Gastroparesis: A Comprehensive Approach to Evaluation and Management [1st ed. 2020] 978-3-030-28928-7, 978-3-030-28929-4

Table of contents :
Front Matter ....Pages i-xii
Front Matter ....Pages 1-1
Normal Gastric Motility (Kirstie E. Jarrett, Robert E. Glasgow)....Pages 3-20
Etiology and Clinical Presentation of Gastroparesis (Laura A. Pace)....Pages 21-31
Diagnostic Evaluation of Gastroparesis (Michael Cline, Carol Rouphael)....Pages 33-41
Front Matter ....Pages 43-43
Medical Management of Gastroparesis (Klaus Bielefeldt, Patrick McKenzie, John C. Fang)....Pages 45-54
Endoluminal Management of Gastroparesis (Alisan Fathalizadeh, John Rodriguez)....Pages 55-76
Gastric Electrical Stimulation (Andrew Kastenmeier)....Pages 77-89
Laparoscopic Pyloroplasty (Amber Shada)....Pages 91-97
Front Matter ....Pages 99-99
Post-Surgical Gastroparesis (Mac Kenzie Landin, Philip Omotosho)....Pages 101-109
Management of Gastroparesis in the Setting of Gastroesophageal Reflux Disease (Nadia V. Guardado, Edward D. Auyang)....Pages 111-115
Managing Gastroparesis in the Setting of Obesity (Jessica Blumhagen, Eric Volckmann)....Pages 117-120
Back Matter ....Pages 121-125

Citation preview

Gastroparesis A Comprehensive Approach to Evaluation and Management Anna Ibele Jon Gould  Editors

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Gastroparesis

Anna Ibele  •  Jon Gould Editors

Gastroparesis A Comprehensive Approach to Evaluation and Management

Editors Anna Ibele Division of General Surgery University of Utah Salt Lake City, UT USA

Jon Gould Division of General Surgery Medical College of Wisconsin Milwaukee, WI USA

ISBN 978-3-030-28928-7    ISBN 978-3-030-28929-4 (eBook) https://doi.org/10.1007/978-3-030-28929-4 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

This book is dedicated to our patients, with the hope that we can continue as a profession to add to our current body of knowledge and increase our repertoire of durable solutions for complicated foregut problems. We would also like to give special thanks to our surgical partners and colleagues from whom we have received advice, support, and friendship. Dr. Gould would like to thank his amazing wife, Beth, and his children, Anna, Jack, and Max, for their love and support. Dr. Ibele would like to thank her husband, Michael, for his sense of humor, love, and support and her children, Katharine and Davin, who are a constant source of joy in her life and a reminder of how important it is to help our patients enjoy a good quality of life with their own families. Jon Gould, MD, FACS Anna Ibele, MD, FACS

Preface

Gastroparesis is a challenging and poorly understood medical condition that can substantially impact patient’s quality of life. While significant therapeutic advances have been made, translational scientists, clinicians, and surgeons still have much to discover about helping people with this lifestyle-limiting condition. Gastroparesis covers the fundamental components of evaluation of the patient presenting with gastroparesis and offers a comprehensive review of the currently employed medical, endoluminal, and operative management strategies for these often complicated patients. We are very excited to offer the contributions of several experienced clinicians and surgeons who are experts in their fields. We would like to thank the contributing authors for their time and effort as well as the editors and staff at Springer for helping bring this text to publication. Wallace Stevens said “It is the unknown that excites the ardor of scholars.” We hope the knowledge and experience as relayed by our authors will inspire investigation and innovation and lead to advances in care for current and future patients. Salt Lake City, UT, USA Milwaukee, WI, USA

Anna Ibele Jon Gould

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Contents

Part I Etiology and Diagnosis 1 Normal Gastric Motility����������������������������������������������������������������������������   3 Kirstie E. Jarrett and Robert E. Glasgow 2 Etiology and Clinical Presentation of Gastroparesis������������������������������  21 Laura A. Pace 3 Diagnostic Evaluation of Gastroparesis ��������������������������������������������������  33 Michael Cline and Carol Rouphael Part II Management 4 Medical Management of Gastroparesis ��������������������������������������������������  45 Klaus Bielefeldt, Patrick McKenzie, and John C. Fang 5 Endoluminal Management of Gastroparesis������������������������������������������  55 Alisan Fathalizadeh and John Rodriguez 6 Gastric Electrical Stimulation������������������������������������������������������������������  77 Andrew Kastenmeier 7 Laparoscopic Pyloroplasty������������������������������������������������������������������������  91 Amber Shada Part III Special Considerations 8 Post-Surgical Gastroparesis���������������������������������������������������������������������� 101 Mac Kenzie Landin and Philip Omotosho 9 Management of Gastroparesis in the Setting of Gastroesophageal Reflux Disease�������������������������������������������������������� 111 Nadia V. Guardado and Edward D. Auyang 10 Managing Gastroparesis in the Setting of Obesity �������������������������������� 117 Jessica Blumhagen and Eric Volckmann Index�������������������������������������������������������������������������������������������������������������������� 121 ix

Contributors

Edward D. Auyang, MD, MS FACS  Department of Surgery, University of New Mexico School of Medicine, Albuquerque, NM, USA Klaus  Bielefeldt, MD, PhD  Division of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, UT, USA Veterans Administration Medical Center, Salt Lake City, UT, USA Jessica Blumhagen, MD  University of Utah Health, Salt Lake City, UT, USA Michael Cline, DO  Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH, USA John C. Fang, MD  Division of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, UT, USA Alisan  Fathalizadeh, MD, MPH  Minimally Invasive Surgery and Surgical Endoscopy, Cleveland Clinic Foundation, Cleveland, OH, USA Robert E. Glasgow, MD, FACS  Department of Surgery, University of Utah, Salt Lake City, UT, USA Nadia V. Guardado, MD, MS  Department of Surgery, University of New Mexico School of Medicine, Albuquerque, NM, USA Kirstie E. Jarrett, MD  Department of Surgery, University of Utah, Salt Lake City, UT, USA Andrew Kastenmeier, MD  Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA Mac  Kenzie  Landin, MD  Department of Surgery, Rush University Medical Center, Chicago, IL, USA Patrick McKenzie, MD  Division of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, UT, USA Philip Omotosho, MD  Department of Surgery, Rush University Medical Center, Chicago, IL, USA

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Contributors

Laura  A.  Pace, MD, PhD  Department of Internal Medicine, Division of Gastroenterology, Hepatology, & Nutrition, University of Utah, Salt Lake City, UT, USA John Rodriguez, MD, FACS  Minimally Invasive Surgery and Surgical Endoscopy, Cleveland Clinic Foundation, Cleveland, OH, USA Carol Rouphael, MD  Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH, USA Amber Shada, MD, FACS  University of Wisconsin, Madison, WI, USA Eric Volckmann, MD  University of Utah Health, Salt Lake City, UT, USA

Part I Etiology and Diagnosis

1

Normal Gastric Motility Kirstie E. Jarrett and Robert E. Glasgow

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.

K. E. Jarrett ∙ R. E. Glasgow (*) Department of Surgery, University of Utah, Salt Lake City, UT, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 A. Ibele, J. Gould (eds.), Gastroparesis, https://doi.org/10.1007/978-3-030-28929-4_1

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K. E. Jarrett and R. E. Glasgow

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. 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

Cutaneous electrodes 3 cpm EGG waves 500 µV 60 s A

Fundus

Pacemaker region B

Corpus

Pylorus

Serosal electrodes 3 cpm slow waves

Slow wave (Pacesetter potentials)

C Duodenum

D Antrum 1 mV

60 s

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].)

1  Normal Gastric Motility

5 Slow waves

Intracellular recording

0 mv

1

Extracellular recording

1

2

–70

Action potentials 2

3 mv 4 5g

3

3

5

Tension 0

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])

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]. 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.

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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).

Active propagation of slow waves in ICC network

Interstitial cell network in pacemaker region (MY-ICC) Smooth muscle cells Intramuscular ICC (IM-ICC)

Enteric motor neuron Varicose terminals

Spontaneous activation of pacemaker current

Electrotonic conduction of slow waves via gap junctions

Depolarization and activation of L-type Ca+ channels in SMC Neural input to IM-ICC conditions responses of smooth muscles to slow waves

IM-ICC and MY-ICCs are electrically coupled to smooth muscle cells via gap junctions

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])

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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.

 nteric Nervous System E 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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To prevertebral ganglia, spinal cord, and brain stem

Sympathetic (mainly postganglionic)

Parasympathetic (preganglionic)

Myenteric plexus

Submucosal plexus Sensory neurons Epithelium

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. 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.

1  Normal Gastric Motility 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])

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Esophagus

Left vagus nerve Right vagus nerve

Anterior vagal trunk Esophageal plexus

Stomach

Posterior vagal trunk

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].

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Afferent vagus nerve

TS Glu

AP

NTS

GABA NE DMV

Nodose ganglion

Efferent vagus nerve

ACh

ACh

NANC

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])

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,

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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 the “activity front.” Over the course of 90–120 minutes, the activity front migrates from the antrum to the distal ileum. If fasting continues, another activity front will begin at the antrum at the end of the 90- to 120-minute period. Contractions during phase 3 allow gastric emptying of fibrous, nondigestible solids. Phase 4 is characterized by a rapid decrease in contractions prior to the reappearance of phase 1. The MMC pattern stops immediately once food is ingested [10, 23]. Regulation of the MMC pattern is incompletely understood, though it is likely multifactorial. The neurons of the ENS appear to have a significant role in the generation of contractions during phases 2 and 3. During phase 1, slow waves are present, but there is no concurrent excitation from ENS neurons. Excitation begins intermittently in phase 2, then regularly in phase 3, which depolarizes smooth muscle cells to the contraction threshold. These ENS neurons are hypothesized to fire based on an intrinsic timing mechanism that is inhibited by the presence of food in the upper GI tract [24]. Motilin, a polypeptide hormone produced by endocrine cells of the duodenum and jejunum, also plays an important role in the regulation of MMCs. In both humans and dogs, administration of exogenous motilin induces premature phase 3 contractions [25, 26]. In humans, plasma motilin levels fluctuate during fasting and peak during phase 3 of the gastric MMC [27]. The release of motilin is regulated by unclear mechanisms; however, bile acids appear to be involved. Levels of bile acids correlate with fluctuations in plasma motilin levels during the fasting state [28]. Further, postcholecystectomy patients have shown a decreased frequency and shorter duration of phase 3 contractions when compared to healthy volunteers [29]. These findings indicate a possible link between gallbladder emptying and the origin of the MMC [24].

Gastric Motility in the Fed State The fed state is characterized by prolonged periods of contractile activity in which peristaltic contractions occur more frequently but are less powerful than contractions associated with MMCs. Fed state motility results from the coordination of slow waves, intrinsic and extrinsic innervation, hormonal inputs, and the type/ caloric content of the ingested substances.

Gastric Response to Ingestion of Solid Foods Receptive Relaxation As swallowed food enters the stomach, the gastric fundus undergoes receptive relaxation, which allows gastric volume to increase without a corresponding increase in gastric pressure. This accommodation response is mediated by a vagovagal reflex (see Fig.  1.7). During fasting, vagal input to the fundus is predominantly cholinergic (excitatory) and the stomach is collapsed. Fundic and esophageal distension stimulates mechanoreceptors, which send afferent signals to the medulla via the vagus nerve. Efferent signals are then relayed to the fundus, causing the

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Fundic relaxation

Fundic contraction: emptying

Antral peristalsis: emptying Pyloric resistance

Corpus: antral filling/mixing Duodenal resistance Antropyloroduodenal coordination

Fig. 1.7  Summary of gastric motility after ingestion of a solid meal. The fundus initially relaxes in order to accommodate the increase in gastric contents. The fundus then contracts to propel ingested food into the corpus/antrum. Once in the corpus/antrum, food is triturated by recurrent peristaltic waves to produce chyme. Antral peristaltic contractions, indicated by the ring in the above diagram, then empty chyme through the pylorus and into the duodenum. Antropyloroduodenal coordination occurs when the antral contraction occurs in conjunction with pyloric and duodenal relaxation, thus maximizing the efficiency of emptying. (Modified from Koch [30])

release of nitrergic (inhibitory) input to the smooth muscle cells. Inhibition of smooth muscle cells allows fundic relaxation and the accommodation of the ingested food [31]. After the initial period of relaxation, the fundus begins to have intermittent contractions that push ingested food into the corpus and antrum. This process allows a gradual redistribution of ingested food during the postprandial period.

Trituration When food is ingested, excitatory vagal stimulation induces action potentials in the distal stomach, thus replacing the MMC pattern of the fasting state with regular peristaltic waves. Like contractions associated with MMCs, peristaltic contractions occur at a rate of three per minute. However, unlike MMC contractions, peristaltic contractions recur continuously throughout the fed state. As contractions in the fundus begin to push accommodated food into the corpus and antrum, peristaltic waves triturate food into small particles. The particles are then mixed with gastric juices in order to produce chyme.

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Gastric Emptying Peristaltic contractions propagate in the direction of the pylorus; however, some of them stop before reaching the terminal antrum. If the peristaltic wave does not reach the terminal antrum, there is no associated pyloric contraction and a larger aliquot of chyme is delivered to the duodenum. If a peristaltic wave does make it to the terminal antrum, it causes contraction and closure of the pyloric sphincter. When the sphincter is closed, only chyme and food particles  protein > carbohydrate) Volume Undigestible fibers Fatty acids in duodenum or ileum Systemic factors Hypoglycemia Hyperglycemia Illusory self-motion (vection)c

Effect on rate of gastric emptying Accelerate Accelerate Delay Delay Delay Delay Delay Delay Delay Proportional to ingested volume Delay Delay (duodenal or ileal brake) Accelerate Delay Delay

Modified from Feldman et al. [33], Table 49-1 a Pylorospasm refers to the sudden closure of the pylorus due to spasm of the pyloric smooth muscle. This leads to delay in emptying and can cause vomiting. Seen in conditions that impair the normal function of gastric neuromuscular signaling, such as diabetic gastroparesis b Tachygastria is defined as pacemaker frequency greater than or equal to 3.6 cpm [34] c Vection is the perception of movement in space caused by visual stimulation alone (e.g., the sensation of physical motion while watching a film in 3D or while playing a virtual reality video game)

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cholecystokinin (CCK). CCK release is increased when the duodenum is exposed to fatty acids. CCK stimulation acts on the stomach to decrease the rate of gastric emptying. This is accomplished by the relaxation of fundic tone, inhibition of antral contractions, and stimulation of pyloric tone. The distal gut is also thought to influence gastric emptying via the production of a hypothetical enterogastrone. It is possible that this agent is peptide YY, which has been shown to decrease gastric emptying in a hormonal fashion [35].

Gastric Response to Ingestion of Liquids The gastric actions required to mix and empty liquids are very different from those required for digestible solids. In contrast to solid foods, which are accommodated in the fundus and then triturated in the distal stomach, liquids are rapidly accommodated throughout the entire stomach. Figure 1.9 depicts 3D ultrasound images taken before and after the ingestion of 500 mL of soup [37]. Within the first 10 minutes following ingestion, volume is evenly distributed between the proximal and distal stomach. This indicates rapid relaxation of not only the fundus (as seen with accommodation of solid foods) but also of the corpus and antrum. b

a

Fundus

Corpus Antrum

Fig. 1.9  3D reconstructed ultrasound images of the stomach before and after ingestion of a 500 mL soup meal. Panel A shows the stomach in the fasted state, during which time the intragastric volume is about 38 mL. Panel B depicts the stomach 10 minutes after soup ingestion. The entire stomach is now distended, indicating relaxation and of the fundus, corpus, and antrum. (Modified from Gilja et al. [36] and Maurer et al. [32])

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Because liquids do not need to be triturated, they are emptied more rapidly than solids. Calorie-rich liquids are retained in the antrum longer than noncaloric liquids. Noncaloric liquids have no lag phase and proceed straight from accommodation to emptying in a linear fashion (Fig. 1.8b) [38]. Forces that contribute to the emptying of liquids include stomach-duodenum pressure gradients, antral peristaltic contractions, and duodenogastric reflux events [39, 40]. Additionally, a larger volume of ingested liquid increases the rate of gastric emptying. Liquids with a higher osmolality or higher viscosity or those that contain protein, fats, and/or acid will empty more slowly [37–40].

Perturbations in Normal Gastric Motility Diabetic Gastroparesis Diabetic gastroparesis (DGP) accounts for up to 1/3 of all gastroparesis cases. It is typically more common in patients with type 1 diabetes; however, the incidence in type 2 diabetics ranges from 30% to nearly 50% [41]. DGP is usually a consequence of long-standing disease and poorly controlled blood glucose. Hyperglycemia is the primary contributor to the development of DGP. In both diabetic and nondiabetic test subjects, acute hyperglycemia (>220 mg/dL) is associated with delayed emptying and gastric dysrhythmias [42–45]. Other abnormalities such as ICC loss [46, 47], abnormal contractions of the pylorus [48], and decreased motility in the antrum have also been associated with hyperglycemia [49]. Neuromuscular abnormalities found specifically in patients with type 1 diabetes include impaired receptive relaxation and antral dilation [49, 50]. Pathologic findings in patients with known DGP include ICC depletion and abnormal enteric nerve endings [51, 52]. Some patients with DGP also have dysfunctional smooth muscle. These findings provide an explanation for the impaired response to food ingestion and gastric dysrhythmias that are characteristic of DGP. Symptoms of DGP primarily include nausea and vomiting, early satiety, abdominal discomfort, and bloating. In insulin-dependent patients, DGP can also cause unexpected postprandial hypoglycemia (especially when insulin is given before meals). When gastric emptying is delayed, so is absorption of glucose in the small bowel. Preprandial insulin, therefore, will act unopposed and decrease the blood glucose by more than predicted, leading to unexpected hypoglycemia (see Chap. 2) [53].

Idiopathic Gastroparesis Idiopathic gastroparesis (IGP) accounts for over 1/3 of gastroparesis cases [54]. While the exact pathophysiology is unknown, some cases may occur as a result of a viral infection that damages gastric neuromuscular structures. Fifteen percent of patients with IGP reported a “herald” illness several months prior to the onset of gastroparesis symptoms [55, 56]. These illnesses were usually described as flulike

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with fever, nausea, and vomiting. Compared to that from patients with DGP, histologic findings from IGP patients have shown a greater degree of both ICC loss and ENS nerve abnormalities [51, 52]. However, unlike DGP, smooth muscle cells appear to be unaffected. Patients with IGP experience typical symptoms associated with gastroparesis (nausea, vomiting, early satiety, bloating) but also tend to have more abdominal pain than patients with other types of gastroparesis. IGP can have permanent effects or may completely resolve within 1–2 years.

Postsurgical Gastroparesis Disruption of normal gastric motility can occur as a result of many surgical procedures that involve the stomach and/or distal esophagus. In most cases, motility dysfunction arises from injury to a branch of the vagus nerve. When the vagus nerve is transected, the fundus fails to relax upon ingestion of food, causing the food to be transferred through the stomach and into the duodenum much more quickly [57]. Because vagal innervation modulates the intrinsic neuromuscular activity of the stomach, vagotomy is also associated with gastric dysrhythmias and reduced frequency of antral contractions [58]. If a truncal vagotomy is performed (indicated in some cases of refractory peptic ulcer disease), peristalsis is severely disrupted and antral contractions become so weak that the patient must also have a pyloroplasty. Pyloroplasty reduces pyloric resistance in order to facilitate gastric emptying. Because vagotomy can disrupt the vagal-mediated receptive relaxation of the stomach, patients are at risk for dumping syndrome. With dumping, loss of the accommodation response leads to a rapid transit of food into the small bowel. Hyperosmolar substances in the lumen trigger sympathetic nervous responses, leading to abdominal cramping, diarrhea, heart palpitations, and dizziness. Interestingly, patients can often recover from vagotomy. However, in patients who also need resection of the antrum and corpus, prolonged and even permanent dysfunction may occur. Postsurgical dysfunction of gastric motility can also arise from the loss of ICCs. For example, severe dysmotility can develop in patients who undergo antrectomy for the treatment of gastric cancer or refractory peptic ulcer disease [59, 60]. In such procedures, variable amounts of the antrum and corpus (including unknown amounts of the pacemaker region) are resected. This causes a significant decrease in the stomach’s ability to triturate food. Without effective trituration, ingested food is retained in the fundus, food does not get broken down in the corpus, and gastric emptying into the duodenum fails [61].

References 1. Koch KL. Electrogastrography. In: Feldman M, Friedman L, Brandt L, editors. Sleisenger and Fordtran’s gastrointestinal and liver disease. Philadelphia: Saunders; 2016. p. 811. 2. Kim C, Malagelada J. Electrical activity of the stomach: clinical implications. Mayo Clin Proc. 1986;61(3):205–10.

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3. Sanders K, Ward S, Koh S. Interstitial cells: regulators of smooth muscle function. Physiol Rev. 2014;94(3):859–907. 4. Kraichely R, Farrugia G.  Mechanosensitive ion channels in interstitial cells of Cajal and smooth muscle of the gastrointestinal tract. Neurogastroenterol Motil. 2007;19:245–52. 5. Sanders K, Koh S, Ward S. Interstitial cells of Cajal as pacemakers in the gastrointestinal tract. Annu Rev Physiol. 2006;68:307–43. 6. Ordog T, Ward S, Sanders K. Interstitial cells of Cajal generate electrical slow waves in the murine stomach. J Physiol. 1999;518:257–69. 7. Horowitz B, Ward S, Sanders K.  Cellular and molecular basis for electrical rhythmicity in gastrointestinal muscles. Annu Rev Physiol. 1999;61:19–43. 8. Komuro T. Structure and organization of interstitial cells of Cajal in the gastrointestinal tract. J Physiol. 2006;576:653–8. 9. Huizinga J.  Physiology and pathophysiology of the interstitial cell of Cajal: from bench to bedside II. Gastric motility: lessons from mutant mice on slow waves and innervation. Am J Phys. 2001;281:G1129–34. 10. Koch KL.  Gastric neuromuscular function and neuromuscular disorders. In: Feldman M, Friedman L, Brandt L, editors. Sleisenger and Fordtran’s gastrointestinal and liver disease, vol. 2. 10th ed. Philadelphia: Saunders; 2016. 11. Ward S, Ordog T, Koh S, et al. Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria. J Physiol. 2000;525:355–61. 12. Lee H, Hennig G, Fleming N, et al. Septal interstitial cells of Cajal conduct pacemaker activity to excite muscle bundles in human jejunum. Gastroenterology. 2007;133:907–17. 13. Won K, Sanders K, Ward S. Interstitial cells of Cajal mediate mechanosensitive responses in the stomach. Proc Natl Acad Sci U S A. 2005;102:121–6. 14. Hall JE. General principles of gastrointestinal function – motility, nervous control, and blood circulation. In: Guyton and Hall textbook of medical physiology. 13th ed. Philadelphia: Elsevier; 2016. 15. Grundy D, Schemann M. Enteric nervous system. Curr Opin Gastroenterol. 2007;23:121–6. 16. Benarroch E.  Enteric nervous system: functional organization and neurologic implications. Neurology. 2007;69:1953–7. 17. Gershon M, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132:397–414. 18. Huizinga J.  Gastrointestinal peristalsis: joint action of enteric nerves, smooth muscle, and interstitial cells of Cajal. Microsc Res Tech. 1999;47:239–47. 19. Drake RL, Vogl AW, Mitchell AW. Gray’s anatomy for students. 4th ed. Philadelphia: Elsevier; 2019. p. 123–247. 20. Ward S, Sanders K.  Interstitial cells of Cajal: primary targets of enteric motor innervation. Anat Rec. 2001;262:125–35. 21. Travagli RA, Anselmi L. Vagal neurocircuitry and its influence on gastric motility. Nat Rev Gastroenterol Hepatol. 2016;13(7):389–401. 22. Lomax A, Vanner S. Presynaptic inhibition of neural vasodilator pathways to submucosal arterioles by release of purines from sympathetic nerves. Am J Physiol Gastrointest Liver Physiol. 2010;298:G700–5. 23. Takahashi T. Interdigestive migrating motor complex -its mechanism and clinical importance. J Smooth Muscle Res. 2013;49:99–111. 24. Deloose E, et al. The migrating motor complex: control mechanisms and its role in health and disease. Nat Rev Gastroenterol Hepatol. 2017;9(5):271–85. 25. Vantrappen G, et al. Motilin and the interdigestive migrating motor complex in man. Dig Dis Sci. 1979;24:497–500. 26. Itoh Z, et  al. Motilin-induced mechanical activity in the canine alimentary tract. Scand J Gastroenterol Suppl. 1976;39:93–110. 27. Boivin M, Riberdy M, Trudel L, St-Pierre S, Poitras P. Plasma motilin variation during the interdigestive and digestive states in man. Neurogastroenterol Motil. 1990;2:240–6.

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28. Qvist N, et al. Increases in plasma motilin follow each episode of gallbladder emptying during the interdigestive period, and changes in serum bile acid concentration correlate to plasma motilin. Scand J Gastroenterol. 1995;30:122–7. 29. Perdikis G, et  al. Altered antroduodenal motility after cholecystectomy. Am J Surg. 1994;168:609–14. 30. Koch KL. Physiological basis of electrogastrography. In: Feldman M, Friedman L, Brandt L, editors. Sleisenger and Fordtran’s gastrointestinal and liver disease. Philadelphia: Saunders; 2016. p. 816. 31. Tack J, Demedts I, Meulemans A, et  al. Role of nitric oxide in the gastric accommodation reflex and in meal induced satiety in humans. Gut. 2002;51:219–24. 32. Maurer AH, Parkman HP, Knight LC, Fisher RS. Scintigraphy. In: Feldman M, Friedman L, Brandt L, editors. Sleisenger and Fordtran’s gastrointestinal and liver disease. Philadelphia: Saunders; 2016. p. 818. 33. Feldman M, Friedman L, Brandt L, editors. Sleisenger and Fordtran’s gastrointestinal and liver disease. Philadelphia: Saunders; 2016. 34. Parkman HP, Hasler WL, Barnett JL, Eaker EY. Electrogastrography: a document prepared by the gastric section of the American Motility Society Clinical GI Motility Testing Task Force. Neurogastroenterol Motil. 2003;15(2):89–102. 35. Pappas T, Debas H, Taylor I. Enterogastrone-like effect of peptide YY is vagally mediated in the dog. J Clin Invest. 1986;77(1):490–53. 36. Gilja OH, Detmer PR, Jong JM, et al. Intragastric distribution and gastric emptying assessed by three-dimensional ultrasonography. Gastroenterology. 1997;113:38–49. 37. Camilleri M, Malagelada J, Brown M, et al. Relation between antral motility and gastric emptying of solids and liquids in humans. Am J Phys. 1985;249:G580–5. 38. Moran T, Wirth J, Schwartz G, McHugh P. Interactions between gastric volume and duodenal nutrients in the control of liquid gastric emptying. Am J Phys. 1999;276:R997–R1002. 39. Indireshkumar K, Brasseur J, Faas H, et  al. Relative contributions of “pressure pump” and “peristaltic pump” to gastric emptying. Am J Phys. 2000;278:G604–16. 40. Savoye-Collet C, Savoye G, Smout A. Determinants of transpyloric fluid transport: a study using combined real-time ultrasound, manometry, and impedance recording. Am J Phys. 2003;285:G1147–52. 41. Intagliata N, Koch K. Gastroparesis in type 2 diabetes mellitus: prevalence, etiology, diagnosis and treatment. Curr Gastroenterol Rep. 2007;9:270–9. 42. Coleski R, Hasler W. Coupling and propagation of normal and dysrhythmic gastric slow waves during acute hyperglycemiain healthy humans. Neurogastroenterol Motil. 2009;21(5):492–9. 43. Jebbink R, Samsom M, Bruijs P, et al. Hyperglycemia induces abnormalities of gastric myoelectrical activity in patients with type 1 diabetes mellitus. Gastroenterology. 1994;107:1390–7. 44. Hasler W, Soudah H, Dulai G, Owyang C. Mediation of hyperglycemia-evoked gastric slow-­ wave dysrhythmias by endogenous prostaglandins. Gastroenterology. 1995;108:727–36. 45. Shvarcz E, Plamar M, Aman J, et  al. Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes. Gastroenterology. 1997;113:60–6. 46. He C, Soffer E, Ferris C, et al. Loss of interstitial cells of Cajal and inhibitory innervation in insulin-dependent diabetes. Gastroenterology. 2001;121:427–34. 47. Ordog T.  Interstitial cells of Cajal in diabetic gastroenteropathy. Neurogastroenterol Motil. 2008;20:8–18. 48. Fraser R, Horowitz M, Dent J. Hyperglycemia stimulates pyloric motility in normal subjects. Gut. 1991;32:475–8. 49. Malagelada J, Rees W, Mazzotta L, Go V. Gastric motor abnormalities in diabetic and postvagotomy gastroparesis: effect of metoclopramide and bethanechol. Gastroenterology. 1980;78(2):286–93. 50. Samsom M, Roelofs J, Akkermans L, et al. Proximal gastric motor activity in response to a liquid meal in type I diabetes mellitus with autonomic neuropathy. Dig Dis Sci. 1998;43(3):491–6.

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51. Grover M, Farrugia G, Lurken M, et al. Cellular changes in diabetic and idiopathic gastroparesis. Gastroenterology. 2011;140:1575–85. 52. Faussone-Pellegrini M, Pasricha P, Bernard C, et al. Ultrastructural differences between diabetic and idiopathic gastroparesis. J Cell Mol Med. 2011;16:1573–81. 53. Koch K.  Diabetic gastropathy: gastric neuromuscular dysfunction in diabetes mellitus. A review of symptoms, pathophysiology, and treatment. Dig Dis Sci. 1999;44:1061–75. 54. Soykan I, Sivri B, Saroseik I, et al. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci. 1998;43:2398–404. 55. Parkman H, Yates K, Hasler W, et al. Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying and severity of gastroparesis. Gastroenterology. 2011;140:101–15. 56. Oh J, Kim C. Gastroparesis after a presumed viral illness: clinical and laboratory features and natural history. Mayo Clin Proc. 1990;65:636–42. 57. Cowley D, Vernon P, Jones T, et al. Gastric emptying of solid meals after truncal vagotomy and pyloroplasty in human subjects. Gut. 1972;13:176–81. 58. Hinder R, Kelley K. Human gastric pacesetter potential: site of origin, spread, and response to gastric transection and proximal vagotomy. Am J Surg. 1997;133:29–33. 59. Fich A, Neri M, Camilleri M, et al. Stasis syndromes following gastric surgery: clinical and motility features of 60 symptomatic patients. J Clin Gastroenterol. 1990;12:505–12. 60. Eagon J, Miedema B, Kelly K.  Postgastrectomy syndromes. Surg Clin North Am. 1992;72:445–65. 61. Le Blanc-Louvry I, Savoye G, Maillot C, et al. An impaired accommodation of the proximal stomach to a meal is associated with symptoms after distal gastrectomy. Am J Gastroenterol. 2003;98:2642–7.

2

Etiology and Clinical Presentation of Gastroparesis Laura A. Pace

Gastroparesis is a clinical syndrome characterized by delayed emptying of solid food from the stomach in the absence of a mechanical obstruction, which results in a constellation of symptoms including nausea, early satiety, postprandial fullness, gastroesophageal reflux, abdominal pain, and often vomiting. The prevalence of diagnosed gastroparesis in the U.S. population is estimated at 24.2 per 100,000 persons [1]. However, based on a population survey from Olmstead County, Minnesota, up to 1.8% of the general population may have delayed gastric emptying, suggesting that gastroparesis may be greatly underdiagnosed [2]. There is a dramatic sex differential in gastroparesis, with the Rochester Epidemiology Project calculating the prevalence of gastroparesis at 9.6 for males and 37.8 for females per 100,000 persons [2]. This same study also found that the overall survival of individuals with gastroparesis is significantly lower than that of age- and sex-specific expected survival. There are three broad categories of gastroparesis: diabetic, postsurgical, and idiopathic. The idiopathic category of gastroparesis is by far the most common, and within the idiopathic category nearly 80% of affected individuals are female.

Etiology of Gastroparesis The neuromuscular dysfunction of gastroparesis arises from disorders in extrinsic neuronal control, dysfunction of the elaborate interconnections of intrinsic nerves and interstitial cells of Cajal (ICC), described by Camilleri et al. as the electrical syncytium, dysfunction of smooth muscle, or some combination thereof [3]. The normal function of the stomach in response to eating has been described in detail

L. A. Pace (*) Department of Internal Medicine, Division of Gastroenterology, Hepatology, & Nutrition, University of Utah, Salt Lake City, UT, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 A. Ibele, J. Gould (eds.), Gastroparesis, https://doi.org/10.1007/978-3-030-28929-4_2

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within Chap. 1; therefore for the purposes of this chapter, it will only be discussed briefly to highlight the potential derangements that can occur in gastroparesis. Ingested food is broken down within the stomach by a process of acid digestion and shear forces created by coordinated gastric contractions against a closed pylorus. This process requires coordination from extrinsic innervation, primarily from the vagus nerve, coordinated with activity from intrinsic cholinergic and nitrergic neurons, which is transmitted through the ICCs to the smooth muscle cells of the stomach [4]. This process results in coordinated gastric contractions that commence in the proximal stomach and terminate in the distal stomach (gastric antrum). Gastroparesis can arise when any of these coordinated actions break down. A study using CD-177 immunostaining to compare the cellular changes in full-­ thickness gastric body biopsy specimens of individuals with gastroparesis demonstrated that both individuals with diabetic gastroparesis and idiopathic gastroparesis have a reduction in the number of ICCs [4]. The same study reported a reduction in neuronal nitric oxide synthase (nNOS) expression in 40% of patients with idiopathic gastroparesis, compared with only 20% of diabetic gastroparetics. They also noted a marked alteration in nerve ending morphology within the idiopathic group using transmission electron microscopy (TEM). Both diabetic and idiopathic groups had a reduction in the number of ICCs, and all nerve endings were found to be devoid of neurotransmitters, a phenomenon that has also been reported in achalasia [5], strongly suggesting that the mechanisms underlying gastroparesis and achalasia may be similar across these disease states. The NIH NIDDK Gastroparesis Clinical Research Consortium (GpCRC) also evaluated full-thickness gastric biopsy samples, which showed ICC and enteric nerve fiber loss in the stomachs of gastroparetics [6]. In addition, this study demonstrated myenteric immune infiltrate with a 25% increase over controls in the diabetic group and 30% increase over controls in the idiopathic group. They then evaluated the association between these findings and severity of gastroparesis. For the diabetic group, ICC or enteric nerve loss did not correlate with symptom severity. However, in the idiopathic group, myenteric immune infiltrate correlated with more severe gastroparesis symptoms [6]. Another recent study by the GpCRC reported that 65 genes were found to be differentially expressed in both diabetic and idiopathic gastroparetics, with most of these genes being involved in immune signaling pathways. This study also found that most idiopathic gastroparetic patients differentially expressed genes that are associated with a proinflammatory (M1) macrophage phenotype [7], strongly implicating immune dysregulation in the pathophysiology of gastroparesis. The precise mechanism that results in the observed decrease in nNOS expression in gastroparetics remains the subject of ongoing research. In nonobese diabetic mice, upregulation of heme oxygense-1 (HO-1) was protective against the development of gastrointestinal complications of diabetes and could reverse the cellular changes that are thought to lead to the development of gastroparesis [8]. This study also demonstrated that downregulation of HO-1 led to increased reactive oxygen species, decreased nNOS expression, and a decrease in ICCs. NOS expression and nitric oxide levels have been shown to be altered in disease processes that also have high rates of gastroparesis, such as collagen-vascular disorder and systemic sclerosis [9].

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Idiopathic gastroparesis is the most common etiology of gastroparesis. However, in many idiopathic cases of gastroparesis, if a thorough investigation is undertaken, a true etiology can be identified. Therefore, for the purposes of this chapter, idiopathic gastroparesis will be further subdivided into several more specific categories as it likely encompasses a number of underrecognized causative processes. Some have postulated that the higher prevalence of gastroparesis in females is due to health-seeking behavior or hormones [10]. However, many cases of the idiopathic form of gastroparesis occur in female predominant disorders, including autoimmune disease, dysautonomia, collagen-vascular diseases, and other disorders of connective tissue [11]. The precise risk factors and mechanisms by which gastroparesis develops remains an active area of research and hopefully soon will be able to explain this dramatic sex differential and provide more effective treatments.

Diabetic Gastroparesis It is estimated that up to 50% of all diabetics, both Type I and Type II, have gastroparesis. The mechanism by which diabetes mellitus results in gastroparesis is thought to be the same for both Type I and Type II diabetes [3]. In healthy individuals, acute hyperglycemia has been shown to delay gastric emptying [12], and hypoglycemia has been shown to speed up gastric emptying [3]. Both these mechanisms serve to help regulate blood glucose levels. Blood glucose level feedback on gastric emptying may in fact represent another biological mechanism to maintain normoglycemia. It is important to note that gastroparesis can complicate blood glucose control in diabetics and result in fatal hypoglycemia when not recognized and insulin timing is not adjusted accordingly. Therefore, in any poorly controlled diabetic patient, gastric emptying should be measured as this could serve as a mechanism by which to improve glycemic control. The precise mechanism by which gastroparesis develops in diabetics is not yet known. However, it is very likely a multifactorial process. Gastroparesis is more likely to occur in individuals with concomitant neuropathy, as evidenced by retinopathy [13] and the development of an autonomic nervous system dysfunction [14] (dysautonomia). In one study of diabetics thought to have an underlying dysautonomia, they were found to be more likely to have concomitant esophageal dysmotility. It would have been interesting to interrogate small intestinal and colonic motility in this population as well, given that it is unlikely that a systemic dysautonomia would target only the foregut.

Postsurgical Gastroparesis Gastroparesis secondary to surgery can occur after any operation in which an entrapment, injury, or complete severing of the vagus nerve may occur. Postsurgical gastroparesis is most commonly reported after fundoplication or partial gastrectomy. Gastrectomy with associated vagotomy [15] can result in postsurgical

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gastroparesis for two reasons: (1) due to antrectomy, which will negatively impact the stomach’s ability to process ingested food as shear force generation against a closed pylorus can no longer occur, and (2) associated vagotomy. Less common cases of postsurgical gastroparesis can occur after heart or lung transplant, radio frequency ablation for atrial fibrillation, anterior approach for spinal surgery, esophagectomy, mobilization of the vagus nerve during Heller cardiomyotomy, or reconstruction after pancreatectomy [13]. There are even more rare reports of postsurgical gastroparesis after variceal sclerotherapy or botulin toxin injections for the treatment of achalasia.

Idiopathic Gastroparesis Idiopathic gastroparesis encompasses a broad category of potential etiologies. Because of the complexity of the systemic disorders associated with gastroparesis, there is likely a significant degree of overlap and multiplicity in the underlying pathophysiology that results in the development of delayed gastric emptying resulting from systemic disease. Broadly speaking, there are immunologic, neurologic, neuroimmunologic, neuromuscular, connective tissue, and metabolic disorders that may contribute to the development of idiopathic gastroparesis. There is also a significant amount of overlap between many of these categories.

I mmunologic, Neurologic, and Neuroimmunologic Disorders Some individuals will develop gastroparesis after acute infections, such as Epstein-­ Barr virus (EBV), herpes simplex virus (HSV), cytomegalovirus (CMV), varicella zoster virus (VZV), and norovirus [13]. A small fraction of these individuals will also go on to develop an autoimmune encephalitis [16], which itself can result in numerous neurological and gastrointestinal complications. The gastrointestinal motility disorders that develop after a viral infection or in the presence of an immune disorder are likely due to an underlying neuroimmune process. In addition, some of these individuals will also develop a postinfectious dysautonomia, which likely is also the result of a neuroimmune mediated process. Neuroimmune processes targeting components of the nervous system and a systemic dysautonomia can result in gastrointestinal dysmotility, including gastroparesis. Individuals with autoimmune gastritis have been shown to have high rates of dysautonomia and the severity of dysautonomia correlated with the severity of gastroparesis [17]. In a small study, 14 patients with medication and device refractory gastroparesis and evidence of autoimmunity were successfully treated with intravenous immunoglobulin (IVIG) therapy [18]. IVIG therapy resulted in significant improvements in the symptoms of nausea, vomiting, early satiety, and abdominal pain. In another small study involving 23 patients with chronic gastrointestinal dysmotility, including gastroparesis, that were treated with immunotherapy, the patients were shown to have improvement in chronic symptoms, along with objective improvements in gastrointestinal motility and autonomic testing [19]. Given the degree of overlap in symptoms and the number of systems affected in immune, neurological, and neuroimmune

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disorders, a thorough clinical evaluation is often required to identify potential etiologies and contributing factors as these can have a great influence on the selection of the appropriate treatment for the affected individual.

 euromuscular, Neuroimmunologic, and Connective Tissue N Disorders Intestinal manometry has long been considered the gold standard for diagnosing many gastrointestinal motility disorders because it has been thought that this technique could differentiate neurological and myopathic disorders [20]. However, a small study comparing intestinal manometry results with that of full-thickness small intestinal histopathology demonstrated that manometric pattern was not predictive of underlying pathophysiology [21]. This study demonstrated that of the individuals diagnosed with a neuropathic disorder based on manometric patterns and found to have abnormal histopathology, only 23% had an underlying enteric neuropathy, while 62% had evidence of an inflammatory neuromyopathy with predominant lymphocytic, eosinophilic, or mast cell infiltrate, and the other 15% had evidence of an underlying myopathy. None of the individuals diagnosed with a myopathic disorder based on manometric patterns were found to have an underlying myopathy despite all of them having abnormal histopathology. This highlights the importance of obtaining a histopathological diagnosis when able as part of the evaluation of severe or refractory gastrointestinal motility disorders. Connective tissue disorders, including joint hypermobility syndrome, Ehlers-­ Danlos syndrome (EDS), and systemic sclerosis have very high rates of gastrointestinal morbidity, including gastrointestinal motility disorders [22–25]. At this time, it is not clear if the gastrointestinal comorbidity observed in these populations is due to the connective tissue disorder itself or the comorbid immune, neuroimmune, and metabolic disorders commonly associated with these connective tissue disorders. Metabolic Multiple classes of medications can result in delayed gastric emptying, and a careful review of a patient’s medications is an essential component of the clinical evaluation of gastroparesis. Proton pump inhibitors may negatively affect gastric emptying by two mechanisms: the first due to gastric acid suppression, which can impair peptic digestion and therefore the mechanical disruption of ingested solid food [26], and the second by reducing nitric oxide levels [27]. Opioids cause numerous gastrointestinal motility disorders [28], including gastroparesis. Activation of μ-opioid receptors by exogenous opioids inhibit excitatory and inhibitory neural pathways within the entire enteric nervous system, which results in decreased strength of peristaltic contractions and increased resting muscle tone [29]. In gastroparesis, μ-opioid receptor agonists cause delayed gastric emptying by reducing antral contractions and increasing pyloric contractions [13]. Many other common and uncommon medications have deleterious effects on gastrointestinal motility, and therefore medications should always be considered as potential contributing factors in gastroparesis.

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Other Etiologies Solid organ and hematopoietic cell transplantation are also associated with gastroparesis, although the mechanisms are not known [30]. It is likely that this is also a multifactorial process with immune, neurological, and metabolic factors all contributing. Chronic renal [31, 32] and hepatic failure [33] can be associated with gastroparesis, and when gastroparesis is present, it can have a negative impact on nutrition. In hepatic failure patients with concomitant gastroparesis, there is also a high prevalence of dysautonomia, which can further complicate the treatment of symptoms and negatively impact nutrition. A retrospective study in children demonstrated that 18% of gastroparesis cases occurred after viral infection, while 8% were associated with an underlying metabolic disorder involving the mitochondria [34, 35]. An example of very early onset gastroparesis in children has been shown to involve a defect in oxidative phosphorylation within the mitochondrial electron transport chain [36]. In summary, the etiology of gastroparesis is complex and multifactorial and can be associated with many other chronic systemic and genetic disorders. Gastroparesis can also serve as a clinical indicator of other gastrointestinal motility disorders as they commonly occur together. Not surprisingly, the clinical presentation of gastroparesis can also be complex and is often dependent on comorbid conditions.

Clinical Presentation Symptoms associated with gastroparesis are broad and share a significant amount of overlap with other disorders, making the diagnosis complicated. This may explain the potential for underdiagnosis of this disorder [1, 37]. A recently published metanalysis found that delays in gastric emptying correlated with symptoms of nausea, vomiting, abdominal pain, and early satiety [38]. Other commonly reported symptoms in the gastroparesis population include heartburn, abdominal bloating, and postprandial fullness. Nausea may be the most prominent symptom and typically arises within a few hours of eating. However, for more severe cases, nausea may be present the  majority of the time, with the potential for exacerbation after eating. Unfortunately, even after total gastrectomy, nausea may not resolve [39]. The original Gastroparesis Cardinal Symptom Index (GCSI) [40] (Fig.  2.1) was recently updated by the American Neurogastroenterology and Motility Society (ANMS) (ANMS GCSI-DD) (Fig. 2.2) to meet the Food and Drug Administration recommendations for a patient-reported outcome (PRO) tool to support a symptom- based clinical trial endpoint to be utilized in gastroparesis-related clinical trials [41]. A major feature of this update is related to the use of a Daily Diary (DD) system rather than a two-week recall of symptom questionnaire employed by the original GCSI. The ANMS GCSI-DD requires further validation for use in clinical practice. The GCSI utilizes a six-point Likert response scale (0  =  none, 1  =  very mild, 2 = mild, 3 = moderate, 4 = severe, 5 = very severe) to rate symptoms over a two-­ week recall period. Subscale scores are calculated by taking the mean of the items in each subscale. Three subscales are used in the GCSI: nausea/vomiting (three items, questions 1, 2, and 3), postprandial fullness/early satiety (four items,

2  Etiology and Clinical Presentation of Gastroparesis None Very mild

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6. Feeling excessively full after meals

0

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7. Loss of appetite

0

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8. Bloating (feeling like you need to loosen your clothes)

0

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4. Stomach or belly visibly larger

0

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Fig. 2.1  Gastroparesis Cardinal Symptom Index (GCSI). (Previously published instructions for use [40]) This questionnaire asks you about the severity of symptoms you may have related to your gastrointestinal problem. There are no right or wrong answers. Please answer each question as accurately as possible For each symptom, please circle the number that best describes how severe the symptom has been during the past 2 weeks. If you have not experienced this symptom, circle 0. If the symptom has been very mild, circle 1. If the symptom has been mild, circle 2. If it has been moderate, circle 3. If it has been severe, circle 4. If it has been very severe, circle 5. Please be sure to answer every question. Please rate the severity of the following symptoms during the past 2 weeks.

None

Mild

Moderate

Severe

Very severe

1. Nausea (feeling sick to your stomach as if you were going to vomit or throw up) 2. Not able to finish a normal-sized meal (for a healthy person) 3. Feeling excessively full after meals

4. Upper abdominal pain (above the navel) The next question asks you to record the number of times vomiting occurred in the last 24 hours. Please record the number of vomits (throwing up with food or liquid coming out) that occurred in the last 24 hours. Record zero, if you have not vomited during the past 24 hours. If you vomited, write down the number of all vomits. If you vomited once, record one. If you vomited three times during the day, record three. If you vomited three times, whether it was during the same trip to the bathroom or three separate trips, record three as the number of episodes of vomiting. 5. During the past 24 hours, how many episodes of vomiting did you have?

*

Fig. 2.2  American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary (ANMS GCSI-DD) Instrument. (Previously published instructions for use [41]) These questions ask about symptoms you may have each day. Please complete the daily diary at about the same time every evening. For each symptom listed below, please mark with an X the box that best describes the worst severity of each symptom during the past 24 hours. Please be sure to answer each question. ∗The maximum recorded value is 4 to correspond with the maximum score for all other symptoms. Therefore, if a patient records 6 vomiting episodes in one 24-hour period, this will be recorded as 4.

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questions 4, 5, 6, and 7), and bloating/distention (two items, questions 8 and 9). The total score is calculated by taking the mean of the three subscales [42]. A lower score is associated with less severe symptoms. A reduction in GCSI score represents an improvement in symptoms. The ANMS GCSI-DD utilizes a five-point Likert response scale for the interpretation of patient responses (0  =  none, 1  =  mild, 2 = moderate, 3 = severe, 4 = very severe). The patient rates their severity of nausea, early satiety, postprandial fullness, and upper abdominal pain over the last 24 hours. In addition, patients record the number of vomiting episodes in the past 24 hours as well. A daily composite score is calculated as the average of the 5 symptom scores utilizing a maximum score of 4 for vomiting episodes reported in the past 24 hours. A lower score is associated with less severe symptoms. A reduction in ANMS GCSI-DD score is suggestive of an improvement in symptoms. For the ANMS GCSI-DD, it was reported that a moderate effect size is represented by a 0.5–0.8 change and a large effect size is represented by a >0.8 change [42]. In diabetic patients, heartburn and poor glycemic control may be the only presenting symptoms of delayed gastric emptying. Episodes of hypoglycemia in a diabetic should prompt an evaluation for underlying gastroparesis. This is relevant for both insulin-dependent and noninsulin-dependent diabetics as even the absorption of oral hypoglycemic agents can be affected by gastroparesis. As discussed above, gastroparesis should be considered in this population as its recognition and subsequent appropriate interventions may improve glycemic control and reduce the risk of further complications. The significant overlap of gastroparesis-related symptoms with other disorders continues to be acknowledged. Functional dyspepsia is defined as bothersome early satiety, fullness, or epigastric pain or burning [43]. The Rome IV criteria describes two subtypes of functional dyspepsia: postprandial distress syndrome and epigastric pain syndrome [43, 44]. Rome IV diagnostic criteria for postprandial distress syndrome includes bothersome postprandial fullness or early satiety severe enough to impact on regular activities or finishing a regular size meal for three or more days per week in the past three months, with a least a six-month history. Rome IV criteria for epigastric pain syndrome is bothersome epigastric pain or epigastric burning one or more days per week in the past three months, with at least a six-month history. Gastroparesis is reported in 20% of individuals with a Rome IV diagnosis of functional dyspepsia demonstrating the significant overlap in these disorders [43]. Individuals with functional dyspepsia also report high rates of nausea and heartburn, often making the distinction between functional dyspepsia and gastroparesis difficult to clinically discern. In individuals with a diagnosis of gastroparesis, the stomach may not be the only affected organ as these individuals appear to have higher rates of esophageal dysmotility, small intestinal dysmotility, and colonic dysmotility [45]. Therefore, a more extensive evaluation may be warranted based on symptoms. The SmartPill (Medtronic, Minneapolis, MN) wireless motility capsule may be considered as this can provide information not only regarding the strength and frequency of antral contractions along with gastric emptying time but also of small intestinal transit, colonic transit, and global gastrointestinal transit times [46]. In addition,

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assessment with a wireless motility capsule can easily be performed in an outpatient setting [47]. Individuals presenting with immune disorders, neurological disorders, or connective tissue disorders in addition to gastrointestinal symptoms should be evaluated for gastroparesis and other gastrointestinal motility disorders, given the association in these populations [19, 48–51]. Research is ongoing that will eventually elucidate the pathophysiological mechanisms of gastrointestinal dysmotility, and with that, hope for better treatments exist.

References 1. Rey E, Choung RS, Schleck CD, Zinsmeister AR, Talley NJ, Locke GR. Prevalence of hidden gastroparesis in the community: the gastroparesis “iceberg”. J Neurogastroenterol Motil. Korean Society of Neurogastroenterology and Motility. 2012;18(1):34–42. 2. Jung H-K, Choung RS, Locke GR, Schleck CD, Zinsmeister AR, Szarka LA, et al. The incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006. Gastroenterology. 2009;136(4):1225–33. 3. Camilleri M, Chedid V, Ford AC, Haruma K, Horowitz M, Jones KL, et al. Gastroparesis. Nat Rev Dis Primers. Nature Publishing Group. 2018;4(1):41. 4. Grover M, Farrugia G, Lurken MS, Bernard CE, Faussone-Pellegrini MS, Smyrk TC, et  al. Cellular changes in diabetic and idiopathic gastroparesis. Gastroenterology. 2011;140(5):1575–8. 5. Faussone-Pellegrini MS, Cortesini C.  The muscle coat of the lower esophageal sphincter in patients with achalasia and hypertensive sphincter. An electron microscopic study. J Submicrosc Cytol. 1985;17(4):673–85. 6. Grover M, Bernard CE, Pasricha PJ, Lurken MS, Faussone-Pellegrini MS, Smyrk TC, et al. Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium. Neurogastroenterol Motil. John Wiley & Sons, Ltd (10.1111). 2012;24(6):531–9, e249. 7. Grover M, Gibbons SJ, Nair AA, Bernard CE, Zubair AS, Eisenman ST, et al. Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis. BMC Med Genomics. BioMed Central. 2018;11(1):62. 8. Choi KM, Gibbons SJ, Nguyen TV, Stoltz GJ, Lurken MS, Ordog T, et al. Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis. Gastroenterology. 2008;135(6):2055–64, 2064.e1–2. 9. Allanore Y, Borderie D, Hilliquin P, Hernvann A, Levacher M, Lemaréchal H, et al. Low levels of nitric oxide (NO) in systemic sclerosis: inducible NO synthase production is decreased in cultured peripheral blood monocyte/macrophage cells. Rheumatology (Oxford). Oxford University Press. 2001;40(10):1089–96. 10. Ravella K, Al-Hendy A, Sharan C, Hale AB, Channon KM, Srinivasan S, et al. Chronic estrogen deficiency causes gastroparesis by altering neuronal nitric oxide synthase function. Dig Dis Sci. Springer US. 2013;58(6):1507–15. 11. Fikree A, Grahame R, Aktar R, Farmer AD, Hakim AJ, Morris JK, et al. A prospective evaluation of undiagnosed joint hypermobility syndrome in patients with gastrointestinal symptoms. Clin Gastroenterol Hepatol. 2014;12(10):1680–7. 12. Schvarcz E, Palmér M, Aman J, Horowitz M, Stridsberg M, Berne C. Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes mellitus. Gastroenterology. 1997;113(1):60–6. 13. Vijayvargiya P, Camilleri M. Gastroparesis. In: Lacy BE, DiBaise JK, Pimentel M, Ford AC, editors. Essential medical disorders of the stomach and small intestine. A clinical casebook. Cham: Springer; 2019. p. 23–50.

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14. Boronikolos GC, Menge BA, Schenker N, Breuer TGK, Otte J-M, Heckermann S, et al. Upper gastrointestinal motility and symptoms in individuals with diabetes, prediabetes and normal glucose tolerance. Diabetologia. Springer Berlin Heidelberg. 2015;58(6):1175–82. 15. Camilleri M.  Functional dyspepsia and gastroparesis. Dig Dis. Karger Publishers. 2016;34(5):491–9. 16. Dale RC, Nosadini M.  Infection-triggered autoimmunity: The case of herpes simplex virus type 1 and anti-NMDAR antibodies. Neurol Neuroimmunol Neuroinflamm. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 2018;5(4):e471. 17. Kalkan Ç, Soydal Ç, Özkan E, Maden A, Soykan I, et  al. Clin Auton Res. Springer Berlin Heidelberg. 2016;26(3):189–96. 18. Ashat M, Lewis A, Liaquat H, Stocker A, McElmurray L, Vedanarayanan V, et al. Intravenous immunoglobulin in drug and device refractory patients with the symptoms of gastroparesis-an open-label study. Neurogastroenterol Motil. John Wiley & Sons, Ltd (10.1111). 2018;30(3). 19. Flanagan EP, Saito YA, Lennon VA, McKeon A, Fealey RD, Szarka LA, et al. Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility. Neurogastroenterol Motil. John Wiley & Sons, Ltd (10.1111). 2014;26(9):1285–97. 20. Patcharatrakul T, Gonlachanvit S.  Technique of Functional and Motility Test: How to Perform Antroduodenal Manometry. J Neurogastroenterol Motil. Korean Society of Neurogastroenterology and Motility. 2013;19(3):395–404. 21. Malagelada C, Karunaratne TB, Accarino A, Cogliandro RF, Landolfi S, Gori A, et  al. Comparison between small bowel manometric patterns and full-thickness biopsy histopathology in severe intestinal dysmotility. Neurogastroenterol Motil. John Wiley & Sons, Ltd (10.1111). 2018;30(3):e13219. 22. Zarate N, Farmer AD, Grahame R, Mohammed SD, Knowles CH, Scott SM, et al. Unexplained gastrointestinal symptoms and joint hypermobility: is connective tissue the missing link? Neurogastroenterol Motil. John Wiley & Sons, Ltd (10.1111). 2010;22(3):252–78. 23. Fikree A, Chelimsky G, Collins H, Kovacic K, Aziz Q. Gastrointestinal involvement in the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):181–7. 24. Yang H, Xu D, Li M, Yao Y, Jin M, Zeng X, et  al. Gastrointestinal manifestations on impaired quality of life in systemic sclerosis. J Dig Dis. John Wiley & Sons, Ltd (10.1111). 2019;20(5):256–61. 25. Kovacic K, Chelimsky TC, Sood MR, Simpson P, Nugent M, Chelimsky G. Joint hypermobility: a common association with complex functional gastrointestinal disorders. J Pediatr. 2014;165(5):973–8. 26. Moshiree B, Potter M, Talley NJ.  Epidemiology and pathophysiology of gastroparesis. Gastrointest Endosc Clin N Am. 2019;29(1):1–14. 27. Ghebremariam YT, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, et al. Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation. 2013;128(8):845–53. 28. Ortiz V, García-Campos M, Sáez-González E, delPozo P, Garrigues V.  A concise review of opioid-induced esophageal dysfunction: is this a new clinical entity? Dis Esophagus. 2018;31(5):424. 29. Leppert W. The impact of opioid analgesics on the gastrointestinal tract function and the current management possibilities. Contemp Oncol (Pozn). Termedia. 2012;16(2):125–31. 30. Eagle DA, Gian V, Lauwers GY, Manivel JC, Moreb JS, Mastin S, et al. Gastroparesis following bone marrow transplantation. Bone Marrow Transplant. Nature Publishing Group. 2001;28(1):59–62. 31. Schoonjans R, Van VB, Vandamme W, Van HN, Verdievel H, Vanholder R, et al. Dyspepsia and gastroparesis in chronic renal failure: the role of Helicobacter pylori. Clin Nephrol. 2002;57(3):201–7. 32. De Schoenmakere G, Vanholder R, Rottey S, Duym P, Lameire N. Relationship between gastric emptying and clinical and biochemical factors in chronic haemodialysis patients. Nephrol Dial Transplant. Oxford University Press. 2001;16(9):1850–5.

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33. Verne GN, Soldevia-Pico C, Robinson ME, Spicer KM, Reuben A. Autonomic dysfunction and gastroparesis in cirrhosis. J Clin Gastroenterol. 2004;38(1):72–6. 34. Rodriguez L, Irani K, Jiang H, Goldstein AM. Clinical presentation, response to therapy, and outcome of gastroparesis in children. J Pediatr Gastroenterol Nutr. 2012;55(2):185–90. 35. Chumpitazi B, Nurko S. Pediatric gastrointestinal motility disorders: challenges and a clinical update. Gastroenterol Hepatol (N Y). 2008;4(2):140–8. 36. Chitkara DK, Nurko S, Shoffner JM, Buie T, Flores A. Abnormalities in gastrointestinal motility are associated with diseases of oxidative phosphorylation in children. Am J Gastroenterol. 2003;98(4):871–7. 37. Kim BJ, Kuo B. Gastroparesis and functional dyspepsia: a blurring distinction of pathophysiology and treatment. J Neurogastroenterol Motil. Korean Society of Neurogastroenterology and Motility. 2019;25(1):27–35. 38. Vijayvargiya P, Jameie-Oskooei S, Camilleri M, Chedid V, Erwin PJ, Murad MH. Association between delayed gastric emptying and upper gastrointestinal symptoms: a systematic review and meta-analysis. Gut. BMJ Publishing Group. 2018;68(5). https://doi.org/10.1136/ gutjnl-2018-316405. 39. NORD. National Organization for Rare Disorders. https://rarediseases.org/. 40. Revicki DA, Rentz AM, Dubois D, Kahrilas P, Stanghellini V, Talley NJ, et al. Development and validation of a patient-assessed gastroparesis symptom severity measure: the Gastroparesis Cardinal Symptom Index. Aliment Pharmacol Ther. John Wiley & Sons, Ltd (10.1111). 2003;18(1):141–50. 41. Revicki DA, Lavoie S, Speck RM, Puelles J, Kuo B, Camilleri M, et al. The content validity of the ANMS GCSI-DD in patients with idiopathic or diabetic gastroparesis. J Patient Rep Outcomes. SpringerOpen. 2018;2(1):61. 42. Pasricha PJ, Camilleri M, Hasler WL, Parkman HP. White paper AGA: gastroparesis: clinical and regulatory insights for clinical trials. Clin Gastroenterol Hepatol. W.B.  Saunders. 2017;15(8):1184–90. 43. Talley NJ, Goodsall T, Potter M.  Functional dyspepsia. Aust Prescr. NPS MedicineWise. 2017;40(6):209–13. 44. Aziz I, Palsson OS, Törnblom H, Sperber AD, Whitehead WE, Simrén M.  Epidemiology, clinical characteristics, and associations for symptom-based Rome IV functional dyspepsia in adults in the USA, Canada, and the UK: a cross-sectional population-based study. Lancet Gastroenterol Hepatol. 2018;3(4):252–62. 45. Evans PR, Bak YT, Shuter B, Hoschl R, Kellow JE. Gastroparesis and small bowel dysmotility in irritable bowel syndrome. Dig Dis Sci. 1997;42(10):2087–93. 46. Kuo B, McCallum RW, Koch KL, Sitrin MD, Wo JM, Chey WD, et al. Comparison of gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther. John Wiley & Sons, Ltd (10.1111). 2008;27(2):186–96. 47. Diaz Tartera HO, Webb D-L, Al-Saffar AK, Halim MA, Lindberg G, Sangfelt P, et al. Validation of SmartPill® wireless motility capsule for gastrointestinal transit time: Intra-subject variability, software accuracy and comparison with video capsule endoscopy. Neurogastroenterol Motil. 12 ed. John Wiley & Sons, Ltd (10.1111). 2017;29(10):1–9. 48. Cojocaru M, Cojocaru IM, Silosi I, Maedica CV. Gastrointestinal manifestations in systemic autoimmune diseases. Maedica. 2011;6(1):45–51. 49. Lobrano A, Blanchard K, Abell TL, Minocha A, Boone W, Wyatt-Ashmead J, et  al. Postinfectious gastroparesis related to autonomic failure: a case report. Neurogastroenterol Motil. John Wiley & Sons, Ltd (10.1111). 2006;18(2):162–7. 50. Pasha SF, Lunsford TN, Lennon VA. Autoimmune gastrointestinal dysmotility treated successfully with pyridostigmine. Gastroenterology. 2006;131(5):1592–6. 51. Dhamija R, Tan KM, Pittock SJ, Foxx Orenstein A, Benarroch E, Lennon VA.  Serologic profiles aiding the diagnosis of autoimmune gastrointestinal dysmotility. Clin Gastroenterol Hepatol. W.B. Saunders. 2008;6(9):988–92.

3

Diagnostic Evaluation of Gastroparesis Michael Cline and Carol Rouphael

Abbreviations C Carbon CO2 Carbon dioxide FDA Food and Drug Administration GES Gastric emptying scintigraphy MRI Magnetic resonance imaging WMC Wireless motility capsule

Gastroparesis is suspected in patients with abdominal pain, nausea, vomiting, bloating, or when those symptoms occur postprandially. Those patients warrant testing to evaluate for gastroparesis once an upper endoscopy is performed to rule out peptic ulcer disease or gastric outlet obstruction as a cause of their symptoms. A variety of tests are available for the diagnosis of gastroparesis (Table 3.1) with gastric emptying scintigraphy (GES) being the gold standard.

Gastric Emptying Scintigraphy GES was first described in 1966 by Griffith et al. [1] and is currently considered the gold standard for the diagnosis of gastroparesis. In this test, and after an overnight fast, the patient ingests a standardized, radiotracer-bound, low-fat meal (255 kcal)

M. Cline (*) · C. Rouphael Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 A. Ibele, J. Gould (eds.), Gastroparesis, https://doi.org/10.1007/978-3-030-28929-4_3

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Table 3.1  Strengths and limitations of diagnostic tests to evaluate gastric emptying Study evaluating gastric emptying Gastric emptying scintigraphy (gold standard) Stable isotope breath test

Strengths Well validated, reproducible [4] Noninvasive [4] Ability to assess both solid and liquid phases [12] No radiation exposure [4] Reproducible and correlates with the gold standard [15, 18]

Wireless motility capsule

No radiation exposure [19] Allows the assessment of extragastric motility [24]

Antroduodenal manometry

Helps distinguish between myopathic vs. neuropathic etiology of impaired gastric motility [4]

Transabdominal ultrasonography

Can provide data on transpyloric flow and intragastric meal distribution [4, 36] No radiation exposure Can measure gastric emptying, accommodation, and gastric secretions [3] No radiation exposure

Magnetic resonance imaging

Limitations Radiation exposure [4] Solid meal might not be tolerated if severe symptoms [13] Limited use in patients with malabsorption, liver, or lung diseases [19, 20] Affected by physical activity [19] Lack of standardized mathematical analysis of results [19] Capsule emptying might not match physiologic emptying [29] Risk of retention or obstruction [19] Requires further validation in patients with suspected gastroparesis [31] Invasive Not readily available [34] Requires expertise [35] Technically cumbersome Operator dependent Performs poorly in obese patients [4] Cost Lack of standardization Requires specialized equipment Requires expertise [4, 7]

resembling a physiologic meal within 10 minutes. A longer time of ingestion can alter results. Most institutions use 99mTc sulfur colloid-labeled egg sandwich [2] or Egg Beaters egg whites (120 g) with 1–2 slices of bread, strawberry jam (30 g), and water (120  mL). For accurate quantification of gastric emptying, the radiotracer should be tightly bound to the solid phase to prevent it separating from the solid meal and emptying with the liquid phase, generating false-negative results [3, 4]. While earlier studies labeled both solids and liquid phases of a meal, current standardized tests only label the solid phase of a meal, because liquid emptying becomes abnormal only at very advanced stages of gastroparesis. Testing liquid emptying is of value however when evaluating for postsurgical anatomic problems or ruling out dumping syndrome in postsurgical patients [4]. After ingestion, standard imaging of the gastric area is performed with the patient standing after meal consumption

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Fig. 3.1  Abnormal gastric emptying scintigraphy at 4 hours: 1.0 mCi Tc-99 m sulfur colloid was given orally in a meal consisting of 4 oz Egg Beaters, 1 slice of toast, 30 g jelly, and 4 oz water, consumed over 5–10 minutes with 17% of radioactive material retained at 4 hours (normal 60% retention at 2 hours and/or >10% retention at 4 hours [5–7] (Fig. 3.1). The emptying half-time can also be calculated by extrapolation using the power exponential curve; however, results would only be accurate if the patient does actually empty at least 50% of the ingested meal at the time of imaging [8]. While a 2-hour GES was previously performed to determine gastric emptying, recent studies have proposed a longer duration of 4 hours for a more reliable assessment [9–11]. A study comparing a 2–4-hour GES found a 29% increase in the number of abnormal studies at 4 hours compared to 2-hour tests [11]. In preparation for the test, patients are asked to discontinue all medications that could alter gastrointestinal motility for 2–7 days prior to the procedure, including prokinetics, narcotics, anticholinergics, and alcohol. On the day of the test, fasting blood glucose should be 3 units. Small bowel transit time normally takes 2.5–6 hours and is determined from the time the pH increases by >3 units to the time it drops by >1 unit and is sustained for at least 30 minutes. This drop marks the passage of the capsule to the cecum. Colon transit time (normal if 59 hours or less) is determined from the time the WMC enters cecum until it is expelled from the body, marked by sudden drop in temperature or loss of signal [24]. Testing begins in the morning after an overnight fast. Patients are instructed to refrain from taking medications that would alter gastric emptying 2–3  days prior to the test day. Similarly, acid suppressant medications are held to prevent interfering with the pH measurements of the WMC. Proton pump inhibitors are held 7 days prior and histamine receptor blockers 3 days prior to the procedure. On the day of testing, patients ingest a standardized meal consisting of a nutrient bar: Smartbar® followed by 50 cc of water. Patients fast for

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the 6 hours following meal consumption. They are asked to push the EVENT button and make entry in diary for certain events for the duration of the study after which the receiver is collected and data is downloaded for analysis [24].

Strengths WMC is a safe alternative to gastric emptying testing, free of radiation exposure, and need for gamma camera [19]. Recent studies also showed that pressure measurements can further enhance its utility where pressure can be used to distinguish between diabetic gastroparesis characterized by lower number of contractions and motility indices compared to healthy individuals [25]. Another advantage to using WMC in the diagnosis of gastroparesis is the ability to investigate extragastric motility with a single test. This is useful as extragastric impaired motility occurs in >40% of patients with suspected gastroparesis [26] and because gastrointestinal symptoms correlate poorly with the gastrointestinal segment affected [26–28]. Investigating the rest of the gastrointestinal tract along with gastric emptying provides insights about motility in the various segments of the gut which can alter management and improve symptoms [26].

Limitations The WMC is a big capsule that can be challenging to swallow, and its emptying from the stomach might not occur with the physiologic emptying of food [29]. Another limitation is its risk of retention or obstruction. In all reported cases, however, the capsule was amenable to endoscopic retrieval or passed with a prokinetics [19]. WMC testing is approved in patients with suspected slow transit constipation but still not approved by the FDA to investigate gastric motility in isolation. One study compared gastric emptying time using WMC to GES and found a moderate correlation between both studies done concurrently [30]. Hasler et al. expanded on the previous study by looking at liquid emptying but found device agreement of only 52.8% between WMC and nuclear gastric emptying, which implies that further studies are required for WMC validation in patients with suspected gastroparesis [31].

Antroduodenal Manometry Antroduodenal manometry provides information about gastric and duodenal contractions and consists of inserting a manometry catheter or transducer with pressure sensors into the pyloric channel endoscopically or under radiographic fluoroscopy [7, 32, 33]. Pressure measurements of the antral, pyloric, and duodenal contraction waves are obtained in fasting and postprandial states. The test can be performed over 5–8 hours in a stationary setting or in a 24-hour ambulatory setting with the latter used to characterize duodenal motor function. In gastroparesis, antroduodenal manometry demonstrates a reduced antral motility index [7, 33].

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Strengths Antroduodenal manometry helps distinguish between a myopathic (i.e., scleroderma, amyloidosis) and a neuropathic (i.e., diabetes mellitus) cause of impaired motility. In patients with a myopathic condition, the test exhibits a decreased frequency and a lower amplitude of migrating motor complexes. In patients with a neuropathic etiology of the disease, the migrating motor complexes have a normal amplitude but are poorly coordinated with loss of propagation [4, 33].

Limitations This test is not readily available and more validation studies are needed [34]. It is an invasive test and requires expertise to perform the procedure and interpret the results. Moreover, it can be technically cumbersome, and the catheter can migrate from the pylorus when the patient is fed and the stomach dilates [35].

Other Imaging Modalities Transabdominal ultrasonography and magnetic resonance imaging (MRI) have been proposed as noninvasive diagnostic tools for gastroparesis, but their use remains limited to research purposes for reasons discussed below. Two-dimensional ultrasonography can provide data about gastric emptying by measuring changes in the antral area, and complete gastric emptying is determined once the antral area returns to its preprandial baseline. Three-dimensional ultrasound can add data on meal distribution and volume inside the stomach [36]. Duplex sonography has also been proposed to look at transpyloric flow and liquid contents [4]. While ultrasound seems to be an appealing noninvasive technique, its use remains limited [3] in the clinical setting because of the significant expertise it requires and given poor performance in obese patients [4]. MRI is another appealing tool that can measure gastric accommodation and emptying every 15 minutes using transaxial abdominal images [3]. It can also differentiate gastric meal from air and hence give information about gastric emptying and gastric secretions [37]. It is expensive however, requires specialized equipment, and is not standardized across centers limiting its use to research only, except for some European centers [4, 7].

References 1. Griffith GH, Owen GM, Kirkman S, Shields R. Measurement of rate of gastric emptying using chromium-51. Lancet. 1966;1(7449):1244–5. 2. Parkman HP, Harris AD, Krevsky B, Urbain JL, Maurer AH, Fisher RS. Gastroduodenal motility and dysmotility: an update on techniques available for evaluation. Am J Gastroenterol. 1995;90(6):869–92.

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3. Kim DY, Myung SJ, Camilleri M. Novel testing of human gastric motor and sensory functions: rationale, methods, and potential applications in clinical practice. Am J Gastroenterol. 2000;95(12):3365–73. 4. Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology. 2004;127(5):1592–622. 5. Abell TL, Camilleri M, Donohoe K, Hasler WL, Lin HC, Maurer AH, et  al. Consensus recommendations for gastric emptying scintigraphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J Gastroenterol. 2008;103(3):753–63. 6. Tougas G, Eaker EY, Abell TL, Abrahamsson H, Boivin M, Chen J, et  al. Assessment of gastric emptying using a low fat meal: establishment of international control values. Am J Gastroenterol. 2000;95(6):1456–62. 7. Tang DM, Friedenberg FK. Gastroparesis: approach, diagnostic evaluation, and management. Dis Mon. 2011;57(2):74–101. 8. Camilleri M, Hasler WL, Parkman HP, Quigley EM, Soffer E. Measurement of gastrointestinal motility in the GI laboratory. Gastroenterology. 1998;115(3):747–62. 9. Thomforde GM, Camilleri M, Phillips SF, Forstrom LA. Evaluation of an inexpensive screening scintigraphic test of gastric emptying. J Nucl Med. 1995;36(1):93–6. 10. Guo JP, Maurer AH, Fisher RS, Parkman HP. Extending gastric emptying scintigraphy from two to four hours detects more patients with gastroparesis. Dig Dis Sci. 2001;46(1):24–9. 11. Ziessman HA, Bonta DV, Goetze S, Ravich WJ. Experience with a simplified, standardized 4-hour gastric-emptying protocol. J Nucl Med. 2007;48(4):568–72. 12. Desai A, O’Connor M, Neja B, Delaney K, Camilleri M, Zinsmeister AR, et al. Reproducibility of gastric emptying assessed with scintigraphy in patients with upper GI symptoms. Neurogastroenterol Motil. 2018;30(10):e13365. 13. Camilleri M, Chedid V, Ford AC, Haruma K, Horowitz M, Jones KL, et al. Gastroparesis. Nat Rev Dis Primers. 2018;4(1):41. 14. Ciferri O. Spirulina, the edible microorganism. Microbiol Rev. 1983;47(4):551–78. 15. Ghoos YF, Maes BD, Geypens BJ, Mys G, Hiele MI, Rutgeerts PJ, et  al. Measurement of gastric emptying rate of solids by means of a carbon-labeled octanoic acid breath test. Gastroenterology. 1993;104(6):1640–7. 16. Clegg ME, Shafat A.  Procedures in the 13C octanoic acid breath test for measure ment of gastric emptying: analysis using Bland-Altman methods. Scand J Gastroenterol. 2010;45(7–8):852–61. 17. Maes BD, Geypens BJ, Ghoos YF, Hiele MI, Rutgeerts PJ. 13C-Octanoic acid breath test for gastric emptying rate of solids. Gastroenterology. 1998;114(4):856–9. 18. Choi MG, Camilleri M, Burton DD, Zinsmeister AR, Forstrom LA, Nair KS. Reproducibility and simplification of 13C-octanoic acid breath test for gastric emptying of solids. Am J Gastroenterol. 1998;93(1):92–8. 19. Shin AS, Camilleri M.  Diagnostic assessment of diabetic gastroparesis. Diabetes. 2013;62(8):2667–73. 20. van de Casteele M, Luypaerts A, Geypens B, Fevery J, Ghoos Y, Nevens F. Oxidative breakdown of octanoic acid is maintained in patients with cirrhosis despite advanced disease. Neurogastroenterol Motil. 2003;15(2):113–20. 21. Perri F, Bellini M, Portincasa P, Parodi A, Bonazzi P, Marzio L, et  al. (13)C-octanoic acid breath test (OBT) with a new test meal (EXPIROGer): toward standardization for testing gastric emptying of solids. Dig Liver Dis. 2010;42(8):549–53. 22. Pasricha PJ, Parkman HP. Gastroparesis: definitions and diagnosis. Gastroenterol Clin N Am. 2015;44:1):1–7. 23. Rao SS, Camilleri M, Hasler WL, Maurer AH, Parkman HP, Saad R, et  al. Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies. Neurogastroenterol Motil. 2011;23(1):8–23. 24. Saad RJ, Hasler WL.  A technical review and clinical assessment of the wireless motility ­capsule. Gastroenterol Hepatol (N Y). 2011;7(12):795–804.

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25. Kloetzer L, Chey WD, McCallum RW, Koch KL, Wo JM, Sitrin M, et  al. Motility of the antroduodenum in healthy and gastroparetics characterized by wireless motility capsule. Neurogastroenterol Motil. 2010;22(5):527–33, e117. 26. Rouphael C, Arora Z, Thota PN, Lopez R, Santisi J, Funk C, et al. Role of wireless motility capsule in the assessment and management of gastrointestinal dysmotility in patients with diabetes mellitus. Neurogastroenterol Motil. 2017;29(9):e13087. 27. Kuo B, Maneerattanaporn M, Lee AA, Baker JR, Wiener SM, Chey WD, et al. Generalized transit delay on wireless motility capsule testing in patients with clinical suspicion of gastroparesis, small intestinal dysmotility, or slow transit constipation. Dig Dis Sci. 2011;56(10):2928–38. 28. Arora Z, Parungao JM, Lopez R, Heinlein C, Santisi J, Birgisson S. Clinical utility of wireless motility capsule in patients with suspected multiregional gastrointestinal dysmotility. Dig Dis Sci. 2015;60(5):1350–7. 29. Sarosiek I, Selover KH, Katz LA, Semler JR, Wilding GE, Lackner JM, et al. The assessment of regional gut transit times in healthy controls and patients with gastroparesis using wireless motility technology. Aliment Pharmacol Ther. 2010;31(2):313–22. 30. Kuo B, McCallum RW, Koch KL, Sitrin MD, Wo JM, Chey WD, et al. Comparison of gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther. 2008;27(2):186–96. 31. Hasler WL, May KP, Wilson LA, Van Natta M, Parkman HP, Pasricha PJ, et al. Relating gastric scintigraphy and symptoms to motility capsule transit and pressure findings in suspected gastroparesis. Neurogastroenterol Motil. 2018;30(2):e13196. 32. Soffer E, Thongsawat S. Clinical value of duodenojejunal manometry. Its usefulness in diagnosis and management of patients with gastrointestinal symptoms. Dig Dis Sci. 1996;41(5):859–63. 33. Fraser RJ, Horowitz M, Maddox AF, Dent J. Postprandial antropyloroduodenal motility and gastric emptying in gastroparesis--effects of cisapride. Gut. 1994;35(2):172–8. 34. Patcharatrakul T, Gonlachanvit S. Technique of functional and motility test: how to perform antroduodenal manometry. J Neurogastroenterol Motil. 2013;19(3):395–404. 35. Quigley EM, Donovan JP, Lane MJ, Gallagher TF. Antroduodenal manometry. Usefulness and limitations as an outpatient study. Dig Dis Sci. 1992;37(1):20–8. 36. Hausken T, Odegaard S, Matre K, Berstad A. Antroduodenal motility and movements of luminal contents studied by duplex sonography. Gastroenterology. 1992;102(5):1583–90. 37. Schwizer W, Maecke H, Fried M. Measurement of gastric emptying by magnetic resonance imaging in humans. Gastroenterology. 1992;103(2):369–76.

Part II Management

4

Medical Management of Gastroparesis Klaus Bielefeldt, Patrick McKenzie, and John C. Fang

Introduction Medical management is the cornerstone of treating patients with gastroparesis. The goals should focus on symptom control, maintenance of adequate weight, and prevention of nutritional deficiencies. While gastric emptying as the disease-defining biomarker had been an additional treatment target, the correlation between emptying delay and symptom severity has been poor in cross-sectional and longitudinal studies [1–5]. Pharmacotherapy is thus shifting from an emphasis on prokinetics to approaches that improve symptoms independent of the underlying mechanism, a shift that also matches with FDA guidelines on clinical trials and endpoints in the management of functional GI disorders [6–8]. Recently published investigations reflect this development and typically use composite symptom indices as their primary outcome measures. As most of these trials recruit patients from many sites outside of the more specialized referral centers, they provide some insight into the short-term prognosis of this illness. An important insight for patients and clinicians alike is a relatively high response rate even during placebo interventions [9–12]. While this pattern complicates the design of trials and requires increasingly large sample sizes, it gives room for optimism about the prognosis of an illness that comes with concerning and lasting symptoms with tertiary care centers often reporting high and persistent symptom burdens with frequent need for more complex and invasive therapies [1, 13]. Presently

K. Bielefeldt Division of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, UT, USA Veterans Administration Medical Center, Salt Lake City, UT, USA P. McKenzie · J. C. Fang (*) Division of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, UT, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 A. Ibele, J. Gould (eds.), Gastroparesis, https://doi.org/10.1007/978-3-030-28929-4_4

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there is only one FDA-approved medication for treatment of gastroparesis, and therefore most of the agents described below are used “off-label” for this condition. The components of medical management include nutritional and fluid management and pharmacotherapy with a combination of antiemetics, prokinetics, and neuromodulators. Finally, there is renewed interest in non-­pharmacologic treatments as well.

Nutritional Management Food intake with its link to gastric filling is a common trigger of symptoms. Dietary management can indeed limit such postprandial symptoms. In addition, nutritional needs must be addressed to prevent deficiencies that may otherwise develop. Considering the role of gastric filling and distension in the development of discomfort, limiting meal size and compensating by an increased meal frequency has been a cornerstone of gastroparesis management. Based on our understanding of factors that modulate gastric emptying [14], most clinicians also recommend changes in consistency and composition of ingested food with an emphasis on small, low-fat, low-fiber, and low-residue meals 4–5 times per day. One well-designed trial has truly addressed such approaches and clearly demonstrated a benefit of a small particle-­size diet defined as “food should be easy to mash with a fork into small particle size” or could be blenderized to consistency of mashed potatoes [15]. The fat content of ingested food or liquids significantly contributes to symptoms in gastroparesis and should be limited [16]. Because liquid emptying is often preserved in patients with delayed solid emptying, high calorie liquid formulas or homogenized meals can be added or substituted if solid food is not tolerated. Especially for persons relying on a more restricted diet, micronutrient supplementation should be considered. As many patients struggle with other illnesses, such as diabetes, detailed information and education by dieticians experienced in management of gastroparesis is of great benefit. Optimal glycemic management is important for patients with diabetic gastroparesis as hyperglycemia inhibits gastric emptying and improved glycemic control may improve emptying and reduce symptoms. Medications (e.g., opiates, GLP-1 analogs, anticholinergics) can delay gastric emptying and may contribute to symptoms. This is especially relevant for the glucagon-like peptide-1 receptor agonists, which should be held to assess the relative role in patients with new or worsening symptoms of gastroparesis. For most patients with gastroparesis, the oral route is preferred and more invasive approaches in the form of enteral or even parenteral nutrition are needed in only a small percentage of patients. Data from the National Inpatient Sample Database show that even in the skewed population of patients admitted with gastroparesis as primary diagnosis, feeding tube placement for initiation of nutritional support is listed in less than 2% of the hospitalizations [17, 18]. Considering the fact that only a small fraction of patients with this disorder will require inpatient management [19], this fraction is likely to be much lower in an outpatient cohort. While systematic studies are lacking, many patients will decide against long-term management with venting gastric or enteral tube due to dissatisfaction or side effects [8].

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When enteral nutrition is required, a feeding jejunostomy that bypasses the stomach is preferred. This can be placed endoscopically, radiographically, or surgically depending on local expertise. Given the above issues, a trial of nasojejunal feeding to assess tolerance and patient satisfaction may be useful. Finally, enteral feeding is always preferred over parenteral nutrition due to cost, potential for complications, and ease of delivery.

Pharmacotherapy Antiemetics  Nausea and vomiting are hallmark symptoms of gastroparesis, which often persist despite appropriate dietary or medical therapy. Thus, up to 70% of patients described in larger studies use antiemetics [8, 20]. While there is limited data for specific antiemetics for patients with gastroparesis, the use of many of these agents is extrapolated from treatment of chemotherapy-related nausea and motion sickness. Ondansetron (a 5-HT3 agonist) and phenothiazines (promethazine, prochlorperazine) are the most commonly prescribed agents due to their wide availability and coverage by insurance. Ondansetron is available as an orally disintegrating tablet, and promethazine is available in liquid and suppository formulation which may improve drug delivery in patients with oral intolerance. Other medications indicated for motion sickness including antihistamines (H1 receptor blockers) like meclizine and transdermal scopolamine (a cholinergic receptor antagonist) have been used off-label. While intuitively appropriate, clinical investigations of antiemetics typically focus on chemotherapy-induced nausea, which conceptually differs from the chronic symptoms that characterize gastroparesis. Two small open-label studies of transdermal granisetron (another 5-HT3 receptor agonist) supported the approach and showed a moderate benefit in patients with otherwise refractory symptoms of gastroparesis [21, 22]. The NK1 receptor blocker aprepitant has both central and peripheral antiemetic effects and is approved for chemotherapy-induced nausea and vomiting. A placebo-controlled trial in patients with gastroparesis or gastroparesis-­ like symptoms did not meet its primary outcome in decreasing nausea severity but did demonstrate improvements in nausea, vomiting, and overall symptom scores [23]. Based on these admittedly limited data, it is reasonable to extrapolate from other scenarios with nausea or vomiting as defining manifestations and use agents effective in such settings. (See Table 4.1.)

Prokinetics Dopamine Antagonists  Metoclopramide is both an antiemetic through centrally acting dopamine D2 receptor antagonist and 5-HT4 receptor agonist in the brain and prokinetic through 5-HT4 receptor agonist in the gut. Currently, metoclopramide remains the only FDA-approved medication for gastroparesis and is ­available in oral, oral dissolving tablet, liquid, intranasal, and parenteral f­ormulations that may be administered intravenously, intramuscularly, or subcutaneously. However, its use is associated with significant extrapyramidal motor dysfunction including acute dysto-

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Table 4.1  Antiemetics and neuromodulators useful for gastroparesis Medication Promethazine

Prochlorperazine

Mechanism (receptor) Dopamine (D1, D2) Histamine (H1) Dopamine (D1, D2) Histamine (H1)

Dose 12.5–25 mg q4 hours

Available routes Oral, liquid, rectal, IM, IV

5–10 mg QID 25 mg q12 rectal

Oral, rectal, IM, IV

Scopolamine

Muscarinic (M1)

1.5 mg/3 days

Transdermal patch

Ondansetron

Serotonin (5-HT3)

4–8 mg TID

Granisetron

Serotonin (5-HT3)

3.1 mg/24 hours

Oral, oral disintegrating tablet, IV Transdermal patch

Aprepitant

Neurokinin-1

125 mg/day

Oral, liquid, IV

Tricyclic antidepressants Mirtazapine

Serotonin, norepinephrine Tetracyclic antidepressant Serotonin (5-HT1)

25–100 mg/day

Oral

7.5–30 mg/day

Oral

5–20 mg TID

Oral

Buspirone

Limitations/adverse Somnolence, QT prolongation, tardive dyskinesia Somnolence, QT prolongation, tardive dyskinesia, neuroleptic malignant syndrome Drying of mucus membranes, anticholinergic Headache, constipation, QT prolongation Headache, constipation, QT prolongation Constipation, diarrhea, Stevens Johnson Somnolence, dry eyes, constipation Somnolence, weight gain Dizziness, drowsiness Do not use with MAO inhibitor

nias, Parkinson-type movements, and tardive dyskinesia [24, 25]. The tardive dyskinesia which occurs in