Gastroparesis: a turning point in understanding and treatment

Abstract

Gastroparesis is defined by delayed gastric emptying (GE) and symptoms of nausea, vomiting, bloating, postprandial fullness, early satiety and abdominal pain. Most common aetiologies include diabetes, postsurgical and postinfectious, but in many cases it is idiopathic. Clinical presentation and natural history vary by the aetiology. There is significant morbidity and healthcare utilisation associated with gastroparesis. Mechanistic studies from diabetic animal models of delayed GE as well as human full-thickness biopsies have significantly advanced our understanding of this disorder. An innate immune dysregulation and injury to the interstitial cells of Cajal and other components of the enteric nervous system through paracrine and oxidative stress mediators is likely central to the pathogenesis of gastroparesis. Scintigraphy and ¹³C breath testing provide the most validated assessment of GE. The stagnant gastroparesis therapeutic landscape is likely to soon see significant changes. Relatively newer treatment strategies include antiemetics (aprepitant), prokinetics (prucalopride, relamorelin) and fundic relaxants (acotiamide, buspirone). Endoscopic pyloromyotomy appears promising over the short term, especially for symptoms of nausea and vomiting. Further controlled trials and identification of the appropriate subgroup with pyloric dysfunction and assessment of long-term outcomes are essential. This review highlights the clinical presentation, diagnosis, mechanisms and treatment advancements for gastroparesis.

Keywords: GASTRIC EMPTYING; GASTROPARESIS; INTERSTITIAL CELLS OF CAJAL; MACROPHAGES; PROKINETIC AGENT.

Figure 1:. Gastrointestinal pathophysiological changes in human gastroparesis.

Physiological changes such as impaired accommodation of the gastric fundus/body, motor abnormalities including antral hypomotility, impaired pyloric relaxation and small intestinal dysmotility can result in impaired gastric emptying and clinical manifestations of gastroparesis. At a cellular level, loss of interstitial cells of Cajal (ICC) has been reported in over half of the gastroparesis patients and nearly all of the patients had signs of injury to ICC on ultrastructural studies. The loss of ICC correlated with delayed gastric emptying in diabetic gastroparesis. Ultrastructural studies also showed changes in nerves and smooth muscle cells which were less appreciable on immunohistochemistry. More recently, human studies have shown loss of macrophages with anti-inflammatory phenotype (CD206 positive, M2 or alternatively activated macrophages) and increased expression of genes associated with pro-inflammatory macrophages on transcriptomic analysis of full thickness biopsies. This is complemented by animal model studies of diabetic gastroparesis where an altered macrophage activation was shown to mediate injury to ICC likely through paracrine mediators. Additionally, CSF1op/op mice lacking macrophages were protected from development of gastroparesis in spite of having diabetes suggesting an essential role for immune cells in development of delayed gastric emptying. Immune mediated mechanisms likely play a critical role in pathogenesis of gastroparesis.

Figure 2:

Summary of human studies highlighting cellular and molecular changes in gastroparesis