Sensory dysfunction in gastroparesis

Gastroparesis occurs commonly as a complication of long-standing diabetes, but the in the largest group of patients no cause can be established and these are referred to as idiopathic gastroparesis patients. While delayed gastric emptying is a defining feature of gastroparesis, gastric emptying rate is inconsistently linked with symptoms and choice of or response to therapy. Hence, there are other mechanisms contributing to the pathophysiology of gastroparesis, and amongst these, visceral hypersensitivity is an important factor. This manuscript reviews methods to assess visceral sensitivity, the concept of visceral hypersensitivity, its impact on symptom pattern and severity, and the implications for treatment.

Introduction

Gastroparesis is a syndrome characterized by upper gastrointestinal symptoms including nausea or vomiting, and delayed gastric emptying in the absence of mechanical obstruction . Gastroparesis occurs in several clinical settings, particularly as a complication of diabetes mellitus, but also as a complication of upper gastrointestinal surgery, neurological disease, collagen vascular disorders, viral infections, drugs, etc. In the majority of cases no underlying cause is found and gastroparesis is termed idiopathic .

Delayed gastric emptying is a defining feature of gastroparesis, as indicated above. However, the presence and severity of slowed gastric emptying does not determine the symptom pattern, the impact on quality of life and the response to treatment . Hence, several other pathophysiological factors have been proposed to be involved in symptom generation in gastroparesis, including gastric arrhythmia, impaired gastric accommodation, redistribution of the meal within the stomach, gastro-esophageal reflux, small bowel dysmotility and visceral hypersensitivity .

Visceral hypersensitivity as a pathophysiological mechanism in gastrointestinal disorders

Visceral hypersensitivity is now well established as a leading mechanism of symptom generation in several gastrointestinal disorders . In many of these conditions, it plays a key role in determining symptom pattern and symptom severity . Visceral hypersensitivity can be experimentally demonstrated as a significantly lowered threshold for first perception and for discomfort or pain during balloon distention of a hollow organ, and in case of gastroparesis, the stomach. However, gastric balloon distention studies are done using a gastric barostat device, a procedure which is technically difficult, invasive and which generates major discomfort to the patient . Hence, this method has never reached routine clinical application and there are very few studies in gastroparesis .

Nutrient challenge drink tests have also been used to assess gastric sensitivity Nutrient challenge drink tests are being perceived by clinicians as the way to test for sensory dysfunction, including in gastroparesis. However, the endpoint of these drink tests, generally volume consumed, is likely to be determined not only by gastric sensitivity, but also by gastric accommodation, gastric emptying, duodenal factors, and the palatability of the nutrient used .

Reports on visceral hypersensitivity in gastroparesis

Very limited addressed this issue using stated of the art gastric barostat distention paradigms. In a pathophysiological study in 58 patients with idiopathic gastroparesis, hypersensitivity to gastric distention was found in 29%. In this cohort, gastric emptying rate failed to correlate to the symptom pattern, but sensitivity to gastric distention was associated with higher total symptom severity, and also with higher severity of epigastric pain, belching and a tendency to have more early satiation ( Fig. 7.1 ). In this study, only gastric sensitivity status was significantly correlated to the overall symptom severity . Furthermore, the barostat protocol in this study also involved measurement of gastric accommodation, showing a high prevalence of impaired accommodation (43%) which was correlated with symptoms of early satiation . In diabetic gastroparesis, a similar but much smaller study, including 18 patients also found a high prevalence of impaired accommodation and hypersensitivity to gastric distention . Perhaps due to the small numbers, no significant correlation with the symptom pattern was found.

Hypersensitivity is a major determinant of symptom pattern in functional disorders of both the upper and lower gastrointestinal tract. Based on the 2 studies in gastroparesis, it seems reasonable to propose that gastric hypersensitivity, is present in a subset of patients with gastroparesis, where it may contribute to symptom pattern and severity.

The pathophysiological basis for visceral hypersensitivity

In spite of its prevalence and relevance, the origin and even the nature of visceral hypersensitivity are not established. Diagnosing visceral hypersensitivity is based on symptom ratings, and early reaching of perception or discomfort thresholds during stepwise distention of a hollow organ . There is a potential for reporting bias and, indeed, some studies have associated visceral hypersensitivity with somatization, which is characterized by enhanced and multiple symptom reporting .

On the other hand, sensitization of gut-brain, or in this case gastric-brain, afferent pathways may also generate increased sensory ratings during visceral stimulation, not based on symptom reporting biases but on enhanced sensory afferent signaling . Analyses in functional dyspepsia have indicated that tension-sensitive mechanoreceptors mediate (hyper-)sensitivity to gastric balloon distention and up-regulation of these receptors or their activity can underlie gastric hypersensitivity. This issue has not been addressed in depth, as the molecular nature of the tension-sensitive gastric mechanoreceptor has not been identified. Finally, altered central processing of incoming gastric signals, with lack of antinociceptive circuit activity, may also contribute to visceral hypersensitivity generation . Again, this has not been addressed in gastroparesis but there is some evidence from the related condition of functional dyspepsia . At least in theory, diabetic neuropathy could also contribute to altered sensory processing and visceral hypersensitivity generation in diabetic gastroparesis .

Tension sensitive receptors are under major influence of changes in tone of the hollow organ . In functional dyspepsia, it has been established that impaired gastric accommodation contributes to hypersensitivity to gastric distention after a meal, when symptoms predominantly occur . In both idiopathic and diabetic gastroparesis, a subset of patients have impaired accommodation which may also contribute to hypersensitivity-related postprandial symptoms .

Therapeutic implications

In spite of its prevalence and relevance for symptom generation in several types of gastrointestinal disorders, no specific treatment for visceral hypersensitivity has been established. In many of the functional disorders, centrally acting neuromodulators such as antidepressants and delta ligands are used, based on the assumption that they address visceral hypersensitivity, but this has not really been proven .

In gastroparesis, especially in idiopathic gastroparesis, the available evidence argues against success of such approach. In the NORIG trial, nortryptiline was not superior to placebo in alleviating symptoms of idiopathic gastroparesis . In a controlled trial in functional dyspepsia treated with amitryptiline, escitalopram or placebo, only amitryptiline provided symptom relief, but this was not the case in the subgroup with delayed gastric emptying at baseline . Hence, at this point there is no evidence that empirical neuromodulator therapy, aimed at presumed underlying hypersensitivity, is able to provide symptom benefit in gastroparesis. This does not exclude the possibility of a beneficial effect of neuromodulators in subgroups with demonstrated visceral hypersensitivity at baseline, but such studies have not been performed to date. In a small study in diabetic gastroparesis, the alpha-2 adrenergic agonist clonidine was reported to provide symptomatic benefit . This agent was shown to decrease sensitivity to gastric distention in functional dyspepsia . In theory, enhancing accommodation may improve symptoms in gastroparesis patients in whom impaired accommodation generates postprandial hypersensitivity to the stomach . However, studies evaluating such agents, including buspirone, acotiamide or nitrates , in gastroparesis, are lacking.