Gastric dysmotility at the organ level in gastroparesis





Introduction


Gastric motor functions represent a complex series of regional relaxations (e.g., fundus and pylorus) and contractions (gastric body and antrum) that are regulated by circulating blood glucose and hormones such as incretins, extrinsic sympathetic and parasympathetic neural control from the brain and spinal cord, the enteric nervous system (ENS), the interstitial cells of Cajal and other excitatory cells (PDGFRα positive cells), smooth muscle cells, and locally released neurotransmitters . The gastric fundus receives and stores food, and the antrum triturates ingested food into chyme. To maximize nutrient absorption and digestion, the antrum and pylorus empty chyme into the duodenum through carefully regulated functions. Alterations in these functions lead to delayed gastric emptying and clinical symptoms such as nausea, vomiting, early satiety, postprandial fullness, anorexia, bloating, or pain. To better understand the underlying mechanisms that characterize gastric dysmotility at the organ level, it is important to understand the normal gastric motor physiology. This chapter addresses control, physiology, investigation, and clinical associations of dysfunction of each element of gastric motility, as well as the resulting overall pathophysiology of gastric dysmotility.


Control of gastric motor function


The neural control of gastric motor functions includes the extrinsic and enteric nervous systems ( Fig. 5.1 ).




Figure 5.1


Mechanisms of gastric accommodation and emptying. The stomach receives extrinsic excitatory innervation from the vagus nerve, which induces antral contractility predominantly through cholinergic mechanisms; gastric accommodation is induced through inhibitory nitrergic nerves. The extrinsic nerves interact with intrinsic excitatory pathways, and electrical connectivity to smooth muscle cells (SMCs) is facilitated by interstitial cells, which causes the tunica muscularis (smooth muscle) to behave as a multicellular electrical syncytium. The interstitial cells of Cajal (ICCs) and platelet-derived growth factor receptor- α (PDGFRα)-positive cells in the smooth muscle layer are regarded as the pacemakers that convey stimulation from extrinsic vagal fibers and intrinsic enteric nerves to stimulate the SMCs.

Reproduced with permission from Camilleri M, Chedid V, Ford AC, Haruma K, Horowitz M, Jones KL, et al. Gastroparesis. Nat Rev Dis Primers 2018;4(1):41.


The ENS, sometimes called the “gut brain”, is a collection of more than 100 million neurons organized in ganglia that are capable of functioning independently of extrinsic control; however, the ENS integrates signals from the autonomic and central nervous systems. The ENS consists of several networks of ganglia: myenteric, deep mucosal and submucosal plexi. The myenteric or Auerbach plexus is involved in control of gastrointestinal motility. The submucosal or Meissner plexus is involved in the control of absorption, secretion, and mucosal blood flow. Excitatory cells serve as a non-neuronal pacemaker system that creates the basic electrical rhythm for gastric propulsion, the migrating motor complex, and sensation; these cells include the interstitial cells of Cajal (ICC) and fibroblast-like cells that express PDGFRα receptors located between the circular and longitudinal muscle layers in the stomach wall . The excitatory cells communicate signals between the ENS neurones and smooth muscle cells. Electrical control activity spreads through the contiguous segments of the gut through neurochemical activation by excitatory [e.g., acetylcholine (Ach), substance P] and inhibitory [e.g., nitric oxide (NO), somatostatin, vasoactive intestinal peptide (VIP)] transmitters.


The autonomic regulation of gastric motor functions consists of extrinsic control by the parasympathetic and sympathetic nervous systems ( Table 5.1 , ). Parasympathetic pathways reach the stomach through the vagus nerve. Vagal efferents arise in the dorsal motor nucleus of the vagus nerve and, to a lesser extent, from the nucleus ambiguous. The nucleus of the tractus solitarius is predominantly involved in afferent (sensory) functions. The sympathetic nervous system connects to the stomach from the intermediolateral columns of the spinal cord at the T 5 to T 10 levels, synapsing in the celiac ganglia. Splanchnic adrenergic efferents arising in the celiac ganglia supply the myenteric ganglia within the stomach wall, mostly innervating the pyloric sphincter .



Table 5.1

Wiring and functions of extrinsic neural control to the stomach.

Reproduced with permission from Camilleri M. Autonomic regulation of gastrointestinal motility. In: Low PA, editor. Clinical autonomic disorders: evaluation and management. 2nd ed. Philadelphia: Lippincott-Raven Publishers; 1997. p. 597–612.

























Parasympathetic Sympathetic Central mechanism
Wiring Function Wiring Function
Vagus nerve


  • Peristalsis (cholinergic),



  • Inhibitory (nonadrenergic), (e.g. receptive relaxation)




  • Celiac ganglion



  • T 6–9 spinal cord

Inhibition and relaxation (e.g. antro-fundal reflex)


  • Motor and sensory:



  • Dorsal motor nucleus of vagus, thoracic spinal cord; nucleus ambiguus

Vagus nerve Stretch and chemosensation Spinal root ganglia T 7–11 Mechanosensation (e.g. gastrogastric or enterogastric distention or nutrient reflexes)


Myogenic factors regulate the electrical activity generated by gastrointestinal smooth muscle cells and transmission of electrical activity across to the duodenum , resulting in integrated and coordinated contractions across the antroduodenal junction . The smooth muscle cells that control gastric motility have specific receptors for amines, peptides, and other transmitters that reach the smooth muscle membrane by neurocrine, endocrine, or paracrine routes. The ICCs and excitatory PDGFRα cells are in close proximity to the smooth muscle cells and are responsible for integration and coordination of the electrical slow wave spreading through the smooth muscle syncytium to produce circumferential contractions .


The motor function unit in the gastrointestinal tract responsible for the transfer of food from the stomach into the small intestine is the peristaltic reflex. This reflex is initiated either by luminal distention (mechanical stimulus) or by a chemical stimulus. Mucosal sensation is transmitted by intrinsic primary afferent neurons and leads to a contraction in the orad (more proximal) segment that is mediated by excitatory transmitters, chiefly Ach, substance P, and serotonin. Relaxation in the aborad segment allows transport of the incoming bolus, and this is mediated by inhibitory neurotransmitters such as NO and VIP. Interneurons such as opiates or somatostatin coordinate these functions.


Physiology of gastric motor functions


The fasting and postprandial periods have unique motility patterns in healthy individuals. The fasting period is characterized by a highly regulated cyclic motor pattern in the body and antrum called the migrating motor complex (MMC) . The MMC cycle lasts approximately 60–90 minutes in healthy individuals and consists of three phases: phase I is a period of quiescence, with no contractile activity recorded; phase II is characterized by intermittent irregular phasic pressure activity; phase III, also called the activity front, consists of phasic contractile activity at frequencies that are maximal for each specific region, as governed by the underlying electrical control activity, that is, up to 3 per minute in the stomach and up to 12 per minute in the upper small intestine. There is a gradient in the maximum contractile activity in the small intestine with lower frequency more distally, that is, from ~12 per minute in the duodenum to ~8 per minute in the ileum. Phase III migrates for a variable distance down the small intestine. During fasting, the stomach participates in the MMC that propagates through the antrum, thereby emptying nondigestible solid residue from the stomach into the duodenum. Approximately 50% of phase III activity fronts originates in the stomach during fasting . Since nondigestible solids are not typically found in the stomach after 8 hours fasting, antral contractions during phase III of the MMC are efficient in clearing nondigestible solids from the stomach, despite the fact that only 50% of MMCs has an antral component. However, finding some nondigestible food in the stomach after overnight fasting does not imply gastric dysmotility, since MMCs may not have included the antral component during the night, despite the fact that there are more MMCs observed during the nighttime than daytime as there is no food intake during sleep. Conversely, food intake during the daytime inhibits the occurrence of the MMC .


The two functional regions of the stomach, the fundus and antrum, are responsible for the reservoir, grinding and pump activity in the postprandial period. The stomach muscle is organized in three layers with fibers organized on different axes: circular, oblique, and longitudinal. These morphological characteristics are displayed in vivo with novel radiological imaging, and have been applied predominantly in the esophagogastric junction . These different muscle layers are innervated by excitatory and inhibitory motor neurons of the ENS. The mid-portion of the greater curvature of the stomach is considered to be the functional site of the gastric electrical pacemaker, although excitatory cells which have spontaneous firing potential are located throughout the stomach, and the cellular pacemaker activity coordinates rings of contractions that sweep from proximal regions towards the antrum.


During fasting, the fundus is tonically contracted; after food is ingested, a vagally- mediated reflex during swallow (receptive relaxation) relaxes the proximal stomach to receive the meal. Food is then transferred from the esophagus into the fundus, which acts as a reservoir to the ingested meal in gastric accommodation. The decreased tone in the fundus allows solid or liquid food ingestion with little or no increase in intragastric pressure, thus avoiding postprandial symptoms such as fullness and pain . During receptive relaxation and stimulation of mechanoreceptors by the arrival of food in the stomach, vagal afferents and vagovagal reflexes are activated, stimulating the intrinsic inhibitory neurotransmitters such as NO and VIP. Receptive relaxation is triggered by distention of the gastric reservoir . This process facilitates the initial chemical digestion of food by acid and proteases before contents are transferred to the antrum. Fundic relaxation is impaired in patients with fundoplication due the mechanical effects of the operation, as well as a result of vagal injury . Such patients are likely to have a lower threshold for postprandial fullness and pain.


Another important function of the fundus is to contract and transfer the contents of the gastric reservoir into the antral pump . Thus, the fundus produces contractile events that are most easily demonstrable as phasic volume changes by using a barostatically controlled balloon .


The proximal antrum contracts at a frequency of 3 per minute during the postprandial period; some, but not all of these contractions propagate all the way to the pylorus. The antrum produces high amplitude contractions that grind solids by physical and liquid shearing forces. Particles that have not been reduced to 1–2 mm size are continually forced towards, and retropulsed from the distal stomach by an occluded pylorus until liquid shearing and chemical digestion achieve adequate trituration. Chyme, which is composed of solid particles that have been reduced to a 1–2 mm size suspended in gastric juice, is then able to empty through the pylorus . In contrast, interdigestive antral motor function during phase III of the MMC clears the stomach of nondigestible solid particles whose size has not been reduced by trituration.


The pylorus is mostly composed of thickened circular muscle and presents a zone of high resting pressure controlled predominantly by Ach and NO. Through antropyloroduodenal coordination, 2–4 mL of chyme is emptied into the duodenum through phasic contractions that occur at a maximum rate of three per minute. Antropyloroduodenal coordination coordinates antral peristalsis with decreased duodenal pressure and pyloric resistance to ensure optimal emptying of gastric contents .


Physical characteristics, volume, and macronutrient content of ingested food determine the gastric emptying rate of a meal ( Fig. 5.2 ), . Gastric emptying of liquids is faster than emptying of solids and follows a simple exponential model for non-nutrient liquids . The emptying of high nutrient liquids or fully homogenized solids approximates a linear model. The gastric emptying half-time for non-caloric liquids is approximately 20 minutes for healthy individuals. Non-nutrient liquids empty from the stomach exponentially , but, with increasing caloric content of liquids, the gastric emptying rate is approximately 200 kcal/hr .




Figure 5.2


Patterns of gastric emptying of liquids and solids in health and in gastroparesis. Gastric emptying curves for liquids and solids were derived from the published literature. Low-fat solid meal is a 2% fat, 255-kcal meal; high-fat meal is 32% fat, 296-kcal meal.

Reproduced with permission from Camilleri M, Shin A. Editorial: novel and validated approaches for gastric emptying scintigraphy in patients with suspected gastroparesis. Dig Dis Sci 2013;58(7):1813–5.


Gastric emptying of solids is characterized by two stages: an initial lag phase during which no food is emptied from the stomach, followed by a post-lag emptying phase which tends to be linear . The lag phase is associated with the time when there is accommodation of solids in the fundus and the transfer of food into the corpus and antrum for trituration and grinding. The duration of the lag phase depends on several meal factors such as macronutrient content [e.g., it is longer with higher fat or calorie content of the meal ], the chewing process, or the degree to which the food is homogenized before ingestion or is easily digestible or easily triturated. The lag phase duration typically lasts up to 60 minutes. In healthy volunteers, a positive correlation between antral motility and overall emptying of solids has been demonstrated . The lag time duration is inversely related to the antral motility index, consistent with the concept that more effective antral contractions facilitate trituration and the commencement of emptying. The emptying of liquids is significantly associated with antral contractility only after the lag time for trituration of solids has been completed and pyloric closure coincident with antral contractions is no longer required .


Overall gastric emptying of a liquid nutrient meal (Ensure Plus®, 350 kcal, 28% fat) was similar to that of a standardized, low fat, egg white sandwich solid meal (255 kcal with 2% fat). The liquid nutrient meal empties without a lag phase and takes slightly longer to empty from the distal stomach, which is probably due to its higher fat content. The minor differences in overall emptying are likely due to early accommodation with retention of the low fat solids in the proximal stomach and the need for trituration of solids by the distal stomach, in contrast to the caloric liquid meal which is not retained in the fundus and does not require trituration .


Gastric dysmotility


Gastric motor dysfunction or dysmotility is typically characterized by an abnormality in the fundus, antrum, or pylorus. Alterations in the ENS, pacemaker cells (ICCs and PDGFRα fibroblast-like cells), or smooth muscle cells have been described in gastric dysmotility. Neuropathic or myopathic disorders can affect the mechanisms that control gastric motor functions leading to gastric dysmotility, such as diabetes mellitus, sarcoidosis, amyloidosis, among others. Similarly, there are data suggesting that the ICC pathology in diabetic gastroparesis and abnormal PDGFRα fibroblast-like cells in idiopathic gastroparesis may cause the impaired motor functions . Different pathophysiological processes may cause impaired intragastric distribution of food and delayed emptying of the stomach, and they include impaired fundic relaxation (or accommodation), antral hypomotility, and pylorospasm.


Impaired stomach accommodation due to a lack of extrinsic vagal or nitrergic innervation, simulation of fundic contraction (e.g., with erythromycin), loss of feedback regulation by enteric hormones (e.g., cholecystokinin or GLP-1), or surgical fundoplication leads to a rise of intragastric pressure with induction of upper gastrointestinal symptoms . In addition, failure of proximal stomach accommodation may result in redistribution of the meal to the antrum, resulting in abnormal gastric perception .


Methods of measurement


Barostat


Using an infinitely compliant polyethylene balloon placed in the proximal stomach under a constant pressure maintained by a barostat , it is possible to assess gastric compliance, sensitivity to gastric distention, and gastric accommodation. The barostat is the only method used in research or clinical practice for directly measuring gastric accommodation, that is, the reduction in gastric tone postprandially. All other measurements are based on imaging and appraise changes in volume, which is an indirect measurement of gastric accommodation. The effects of disease states such as functional dyspepsia , acute anxiety and anxiety disorders , post-gastric surgery including post-Nissen fundoplication , as well as effects of diverse pharmacological agents have been reported using this gold standard technique. Moderately increased HbA1c [mean (±SEM) 7.2±1.6 mg/dL], 94% documented peripheral neuropathy, 66% nephropathy (proteinuria and/or elevated plasma creatinine), 55% retinopathy, gastric hypersensitivity, and reduced gastric accommodation have been demonstrated on barostat studies in patients on insulin treatment for long-standing diabetes (23.3±6.4years) ( Fig. 5.3 ) .




Figure 5.3


Left panel: Gastric hypersensitivity based on sensory thresholds (pressure) for discomfort during phasic balloon distension of the stomach. Right panel: Barostat balloon volume after the test meal in patients with diabetes and in controls.

Reproduced with permission from Kumar A, Attaluri A, Hashmi S, Schulze KS, Rao SS. Visceral hypersensitivity and impaired accommodation in refractory diabetic gastroparesis. Neurogastroenterol Motil 2008;20(6):635–42.


On the other hand, a study of the proximal stomach in patients with type 2 diabetes with accelerated gastric emptying of liquids demonstrated variable gastric tone and increased phasic volume events ( Fig. 5.4 ) .




Figure 5.4


Examples of original tracing showing postprandial gastric responses in (A) a healthy nondiabetic subject and (B) a patient with NIDDM. Note the increase in the baseline volume of the barostatic balloon indicating an accommodation response and the greater phasic volume events in the patient with NIDDM compared with the healthy control. Distal antral phasic pressure activity is similar in the two examples.

Reproduced with permission from Frank JW, Saslow SB, Camilleri M, Thomforde GM, Dinneen S, Rizza RA. Mechanism of accelerated gastric emptying of liquids and hyperglycemia in patients with type II diabetes mellitus. Gastroenterology 1995;109(3):755–65.


Reproducibility of gastric volume measurements with the barostat measured on different days in 13 patients with dyspepsia and 9 healthy subjects, with interval median of 45 days (range 28–76 days), showed no significant difference in the two measurements in each subgroup . In addition, there was excellent correlation between the two estimates (R=0.71 and 0.74 in healthy subjects and dyspeptic patients, respectively). The range of variation in the barostat measurements of accommodation (of proximal stomach) were +180 to −220 mL , which encompasses the entire range of accommodation volumes of the whole stomach observed with SPECT in 433 participants.


Pitfalls


Pitfalls for barostat measurements include the need for intubation and balloon distension, which are often stressful and induce discomfort to patients during this test. This test is rarely, if ever, performed in clinical practice.


Ultrasonography


Imaging-based methods to measure gastric volume include analysis of surface geometry of human stomach using real-time, 3-dimensional (3D) ultrasonography or 3D reconstruction of images acquired by ordinary ultrasonography assisted by magnetic scan-head tracking .


Patients with type 1 diabetes and low vagal tone have impaired postprandial gastric meal distribution and smaller proximal gastric area (measured in sagittal axis, but not in the frontal axis), suggesting reduced anteroposterior depth of the proximal stomach .


Three-dimensional ultrasonography has been applied in adolescents and compared to simultaneously measured gastric volumes by SPECT; further validation and standardization are necessary . A limitation of 3D ultrasonography is that it allows assessment of only the stomach’s response to a liquid meal.


Single photon emission computed tomography (SPECT)


SPECT imaging is the gastric volume measurement method on which there is the largest body of publications in the literature. It requires intravenous administration of 10 mCi 99 m Tc-pertechnate, which is taken up by the parietal and mucin-secreting cells of the gastric mucosa. Tomographic images of the stomach are acquired with the patient supine using a large field-of-view, dual-headed gamma camera . From the transaxial images of the stomach, 3D images are reconstructed, and the total gastric volume can be measured during fasting and during the first 10 minutes following 300 kcal of a liquid nutrient meal (Ensure®). SPECT demonstrates the effects of disease on post-meal change in gastric volume, a surrogate of gastric accommodation . SPECT has demonstrated excellent intra-observer and inter-observer variance, even when studies are performed with different meals (solid vs. liquid equicaloric meals) or many months apart. Therefore, SPECT is a highly reproducible imaging modality for the measurement of gastric volume in response to meal ingestion .


Of all the methods to measure gastric accommodation, SPECT is the most extensively validated in vitro and in vivo for the measurement of gastric volumes during fasting and postprandially. First, it was validated in comparison with the gastric barostat ( Fig. 5.5 ) . Second, the COV INTER for all subjects in the study (n = 433) was 16.0% fed volume and 19.0% accommodation (fed – fasting) volume. The COV INTRA for 47 subjects with repeat estimates of gastric volume was 17.6% fed and 22.0% accommodation (fed – fasting) volume. COV INTRA was stable over the time interval from 2 to 60 months. There were no significant differences by gender or BMI subgroups .




Figure 5.5


Correlations of known balloon volumes with volumes measured in vitro (left) and postprandial accommodation ratios, as measured by SPECT and gastric barostat in 16 healthy volunteers (right).

Reproduced with permission from Bouras EP, Delgado-Aros S, Camilleri M, Castillo EJ, Burton DD, Thomforde GM, et al. SPECT imaging of the stomach: comparison with barostat, and effects of sex, age, body mass index, and fundoplication. Single photon emission computed tomography. Gut 2002;51(6):781–6.


SPECT measurements of gastric volume and accommodation have been conducted in over a thousand patients in clinical practice at Mayo Clinic , as well as in research studies and have demonstrated the expected effects of pharmacological agents such as erythromycin which reduces accommodation, or several medications that increase accommodation including nitrates, clonidine, and GLP-1, and GLP-1 receptor agonists ( Table 5.2 ) .



Table 5.2

Effects of pharmacological agents on gastric accommodation.








































































































































Medication Subject NHV/Pt Effect on fasting gastric volume Effect on post-prandial gastric volume or ratio Reference No.
Alginate Ow/ob
Isosorbide dinitrate SL NHV Increased Decreased
L -NMMA, NOS inhibitor NHV
Alosetron, 5-HT 3 antagonist NHV
Aprepitant, NK 1 antagonist NHV Increased Increased
Yohimbine, α2 antagonist NHV increased
Asimadoline, κ opioid agonist NHV


  • Increased in F



  • Decreased in M

Increased in F
CCK1 agonist, GI181771X NHV Increased Increased ( P =0.056)
GLP-1


  • NHV,



  • DM- VN

Increased Increased
GLP-1 DM +VN
Vildagliptin, DPP-IV inhibitor DM2
Octreotide, somatostatin analog NHV Increased Decreased
i.v. erythromycin, motilin agonist NHV Decreased
Itopride, 5HT 4 agonist NHV Decreased
Tegaserod, 5HT 4 agonist NHV Increased Decreased
rHuGhrelin (physiological) NHV/ob Decreased ( P =.059)
Relamorelin, ghrelin agonist NHV
Amitriptyline 25, 50 mg NHV
Paroxetine, SSRI NHV
Ventafaxine, SNRI NHV Increased
Buspirone, 5-HT 1A agonist NHV

DM diabetes mellitus, VN vagal neuropathy; “-”=no effect; ob=obese; ow=overweight.


The pitfalls of SPECT are availability, the use of radioactivity [with exposure approximately three times that of a standard nuclear medicine solid–liquid gastric emptying study: He (entrance skin exposure) for 99 m Tc-SPECT 619 mRem, 111 In-DTPA 142 mRem, and 99 m Tc-sulfur colloid 90 mRem], and the need for a SPECT camera and sophisticated software to perform the 3D reconstruction and calculate volumes.


Magnetic resonance imaging (MRI)


The stomach is imaged under fasting and postprandial conditions [i.e., after ingestion of Ensure® (296 mL), labeled with gadolinium (4 mL), through a straw] in the supine position using a torso phased array coil and a 1.5 T magnet MRI. Typical imaging programs provide 3D axial gradient echo (LAVA) sequence (i.e., 4 mm slices with 2 mm overlap) or coronal 2D half-Fourier acquisition single-shot turbo spin echo (HASTE) sequence (5 mm slices with 0 mm gap). Magnetic resonance images are processed by a variety of algorithms using software such as ANALYZE™ (similar to SPECT). MRI has the advantage that it can differentiate the volumes occupied by air and fluid in the stomach, in contrast to SPECT ( Fig. 5.6 ) .


Feb 4, 2021 | Posted by in GASTROENTEROLOGY | Comments Off on Gastric dysmotility at the organ level in gastroparesis
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