Endoscopic Approaches for Gastroparesis

Introduction

The word gastroparesis is derived from the Greek words gastro and pa'resis, and translates to partial paralysis of the stomach. The diagnosis of gastroparesis is defined as delayed gastric emptying in the absence of mechanical obstruction, associated with one or more of the following symptoms: postprandial fullness, early satiety, nausea, vomiting, and bloating. Whereas gastroparesis can be associated with diabetes mellitus, neuromuscular and connective tissue diseases, vagal injury, or some medications, in the majority of patients, no underlying etiology is identified, and they are presumed to be idiopathic. For reasons that are not entirely clear, there is a marked gender discrepancy in all subgroups, with women being affected far more often than men. True prevalence data are unclear, with estimates of up to 3%. One large study performed at the Mayo Clinic estimated a community prevalence of 1.8%. However, this may be a significant underestimate of true prevalence, as approximately 40% of patients with functional dyspepsia have delayed gastric emptying on evaluation, and the prevalence of functional dyspepsia has been suggested to be approximately 10% to 15% worldwide. In addition, the societal impact of gastroparesis is significant. Worsening symptoms are accompanied by poor food intake, weight loss, malnutrition, impaired function, and more emergency room visits. Data suggest that hospital admissions for gastroparesis in the United States now exceed those for gastroesophageal reflux, peptic ulcer disease, gastritis, and nausea.

One of the most frustrating aspects of gastroparesis is the paucity of treatment options that are currently available. The only medication that is approved by the Food and Drug Administration (FDA) at present is metoclopramide, which also has an associated black box warning related to tardive dyskinesia. Other drugs that have shown efficacy in controlled trials are either not available in the United States (domperidone) or have been pulled from the market due to safety concerns (cisapride). Gastric electrical stimulation (GES) was given a Humanitarian Device Exemption by the FDA in 2000 based on the results of a double-blind controlled trial. The lack of established treatment options, in tandem with the significant symptom burden associated with gastroparesis, has led to intense interest in alternative diagnostic and treatment paradigms. In particular, endoscopic options for both diagnosis and therapy have risen to the forefront in recent years, driven by a number of factors: (1) the paucity of accepted medical treatment options, (2) increased understanding regarding the pathophysiology of gastroparesis, and (3) technical advances in endoscopy that have expanded the feasibility of interventional endoscopic options. In this chapter, we will present our understanding of the current role of endoscopy in the diagnosis and treatment of gastroparesis, and will speculate on what the near future holds.

Physiology of Gastroparesis

Although delayed gastric emptying is the sine qua non of gastroparesis, it is well-recognized that multiple mechanisms are at play in addition to gastric emptying with regards to symptom pathogenesis. The National Institutes of Health (NIH) Gastroparesis Clinical Research Consortium, consisting of six Academic Motility Centers, has played an integral role in advancing our understanding of pathogenesis, but much remains to be learned. In addition to objective impairment of gastric emptying, subsets of affected patients have also been shown to have impaired fundic accommodation, gastric dysrhythmias, impaired gastroduodenal coordination, abnormal duodenal signaling, autonomic dysfunction, visceral hypersensitivity, and abnormal central processing of peripheral stimulation. Each of these mechanisms may play a role in the clinical presentation of subsets of affected patients, and it is unlikely that symptoms can be attributed to a uniform origin.

This recognition of gastroparesis as a heterogeneous process is perhaps best exemplified through the lens of histopathology. Recent studies undertaken through the NIH gastroparesis consortium have utilized full-thickness gastric biopsies to evaluate for histopathologic changes that may provide evidence as to underlying mechanisms. These investigations have led to intriguing observations, including loss of interstitial cells of Cajal (ICCs), abnormal macrophage-related immune infiltrates, and decreased nerve fibers. One common theme that has emerged is that the histopathologic pattern observed in these patients can be variable. For example, a depletion of ICC numbers in the smooth muscle of the antrum or gastric body has been recognized in up to 40% of severe gastroparetics not responding to medical therapies and requiring surgery to place a gastric electrical stimulator device (Enterra, Medtronic, Minneapolis, MN). However, approximately 50% of such severely symptomatic patients had a normal number of ICCs.

Recent research (2016) has also expanded our understanding of the role of pylorus in gastroparesis through looking at the histopathology of this region in patients with severe disease who underwent surgery to insert a gastric electric stimulator and/or perform a pyloroplasty. In one series, approximately 70% of gastroparetic patients had pyloric ICC loss. Moreover, collagen fibrosis was observed in the pylorus of more than 80% of these patients. These findings may help explain pyloric dysfunction in gastroparesis, making interventions in the pyloric region a reasonable therapeutic approach in these patients. This study also identified eosinophilic inclusion bodies in the antrum and/or the pylorus, which were limited to diabetic gastroparetic patients. The clinical role of these inclusion bodies remains unclear, and further investigation is needed.

Studies of the histopathology of the stomach in gastroparesis have relied on patients with severe cases who underwent surgery, which allowed full-thickness biopsies of the gastric wall to be taken. Therefore, a knowledge gap still remains in regard to patients with mild or moderate symptoms who are treated medically. Minimally invasive techniques such as percutaneous endoscopically assisted transenteric full-thickness gastric biopsy or biopsies utilizing endoscopic ultrasound guidance may allow us to study the gastric tissue in patients with less severe gastroparesis and provide further insight into the potential mechanisms of disease pathogenesis and progression.

Overall, there does not appear to be any single gold standard histopathologic marker for gastroparesis as the disorder is currently defined. It is likely that our current definition of gastroparesis, which relies on symptoms in tandem with gastric emptying, lumps many related subgroups under the same umbrella. As data emerge, there will be refinement of the underlying mechanisms of symptom pathogenesis and the relative importance of each mechanism in the development of individual symptoms, and there will also likely be a change in disease nomenclature based on recognition of clinically meaningful subgroups.

The Role of Endoscopy

The role of endoscopy in the diagnosis and management of gastroparesis has evolved in the past decade. Endoscopy has always been required to exclude gastric outlet obstruction, peptic ulcer disease, malignancy, or significant inflammation prior to establishment of the diagnosis of gastroparesis, a functional disorder of gastric emptying. However, the role of endoscopy has recently expanded to include more in-depth diagnostic investigations, as well as novel treatment options. In this chapter, we will focus on the numerous primary roles endoscopy plays in the diagnosis and management of gastroparesis. Specifically, we will review the data regarding endoscopic therapeutic advances in subsets of patients who may have primary pyloric dysfunction (either in isolation or in tandem with other defects); examine the role of endoscopy in the acquisition of full-thickness biopsies; evaluate the role of endoscopic temporary GES; and review the data regarding endoscopic venting/feeding options for patients with refractory symptoms. This is by no means an exhaustive account of all the ways in which endoscopy can be of benefit in gastroparesis; however, we have tried to highlight recent advances and the state of the art as we see it today.