Gastroparesis: A Comprehensive Approach to Evaluation and Management

​This book presents a comprehensive approach to the diagnostic evaluation of gastroparesis and the medical and surgical treatment options available for this disorder.  The initial chapters address the different etiologies, pathophysiology and diagnostic evaluation of this disease. Medical management, nutritional support and co-morbid conditions are also discussed.  Subsequent chapters focus on endoscopic and surgical options for management and the current outcomes data for these procedures.  A brief review of the existing literature addressing the particular topic is included in each section.
Written by experts in the field, Gastroparesis covers each of these treatment sections that address patient selection, technical conduct and complications of the most common endoscopic procedures and operations, and anticipated outcomes of therapy. 

• Language: English
• Publisher: Springer
• Release date: Nov 8, 2019
• ISBN: 9783030289294

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Part IEtiology and Diagnosis

© Springer Nature Switzerland AG 2020

A. Ibele, J. Gould (eds.)Gastroparesishttps://doi.org/10.1007/978-3-030-28929-4_1

1. Normal Gastric Motility

Kirstie E. Jarrett¹   and Robert E. Glasgow¹  

(1)

Department of Surgery, University of Utah, Salt Lake City, UT, USA

Kirstie E. Jarrett

Email: [e-mail]

Robert E. Glasgow (Corresponding author)

Email: [e-mail]

Keywords

Gastric motilitySlow wavesInterstitial cells of CajalEnteric nervous systemReceptive relaxationTriturationGastric emptyingGastroparesis

Normal gastric motility occurs as the result of a complex coordination of many intrinsic and extrinsic stimuli. The basis of gastric neuromuscular function is the spontaneously generated cellular depolarizations called slow waves, which are then modulated by stimuli from the autonomic nervous system (ANS), enteric nervous system (ENS), and a variety of gastrointestinal (GI) hormones. The result is a cyclic pattern of rhythmic contractions that changes based on the presence/absence of food, as well as the type and caloric content of ingested food.

When food is ingested, three key functions are required in order to effectively process and transfer it to the duodenum for nutrient absorption. First, receptive relaxation must occur so that the food can enter the stomach without causing an increase in intraluminal pressure. Second, peristaltic contractions must break the foodstuffs into very small particles and mix them with gastric juices to form chyme. Finally, peristaltic contractions must allow the emptying of chyme into the duodenum. When these critical functions are interrupted, patients can experience nausea, vomiting, early satiety, and bloating, as well as many other symptoms related to dysfunctional gastric emptying.

Electrophysiology of Gastric Motility

Gastric Slow Waves and Action Potentials

The primary source of gastric myoelectrical activity is the slow wave (also known as a pacesetter potential). A slow wave is an organized electrical event that depolarizes smooth muscle cells and brings them closer to the threshold required for muscle contraction. Slow waves are generated spontaneously by interstitial cells of Cajal (ICCs), which are located in the gastric wall along the greater curvature. They propagate distally and circumferentially from the corpus toward the pylorus (Fig. 1.1). They occur regularly at a rate of approximately 3 cycles per minute (cpm). Slow-wave activities provide the cyclic depolarization of smooth muscle cells in the stomach and is therefore the basis for the regulation and pacing of gastric smooth muscle contractions.

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Fig. 1.1

Gastric electrical activity recorded from electrodes on the serosa at various positions from the fundus to the antrum (A–D). Slow waves are generated in the pacemaker region along the greater curvature, then propagate distally and circumferentially (dotted lines with arrowheads). Electrode A, positioned at the fundus, has no slow-wave activity. Electrodes B-D show 3-per-minute depolarizations, indicating slow waves. (Modified from Koch [1].)

A single slow wave consists of an initial upstroke, followed by a plateau potential, then a return to baseline (Fig. 1.2) [2]. Slow waves by themselves do not necessarily cause muscle contraction. This is because the plateau potential does not always depolarize the gastric smooth muscle cell enough to reach the contraction threshold. When contraction does occur, it is because the amplitude of the plateau potential reaches the activation threshold for L-type Ca²+ channels, causing Ca²+ influx and muscle contraction. In the corpus, antrum, and pylorus, slow waves alone can be sufficient to trigger muscle contraction [3]. The intensity of muscle contraction is determined by the amplitude and duration of the plateau potential [3, 4].

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Fig. 1.2

Schematic representation of gastric electrical potentials. Intracellular recordings of slow waves show an initial upstroke in potential (1), followed by a plateau potential (2), then a return to baseline. Corresponding extracellular recordings during a slow wave show initial change in potential (3), followed by a return to baseline (4). Note that the slow wave has no corresponding change in tension (i.e., no muscle contraction). In contrast, action potentials are associated with changes in muscle tension. The plateau potential of an action potential is much higher than in the slow wave. Further, the extracellular recording during an action potential shows a downward deflection (5). (From Kim and Malagelada [2])

The frequency and force of contractions associated with slow waves differ based on the region of the stomach in which the smooth muscle is found. This is because smooth muscle cells in different regions exhibit unique electrical characteristics. One key difference is the resting membrane potentials, ranging from −48 to −75 mV. Smooth muscle cells from the corpus to the pylorus have resting membrane potentials that are lower (more negative) than the contraction threshold (about −50 mV). This allows muscle relaxation at baseline with contractions caused by slow waves and/or neurohormonal stimuli.

In contrast, the resting membrane potential of fundic smooth muscle cells is higher (less negative) than the threshold required for contraction. This allows fundic cells to sustain contraction and maintain continuous fundic tone during fasting. It also facilitates a high sensitivity to inhibitory and excitatory stimuli when relaxation or further contraction, respectively, of the fundus is required. When food is swallowed, inhibitory vagal stimulation causes hyperpolarization below −50 mV, thus allowing the fundus to relax and accommodate the increase in intragastric volume.

Interstitial Cells of Cajal

ICCs are the pacemaker cells of gastric motility [5–7]. While the exact mechanism of ICC automaticity is still unknown, evidence suggests that Ca²+-activated Cl− channels may be involved [3].

ICCs, located along the greater curvature, are found in submuscular, intramuscular, myenteric, and subserosal layers of the gastric wall [8, 9]. The area of ICCs with the fastest rate of automaticity is termed the pacemaker region and is located at the junction of the fundus and the corpus. Figure 1.3 depicts the anatomical relationships between ICCs in the myenteric plexus (MY-ICCs), intramuscular ICCs (IM-ICCs) within the circular muscle, and neurons of the enteric nervous system (ENS).

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Fig. 1.3

Anatomical location of interstitial cells of Cajal (ICC) in relation to smooth muscle layers and neurons of the enteric nervous system (ENS). Myenteric ICCs (MY-ICCs), located in the myenteric plexus, spontaneously generate slow waves. Slow waves propagate to smooth muscle cells via gap junctions (curved arrow), causing depolarization. Intramuscular ICCs (IM-ICCs) are found within the circular layer of smooth muscle. They are involved in the mediation of neural signals within the ENS (short arrows) and in the transmission of slow waves from MY-ICCs to circular muscles. IM-ICCs also communicate directly with smooth muscle cells via gap junctions. Because of these connections, neural stimulation from the ENS can propagate from the IM-ICCs to smooth muscle cells, then to the MY-ICC network. This allows the ENS to modulate both the timing and amplitude of slow-wave depolarizations; excitatory ENS signals increase chronotopy and amplitude, while inhibitory ENS signals can stabilize membranes and decrease slow-wave depolarization. (Modified from Koch [10])

MY-ICCs are considered the true pacemaker cells because they spontaneously depolarize to create slow waves. Slow waves then propagate through the ICC network via gap junctions. These connections allow slow waves to activate L-type Ca²+ channels in smooth muscle cells, potentially causing contraction [11]. Gap junctions also help maintain the pacemaker frequency (3 cpm) because they allow slow waves generated in the pacemaker region to reach more distal ICCs that have a slower rate of automaticity. When slower ICCs are depolarized by more proximal slow waves, they are prevented from generating their own dyssynchronous slow waves and the pacemaker frequency is maintained.

Smooth muscle cells lack the ion channels necessary for regenerating slow waves. As such, IM-ICCs are required to facilitate the spreading of slow waves from the MY-ICCs to the adjacent layers of circular smooth muscles [12]. From the corpus to the pylorus, IM-ICCs coordinate slow waves and their corresponding muscle contractions. Because the fundus does not have slow waves that need to spread through the muscle layers, fundic IM-ICCs play a different role. Fundic IM-ICCs interact with afferent and efferent fibers of the vagus nerve in order to facilitate receptive relaxation and accommodation. They function as mechanoreceptors with interconnections to vagal afferent neurons and are also innervated by efferent inhibitory vagal fibers that promote smooth muscle relaxation [13].

Nervous System Innervation

While the ICC network displays automaticity independent of external innervation, it is also influenced by neural stimuli. Neural stimuli to the MY-ICCs can modulate the rate of automaticity and the amplitude of depolarizations, thus modifying the pacemaker frequency and the force of peristaltic contractions.

Enteric Nervous System

The enteric nervous system (ENS) consists of neurons in the submucosal and myenteric plexuses in the gut wall. Neurons in this system are both excitatory (acetylcholine, serotonin, substance P) and inhibitory (nitric oxide, vasoactive intestinal polypeptide).

The ENS functions independently from the autonomic nervous system (ANS) to regulate GI tract motility, secretion, and blood flow. ENS neurons organize into local reflex circuits consisting of afferent neurons in the mucosa, interneurons in the myenteric plexus, and efferent neurons that innervate gastric smooth muscle and glands (Fig. 1.4) [15, 16]. These local circuits augment peristaltic contractions by sequentially inhibiting smooth muscle distal to the peristaltic wave and contracting the more proximal segments [17, 18]. Neurons of the ENS exert additional neural control by forming gap junctions with ICCs in the myenteric plexus. This allows the ENS to directly modulate the timing and force of peristaltic contractions. Finally, the ENS also communicates with the ANS to relay sensory information and modulate the ANS’s response.

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Fig. 1.4

Local reflex circuits of the ENS. Sensory neurons in the mucosa (dashed lines) relay information about the gastric wall to interneurons in the myenteric plexus. Interneurons then stimulate efferent neurons in the submucosal plexus, leading to a change in gastric secretomuscular function. The ENS interacts closely with neurons of the sympathetic and parasympathetic nervous systems (red lines), which can modulate the ENS response to afferent stimuli. Sensory neurons also relay information directly to the CNS to further integrate the secretomuscular response. (From Hall [14])

Parasympathetic Innervation

Parasympathetic innervation of the stomach is provided by the left and right vagus nerves, which travel from the brainstem, along the esophagus, to the stomach. During embryogenesis, the stomach rotates 90° such that the left vagus and right vagus nerves become the anterior and posterior vagus nerves, respectively (Fig. 1.5). Preganglionic vagal fibers synapse with postganglionic fibers in the submucosal (Meissner’s) and myenteric (Auerbach’s) plexuses in the gastric wall.

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Fig. 1.5

Distribution of the vagus nerve in the thorax and proximal stomach. The left vagus nerve courses laterally to the proximal esophagus, transitioning anteriorly at the distal esophagus and becoming the anterior vagus nerve. Similarly, the right vagus nerve courses laterally until the distal esophagus, at which point it becomes the posterior vagus nerve (not shown). This transition occurs as the result of a 90° rotation of the stomach during fetal development. (From Drake et al. [19])

The primary effect of parasympathetic stimulation is to activate GI functions. Afferent vagal fibers relay information about the tone of the gastric wall to the nucleus of the tractus solitarius (NTS) , located in the medulla [20]. Preganglionic fibers release excitatory acetylcholine (ACh) onto postganglionic fibers within the gastric wall. Postganglionic fibers can be excitatory or inhibitory, leading to an increase or decrease gastric tone, respectively. This type of a response circuit is termed a vagovagal reflex (Fig. 1.6). Excitatory neurotransmitters that cause contraction include ACh and substance P. The primary inhibitory neurotransmitter-causing relaxation is nitric oxide (NO). However, vasoactive intestinal peptide (VIP) is also involved.

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Fig. 1.6

Vagovagal reflex neurocircuitry . Vagal afferent fibers (yellow) relay sensory information from the upper GI tract to the tractus solitarius (TS) of the medulla, the cell bodies of which are located in the nucleus tractus solitarius (NTS). NTS neurons integrate the sensory information and then relay it to the adjacent dorsal motor nucleus of the vagus (DMV). Preganglionic parasympathetic neurons of the DMV use ACh to stimulate nicotinic receptors on postganglionic ENS neurons and/or ICCs. Vagal motor activation of postganglionic fibers can induce excitatory effects if the postganglionic fiber releases ACh or inhibitory effects if the postganglionic fiber releases nonadrenergic noncholinergic (NANC) neurotransmitters such as nitric oxide (NO) or vasoactive intestinal polypeptide (VIP). The vagovagal reflex pathway is involved in several GI responses, including receptive relaxation. (Modified from Travagli and Anselmi [21])

Sympathetic Innervation

Sympathetic innervation of the stomach originates from the T6 to T8 spinal nerves. Preganglionic fibers synapse with postganglionic neurons at the celiac ganglion. Postganglionic fibers then travel with the blood supply to innervate the stomach.

The sympathetic nervous system has both direct and indirect effects on gastric motility. Sympathetic stimulation acts directly on the pylorus (as well as other sphincters), causing it to constrict and preventing GI transit into the duodenum. Indirectly, sympathetic stimulation inhibits ACh release from neurons of the ENS to further reduce motility [22].

Gastric Motility in the Fasting State

In the fasting state, slow waves generated by the ICCs cause a cyclic pattern of motility that propagates distally toward the antrum. This pattern is termed the migrating motor complex (MMC) . Each MMC occurs in four phases, all of which recur every 90–120 minutes during fasting. Phase 1 is a period in which virtually none of the slow-wave depolarizations reach the contraction threshold, and little to no contractile activity is present. Phase 2 is characterized by random contractions. In phase 3, regular, high-amplitude contractions occur at a rate of three per minute (the pacemaker frequency). Phase 3 contractions occur in 5- to 10-minute bursts, also known as