Updates from the Gastroparesis Clinical Research Consortium

Gastroparesis is a complex medical problem associated with a significant degree of morbidity and suffering. In 2006, the National Institute of Diabetes and Digestive and Kidney Diseases established the Gastroparesis Clinical Research Consortium (GPCRC) to advance the knowledge of the natural history of gastroparesis, its pathophysiology and pathogenesis, and therapy; with the goals of (a) building a large registry and biorepository from carefully phenotyped patients and (b) performing rigorous treatment trials. Through these studies, the consortium has confirmed the burden and persistence of illness in these patients and has identified several factors associated with prognosis. Surprisingly, we found that obesity is common among patients with gastroparesis and is associated with differences in clinical phenotype with a worse outcome. Further, small bowel and colonic dysmotility are seen in a significant number of patients.

Critical new knowledge has also been gained in several other areas. Thus, we now have good insight into the pathological basis of gastroparesis. Analysis of full-thickness gastric biopsies shows that the major cellular defect involves interstitial cells of Cajal (ICC) and not neurons or smooth muscle. Further, ICC loss correlates with delays in gastric emptying. These changes are accompanied by a significant pro-inflammatory macrophage infiltrate, suggesting an underlying immune dysregulation as the driving factor. Other studies have shown that molecular variants in the key ICC ion channel, Ano-1, are more prevalent in diabetic patients with gastroparesis than in those without it. These advances have, for the first time, raised hopes for rational, disease-modifying therapy. Thus, specific drugs that address ICC loss, dysfunction or channelopathies/arrhythmias could potentiallybe very useful in treating gastroparesis. Other new pharmacological approaches that could go even further include suppression of the macrophagedriven immune response that may underlie these changes, raising the hope for a real cure.

While awaiting these exciting future developments, it is also important to find more immediate solutions to relieve the suffering that so many of these patients undergo on a daily basis. A major objective of the consortium is to conduct rigorous trials of such drugs so that their widespread use can be supported. Unfortunately, the Nortriptyline for Idiopathic Gastroparesis (NORIG) trial conducted by the GPCRC failed to demonstrate the efficacy of low-dose nortriptyline, an antidepressant and neuromodulator, which is used based on the hypothesis that visceral hypersensitivity plays a significant role in the pathogenesis of symptoms. Our hopes are now centered on the results of the recently concluded Aprepitant for the Relief of Nausea in Patients With Chronic Nausea and Vomiting of Presumed Gastric Origin Trial (APRON) trial that examined the efficacy of aprepitant, an inhibitor of theneurokinin-1 receptor, currently indicated for the treatment of chemotherapy-induced nausea and vomiting.

Diabetic gastroparesis, although similar in some ways to the idiopathic variety, poses its own unique challenges for management, particularly with respect to insulin-dependent diabetes. In general, endocrinologists have struggled with the question of aggressive insulin management in such patients, fearing the risk of hypoglycemia from unpredictable gastric emptying of ingested calories. The GPCRC looked at this issue in its Continuous Glucose Monitoring and Insulin Pump Therapy in Diabetic Gastroparesis (GLUMIT) trial, which required patients to be treated with an insulin pump and continuous glucose monitoring. Preliminary results, presented at Digestive Disease Week® 2015, show that such an approach is safe and not only improves glycemic control but is also associated with improvement in gastroparetic symptoms.

Consortium Contributors

Clinical Sites
Johns Hopkins University (PJ Pasricha, J Clarke, S Dhalla, E Stein)
Temple University (H Parkman) University of Louisville (T Abell)
Wake Forest University (K Koch) Texas Tech University (R McCallum, I Sorastiek)
Stanford University (L Nguyen)
California Pacific Medical Center (W Snape)

Data Coordinating Centers
Johns Hopkins Bloomberg School of Public Health (J Tonascia)
Pathology Resource Center Mayo Clinic, Rochester (G Farrugia, M Grover)

F Hamilton

Other results may have far-reaching implications for the field of gastrointestinal motility, including the traditional divide between “organic” and “functional” disorders. Thus physicians have conceptually categorizedsymptoms (nausea and vomiting, along with early satiety and postprandial discomfort and distention) on the basis of a gastric emptying test. If this is delayed, the patient is diagnosed as having gastroparesis. If normal, the label that is most often applied is functional dyspepsia, described in GPCRC studies as CUNV (chronic unexplained nausea and vomiting). We have shown that these patients are clinically indistinguishable from those with delayed gastric emptying in terms of both the nature and severity of symptoms, and further clinical outcomes at one year and beyond are similar regardless of gastric emptying. Emerging data now suggests that macrophage infiltration and ICC loss, albeit to a lesser extent, are similar to what is observed in classical gastroparesis. So it is possible that patients with gastroparesis and at least some patients with “functional dyspepsia” are part of a broader spectrum of gastric neuromuscular disease.

In summary, GPCRC has provided a detailed understanding of the clinical characteristics and course of patients, has identified specific pathological changes and has implicated putative etiologies, setting the stage for disease-modifying therapy. Together with planned future research, these results are expected to eventually transform the outcomes for our patients.

Dr. Pasricha holds equity in several companies in the gastroenterology field.

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