Pathology of gastroparesis: ICC, enteric neurons and fibrosis

Introduction

Gastroparesis is a disease that affects the stomach’s motility and digestion, preventing proper stomach emptying. As a complex organ, the stomach empties both solid food and liquids at different rates, with liquids normally emptying faster than solids. In the absence of obvious mechanical outlet obstruction, gastroparesis is classified as delayed emptying of food from the stomach into the small intestine .

Gastroparesis is a distressingly painful disorder with a nationwide prevalence of 0.16% in the United States with a rising trend, particularly among children and minorities, mainly due to an increase in diabetes .

Characterized by a constellation of upper gastrointestinal (GI) symptoms in association with delayed gastric emptying (GE), major symptoms of gastroparesis can include early satiety or postprandial fullness, postprandial nausea, vomiting, abdominal bloating, heartburn, gastroesophageal reflux, lack of appetite, weight loss, malnutrition and abdominal or epigastric pain. Often gastroparesis is prominent in both type 1 and type 2 diabetes .

The pathogenesis of gastroparesis is poorly understood, in part because of a lack of comprehensive studies of gastric pathology and histology in these patients. Recent studies aimed to investigate the underlying mechanisms of gastroparesis through looking at the pathology of the stomach . This chapter summarizes pathological findings of gastroparesis by looking at different elements of the gastric movement including enteric neurons, interstitial cells of Cajal (ICC), and fibrosis. A better understanding of the physiology of gastric emptying and accommodation would help us to better appreciate the underlying pathological changes in gastroparesis.

Physiology of gastric motility

As a smooth muscle organ, the stomach connects the esophagus to the small intestine. Stomach movements are intricate involving both neurogenic and myogenic components. The neurogenic elements arise from the parasympathetic or vagus nerve and the enteric nervous system. The vagus nerve synapses with enteric interneurons that in turn synapse with inhibitory motor neurons releasing nitric oxide (NO) and ATP as a co-neurotransmitter to relax the gastric stomach smooth muscles. Myogenic factors stem from the pacemaker networks near the myenteric plexus that generate electrical slow waves propagating into the circular and longitudinal muscle layers that underly gastric contractions. Electrical slow waves are generated in a network of c-KIT positive cells lining the myenteric plexus in the entire stomach called the myenteric interstitial cells of Cajal (ICC-MY) . Electrical slow waves propagate through the network of ICC both around and down the stomach to produce ring-like peristaltic contractions of the wall every three minutes. The dominant slow waves originate in the mid-stomach or c-Kit positive ICC-MY cells in the corpus , as the dominant pacemaker region for the stomach (see Fig. 8.1 ) .

Other polarized ICC within the muscle layers are intramuscular ICC (ICC-IM) that act as neuroeffectors between enteric inhibitory and excitatory motor nerve terminals and smooth muscle cells (SMC) .

As food propagates into the antrum, the antrum contracts and retropulses solid matter back into the stomach, producing mixing and grinding of food into smaller particles. Only small particles with a diameter of 1–2 mm of viscous liquid food called chyme are normally propelled through the pylorus and into the duodenum (see Fig. 8.2 ).

Gastric accommodation

Gastric filling requires adaptive relaxation of the stomach (see Fig. 8.2 ). Adaptive relaxation is a reflex in which the fundus and upper body of the stomach dilates in response to food entering the stomach. Another reflex which is involved in gastric accommodation is receptive relaxation, which by definition, is a reflex in which the gastric fundus dilates when food passes down the pharynx and the esophagus or during a swallow leading to a decrease in gastric tone. Filling is due to activation of vagal neurons that have cell bodies in the dorsal motor nucleus (DMN) synapsing with enteric interneurons, that in turn synapse with inhibitory motor neurons (IMN) which largely release nitric oxide (NO) from neuronal nitric oxide synthesis positive (nNOS) motor neurons within cell bodies in the enteric nervous system. NO is a major inhibitory co-neurotransmitter, which along with ATP accommodates food by relaxing the gastric smooth muscle .

Interstitial cells and the smooth muscle cell/ICC/PDGFRα ⁺ (SIP) syncytium

Coordinated contractions of the stomach are integrated motor responses. In the last 20 years, dissection of the myogenic elements using genetic, molecular, morphologic, and physiologic approaches have identified several cell types that contribute to these components of gastrointestinal motility. Interstitial cells of Cajal (ICC-MY) in the myenteric regions are recognized as major contributors to gastric and gastrointestinal (GI) motor activity . Dense ICC within the corpus region of the stomach generates dominant electrical slow waves (see Fig. 8.3 ) . These cells are gastric pacemakers, whereas other ICC within the muscle layers, called intramuscular ICC (ICC-IM) act as neuroeffectors between enteric motor nerve terminals and smooth muscle cells (SMC) and are essential for inhibitory and excitatory neurotransmission, whereas others act as gastric stretch receptors and have been found in close proximity to enteric nerves and contribute to neurally-mediated GI motor responses .

A second type of interstitial cells are identified as Platelet-derived growth factor cells (PDGFRα ⁺ ) which form a syncytium . PDGFRα ⁺ cells, like ICC, have also been found in close proximity to enteric nerves and also appear to contribute to neurally-mediated GI neural motor responses. Smooth muscle cells are electrically coupled to ICC and PDGFRα ⁺ cells forming an integrated unit termed the SIP syncytium (see Fig. 8.3 ) . SIP cells express a variety of receptors and ion channels, and conductance changes in any type of SIP cell affects the excitability and response of the entire syncytium. SIP cells are known to provide pacemaker activity, propagation pathways for slow waves, transduction of inputs from motor neurons, and mechanosensitivity .