Pathogenesis of Delayed Gastric Emptying

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Pathogenesis of delayed gastric emptying

AUTHOR: Michael Camilleri, MD
SECTION EDITOR: Nicholas J Talley, MD, PhD
DEPUTY EDITOR: Shilpa Grover, MD, MPH, AGAF
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2024.

This topic last updated: Oct 09, 2023.
INTRODUCTION
Normal gastrointestinal motor function is a complex sequence of events that is controlled by

an extrinsic nerve supply from the brain and spinal cord, the complex plexi and other
intrinsic or enteric pathways within the wall of the stomach and intestine (the enteric brain),
and the effects of locally released transmitters, such as amines and peptides, that alter the
excitability of the smooth muscle of the stomach and intestine. Abnormalities in any of these
locations can lead to delayed gastric emptying (gastric stasis), a disorder that is often
expressed clinically as nausea, vomiting, early or easy satiety, bloating, and weight loss. (See
"Gastroparesis: Etiology, clinical manifestations, and diagnosis".)
The normal physiology of gastric motor function and the pathogenesis of delayed gastric
emptying will be reviewed here. Treatment of this disorder is discussed separately. (See
"Treatment of gastroparesis".)
ANATOMY AND PHYSIOLOGY OF GASTRIC MOTOR FUNCTION
An understanding of the pathogenesis of delayed gastric emptying requires comprehension

of the physiology of normal gastric motor function.
Control of gut motor function — The motor function of the gut is controlled at three main
levels ( figure 1) [1]:
● Parasympathetic and sympathetic nervous systems

● Enteric neurons and interstitial cells of Cajal (ICC)
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● Smooth muscle cells
Autonomic nervous system — Extrinsic neural control by parasympathetic pathways is

conveyed to the stomach and upper intestine through the vagus nerves. Vagal efferents
arise in the dorsal motor nucleus of the vagus nerve and, to a lesser extent, from the nucleus
ambiguus and tractus solitarius. They form characteristic bead-chain-like terminals in the
myenteric plexus throughout the stomach but do not directly innervate muscle [2].
The sympathetic supply reaches the stomach from the intermediolateral columns of the
spinal cord at the T5 to T10 levels via the celiac ganglia. Splanchnic efferents to the stomach
have cell bodies in the celiac ganglia; they supply the myenteric ganglia, give a few fibers to
non-sphincteric muscle of the stomach [3], and densely supply the pyloric sphincter [4,5].
Splanchnic efferents innervating blood vessels contain norepinephrine and neuropeptide Y;
those innervating the submucous ganglia and circular muscle contain norepinephrine and
somatostatin; and fibers to the myenteric ganglia contain only norepinephrine [6].
Enteric nervous system — The enteric nervous system constitutes a vast network of
ganglionated plexi that serves as the integrative circuitry between extrinsic modulation of
gastrointestinal motility (via the sympathetic and parasympathetic nervous systems), and
sensory afferents in the gastric wall (stimulated by luminal stimuli). These neuronal
networks, or plexi, are organized in five layers which are interspersed throughout the wall of
the gut; the best characterized are the myenteric, deep muscular, and submucosal plexi.
The deep muscular plexus is made up of the ICC, pacemakers for the sheets of muscle within
the wall of the gut. Other cells with pacemaker functions are fibroblast-like cells that are
positive for platelet-derived growth factor receptor alpha (PDGFRa). The neurons within the
myenteric plexus may contain more than one transmitter [7]. The neural plexi are involved in
propulsion, the interdigestive migrating motor complex, sensation, and secretion. The most
common gastric cellular defects in gastroparesis are loss of expression of neuronal nitric
oxide and ICC [8]. The loss of these cells may be related to the effects of immune injury or
reactive oxygen species in animal models of gastroparesis [8-10].
Nitric oxide (NO) regulation may be important in gastric emptying [11,12]. NO synthase was
reduced in a murine model of diabetic gastropathy and was restored with insulin treatment
[13]. The cellular basis for the dysfunction of enteric neurons is the subject of ongoing
research. Specifically, there is a cytoprotective role for heme oxygenase-1 (HO-1) in the
pathophysiology of diabetic gastroparesis, and CD206-positive M2 macrophages, which
express HO-1 protect against the development of diabetic gastroparesis in two validated
animal models of diabetes mellitus that demonstrate delayed gastric emptying, and damage
to ICCs by tumor necrosis factor alpha (TNF-alpha) derived from classically activated "M1"
macrophages [14,15]. There are also human data supporting the reduction in numbers of
these "protective macrophages", and a shift by macrophages towards a pro-inflammatory
phenotype has been documented with aging, that causes inflammation-mediated

degeneration of the enteric nervous system [16]. Unfortunately, promising results in diabetic
mice, as observed with administration of interleukin-10 which activates the M2
cytoprotective phenotype of macrophages and induces expression of HO1 protein, have not
been replicated in a human study. Thus, in a single-center, double-blind, placebo-controlled,
randomized clinical trial of hemin, which induces HO-1, was not successful in relief of
symptoms or acceleration of gastric emptying although a poorly sustained effect on HO-1 by
the administered hemin could explain the lack of efficacy in the clinical trial [17-20].
In summary, while the macrophage imbalance hypothesis is potentially relevant to the role
of enteric nervous system or ICC dysfunction in gastroparesis, it has not yet impacted
management (diagnostic or therapeutic of patients with gastroparesis).
Smooth muscle cells — The third level of control of gastrointestinal motility is in the
excitable membrane of smooth muscle cells. Specific receptors in the cell membrane bind to
amines, peptides, and other transmitters that reach the smooth muscle membrane via
neurocrine, endocrine, or paracrine routes. Pacemaker cells which are characterized by
spontaneous depolarization of the resting membrane potential fire action potentials that
contract the cell. Electrical coupling of the neighboring muscle cells, organized in a
syncytium, results in the spread of the contraction around the circumferential and
longitudinal axes of the stomach. There is evidence of increased intercellular fibrosis, loss of
ICC, and loss of fibroblast-like cells in the smooth muscle of patients with diabetic
gastroparesis [21,22].
Peristaltic reflex — The peristaltic reflex is responsible for propulsion of food from the
stomach into the intestine. There are two components to the peristaltic reflex:
● The first change is ascending contraction above the level of luminal stimulation, usually
due to distention by a food bolus. The main transmitters involved in excitation of
gastric muscle are acetylcholine (and, indirectly, serotonin through 5HT4 receptors
located on cholinergic interneurons) and tachykinins, such as substance P and
substance K.
● Descending inhibition below the level of distention is essential for the oncoming bolus
to encounter a minimum of resistance to flow. The main inhibitory transmitters are
nitric oxide and vasoactive intestinal peptide (VIP), although several other transmitters
modulate the interneurons involved in this descending inhibitory pathway, including
opiates, somatostatin, and the excitatory transmitter, gamma-aminobutyric acid [7].
Motor functions of the stomach regions — The stomach muscle has three muscular layers
with fibers organized in different axes: circular, oblique, and longitudinal. The stomach has
traditionally been regarded as having two functional segments: the fundus and the antrum.
The mid-portion of the greater curvature of the stomach is the functional site of the gastric
electrical pacemaker.
During fasting, the stomach participates in the cyclical activity front that propagates through
the gastrointestinal tract and serves as a "housekeeper," propelling nondigestible solid
residue towards the colon. There is some evidence in dogs that the hormone motilin,
released from the duodenal loop, stimulates this gastric component of the migrating motor
complex [23]. Laboratory based studies in healthy humans suggest that only about 50
percent of intestinal migrating motor complexes during fasting are associated with an antral
component [24,25]. This may reflect the efficiency of antral contractions during phase III of
the migrating motor complex in clearing nondigestible solids from the stomach.
Postprandially, the fundus relaxes during swallowing to start the process of accommodation
in which the stomach assumes reservoir functions, facilitating the initial chemical digestion
of food by acid and proteases before transfer toward the antrum [26]. The antrum produces
high amplitude contractions that pulverize solids by physical and liquid shearing forces.
Once solids have been reduced in size to particles of 1 to 2 mm in size (trituration), they are
able to empty through the pylorus [27]. Larger particles are repetitively propelled and
retropulsed from the distal stomach by an occluded gastric outlet segment until liquid
shearing and chemical digestion achieve trituration.
Thus, antral motor function is critical for the grinding, mixing, and emptying of solids from
the stomach. Antral motility also significantly correlates with the rate of emptying of liquids
from the stomach, after the lag time required for trituration to sufficiently reduce particle
size so that pyloric sieving is no longer required [28]. Interdigestive (between meals) antral
motor function clears the stomach of undigestible solid particles whose size has not been
reduced by trituration ( figure 2).
The recovery of proximal gastric tone during the postprandial period is associated with
gastric emptying, with the driving force being provided by the pressure gradient between
the stomach and duodenum. Most non-nutrient liquids have emptied before tone is restored
to normal, suggesting that emptying of liquids may be partly a passive process aided by
gravity and the absence of resistance in the gastric outlet.
The pylorus is radiologically 0.6 to 1.6 cm long. It presents functionally as a zone of high
resting pressure or tone, upon which are superimposed phasic contractions at a rate of three
per minute. These contractions sweep across the antroduodenal junction. There is evidence
of control of pyloric contractions by opiates, acetylcholine, and nitric oxide.
PATHOGENESIS OF DELAYED GASTRIC EMPTYING
There are several abnormalities that may result in motor dysfunction of the stomach and
thereby in delayed gastric emptying. Each of the stomach regions may be affected by
different pathologic processes [29].
Abnormalities of the fundus — There are several diseases that are associated with
abnormal proximal gastric motor function. The accommodation response can significantly
influence the rate of emptying of food from the stomach, even the emptying of the proximal
stomach [30]. Thus, greater accommodation is associated with retardation of gastric
emptying.
Postvagotomy gastric motor dysfunction — The stomach's accommodation response

and phasic contractility in response to distention are abolished following vagotomy and
partial gastric resection [26]. This probably accounts for the observation that there is
immediate early transfer of the liquid phase of the meal to the distal stomach and beyond,
but delayed emptying of solids [31]. One of the most common causes of impaired fundal
accommodation is fundoplication; the impaired relaxation may be aggravated by
concomitant vagal injury [32].
Diabetes mellitus — Patients with diabetes mellitus have impaired antral motor function
and coordination (see 'The antrum and antroduodenal coordination' below), and show
evidence of abnormal postprandial proximal gastric accommodation [33] and contraction.
One study, for example, evaluated eight patients with type 1 diabetes, cardiovascular
autonomic neuropathy, and dyspepsia, and 10 healthy volunteers [34]. Blood glucose levels
were maintained in the normal range during the experiment. An intragastric bag connected
to a barostat was inflated and deflated by stepwise pressure increments, creating pressure
volume curves. There was a larger volume during the pressure increase in the diabetics than
in the controls; this resulted in a significant difference in compliance (dV/dP): 57.2 mL/mmHg
in diabetics versus 43.7 mL/mmHg in controls. In addition, gastric distension induced more
nausea, bloating, and upper abdominal pain in the patients than the volunteers. The post-
meal relaxation response of the stomach is quite variable even in patients with evidence of
cardiovagal dysfunction [35,36]; experimental data also suggest that adaptive mechanisms
may restore gastric relaxation to normal after vagal injury [37]. These observations may
explain the unpredictability of the motor abnormalities over time in patients with diabetic
gut dysmotility.
Increased compliance may explain the prolongation of lag time for emptying solids that is
observed in patients with diabetes. Solids are selectively retained within the stomach during
this time, often in the proximal compartment. Increased fundic contractions are responsible
for accelerated gastric emptying of liquids in this setting [38]. It is important to recognize
that the presence of upper gastrointestinal symptoms in a diabetic does not automatically
imply delayed gastric emptying. In a study of 108 patients with diabetes mellitus and upper
gastrointestinal symptoms (most common symptoms in the cohort being nausea in 80

percent), gastric emptying was rapid in 37 percent, slow in 19 percent and gastric
accommodation was reduced in 39 percent [39].
Inadequate gastric accommodation in diabetes may be due to a defective nitric oxide (NO)
pathway. In one study, for example, gastric relaxation was impaired in rats mainly by
decreased expression of NO synthase in the gastric myenteric plexus [40]. This inadequate
gastric accommodation has also been documented in patients with diabetes, and may
contribute to increased gastric sensitivity resulting in symptoms such as pain, satiation, or
bloating [32,33].
Motility disturbances in functional dyspepsia — Functional dyspepsia (also called

nonulcer or motility-like dyspepsia) is a disorder in which patients complain predominantly of
nausea, early satiety, postprandial fullness, bloating, and pain without obvious evidence of
organic disease (eg, by upper endoscopy or upper gastrointestinal studies). Indeed, a study
from the Gastroparesis Clinical Research Consortium documented the interchangeable
symptoms and baseline characteristics between gastroparesis and functional dyspepsia with
variation of gastric emptying over time that results in criteria that "modify" the diagnosis
[41]. Such variation should not be surprising given the prior evidence that the intra-individual
coefficient for gastric T1/2 and the emptied proportion of the meal from the stomach at four
hours were respectively 23.8 and 12.6 percent based on repeat scintigraphic measurements
of gastric emptying of an egg meal in healthy participants [42].
Gastric compliance is lower in patients with motility-like dyspepsia than in healthy controls,
an abnormality that may contribute to the associated symptoms [32,43]. Reduced
compliance was associated with significant weight loss in another report, suggesting that it
resulted in early satiety and reduced food intake [44]. A summary of the motor and sensory
dysfunctions reported in the literature in nonulcer dyspepsia is shown in the following figure
( figure 3) [45]. Disturbances in proximal gastric function (accommodation or a reduced
gastric volume response to feeding, and gastric hypersensitivity) have also been described in
children with dyspepsia or chronic functional abdominal pain that may result in similar
symptoms to those that result in impaired gastric emptying [46,47]. (See "Functional
dyspepsia in adults", section on 'Epidemiology and pathophysiology'.)
In some patients, there is a clear association with acute onset and a febrile illness suggesting
the possibility that dyspepsia is a post-infectious or post-inflammatory disorder [48]. Such
patients appear to have the same sensory or motor disorders that characterize the
pathophysiology of other dyspeptic patients who do not report this acute onset with a febrile
illness. As in diabetic patients, the upper gastrointestinal symptoms may result from delayed
gastric emptying or reduced gastric accommodation (roughly 25 percent each), and another
25 percent have both abnormal gastric emptying and reduced gastric accommodation [49].
The molecular mechanisms leading to impaired gastric accommodation include NO,

adrenergic, cholinergic, and 5-HT mechanisms as evidenced by pharmacodynamic or
therapeutic effects of agents that modulate gastric compliance or postprandial
accommodation, such as clonidine (alpha-2 adrenergic agonist), acotiamide
(acetylcholinesterase inhibitor), or buspirone (5-HT1A agonist) [50].
The antrum and antroduodenal coordination — As previously mentioned, antral motor

function is critical for the grinding, mixing, and emptying of solids from the stomach. Thus,
in the absence of well-coordinated antral interdigestive motor function, as in the
postvagotomy state or in diabetic autonomic neuropathy, undigestible solid particles may
accumulate over time and eventually form a bezoar.
Abnormalities of antral function can occur by several mechanisms:
● A decreased frequency of antral contractions is the most common form of gastric

motor dysfunction; this is associated with a reduced rate of gastric emptying in patients
with gastroparesis [51]. In neuropathic disorders, this is usually manifested by a lower
frequency of normal amplitude distal antral contractions (>40 mmHg) in response to a
meal. Thus, the frequency averages 0.5 to 0.75 per minute in neuropathic diseases
versus at least 1 per minute in healthy controls [52]. This reduced frequency with
normal amplitude distal antral contractions in patients with non-myopathic
gastroparesis has been confirmed using high resolution and antropyloroduodenal
manometry [53].
● Reduced antral contractile amplitude is rarely observed in infiltrative disorders such as

progressive systemic sclerosis. The average amplitude of contractions is typically less
than 40 mmHg [54]. This abnormality more often results in vomiting because of the
absence of peristaltic forces in the small intestine. (See "Gastrointestinal manifestations
of systemic sclerosis (scleroderma)".)
● There is increasing evidence that several mechanisms of antral motor dysfunction

frequently coexist in patients with diseases that cause gastric stasis or pharmacologic
models of stasis. These mechanisms include antral hypomotility, "pylorospasm" or
isolated pyloric pressure waves (IPPW), and failure of proximal gastric contraction; the
last abnormality inhibits the redistribution of intragastric content for trituration by the
antral segment [55]. The potential impact of pylorospasm is supported by the evidence,
largely in uncontrolled trials, that botulinum toxin injection at the pylorus [56], or
peroral endoscopic myotomy appear to be efficacious in the treatment of gastroparesis
[57]. Further controlled studies are needed to demonstrate efficacy, and to identify
biomarkers of response to these treatments (eg, isolated pylorospasm versus
combined pylorospasm with antral hypomotility); female sex and underlying disease
(diabetes) appear to be predictive of failure based on limited data currently available

[58].
Diabetes mellitus and scleroderma are examples of diseases that may affect multiple
areas of antral function ( image 1).
● Abnormal electrical slow wave rhythms in the stomach may result in reduced antral
motor function. The normal pacemaker function of three contractions per minute is
replaced by a reduced (bradygastria) or increased (tachygastria) frequency, or a mixed
brady/tachygastria ( figure 4). These rhythm alterations have been measured
intraoperatively in patients with gastric atony, in vitro in muscle strips prepared from
atonic stomachs [59], and in vivo in a number of disease states including diabetic
gastroparesis, anorexia nervosa, motion sickness, and vomiting of pregnancy. The
precise mechanism for these dysrhythmias is unclear; prostaglandins have been
implicated since prostaglandin synthesis inhibitors restore normal electrical control
activity both in vitro and in vivo [60,61].
Other abnormalities that may result in impaired antral function are autonomic neuropathy
and hyperglycemia in patients with diabetes mellitus. The concept of "autovagotomy" in
diabetes was introduced in the late 1970s [61]. Gastric acid secretion in response to a
swallowed meal was normal in this initial review, suggesting intact parietal cell function;
however, the acid secretory response to modified sham feeding (chewing but not swallowing
a meal, which is a normally potent vagal stimulus) was reduced. Subsequent morphologic
studies of the vagus nerve and enteric nervous system were normal in a report of patients
with diabetic gastroparesis [62]. Nevertheless, the clinical association with autonomic and,
particularly, vagal dysfunction is frequent in both type 1 and type 2 diabetes [63,64]. (See
"Diabetic autonomic neuropathy of the gastrointestinal tract".)
Several studies have suggested a role for hyperglycemia in the pathogenesis of antral
dysfunction. Acute hyperglycemia can significantly slow gastric motility and the emptying of
solids in normals and patients with diabetes [64,65]. In one study of normal subjects, for
example, gastric contractions were nearly absent at a serum glucose concentration of 250
mg/dL (13.9 mmol/L) and were markedly reduced at concentrations of 140 and 175 mg/dL
(7.8 and 9.7 mmol/L) [65]. However, even physiologic changes in blood glucose within the
normal postprandial range can increase gastric retention of a solid meal [66]. (See "Diabetic
autonomic neuropathy of the gastrointestinal tract", section on 'Gastroparesis'.)
The effect of chronic hyperglycemia is less clear. In one study of 87 randomly selected
diabetic patients, gastric emptying of a liquid meal was slower in those with blood glucose
values above 270 mg/dL (15 mmol/L) [63]. However, there are no data showing that a chronic
improvement in glycemic control enhances gastric emptying. Furthermore, the precise
contribution of chronic hyperglycemia in diabetics, separate from the effects of simultaneous
autonomic dysfunction, remains uncertain. Data suggest that sustained (six month)
improvements in glycemic control do not affect gastric emptying [67]; on the other hand, a
study of 78 patients with type 1 diabetes who participated in the Epidemiology of Diabetes
Interventions and Complications study showed that delayed gastric emptying is associated
with early and long-term hyperglycemia in type 1 diabetes mellitus [68]. Despite this
somewhat contradictory information, it is important to maintain optimal control of diabetes
as uncontrolled diabetes is a risk factor for the development of complications including
neuropathy both peripherally and in the autonomic nervous system. An increasingly
recognized association of delayed gastric emptying in patients with diabetes is the use of
several classes of medications that are used in the treatment of diabetes, specifically GLP-1
receptor agonists [69] and the amylin agonist, pramlintide [70].
Is there a cellular basis for the development of gastroparesis? — Experimental models

of gastroparesis show a reduction or remodeling in the number of interstitial cells of Cajal
(ICC) in the deep muscle plexus. This leads to secondary effects in gastric muscles because of
the lack of trophic factors (eg, stem cell factor) [71-73]. There are a few case reports
documenting the same deficiency in patients with gastroparesis [74-77].
Loss of ICC results from imbalance between the processes that injure ICC networks and
processes that generate and maintain ICC [78]. The relative insulinopenia and IGF-1
deficiency in diabetes leads to reduced production of smooth muscle cell-produced stem cell
factor, an important ICC survival factor [73]. Diabetes is associated with high oxidative stress
which may result from upregulation of macrophage heme oxygenase-1 [9].
Detailed studies of full thickness biopsies of the stomach in patients with idiopathic and
diabetic gastroparesis show no significant differences in nerve or smooth muscle or
inflammatory cell markers on light microscopy, except for greater reduction in expression of
neuronal NO synthase neurons in diabetic compared with idiopathic gastroparesis [8]. At the
ultrastructural level, diabetic gastroparesis was associated with a thickened basal lamina
around smooth muscle cells, and other changes (altered neuronal bodies and nerve endings
and fibrosis around nerves) were more severe in idiopathic than diabetic gastroparesis [79].
The precise functional significance of these changes is unclear, and therefore histological
studies remain predominantly research tools.
The loss of ICC in patients with gastroparesis is significantly associated with delayed gastric
emptying; overall clinical severity and nausea in idiopathic gastroparesis are associated with
the degree of immune cell infiltrate [80].
Does inflammation or oxidative stress contribute to the abnormal cellular functions in

gastroparesis?
● Morphology studies – Loss of antiinflammatory macrophages and increased

expression of genes associated with proinflammatory macrophages have been
reported in full-thickness gastric biopsies from patients with gastroparesis. However,
there may be differences in the morphologic abnormalities in diabetic and idiopathic
gastroparesis in the different studies reported to date. The candidate mechanism
leading to loss of these different pacemaker cells is oxidative stress, possibly resulting
from the depletion of antiinflammatory resident M2 macrophages expressing heme
oxygenase-1, which would protect the pacemaker cells by neutralizing the oxidative
mechanisms [9].
● Proteomics and RNA expression studies – Based on full-thickness gastric body

biopsies and deep RNA sequencing, it was shown that granulocyte adhesion and
diapedesis, as well as a macrophage-based immune dysregulation pathway, are the
most significantly affected pathways altered in both diabetic and idiopathic
gastroparesis. In addition, proteins involved in the complement and prostaglandin
synthesis pathway were associated with diabetic gastroparesis. In the same study,
immune cell analysis revealed no significant differences in enrichment of genes
associated with M1 or M2 macrophages in the biopsies from patients with diabetic
gastroparesis and diabetic control samples [81-83].
In contrast, genes associated with M1 (proinflammatory) macrophages were increased

in idiopathic gastroparesis samples compared to their controls. Finally, innate immune
mechanisms in diabetic gastroparesis seem to be associated with reduced expression
of inflammatory markers on transcriptomics, and paradoxically, they are associated
with M2 macrophage deficiency, which would be expected to be proinflammatory in
diabetic gastroparesis.
Therefore, further studies are needed to clarify the role of inflammatory mechanisms in
gastroparesis and particularly, the impact of vagal denervation, which may be
associated with diabetes mellitus. Moreover, there are still no known treatments to
effectively inhibit oxidative stress in the gut neuromuscular apparatus, and
antiinflammatory approaches or treatments directed at oxidative stress still require
controlled trials.
The pylorus — Two disease processes have been associated with pyloric dysfunction:
idiopathic hypertrophic pyloric stenosis; and diabetic gastroparesis. In the former, a
deficiency of inhibitory NO-containing neurons leads to lack of relaxation or excessive
spasm. In diabetes mellitus, excessive tonic and phasic pressure activity at the level of the
pylorus is present, contrasting with the postprandial antral hypomotility [84]. Experimental
evidence suggests that normalization of blood glucose with insulin treatment or treatment
with the phosphodiesterase-5 inhibitor sildenafil restores normal gastric emptying of liquids
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[13]. Endogenous opioid mechanisms are also important for the control of pyloric sphincter
[85]. Thus, opiates such as enkephalins from enkephalinergic nerves reduce the excitability
of enteric motor neurons and inhibit neurotransmitter release such as NO release, thereby
leading to increased pyloric tone or contraction. The same effects are also observed with
exogenous opioids such as mu- and delta- opioid agonists [86].
The precise contribution of the pylorus alone to impaired gastric emptying in disease is
unclear. However, this may be a moot point, since in most diseases and in pharmacologic
models of gastric stasis, excessive pyloric contractility is most often associated with
significant impairment of antral and probably fundal contractility. Nevertheless, there is
increased interest in pursuing measurements of pyloric diameter and distensibility (using
endoluminal functional lumen imaging probe) as evidence of a pathophysiologic mechanism
contributing to impaired gastric emptying, as well as some evidence showing that these
measurements either at baseline or in response to gastric peroral endoscopic myotomy are
actually predictive of clinical success of the procedure [87-90].
Abnormal small bowel motility — Abnormalities in small bowel motility can result in
delayed gastric emptying of solids [91]. This is true regardless of whether the underlying
process is neuropathic or myopathic [92]. Disturbances of intestinal ICC can also affect the
small bowel and result in impaired gastric emptying (eg, in paraneoplastic dysmotility) [93].
(See "Chronic intestinal pseudo-obstruction: Etiology, clinical manifestations, and diagnosis".)
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Here are the patient education articles that are relevant to this topic. We encourage you to
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● Basics topics (see "Patient education: Gastroparesis (delayed gastric emptying) (The
Basics)")
SUMMARY AND RECOMMENDATIONS
● The motor function of the gut is controlled at three main levels: the parasympathetic
and sympathetic nervous systems, enteric neurons and interstitial cells of Cajal, and
smooth muscle cells. (See 'Control of gut motor function' above.)
● The peristaltic reflex is responsible for propulsion of food from the stomach into the
intestine. The peristaltic reflex includes ascending contraction above the level of luminal
stimulation, usually due to distention by a food bolus, and descending inhibition below
the level of distention. (See 'Peristaltic reflex' above.)
● The stomach has three functional segments: the fundus, the antrum and the pylorus.
The mid-portion of the greater curvature of the stomach is the functional site of the
gastric electrical pacemaker. (See 'Motor functions of the stomach regions' above.)
● During fasting, the stomach participates in the cyclical activity front that propagates
through the gastrointestinal tract and serves as a "housekeeper," propelling
nondigestible solid residue towards the colon.
Postprandially, the fundus relaxes during swallowing (receptive relaxation) to start the
process of accommodation in which the stomach assumes reservoir functions,
facilitating the initial chemical digestion of food by acid and proteases before transfer
toward the antrum. The antrum produces high amplitude contractions resulting in the
grinding, mixing, and emptying of solids from the stomach.
Interdigestive (between meals) antral motor function clears the stomach of

undigestible solid particles whose size has not been reduced by trituration.
The recovery of proximal gastric tone during the postprandial period is associated with
gastric emptying, with the driving force being provided by the pressure gradient
between the stomach and duodenum. (See 'Motor functions of the stomach regions'
above.)
● Delayed gastric emptying may be due to abnormalities of the fundus (post-vagotomy

state, diabetes mellitus, and functional dyspepsia), abnormalities in antroduodenal
contraction (low amplitude, frequency, decreased antral motor function or dysfunction),
pyloric dysfunction (idiopathic hypertrophic pyloric stenosis and diabetic gastroparesis
associated with "pylorospasm") or abnormalities in small bowel motility. (See
'Pathogenesis of delayed gastric emptying' above.)
Use of UpToDate is subject to the Terms of Use.
REFERENCES
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Topic 2638 Version 18.0
GRAPHICS
Control of gastric motility
The motor function of the gut is controlled at three main levels: extrinsic neural control (vagal and
sympathetic); intrinsic neural control; and excitability of smooth muscle cells controlled by
transmitters.
Adapted from: Camilleri M, Prather CM. In: Sleisenger and Fordtran's Gastrointestinal Disease, 6th ed, Feldman M,
Scharschmidt BF, Sleisenger MH (Eds), WB Saunders, Philadelphia 1998. p.572.
Graphic 55162 Version 4.0
Fasting and postprandial gastrointestinal motility
Gastroduodenal manometry shows the normal interdigestive motor complex (left panel), in contrast
to the irregular persistent phasic pressure activity seen postprandially (right panel).
Reproduced from: Manometric Diagnosis of Gastrointestinal Motility Disorders, Malagelada JR, Camilleri M, Stanghellini M
(Eds), Thieme Inc, New York 1986.
Causes of nonulcer dyspepsia
A number of motor and sensory disorders may contribute to nonulcer dyspepsia.
Reproduced with permission from: Camilleri M, Prather CM. Gastric motor physiology and motor disorders. In: Sleisenger and
Fordtran's Gastrointestinal Disease, 6th ed, Feldman M, Scharschmidt BF, Sleisenger MH (Eds), WB Saunders, Philadelphia, PA
1998.
Manometry of the stomach and small intestine differentiates neuropathic

and myopathic disorders
Postprandial gastrointestinal motility in a patient with systemic sclerosis (myopathic disorder, left
panel) is characterized by low amplitude contractions at all levels compared with controls. By
comparison, a neuropathic disorder such as diabetes mellitus (right panel) is characterized by normal
contraction amplitude, but abnormal organization of the contractile response. Specifically, there is a
lack of distal antral contractions, pyloric tonic, and phasic pressure activity, and persistence of
migrating motor complex-like activity postprandially (proximal jejunum rows 2 and 3) despite the
ingestion of a solid-liquid meal.
Adapted from: Camilleri M. Medical treatment of chronic intestinal pseudo-obstruction. Pract Gastroenterol 1991; 15:10.
Tachygastria
Electrogastrography of the gastric antrum shows a brief period of tachygastria between six and seven
minutes, followed by a compensatory pause, and then return of normal pacemaker function with
three contractions per minute.
Adapted from: Chen JD, Pan J, McCallum RW. Clinical significance of gastric myoelectrical dysrhythmias. Dig Dis Sci 1995;
13:275.

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23/2/24, 16:16 Pathogenesis of delayed gastric emptying - UpToDate

Official reprint from UpToDate®

Literature review current through: Jan 2024.

Normal gastrointestinal motor function is a complex sequence of events that is controlled by

ANATOMY AND PHYSIOLOGY OF GASTRIC MOTOR FUNCTION

An understanding of the pathogenesis of delayed gastric emptying requires comprehension

● Parasympathetic and sympathetic nervous systems

● Smooth muscle cells

Autonomic nervous system — Extrinsic neural control by parasympathetic pathways is

phenotype has been documented with aging, that causes inflammation-mediated

PATHOGENESIS OF DELAYED GASTRIC EMPTYING

Postvagotomy gastric motor dysfunction — The stomach's accommodation response

gastrointestinal symptoms (most common symptoms in the cohort being nausea in 80

Motility disturbances in functional dyspepsia — Functional dyspepsia (also called

The molecular mechanisms leading to impaired gastric accommodation include NO,

The antrum and antroduodenal coordination — As previously mentioned, antral motor

Abnormalities of antral function can occur by several mechanisms:

● A decreased frequency of antral contractions is the most common form of gastric

● Reduced antral contractile amplitude is rarely observed in infiltrative disorders such as

● There is increasing evidence that several mechanisms of antral motor dysfunction

(diabetes) appear to be predictive of failure based on limited data currently available

Is there a cellular basis for the development of gastroparesis? — Experimental models

Does inflammation or oxidative stress contribute to the abnormal cellular functions in

● Morphology studies – Loss of antiinflammatory macrophages and increased

● Proteomics and RNA expression studies – Based on full-thickness gastric body

In contrast, genes associated with M1 (proinflammatory) macrophages were increased

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

Interdigestive (between meals) antral motor function clears the stomach of

● Delayed gastric emptying may be due to abnormalities of the fundus (post-vagotomy

Use of UpToDate is subject to the Terms of Use.

1. Camilleri M. Autonomic regulation of gastrointestinal motility. In: Clinical Autonomic Dis

5. Costa M, Gabella G. Adrenergic innervation of the alimentary canal. Z Zellforsch Mikrosk

52. Thumshirn M, Bruninga K, Camilleri M. Simplifying the evaluation of postprandial antral

53. Zheng T, BouSaba J, Sannaa W, et al. Comprehensive characterization of antral and

Control of gastric motility

Graphic 55162 Version 4.0

Fasting and postprandial gastrointestinal motility

Graphic 80945 Version 3.0

Causes of nonulcer dyspepsia

A number of motor and sensory disorders may contribute to nonulcer dyspepsia.

Graphic 78572 Version 4.0

Manometry of the stomach and small intestine differentiates neuropathic

Graphic 51540 Version 6.0

Graphic 66624 Version 3.0

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