantly accelerated at 3 months in GES-OFF (46%) and GES-ON (62%) groups (*P< 0.05), and 39% patients normalized their 4h GE. Patients were randomized to GES-OFF or ON (15 patients per group). GP etiologies were similar in both groups. Baseline GCSI in GES-OFF (3.5±0.2) was comparable to GES-ON (3.7±0.2) group, and significantly improved in 3 months compared to baseline (P< 0.01) in both groups. However, mean GCSI score was significantly better (P< 0.05) in GES-ON than GES-OFF group (Figure). When GES was turned ON in GES-OFF group at 3 months their GSCI significantly improved at 6 months. The frequency of hospitalizations due to vomiting was significantly reduced in GES-ON vs OFF group (P=0.02). There were no post-surgical complications or technical dysfunctions recorded during this trial. Conclusion: Our randomized, double-blind study has revealed for the first time that combining GES with pyloroplasty is statistically more effective than PP alone in controlling GP symptoms and GE is similarly accelerated following PP in both groups.Figure 1.: Changes of Gastroparesis Cardinal Symptom Index (GCSI) at 3 and 6 months in GES-ON versus GES-OFF group compared to baseline. **P<0.01

1285-P: Differentiating between Diabetic and Idiopathic Gastroparesis: A Genetic Perspective

Gastroparesis is a serious medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. An innate immune dysregulation and injury to the interstitial cells of Cajal and other components of the enteric nervous system is likely central to the pathogenesis of gastroparesis. Most common etiologies include diabetes, post-surgical but most cases are idiopathic. Thus far, little is known about the underlying genetic risk factors for gastroparesis. We have done a genome-wide association study comparing idiopathic and diabetic cases with controls as well as contrasting idiopathic versus diabetic cases. We report a novel genetic association of SLC15A4 locus with idiopathic gastroparesis. This signal is driven by multiple variants with top missense variant SLC15A4:NM145648:exon2:c.T716C:p.V239A, rs33990080. Altogether, among EUR cohort we report 69 carriers out of 214 versus controls 165 out of 896 (MAF: cases 0.18; MAF: controls 0.09) and OR: 1.9 (p-value&amp;lt;10^-6) . We furthermore differentiate idiopathic from diabetic gastroparesis with an established diabetes genetic risk score, - result that is statistically significant (p-value&amp;lt;0.0004) . We also delineate a number of significant loci implicated in diabetes risk including (HLA-DQB1,HLA-DQA2, EXOC6B) in the idiopathic versus diabetic gastroparesis analysis. Of particular interest are the Exocyst complex component, 6 (EXOC6/6B) with lead variant rs41420. previously identified to play a role in insulin signaling through its interaction with the glucose transporter GLUT4. Current genetic findings suggest that a mechanism directly connected to macrophage polarization may be implicated in the etiology gastroparesis. The GWAS picture that is emerging implicates novels loci implicated in the pathophysiology of gastroparesis differentiating those of diabetic versus idiopathic etiology. Disclosure S.P.Smieszek: None.

Gastroparesis.

This review highlights recent research advances regarding the pathophysiology and treatment of gastroparesis. Differences in brain activity have been identified on functional MRI imaging in gastroparesis patients with nausea. Abdominal pain is common in patients with gastroparesis and does not correlate with the severity of gastric emptying delay, though may be associated with depression and anxiety. Autonomic dysfunction may play an important role in the pathophysiology of gastroparesis. There is increasing sentiment that gastroparesis should be considered a part of the same spectrum of gastric neuromuscular disorders. The risk of tardive dyskinesia with metoclopramide has likely been significantly overestimated historically. Endoscopic BoTox injection of the pylorus and gastric electrical stimulation remain controversial treatments for gastroparesis. New, highly selective 5-hydroxytryptamine 4 (5-HT4) agonists appear safe and may be effective in improving symptoms of gastric emptying. Long-term data assessing the use of gastric peroral endoscopic myotomy (G-POEM) for the treatment of refractory gastroparesis suggest durable clinical improvement. Altered central processing and autonomic dysfunction may be important factors in the pathogenesis of gastroparesis. While the risk of tardive dyskinesia appears much lower than historically advertised, there is increasing hope for novel therapeutics with the advent of new 5-HT4 agonists, neurokinin-1 receptor (N1KR) antagonists, and G-POEM.

Beyond Metoclopramide for Gastroparesis

Beyond Metoclopramide for Gastroparesis

Gastroparesis and functional dyspepsia: different diseases or different ends of the spectrum?

This review assesses the relationship between gastroparesis and functional dyspepsia, in light of recent research assessing cause, pathophysiology and treatment. The Gastroparesis Cardinal Symptom Index (GCSI) lacks the ability to readily distinguish functional dyspepsia from gastroparesis based on symptoms. Although prior studies found that the extent of delay in gastric emptying did not accurately predict severity of symptoms, when optimally measured, delayed gastric emptying may in fact correlate with gastroparesis symptoms. Enteric dysmotility may be an important risk factor for gastroparesis. Altered central processing may play a role in symptom generation for both gastroparesis and functional dyspepsia based on functional brain MRI. Treatment directed towards reducing low-grade inflammation and improving mucosal barrier function in the duodenum may represent a novel therapeutic target for functional dyspepsia, whereas gastric peroral endoscopy myotomy (G-POEM) remains a promising intervention for refractory gastroparesis. Abnormalities on functional MRI of the brain have been identified in patients with functional dyspepsia and gastroparesis. Small bowel dysmotility and duodenal barrier dysfunction have been implicated in the pathophysiology of gastroparesis and functional dyspepsia, respectively. New treatments for functional dyspepsia may target low-grade duodenal inflammation and barrier dysfunction. The pylorus remains a target in gastroparesis.

Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in gastroparesis: A sex‐ and subtype‐dependent observation

Gastroparesis (GP) is a motility disorder of the stomach presenting with upper gastrointestinal symptoms in the setting of delayed gastric emptying. Endocannabinoids are involved in the regulation of GI function including motility. However, their role in the pathophysiology of GP has not been sufficiently investigated. Our goal was to compare the circulating levels of endocannabinoids and cannabimimetic fatty acid derivatives in GP versus control subjects. The study compared plasma concentrations of endocannabinoids and their lipoamine and 2-acyl glycerol congeners, measured by high-pressure liquid chromatography/tandem mass spectrometry (HPLC-MS-MS), in adult patients with diabetic gastroparesis (DM-GP; n=24; n=16 female), idiopathic gastroparesis (ID-GP; n=19; n=11 female), diabetic patients without GP (DM; n=19; n=10 female), and healthy controls (HC; n=18; n=10 female). Data, presented as mean±SEM, were analyzed with ANOVA (Sidak post hoc). Endocannabinoids anandamide (AEA: 0.5±0.1 nMol/L) and 2-arachidonoyl glycerol (2-AG: 2.6±0.7 nMol/L) were significantly lower in female DM-GP patients vs. DM females (AEA: 2.5±0.7 nMol/L and 2-AG: 9.4±3.3 nMol/L). Other monoacylglycerols including 2-palmitoyl glycerol and 2-oleoyl glycerol were also lower in female DM-GP patients compared to DM females. No changes were observed in men. Endocannabinoids and other fatty acid derivatives with cannabimimetic properties are reduced in female DM-GP patients. Since GP, particularly with diabetic etiology, is more prevalent among women and since cannabinoids are antiemetic, this decrease in levels may contribute to symptom development in these subjects. Targeting the endocannabinoid system may be a future therapeutic option in DM-GP patients.

Gastroparesis in carcinoma gallbladder: a scintigraphic study

Background: Gastroparesis is characterized by delayed gastric emptying in the absence of mechanical gastric outlet obstruction. There is strong association of gastroparesis with carcinoma gallbladder. The aim of the study was to find out the incidence of delayed gastric emptying in carcinoma gallbladder and its correlation with symptoms of stasis and stage of the disease.Methods: Patients diagnosed with carcinoma gallbladder and their matched controls were included in this study. Patients with mechanical gastric outlet obstruction were excluded. All patients underwent contrast enhanced computer tomography scan and radio labeled (Technitium 99) solid meal Scintigraphy study. Normal gastric emptying time was calculated from control group as Mean +2SD.Results: 30 patients were matched with 20 controls after obtaining informed consent. Upper limit of gastric emptying time is 55.09 minutes. Adenocarcinoma was the commonest histological subtype (50%), abdominal pain was the commonest symptom (86.7%) and hepatomegaly was the commonest sign (46.7%), GETt1/2 for patients was 66.72±26.52 minutes while it was 40.53±7.28 minutes in controls (p &lt;0.05). Gastroparesis increased with advancing stage of carcinoma gallbladder (p &lt;0.05). Symptoms of gastric stasis were seen only in 15.6% of patients.Conclusions: Patients with carcinoma gallbladder can have gastroparesis without obvious symptoms of delayed gastric emptying. This delay in gastric emptying can be documented reliably using solid meal scintigraphic study even in patients without symptoms of gastroparesis. The pathophysiology of gastroparesis needs further study. It may be prudent to remember that while performing palliative bypass surgery for gastric outflow obstruction, that in patients with carcinoma gallbladder, the gastrojejunostomy may not function as expected due to delayed gastric emptying.

Gastroparesis: A Review of Current Diagnosis and Treatment Options.

Gastroparesis (GP) is a chronic neuromuscular disorder of the upper gastrointestinal tract. The incidence of GP is not well described; however, the number of individuals affected by symptoms of GP in the United States is estimated to be over 4 million. The etiology of GP is diverse. Approximately 25% of cases are associated with diabetes, whereas nearly 50% are classified as idiopathic; many of these latter cases likely represent a postinfectious process. Connective tissue disorders, autoimmune disorders, prior gastric surgery, ischemia, and medications make up the vast majority of the remaining cases. The pathophysiology of GP is also diverse. Abnormalities in fundic tone, antroduodenal dyscoordination, a weak antral pump, gastric dysrhythmias, and abnormal duodenal feedback all contribute to delays in gastric emptying and symptom expression. Characteristic symptoms of GP include nausea, vomiting, epigastric pain, early satiety, and weight loss. The diagnosis of GP is made using a combination of characteristic symptoms in conjunction with objective evidence of delayed gastric emptying in the absence of mechanical obstruction. Once the diagnosis is made, treatment options include dietary modification, medications to accelerate gastric emptying, antiemetic agents, gastric electrical stimulation, and surgery. In the following sections we will provide an overview of the health care impact of GP, describe the underlying pathophysiology, and review treatment options using an evidence-based approach.

Glucose-induced incretin hormone release and insulin sensitivity are impaired in patients with idiopathic gastroparesis: results from a pilot descriptive study

Incretin hormones [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)] released by the gut modulate gastrointestinal motility and influence gastric emptying (GE). Abnormal secretion or sensitivity to these hormones could contribute to the pathogenesis of gastroparesis. The aim of this study was to investigate incretin hormone secretion during a prolonged oral glucose load in non-diabetic patients with documented idiopathic gastroparesis. Fifteen patients referred for digestive postprandial discomfort with delayed GE demonstrated by a (13) C-labeled octanoate breath test were included and compared with 10 healthy controls. A 75 g oral glucose load was performed, with blood samplings every 30 min for 5 h, to determine glucose, insulin, GIP, and GLP-1 blood levels. Fasting GIP concentration was significantly higher in the patient group (56.1 ± 5.8 pg mL(-1) vs 29.9 ± 7.7 pg mL(-1), P =0.012). Postglucose load GIP concentrations were also significantly elevated in patients with gastroparesis, whereas GLP-1 concentrations during fasting and postglucose load conditions were not different to those of healthy controls. Moreover, glucose tolerance during glucose load was abnormal in patients, combining hyperglycemic insulin resistance and hyperinsulinism patterns, while fasting values for glycemia, insulin sensitivity, and insulin concentrations were normal. Patients with idiopathic gastroparesis exhibit abnormal GIP levels associated with impaired insulin sensitivity during oral glucose load. Further studies are needed to establish the involvement of these defects in the pathophysiology of gastroparesis.

Recent Advances in the Pathophysiology and Treatment of Gastroparesis

Gastroparesis is a clinical disorder characterized by upper gastrointestinal symptoms related with delayed gastric emptying of solids and liquids in the absence of mechanical obstruction. Diabetes mellitus has been the most common cause of gastroparesis and idiopathic gastroparesis also accounts for a third of all chronic cases. The most important mechanisms of gastroparesis, as understood to date, are loss of expression of neuronal nitric oxide synthase and loss of the interstitial cells of Cajal. However, the pathogenesis of gastroparesis is poorly understood. There have been several studies on specific molecules related to the pathogenesis of gastroparesis. Additionally, the Gastroparesis Clinical Research Consortium of the National Institutes of Health has achieved several promising results regarding the pathophysiology of gastroparesis. As the progress in the pathophysiology of gastroparesis has been made, a promising new drug therapy has been found. The pathophysiology and drug therapy of gastroparesis are focused in this review. Until now, the real-world medication options for treatment of gastroparesis are limited. However, it is expected to be substantially improved as the pathophysiology of gastroparesis is elucidated.

Physiology, Injury, and Recovery of Interstitial Cells of Cajal: Basic and Clinical Science

In the last 15 years, our understanding of the cellular basis of gastrointestinal function has been altered irreversibly by the discovery that normal gastrointestinal (GI) motility requires interstitial cells of Cajal (ICC). Research in this relatively short time period has modified our original concept that the core unit that controls motility is made up of nerves and smooth muscle, to one that now includes ICC. This concept has now expanded to beyond the GI tract, suggesting that it may be a fundamental property of the regulation of smooth muscle function that requires rhythmic contraction. ICC are distributed throughout the GI tract, have important functions in the control of GI motility, and are often abnormal in diseased states. Recently, significant steps forward have been made in our understanding of the physiology of ICC as well as mechanisms of injury and recovery. These advances are the focus of this review. The Physiology of ICC Unique motor patterns are intrinsic to every organ of the GI tract, which suit their functions related to mixing, absorption, and anally directed movement. The ICC are an integral part of the control of these motor activities. The distribution of ICC throughout the musculature is associated with nerve structures. Myenteric pacemaker ICC surround the myenteric or Auerbach’s plexus and intramuscular ICC are associated with nerve varicosities throughout the muscle layers (Figures 1 and 2). Other subpopulations of ICC are associated with nonganglionated plexuses of nerve varicosities at the inner borders of the circular muscle layers in the intestine and colon (Figures 1 and 2). The best understood function is that of pacemaker activity in the stomach and small intestine where the ICC generate a periodic depolarization at a characteristic frequency in each of these organs that is called the slow wave or pacemaker activity.

Loss of intramuscular and submuscular interstitial cells of Cajal and associated enteric nerves is related to decreased gastric emptying in streptozotocin‐induced diabetes

Interstitial cells of Cajal (ICC) are associated with afferent innervation and peristalsis of the stomach suggestive of a key role in the pathophysiology of gastroparesis. We studied changes in the density and ultrastructure of ICC and enteric nerves in the streptozotocin-induced diabetes mellitus (STZ-DM) in Wistar rats using immunohistochemistry and electron microscopy. Gastric emptying was studied in vivo by single-photon emission computed tomography. In the STZ-DM antrum, a marked reduction was observed in the density of the intramuscular ICC (ICC-IM) and ICC located at the submucosal border of the circular muscle layer of the antrum (ICC-SM). The surviving ICC showed lamellar bodies and partial vacuolation of the cytoplasm content, loss of connections between ICC-IM and nerves; it appeared that injured ICC-IM developed into fibroblast-like ICC. ICC associated with Auerbach's plexus (ICC-AP) in the antrum and ICC in the fundus were not affected significantly except for a loss of connections with nerve structures. Marked reduction in nerve tissue (Protein Gene Product-9.5 positivity) was also restricted to the muscle layers including nitrergic nerves (neuronal nitric oxide synthase positivity). In vivo assessed gastric emptying was markedly reduced in STZ-DM rats. Our data demonstrate in the STZ-DM rat stomach a decreased density of ICC limited to the antrum and to ICC-IM and ICC-SM, and structural degeneration in ICC-IM and associated nerves with a special emphasis on loss of synaptic connections, accompanied by a decrease in gastric emptying. Hence, in this model of gastroparetic diabetes, regional injury to subsets of ICC and nerves are associated with gastric motor dysfunction.

Beyond Gastric Emptying: A "Toxic" Lesson About Gastroparesis

The first published controlled trial of intrapyloric botulinum toxin for gastroparesis failed to demonstrate a significant effect of treatment on symptoms, despite an improvement in gastric emptying. In this editorial, I discuss the limitations and implications of this study, with particular emphasis on what the use of botulinum toxin can teach us about the pathophysiology of gastroparesis and other gastrointestinal smooth muscle disorders.

Mechanisms of Disease: the pathological basis of gastroparesis—a review of experimental and clinical studies

The pathogenesis of gastroparesis is complicated and poorly understood. This lack of understanding remains a major impediment to the development of effective therapies for this condition. Most of the scientific information available on the pathogenesis of gastroparesis has been derived from experimental studies of diabetes in animals. These studies suggest that the disease process can affect nerves (particularly those producing nitric oxide, but also the vagus nerve), interstitial cells of Cajal and smooth muscle. By contrast, human data are sparse, outdated and generally inadequate for the validation of data obtained from experimental models. The available data do, however, suggest that multiple cellular targets are involved. In practice, though, symptoms seldom correlate with objective measures of gastric function and there is still a lot to learn about the pathophysiology of gastroparesis. Future studies should focus on understanding the molecular pathways that lead to gastric dysfunction, in animal models and in humans, and pave the way for the development of rational therapies.

New management approaches for gastroparesis

Management of patients with gastroparesis is challenging. Although the syndrome has multiple causes and knowledge of the pathophysiology and natural history is far from complete, a number of common management principles can be applied. The relatively poor correlation between upper-gastrointestinal symptoms and disordered gastric emptying represents a major difficulty in the therapeutic approach, and evidence to support the efficacy of current management strategies is often suboptimal, especially in relation to long-term therapy. In this review, the common causes and pathophysiology of gastroparesis are summarized, the diagnostic approach considered, and the evidence to support medical and surgical therapies reviewed. These therapies include currently available prokinetic drugs, novel medical therapies, and the promising technique of gastric electrical stimulation.

Physiology of Gastric Emptying and Pathophysiology of Gastroparesis

Current knowledge of the physiology of gastric emptying implicates a reservoir function for the gastric fundus, grinding and propulsive functions for the antrum, and the concept of the pylorus and duodenum as resistances to gastroduodenal flow. Although these areas differ markedly in their behavior, their contractile activities are coordinated in such a way that the delivery of nutrients to the small intestine occurs in an orderly and controlled manner. In this article we describe the functions of the gastric fundus, antrum, pylorus, and duodenum and how the contractile activities of these regions regulate gastric emptying, according to the composition of the meal and the physiologic and emotional state of the person. In addition we discuss the nature and possible mechanisms of the motor disturbances associated with abnormally slow gastric emptying.