The pyloric revolution: Patient selection

Altered histopathology

Advances in histopathology have contributed significantly to our understanding of gastroparesis over the past decade. Recent studies undertaken through the NIH Gastroparesis Research Consortium have utilized full-thickness gastric biopsies to evaluate for potential histopathologic changes that may provide evidence as to underlying pathophysiology. These investigations have led to intriguing observations, including loss of interstitial cells of Cajal (ICC), abnormal macrophage-related immune infiltrates and decreased nerve fibers in some affected patients . One common theme that has emerged is that the histopathologic pattern observed in gastroparesis patients can be highly 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; however, on the other hand, approximately 50% of such severe symptomatic patients had a normal population of ICC . However the quality and true function of those remaining ICC are unknown and have been questioned in research reports.

Advances in histopathology have specifically expanded our understanding of the role of the pylorus in gastroparesis, particularly through evaluation of histopathology of the pylorus obtained in patients with severe disease who underwent surgery to insert a gastric electrical stimulator and/or pyloroplasty. The largest report came from the research team at Texas Tech University in El Paso where approximately 70% of patients with severe symptoms of gastroparesis had pyloric ICC loss based on surgically obtained biopsies from the smooth muscle of the pyloric sphincter. Perhaps more intriguingly, collagen fibrosis was observed in the pylorus of more than 80% of these patients . This data for the first time provides objective evidence that a potential underlying mechanism might link pyloric dysfunction with underlying histopathology and provide a rationale for intervention. However, to keep this in perspective, this pyloric histopathology was largely derived from full-thickness biopsies of severely affected patients not responding to standard medical therapies and requiring surgery rather than patients with more mild-to-moderate symptom burden. Nevertheless, the findings of discrete changes, and specifically collagen deposition in the region, are intriguing. The more severe patients with gastroparesis have pyloric and antral loss of ICC as well as fibrosis, then there is a clear rationale for pyloric intervention – although one should be clear that therapy directed at pyloric dysfunction likely improves only one aspect of the patient’s underlying disorder and will not change underlying histopathology changes that have already been well described in the antrum.

Of note, one could also hypothesize that loss of ICC and fibrosis in the pylorus and antrum could alter normal motility patterns, perhaps leading to discoordination or loss of antroduodenal coordination of contractions, providing another mechanism by which pyloric dysfunction/fibrosis could impact patients on a more global scale. Of course, the converse could also be seen wherein pyloric dysfunction is seen as an isolated process. In a recent thought-provoking paper, investigators from Wake Forest found normal, if not very prominent, 3 cycle/minute antral slow wave frequency on electrogastrography to be a predictor of response to pyloric intervention – implying that isolated pyloric dysfunction may be at play . However, in our personal experience, patients with presumed pyloric dysfunction rarely have this in the absence of other potential pathophysiology and the electrogastrogram in gastroparesis patients is invariably abnormal regarding dysrhythmias and loss of the usual 3 cycles per minute frequency.

Pylorospasm

Another key hypothesis with regards to pyloric dysfunction that has remained in vogue for the past three decades has been the concept of “pylorospasm” as a potential contributor to impaired gastric emptying and symptoms of gastroparesis. Pyloric pressure patterns can be measured through two modalities: antroduodenal manometry (ADM) and to a lesser extent the wireless motility capsule (WMC). ADM involves placement of a manometry catheter, either via endoscopy or fluoroscopy, with multiple sensors across the pylorus such that sensors are present in both the gastric antrum and proximal small bowel. The initial papers evaluating the role of ADM in assessment of pyloric pressure in health and disease stemmed from investigators at the University of Southern California and the Mayo Clinic in the mid 1980s . Malagelada and Camilleri, investigators at the Mayo Clinic, showed that some patients with gastroparesis had prolonged pyloric pressurization and more intense contraction, which they labeled “pylorospasm”. Our discussion of ADM will be relatively brief as there is a separate chapter on this test specifically; however, this technology has not been widely adopted as a means of assessing pylorospasm as the pylorus is relatively short, migration of the catheter is common, the technique is cumbersome and resource-intensive, and few companies produce the necessary equipment. For these reasons, ADM is largely limited to only a few tertiary referral centers at present – and while it is the traditional means of pyloric pressure assessment, it has not achieved a strong foothold in its three decades of availability primarily due to the reasons above.

More recently, the WMC has entered the clinical arena. This is a wireless, ingestible medical device that measures pH, pressure and temperature throughout the gastrointestinal tract and was approved by the Food and Drug Administration in 2006 for evaluation of gastric emptying in patients with suspected gastroparesis. Given the relative ease of this technology as compared to ADM, there has been speculation that perhaps similar information could be derived with regards to pyloric pressurization without the hassle of performing ADM. However, there are reasons why this may not be feasible as (a) the WMC is not fixed in space but rather allowed to move with food and gastric contractions, making it less reliable for detection of contractile amplitude and frequency at a single or specific site and (b) passage through the pylorus itself with the capsule would be relatively brief, perhaps giving only limited information with regards to pyloric function – and occurring at a time of pyloric expansion. Due to these limitations, data with regards to antroduodenal pressure patterns in patients with gastroparesis are very limited, with only one paper exploring a direct comparison between ADM and WMC . Investigators from Johns Hopkins University published an interesting abstract in 2014 suggesting a correlation between WMC-derived pre-pyloric pressures and gastric emptying; however, this abstract has not been published in full manuscript form . Recently an abstract presented at the 2019 DDW identified extremely prolonged gastric emptying results assessed by WMC in gastroparetic patients who later had a surgical pylorus biopsy showing loss of ICC and fibrosis . In addition, the very prolonged presence of the WMC in the stomach was linked to evidence of the WMC repeatedly trying to pass through the pylorus into the duodenum and being rejected. Taken together, the data from ADM and WMC would suggest that subsets of gastroparesis patients have “pylorospasm” or manometrically-identifiable pyloric abnormalities, and the patterns of WMC emptying from the stomach could be a predictor of pyloric dysfunction.

Vagal nerve dysfunction

The vagus nerve plays a seminal role in regulation of gastrointestinal motility and coordination of sympathetic and parasympathetic signaling. Damage to the vagus nerve results in multiple derangements to gastric motility including decreased fundic accommodation, weakened antral contractions, impaired pyloric relaxation and altered gastroduodenal coordination . Recent investigation highlights the rich vagal innervation of the pylorus . Utilizing a rat model, direct stimulation of the pylorus was shown to enhance pylorus relaxation resulting in a wider opening diameter as measured by magnetic resonance imaging . Given this information, it does make sense that patients with dysfunction attributable to vagal injury (whether that be iatrogenic in the context of foregut surgery, intentional in the context of older surgical procedures, or associated with vagal neuropathy) may have pyloric impairment and could be a theoretic target for pyloric-directed intervention – with the caveat that the pylorus is only one of many areas innervated by the vagus and no therapy to the pylorus in isolation may compensate for the full gamut of impaired vagal function.