Gastroparesis: Pathophysiology, Clinical Presentation, Diagnosis and Treatment

By John Clarke

Gastroparesis: Pathophysiology, Clinical Presentation, Diagnosis and Treatment is a reference book providing a centralized source of data on gastroparesis collected over the last decade. Contents include the pathophysiology, clinical presentation, diagnostic recommendations and treatment options for gastroparesis. The reference is split into broad subsections, with the strategy of first focusing on the key features of the disease and then turning to controversies, recent developments, patient support resources, the spectrum of treatment – including medical and surgical - and future directions.

Chapters will include coverage of important topics like autonomic neuropathy, the brain-gut axis, potential pathophysiological advances at the cellular level, diagnostic and therapeutic options specifically targeted at the pylorus, and the evaluation of the female predominance in gastroparesis. This is a must-have resource for scientists looking to find the next step in their research as well as healthcare professionals ranging from Gastroenterologists to Internists, Surgeons, Nutritionists, Psychiatrists, and Psychologists, Residents and Medical Students who struggle with how to optimally take care of their gastroparetic patients.

• Provides a comprehensive overview of what is known regarding the pathophysiology, clinical presentation, diagnostic considerations and treatment options for gastroparesis
• Includes key updates made in the last decade, including the progress made by the NIH Gastroparesis Consortium
• Presents both sides of key controversies in the field, including the debate between classification of gastroparesis versus functional dyspepsia
• Fully reviews the major advances in pharmacologic agents for therapy, both anti-emetics and prokinetics
• Extensive update on the "Pyloric Revolution" and our understanding of the pathophysiology of gastroparesis and how the focus on the pylorus has literally transformed our treatment strategy with an emphasis on both surgical and endoscopic advances in addressing pyloric dysfunction

• Language: English
• Publisher: Academic Press
• Release date: Sep 30, 2020
• ISBN: 9780128185872

Book preview

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Section I

Introduction & Clinical Presentation

Outline

Chapter 1 Historical perspectives on gastric motility and gastroparesis

Chapter 2 Epidemiology of gastroparesis

Chapter 3 Clinical presentations of gastroparesis

Chapter 4 Natural history of patients with gastroparesis

Chapter 1

Historical perspectives on gastric motility and gastroparesis

Henry Parkman¹ and Richard W. McCallum², ³,    ¹1Temple University School of Medicine, Philadelphia, PA, United States,    ²2Texas Tech University Health Sciences Center, El Paso, TX, United States,    ³3University of Queensland, Brisbane, QLD, Australia

Abstract

Remarkable progress has been made in the study of gastrointestinal (GI) motility, particularly gastric motility, in the last century. This progress in GI motility has proceeded from contributions of a wide range of disciplines with advances in smooth-muscle physiology, electrophysiology, neurohormonal regulation of the GI tract, anatomic/mechanical factors, flow dynamics, as well as basic molecular and cellular biology. Increasingly sophisticated instrumentation, biomedical engineering, and pharmaceutical research have also added to this rich harvest over the past 50 years. A central theme to the progress is the greater understanding of the enteric nervous system, where more than 10⁶ neurons intercommunicate and integrate messages from the gut and brain to organize and coordinate control of GI motility.

Keywords

Gastric motility; Radiographic techniques; Scintigraphy; Gastric slow wave; Electrogastrogram; Pylorus

Introduction

Remarkable progress has been made in the study of gastrointestinal (GI) motility, particularly gastric motility, in the last century. This progress in GI motility has proceeded from contributions of a wide range of disciplines with advances in smooth-muscle physiology, electrophysiology, neurohormonal regulation of the GI tract, anatomic/mechanical factors, flow dynamics, as well as basic molecular and cellular biology. Increasingly sophisticated instrumentation, biomedical engineering, and pharmaceutical research have also added to this rich harvest over the past 50 years. A central theme to the progress is the greater understanding of the enteric nervous system, where more than 10⁶ neurons intercommunicate and integrate messages from the gut and brain to organize and coordinate control of GI motility.

The measurement and quantitation of gut motility has been a constant goal during this era, particularly the study of peristaltic contractions. The measurement of intraluminal pressures started with the use of balloons inflated in the stomach and intestine. In the 1950s, open-tipped catheters began to be used to study the esophagus. Subsequent improvements included the continuous-perfusion catheters with the low-compliance Arndorfer pump, and the development of the Dent sleeve which have facilitated the study of sphincters. At the turn of the century (1900s), gastric flow could be imaged by means of contrast radiograph. By the 1980s, scintigraphy enabled flow studies throughout the GI tract to be performed routinely in clinical practice. Scientific investigation of gut wall movement began with the use of miniature force transducers sewn to the luminal wall. Electromyography has also been used to enhance our understanding of wall movement. Magnetic resonance imaging (MRI) can be used to correlate gut wall motion with intraluminal pressures and other physiologic parameters.

Basic research has focused on neurohormonal regulation and myogenic components of GI motility. In the 1930s, gut motor activity was believed to occur as a result of opposition between excitatory parasympathetic (cholinergic) and inhibitory sympathetic (adrenergic) nerves. Electrical field stimulation of gut muscle preparations led to the discovery of nonadrenergic non-cholinergic (NANC) nerves as the predominant intrinsic inhibitory nerves of the GI tract. The identity of the NANC neurotransmitters, including vasoactive intestinal polypeptide (VIP) and nitric oxide then evolved. Electrical slow waves were appreciated to govern the rhythmicity of contractions, and slow waves of the stomach and small bowel began to be studied extensively by muscle electrophysiologists in the 1950s and 1960s.

W.B. Cannon and F.T. Murphy in 1906-7 reported that gastric emptying and intestinal motility may be inhibited by both central and peripheral mechanisms. In 1943, Wolf and Wolff suggested that certain emotional states can alter gastric motility, secretion and blood flow. Ongoing research defined the influence of GI peptides and hormones on the migrating motor complex (MMC). In a review 10 years after the demonstration of the migrating complex, Wingate noted that neural and hormonal factors are involved in regulation, but ‘specific details remain blurred’ – an observation which is slowly being unraveled.

This chapter is focused on more than a century of historical perspective to help us understand where we are today in the study of gastric motility.

Observation of flow through the gastrointestinal tract

Aside from Beaumont’s famous opportunity in the 1830s in his patient with a gastric fistula [1], no one had any way to examine directly the flow of the gut until more than 50 years later. Beaumont could only make a crude evaluation of gastric flow because his patient’s fistula extended into the fundus, and so Beaumont’s experiments on flow depended on the measurements of residual volumes collected by aspiration. However, he was more interested in gastric juice and digestion than gastric emptying.

The great impetus to the study of flow came with the development of the x-ray tube at the end of the 19th century. Roentgen’s development of the concepts and methods for x-ray soon found application in the study of gastrointestinal flow. The pioneers Bowditch and Cannon examined the stomach and intestine by contrast radiography before the turn of the century [2–4]. Cannon and others were mainly interested in gastric motility and adopted contrast radiography as a new means to visualize peristalsis and flow from the stomach. Physicians soon recognized the ability of contrast radiography to demonstrate morphologic lesions in the stomach. Hurst led this advance in the clinical use of radiography [5,6]. The use of contrast films to observe flow extended to the other organs, including the colon. The biggest problem in the study of flow in the stomach and intestine was the need for rapid changes of film, a need that was resolved only when rapid film-chargers and cineradiography were developed.

By 1933, radiographic techniques had revealed so much that an authoritative textbook could be written on the digestive tract from the point of view of the radiologist [7]. It contained extensive descriptions of flows in all the organs as well as descriptions of peristaltic wall movements and morphologic abnormalities. The descriptions still appear quite modern to the contemporary reader.

Observations by contrast radiography are hard to quantify, cannot easily be repeated for verification, are usually performed with the subject fasting, and use a remarkably unphysiologic material. These problems of radiography to demonstrate motility were overcome with the development of scintigraphy in the 1980s [8]. Scintigraphy made it feasible to do flow studies in routine clinical practice and made flow study more sensitive.

Before the advance of scintigraphy, Hunt had developed a beautifully simple and direct method to advance understanding of gastric emptying, especially of its regulation [9]. He used test meals – liquid volumes of variable composition – passed through a nasogastric tube in various volumes and aspirated at variable times afterward to discover the residual volume. He used anaesthetized human subjects, studying the same subjects repeatedly because habituation eliminates the inhibition produced by anxiety. Thus, he was able to develop data for the rate of gastric emptying as it is regulated by meal composition [10].

Most discussions of flow in the gut have dealt with bulk flows, the mass translocations of fluid. Interest in microflows came about from theoretic considerations of intestinal absorption, in which the presence of an unstirred layer at the luminal surface of the intestine came to be recognized as a limitation to the rate of absorption. Little can be done to study microflows directly, because it requires the use of the principles of fluid mechanics, a discipline that is largely as foreign to gastrointestinal physiologists as gastrointestinal physiology is foreign to fluid-mechanists. The fluid mechanist, Mecagno, who had extensive experience on flow in rivers and seas, was curious about flow in a system that seemed unique to him. A fluid-mechanical approach to flow in the small intestine by Christensen and Macagno yielded a foundation for rigorous rheologic study of gastrointestinal microflow and a host of new methods and ideas in the 1970s [11], an area that remains to be explored more fully.

Scintigraphy

The beginning of the evolution in gastric scintigraphy can be traced back to the 1970s when Jim Meyer, a gastroenterologist at the UCLA Sepulveda VA in Los Angeles took on the challenge of overcoming the problem that when isotope (technetium sulfur colloid) was mixed with and cooked as a meal (e.g. cereal or hamburger) it would dissociate and not be an accurate reflection of the solid phase of a meal. Dr. Meyer adopted the principle of the liver scan where Technetium sulfur colloid injected IV is incorporated into the Kuppfer cells of the liver. Hence if the liver was later prepared for eating by cooking, this isotope would always continue to remain in these Kuppfer cells and truly represent, therefore, a solid meal and not wander into the fluid part of the meal. Hence nuclear medicine departments began to have access to chickens which were sacrificed after receiving IV technetium sulfur colloid, the liver removed and cooked in a microwave oven and presented to patients for eating. In addition to Dr. Meyer, this era was pioneered by Bob Lange and Richard McCallum at Yale University and Leon Malmud, Robert Fisher, Henry Parkman and Alan Maurer at Temple University who subsequently demonstrated that cooking chicken liver from a supermarket was an acceptable substitute. Here the liver is directly injected by technetium sulfa colloid and then cooked in the microwave oven and the isotope remains loyally adherent to the liver cells and hence the gastric emptying study represents a solid meal. This set the stage for dual isotope gastric emptying adding iodine-111 isotope to water while manufacturing the technetium 99 lower component. The evolution in the gastric emptying methodology saga continued in 2000 when the work of Tougas and McCallum was published establishing the gold standard meal with known caloric (250 calories) and fat content (1%) consisting of 2 Egg Beater® eggs (or generic equivalent) injected with the isotope, cooked in a microwave oven and eaten with a piece of toast, butter and jam, and water. The 4-hour standardized meal era was subsequently endorsed and recommended by the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine as the gold standard and is now found in hospitals throughout the USA. The next stage is the development of methods for understanding the intragastric distribution of the ingested meal – specifically the role of the fundus in storage of the meal in addition to analyzing dynamic antral scintigraphy to help grade contraction frequency and the motility index of the antrum thus providing a comprehensive assessment of gastric motor function. This work is being led by Nuclear Medicine physician Dr. Alan Maurer at Temple University and Nuclear Physicist Dr. Marvin Friedman at Mount Sinai, St. Luke’s Hospital in New York.

Observation of pressures in the gastrointestinal tract

The idea that one could study wall motions by the measurement of pressures in the gut lumen, by kymography (or manometry, as it came to be called later), arose quite early, even before the development of radiographic methods to study flow. It began largely with the use of balloons inflated in the stomach and intestine, a method used notably by Bayliss and Starling [12], Carlson [13], and Thomas [14], among others. Investigators could record pressure changes in such balloons easily enough, but they had much trouble interpreting the records. They slowly came to confront the problems of balloon recording, which seem so obvious to us today. The size of the balloon, degree to which it stretches the viscus wall, the compressibility of the recording fluid, and the compliance of the system all restrict the reliability of conclusions about the external forces that alter the pressure in such a closed recording system.

The idea of using open-tip catheters rather than balloons to record pressures was explored in the 1920s, but it was most aggressively developed in the 1950s mainly to examine the esophagus. The principal players in this development, which included Code and Ingelfinger [15], probably sought, at the outset, simply to measure pressures rather than to fully map peristaltic movements. At first, they used air-filled catheters, later changing to water-filled tubes. They adopted catheters with distal openings placed laterally rather than at the tip of the catheters and observed that, in the esophagus, they could measure the characteristics of peristalsis – velocity and force of contraction – with apparent reproducibility and accuracy. The method was soon improved by Dodds and Hogan [16], and others with the introduction of the continuous perfusion of the catheters with a low-compliance pump (the Arndorfer pump, developed by a colleague of Dodds) and other changes, and the technique soon passed into standard clinical use to describe esophageal motor functions. The technique subsequently has found use in the small intestine, but is used much less in the stomach and colon. Subsequent experimentation with methods led to developments of much more complex devices in which pressures are measured from miniature pressure transducers mounted on flexible catheters. These devices, combined with computer-aided analysis of pressure patterns, now provide objective long-term monitoring of motility in the stomach as well as more distally in the small intestine. A pressure transducer mounted on a radio signal generator, the wireless motility capsule, has also found use. Such devices hold the prospect for more careful characterization of gastrointestinal motor disorders.

Perfusion manometry for pressure measurement brought a new importance to the concept of sphincters. Physiologists had long debated the existence of sphincters because, aside from the external anal sphincter, the structures could not be directly observed and radiography was scarcely able to show them satisfactorily. Manometry, however, made it possible to define them, to describe their dimensions, the timing of their opening and closure, and the force with which they occluded the lumen. Thus, both the upper esophageal sphincter and the esophagogastric sphincter were not clearly described until the mid-1950s. The application of a small balloon, the Dent sleeve, named after its inventor – John Dent from Adelaide, Australia – greatly facilitated the study of sphincters in vivo, and it remains the major clinical and investigative technique to study sphincters, finding use especially in the esophagus, pylorus and the anal canal.

Pressures in the GI tract

The Dent sleeve ingenuously overcame the problem with perfused single channels which would move and not loyally reflect the true pressures in a sphincter muscle ranging in length from 2 to 3 cm (ano-rectum, pylorus, and lower esophageal – respectively) and would therefore be able to accurately record the relaxations in these sphincters. Combined with the low compliance perfusion pump this ushered in a very exciting and busy era involving the giants of the esophagus clinically in the 1980–2000 time frame including Raj Goyal, Donald Castell, Joel Richter, Peter Kahrilas, and Ravi Mittal. At the same time, these perfused catheters and Dent sleeve perfusion techniques were actively being studied in the stomach. A pioneer here was the Spanish Master, Juan Malagelada from Barcelona, Spain, working at the Mayo Clinic in the 1980s. With multiple ports in the body, antrum, and pylorus of the stomach as well as the duodenum and small bowel, great information and new light was shed on fasting and fed patterns, neuropathic and myopathic abnormalities, and the effect of putative therapies – particularly pharmacologic agents. Here, the observation by Malagelada and Michael Camilleri of the pyloric spasm as a possible abnormality in diabetics with gastroparesis was first made. The pylorus was better understood for its baseline low sphincter pressures with superimposed phasic contractions acting as a sieve with pyloric contractions increased by fatty meals triggering the release of the hormone CCK. This pyloric function was also pioneered by Robert Fisher, Chief of GI at Temple in the 1980s and 1990s using potential difference to identify the pylorus following the initial work of Jorge Valenzuela at the University of Southern California. Long term – 24 hour – recordings were pursued by Eamonn Quigley at Nebraska and William Snape at Pacific Medical Center in San Francisco. This hectic pace has now slowed down because of the huge time commitments for patients, physicians and antral/small bowel motility is now only practiced in a handful of centers, but the key principles of the recordings and observations remain clinically useful. The next revolutionary change in pressure measurements was orchestrated by Ray Clouse at Washington University in St. Louis in the 1990s, and his legacy is the technology of high-resolution manometry that is now standard for recordings in the esophagus. It utilizes multiple pressure sensors spaced 1 cm apart to comprehensively map a peristaltic or motility event. It is now slowly being utilized for assessing gastric motility, as well as being initially introduced by Parkman and Hasler, among others.

Observation of gastrointestinal wall movements

Magendie knew what little he did know about the movements of the gut wall from the direct observation of the gut in the open abdomen, and this remained a major method until after the end of the century, even receiving extensive discussion by Alvarez as late as 1928 [17]. After that, the methods to examine flows, and hence to infer wall movements, (radiography and manometry) captured most of the attention.

The ability to observe wall movements more directly without the artifacts associated with the opening of the abdomen arose in the 1950s with the development of miniature force transducers that could be sewn to the gut wall. Wires from these transducers leading to chronically-implanted cutaneous plugs in experimental animals permitted investigators to record movements (mainly from the stomach and the intestine) over long periods under varying conditions [18,19]. Investigators further developed the use of electrodes implanted in the gut wall to record the electrical events in muscle associated with contractions. Electrodes had been used much earlier by Alvarez and Mahoney [20] in the 1920s, for example, but they were neglected for four decades, only to be salvaged for use – especially by Bass [21] when it was realized that electromyography tracings greatly supplemented the tracings of wall movements made with chronically-implanted transducers. Now both implanted transducers and implanted electrodes find widespread use in chronic preparations in experimental animals. The obvious problem of providing high resolution is overcome by the use of multiple closely-spaced sensors.

The electric slow waves of the gut

Electrophysiology was a fully developed technical discipline in 1939, yet Wiggers could say virtually nothing of the electrical activity of the gut in his textbook [22] of that year; Numerous attempts have been made to record action potentials from isolated and intact viscera. Unfortunately, the arrangement of muscular tissue in these organs is so complex and the electrical variations derived are so complicated that they are for the present difficult to interpret in terms of functional activity. But electrophysiology was the great biologic technology of the time (just as molecular biology is the great technology of ours), and therefore it was not long before ideas and methods were more fully transferred from the heart (where electrophysiology began) to the gut.

As early as 1932, investigators could detect the characteristic electromyogram of the small intestine [23,24], but it remained a seemingly fresh subject when Daniel’s thorough review appeared in 1963 [25]. The subject advanced rapidly in the 1960s, especially under the guidance of Code and Prosser in America and of Daniel in Canada. The idea of electrical slow waves developed rather slowly, given the ease with which they are detectable and their obvious importance. Thus, it was three decades after the work of Alvarez and Puestow that Code, Daniel, and Prosser took up the subject with their characteristic energy. Investigators focused on the small intestine for a long time, only later extending the method and the concept to the stomach and colon.

From the beginning, investigators recognized that electrical slow waves govern the rhythmicity of contractions. That is, like clocks, the slow waves orchestrate contractions in time and space, not signaling contractions like the cardiac action potentials, but acting purely as pacemaking signals to which the muscle may or may not respond. Indeed, this phenomenon of having strictly a pacemaker or clock function led investigators to give them a variety of names, seemingly because they felt that existing terminology was somehow inadequate. For some years, electrical slow waves, basic electrical rhythm, pacesetter potentials, and electrical control activity competed for usage, to the great confusion of outsiders, and they still do to some extent.

The discovery of the electrical slow waves in the gut satisfactorily unified some old observations. For example, Russian physicians had long toyed with the technology of the electrogastrogram, a device to record the electrical signals of the stomach in analogy with the electrocardiogram. This fascination of the Russians with electrical events in the stomach at a time when they were scarcely thought of in other parts of the world or in other organs reflects the legacy of Pavlov which accounts for the fact that so many of the earliest autonomic neuroanatomists were Russians, or from the Eastern part of Europe. Code, Kelly, Szurszewski [26], and others who later did so much to advance our understanding of slow waves in the stomach validated the electrogastrogram, heretofore largely unknown in the West. It has gained renewed currency if not actual vitality. Similarly, the finding of a declining gradient in slow-wave frequency along the small intestine tied well with the theory of a metabolic gradient along the intestine, which had brought Alvarez to the forefront [17]. The fact that the theory excited some controversy then was partly attributable to the personality of Alvarez and his appeals to the press and to the public. His intestinal gradient theory arose again from the ashes on a firm foundation with the discovery of the intestinal slow-wave frequency gradient.

Although the electrical slow waves generated by the stomach and intestine were known long before, they did not attract detailed scrutiny by muscle electrophysiologists until the 1950s and 1960s [27]. This was true partly because the early investigators were not, for the most part, themselves highly trained in the electrophysiology of smooth muscle, and partly because the electrophysiology of smooth muscle as studied in vitro did not fully develop as a subject until the 1950s. Bozler in the United States and Bulbring in England especially deserve credit for advancing gut smooth muscle electrophysiology forward as a subject worthy of detailed study in vitro by dedicated electrophysiologists. Bozler studied the stomach and intestine, and Bulbring chose the taenia coli of the guinea pig as her model. It was some time, until the mid-1960s, before students of gastrointestinal motility fully realized the significance of the observations of Bozler and Bulbring in their basic electrophysiologic studies.

The electrogastrogram

With the Alvarez legacy substantiating that there was a gastric slow wave, the challenge to document this and record it in a reproducible fashion led to many investigators taking on this task. A physiologist at Penn State, Dr. Robert Stern began to observe changes in the gastric electrical slow wave in an experimental model of motion sickness. He began to work with a clinical collaborator Dr. Kenneth Koch at Hershey Medical Center who began to perform recordings of gastric electrical slow waves in patients with symptoms of nausea, vomiting, and postprandial distress. This was then further enhanced by a young Biomedical Engineer, Jiande Chen, Ph.D., working with Richard McCallum, then Chief of Gastroenterology at the University of Virginia, and their numerous publications and the first textbook on the subject brought this method into the clinical arena as a diagnostic option. They verified that the cutaneous abdominal wall skin electrode signal was indeed truly coordinated with a simultaneous recording from a serosal electrode placed intra-operatively in the antrum. An International Electrogastrography Society was formed and the use of the electrogastrogram (EGG) was advanced by having commercially available equipment, first by Medtronic then by equipment marketed as 3-CPM. Appreciation of the gastric electrical signal recording was facilitated with the approval of the gastric electrical stimulator for neurostimulation of gastric smooth muscle in gastroparetic patients in 2000 followed by the methodology for truly pacing the gastric smooth muscle and entraining gastric slow waves as demonstrated in humans by McCallum, Sarosiek, Lin, Forster, Chen and Ross in 2008. However, it is fair to say that relying on 2–3 electrodes to capture the electrophysiology of the whole stomach is not adequate or accurate and if there will be any future for cutaneous EGG recordings then a multi-electrode array and more comprehensive system will be needed and they are currently being developed.

The interstitial cells of Cajal: the pacemaking system

Experts agree now that the source of the electrical slow waves are the interstitial cells of Cajal rather than the smooth muscle, as previously thought. Cajal did not discover the interstitial cells that bear his name, but he raised them from obscurity at the turn of the century. He viewed these tiny cells as secondary nerve cells forming intermediates in the communication between the axons of enteric nerves and the cells of effector tissues, like smooth muscles and gland cells [27]. He thought of them as forming a terminal syncytium or network of nerve fibers that allowed for integration of communication within the substance of the smooth muscle.

For a long time, neuroanatomists argued about these cells, their function, their distribution, and indeed, their very existence. Cajal’s ideas as to their nature and function were neither disproved nor fully accepted, and they remained cells without a clear function for almost a century. As early as 1925, some investigators proposed that the cells might be responsible for myogenic rhythmic contractions on little evidence. Thuneberg revived the idea in 1982 [28], on better evidence, and stimulated the immigration of others who, in fact, have gathered good evidence in its support [29].

It is ironic that the best evidence for the idea that interstitial cells generate the electrical slow waves comes from the colon (of the cat and dog), one of the latest places where they were described and the organ where motility is less well understood than in any other structure. The interstitial cells of the mammalian colon were only discovered in 1971, by Stach [30], who found them as a neuroanatomist working on the neglected topic of the innervations of the mammalian colon. The electrical slow waves of the mammalian colon first described in detail only about the same time, not by design but by accident, the discoverer simply choosing an unexplored tissue in which to demonstrate the use of a new kind of electrode he had devised [31]. The small intestine and stomach remain the organs where electrophysiology has been concentrated.

Interstitial cells of Cajal

The scientific basis for pursuing recording of gastric electrical slow waves was laid by physiologists in the 1980s and 1990s. The Mayo Clinic continued the work of Joe Szurszewski’s lab but Kenton Sanders as chair of the Department of Physiology at the University of Nevada, Reno readily focused his lab on this area along with his collaborators Terry Smith and Sean Ward, as well as Dr. Jan Huizenga in Canada. At the Mayo Clinic, the interstitial cells of Cajal (ICC) were being intensely studied in animal models of diabetes and obese mice by Gianrico Farrugia who was able to define the changes leading to depletion of ICC cells in gastroparesis patients and provide insight into the role of macrophages [1,2] in preserving ICC function through nitric oxide and hemeoxygenase-2 mechanisms.

Fasting and postprandial rhythmic activity of the gut

The idea that the pattern or quantities of rhythmic contractions in the gut vary as the animal is fed or fasted goes back a long time. Beaumont, with his limited capacity to see gastric motions in his patient with a fistula to the gastric fundus, concluded that gastric contractions occur only in the fed state and the stomach becomes quiet after it has emptied itself into the duodenum. This idea persisted for a long time, but it was not universally held. Carlson [13] cites the writings of an 18th century physiologist, Haller, who believed that hunger represented contractions of the empty stomach, and referred to others who agreed, especially Boldyreff, who had published his observations in 1905 [32]. Recording from balloons inflated in the stomach of conscious dogs, Boldyreff saw alternate periods of powerful rhythmic contractions and absolute or relative quiescence over a period of 3–4 days of starvation. The period of contractions lasted 20–30 minutes, the periods of relative quiescence, 1 ¼ hours or more. Boldyreff noticed that periodic contractions of the intestine accompanied those of the stomach. Hurst later proposed that these periodic contractions gave rise to the sensation of hunger, an idea that Boldyreff had rejected because he saw the contractions become weaker as starvation was prolonged.

Carlson and his colleagues, after further experiments, concluded that hunger is indeed caused by these periodic powerful contractions of the stomach. He described his studies (which involved yet another patient with a gastric fistula) in 1916 [13], and the idea of hunger contractions of a particular force and regularity, remained part of standard teaching in gastrointestinal physiology until about the 1940s, when it appeared to have died out. Boldyreff’s original work and Carlson’s observations both have been fully reviewed by Dr. David Wingate [33].

Although periodicity in gastrointestinal contractions in the fasting animal was established by these studies, the matter soon fell into neglect and was forgotten. The picture of vastly different motility in feeding and fasting did not re-emerge until the work of Ruckebusch [34] in France and of Szurszewski [35] in America. Szurszewski and his colleagues confined themselves to man and the dog, Ruckebusch ranged widely across the animal kingdom. Ruckebusch was able to show that periodicity is consistent in many herbivores that eat constantly, and that eating interrupts the periodic cycle mostly in carnivores that normally eat meals at wide intervals in time. Ruckebusch’s broad interests in comparative animal functions are indicated in his textbook [36].

Thus, the idea of periodicity of gastrointestinal contractions in fasting arose, apparently from causal observation, very long ago, but it found little use then, except by Carlson to explain hunger. It was finally and firmly re-discovered and the periodic activity of the gut in fasting (newly christened the migrating motor complex or the Housekeeper of the Gut), has become deeply entrenched in the body of knowledge [35].

Receptive relaxation

Magendie recognized that the stomach contracts to shift its contents, and by 1886, Hofmeister and Schütz described gastric peristalsis. Only after the advent of radiography could Cannon really visualize it in vivo. Beaumont had proposed that food entering the stomach follows a pathway along the greater curvature to reach the pylorus. Cannon was able to disprove the idea. He could see different motor functions of the antrum and fundus and visualized retropulsion of contents with antral contractions. Cannon’s views on gastric contractions prevailed for a long time. The full complexity of gastric flows, including sieving which is the separation of solids from liquids by the antrum, became clear only after 1960 with Meyer’s review and full account of this development [37,38].

Cannon recognized the reservoir function of the proximal stomach, and realized that it expanded with swallowing by the process now called receptive relaxation. But it was not until 50 years later that vagal inhibition of the stomach received careful study, when Harper [39] observed that the electrical stimulation of the central stump of the severed vagus induced gastric relaxation by way of the other intact vagus. In the 1960s, Jansson [40] and Abrahamsson [41] extended the concept of vagally mediated gastric relaxation by demonstrating several reflexes. The excitation of non-cholinergic, non-adrenergic inhibitory nerves mediates these reflexes, for the most part, but Miolan and Roman [42] showed that receptive relaxation also involves the suppression of activity in tonic excitatory fibers to the gastric fundus.

Barostats, high-resolution manometry, and drink tests

Trying to quantitate and document gastric receptive relaxation came of age with the development of the gastric Barostat – a small tube swallowed through the mouth with an inflatable balloon on the end to be inflated in the proximal stomach. This whole area and its clinical implications were pioneered by Professor Jan Tack from the University of Leuven in Belgium. The ideas of impaired fundic relaxation and premature antral filling and subsequent symptoms come from this work. At the same time, Dr. Michael Camilleri at Mayo Clinic Rochester was introducing the new technology of SPECT analysis of the fundus by imaging in a 360° manner after injection of sulfur pertechnetate which binds to gastric parietal cells in the mucosa of the proximal stomach. Hence when there is an increase in the fundic volume by SPECT – this is relaxation of the fundus. The SPECT method has not transitioned to standard GI testing labs and the Barostat is not well tolerated by patients and used sparingly only in research. Hence this area of proximal stomach relaxation has now been moved into the umbrella of sensory testing as a way to extrapolate – namely drinking water or a caloric liquid will initiate this relaxation. However, liquids quickly empty into the antrum and proximal duodenum limiting the interpretation. Drink tests are more useful for investigating visceral sensitivity – epigastric pain with eating, distension and stretching the proximal stomach. A new method for assessing the fundic relaxation is placing a high-resolution manometry catheter from an esophageal recording into the proximal stomach and monitoring pressure changes with drinking. An even more recent less invasive and potentially more available approach is gastric scintigraphy involving the standardized labeled egg meal where the proximal stomach is identified and mapped by software. Then the emptying of the proximal stomach can be quantitated, and the lack of accommodation or relaxation of the fundus and proximal stomach which results in rapid fundic emptying can be documented. This methodology pioneered with clinically related implications by Henry Parkman will be incorporated as part of a standard gastric emptying test, thus leading to better therapies for these symptoms.

Conclusions

We have attempted to merely provide a snapshot of the history of this field highlighting the advances that have occurred in our knowledge of physiology, recording, technology and diagnostic methodology. This chapter sets the stage for the chapters in this book which are devoted to updating us about the field of gastroparesis and bringing us to the cutting edge of therapy options.

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Chapter 2

Epidemiology of gastroparesis

Prianka Gajula¹, Aylin Tansel² and Eamonn M.M. Quigley¹,    ¹1Lynda K and David M Underwood Center for Digestive Disorders and Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, United States,    ²2Digestive Diseases Center, Medical University of South Carolina, Charleston, SC, United States

Abstract

Gastroparesis, whether idiopathic or related to an underlying disease, is thought to be common but data on the actual community prevalence of the disorder are scanty. Hospital admission data, which, of course are highly selective, suggest that gastroparesis imposes a significant burden on health care systems and is a cause of significant morbidity for the affected individual. One of the major barriers to the generation of accurate epidemiological data is the very definition of gastroparesis – its symptoms are non-specific and the most widely available objective test to document gastric emptying delay involves radiation exposure. The availability of non-invasive and non-radiation emitting alternatives should open the way to providing accurate epidemiological data on this challenging condition and, thereby, close an enormous gap in our understanding.

Keywords

Gastroparesis; Gastric emptying; Epidemiology; Incidence; Prevalence; Community prevalence; Nausea and vomiting

Introduction – the challenge

Gastroparesis is commonly defined on the basis of the combination of symptoms and delayed gastric emptying, in the absence of mechanical obstruction. Therein lies a major challenge to attempts to provide accurate data on the incidence or prevalence of this disorder which must include (i) a definition of what symptoms are to be regarded as relevant, (ii) an accurate measurement of gastric emptying rate and (iii) appropriate testing to exclude gastric outlet or small bowel obstruction.

Symptoms indicative of gastroparesis

Traditionally, nausea and vomiting have been regarded as the classical symptoms of gastroparesis; more recent literature reveals a more inclusive approach with the NIH consensus group incorporating nine symptoms: nausea, retching, vomiting, stomach fullness, inability to finish a meal, excessive fullness, loss of appetite, bloating and abdominal distension in their Gastroparesis Cardinal Symptom Index (GCSI) [1]. It can be readily appreciated that these symptoms overlap with functional gastrointestinal disorders such as functional dyspepsia and irritable bowel syndrome [2]. The more recent adoption of abdominal pain as a symptom of gastroparesis further complicates the use of symptoms as a clinical indicator of gastroparesis. Up to 89% of individuals with gastroparesis are reported to complain of upper abdominal pain [3] and in the NIH cohort this pain was moderate to severe in 66% and did not correlate with gastric emptying rate [4]. Not surprisingly many consume opiates [5,6] which further confuses attempts to interpret gastric emptying studies; forty-one per cent of 583 patients in one report from the Gastroparesis Clinical Research Consortium (GpCRC) Registry were taking opioids [6]. Additional symptoms may be relevant in specific clinical contexts – hypoglycemia in diabetes due to delayed emptying of nutrients and on-off phenomena in Parkinson’s disease due to unpredictable delivery of dopaminergic medications. Taking all of these factors together renders a diagnosis of gastroparesis on the basis of symptoms alone nigh impossible. Indeed, symptoms have proven very poor predictors of gastric emptying rate [7–9] and symptom patterns and severity were very similar when subjects with nausea and vomiting with and without gastric emptying delay were compared [10].

Tests of gastric emptying

There is no shortage of test modalities which have been proposed as valuable in the assessment of gastric emptying rate: plain radiographs, breath tests, radionuclide scintigraphy, ultrasonography, magnetic resonance imaging, pharmacological approaches and SPECT imaging [3]. Because of cost and availability some are clearly unsuitable for large scale epidemiological studies and only one, radionuclide scintigraphy, has been validated in a large multicenter study [11]. Its utility in the general population is also limited by the involvement of radiation exposure. Though this technique is by far the most widely used worldwide in clinical practice its comparability between centers is limited by differences in study meal, protocol and interpretation.

Clinical evaluation

The final hurdle that confronts any attempt at an epidemiological study of gastroparesis is the accurate definition of the phenotype. How thoroughly has gastric outlet obstruction or low grade small bowel obstruction been excluded? How accurately are underlying causes defined? Have iatrogenic causes, such as opiates, anticholinergics and calcium channel blockers, been diligently documented?

Incidence and prevalence

True population-based studies on the incidence and prevalence of gastroparesis are rare. Up until very recently the figures for incidence and prevalence of 6.3 per 100,000 persons per year and 24.2 per 100,000 inhabitants (0.0242%), respectively, obtained by the Rochester Epidemiology Study in Olmsted County, Minnesota were the best estimates available to us [12]. Now, Syed and colleagues in a cross-sectional population-based study based on a total of 43,827,910 medical records surveyed between 1999 and 2014 documented an overall prevalence of 0.16% [13]; a much higher figure, yes, but still well short of prior estimates of 3–5% of the population [2]. In this study, rates for those with type 1 and type 2 diabetes mellitus were higher at 4.59% and 1.31%, respectively [13]. Across all categories, women and Caucasians had the highest prevalence of gastroparesis [13]. It must also be noted that the diagnosis of gastroparesis was confirmed by gastric emptying study and esophago-gastro-duodenoscopy in only 14% [13]. At our institution, an 800-bed tertiary referral hospital, 1292 patients were admitted with gastroparesis as the admission diagnosis over a 5-year period. A random sample of 285 from this total were studied in detail; while 63% had undergone a gastric emptying study, only 20% had completed the recommended 4-hour protocol and 58% were on a narcotic at the time of the study [14]. These real world observations illustrate the difficulties of defining gastroparesis in any context.

The rates described by Syed and colleagues [13] are also consistent with an earlier population-based, historical cohort study, again from the Rochester Epidemiology Project, where cumulative proportions developing gastroparesis over a 10-year period were 5.2% in type 1 diabetes, 1.0% in type 2 diabetes, and 0.2% in controls [15]. It must be remembered that one was a cross sectional [13] and the other a cohort study [15].

In another questionnaire-based study of 15,000 adults in the community, diabetes was associated with an increased prevalence of several upper and lower gastrointestinal symptoms – 5.2% of diabetics (mostly type 2) and 3.5% of non-diabetics suffered from nausea; equivalent rates for vomiting were 1.7% and 1.1% [16]. Though gastric emptying rate was not studied, these symptom rates are again similar to the gastroparesis rates described above. It should be noted that other community-based surveys failed to document an increased prevalence of upper gastrointestinal symptoms in diabetics [17] or between type 1 and type 2 disease [18].

What can we conclude from population-bases studies? Though available data are limited and subject to all of the aforementioned problems with definition, it is evident that gastroparesis, whether in diabetics or in non-diabetics, is not as common as clinical series based on hospitalization or clinic visits would suggest [19]. Though incidence is higher in type 1 than type 2 diabetes, the latter is much more common and increasing rapidly around the world; instances of gastroparesis related to type 2 diabetes are likely to greatly outnumber those related to type 1 diabetes for the foreseeable future.

It is also evident that the incidence of gastroparesis is on the increase [12]; while some of this may reflect changes in diagnostic practice (and even include some misdiagnoses), trends are consistent and suggest that gastroparesis is on the rise. Global increases in obesity and diabetes are certainly contributory.

What can we learn from clinic/hospital-based studies?

Some of the most detailed data come from the many studies produced by the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium and derived from several academic medical centers across the US. What have these studies revealed?

1. Idiopathic gastroparesis is more common than all other causes (at least in the US).

In a Consortium study of 416 patients with gastroparesis, 254 had idiopathic gastroparesis, and 137 had diabetic gastroparesis (78 had type 1, and 59 had type 2 diabetes) [20]. Symptoms that prompted evaluation more often featured vomiting for those with diabetic gastroparesis and abdominal pain for those with idiopathic gastroparesis. More than 50% of patients with type 1 DM had severe retention (>35% at 4 hours); these individuals also used prokinetic agents more frequently, had more hospitalizations and were more likely to be implanted with a gastric electric stimulator [20]. Data on the prevalence of idiopathic gastroparesis from the rest of the world is scant – in a comparison of experiences with gastric electrical stimulation between the US and Europe it was noticeable how few subjects with idiopathic gastroparesis were implanted in Europe in comparison to the US [21]; whether this reflects a real difference in prevalence or variations in diagnostic criteria or management strategies is unclear. It is undoubted that the category idiopathic gastroparesis includes a heterogeneous population which may range from extreme forms of a functional disorder to enteric neuropathology [22–25]. Most problematic are those with functional dyspepsia who undergo a gastric emptying study and are found to exhibit a mild-to-moderate delay; is this gastroparesis?

2. Gastroparesis, regardless of etiology is more common in females.

Data from 718 adult patients with gastroparesis from another NIDDK Gastroparesis Consortium Study revealed a remarkable female predominance; 84% vs 16% [26]. Women were also more likely to be labeled as idiopathic (69%) than men (46%). This has been a consistent finding in many other studies [7,12,13,14], regardless of location or etiology of gastroparesis. In the Olmsted county study, for example, what they defined as definite gastroparesis was 4-fold more common in females than in males [12].

3. Diabetic gastroparesis is more common in blacks and Hispanics.

In the aforementioned study, a higher proportion of non-Hispanic blacks (60%) and Hispanics (59%) had gastroparesis of diabetic etiology than non-Hispanic whites (28%). Blacks also had more severe retching and vomiting and were more likely to have been hospitalized in the past year (66%) [26].

Hospitalizations and health care unitization

While the community prevalence and incidence of gastroparesis may not be as high as our experience as hospital-based gastroenterologists with a special interest in motility disorders would suggest, it is evident that hospitalization rates for this disorder are on the increase and that patients with an admission diagnosis of gastroparesis consume a disproportionate amount of health care expenditure. Even as long ago as 2006, a 138% increase in hospitalization rates for gastroparesis had been noted in the Olmsted county study which incorporated admissions where gastroparesis was either a primary or secondary admission diagnosis [12]. More recently, Nusrat and Bielefeldt, using data from the National Inpatient Sample, documented a more than 18-fold increase in hospitalization rate for gastroparesis between 1994 and 2009 but cautioned that much of this increase may relate to changes in awareness and a shift in diagnostic category and away from functional diagnoses, in particular, rather than to an actual gastroparesis epidemic [27]. Similar trends were noted in another study that tracked admission rates between 1997 and 2013 [28].

Not surprisingly, opioid use is a strong predictor of health care resource utilization [6]. Again, reflective perhaps of the severity of their gastroparesis and the prevalence of comorbidities, hospitalization rates are higher for those with type 1 than type 2 diabetes [20] and for those diabetics with upper gastrointestinal symptoms who also have delayed (rather than normal) gastric emptying [29]. Readmission rates are also high; data from the National Readmissions Database revealed that the 30 and 90-day readmission rates for individuals with a primary diagnosis of gastroparesis were 26.8% and 45.6%, respectively [30].

Based on all of the above it should come as no surprise that gastroparesis is associated with marked impairments in quality of life, ability to work and income [31].

A further contributor to the increasing health care costs related to gastroparesis are emergency department visits; between 2006 and 2013 emergency department visits for gastroparesis and their related costs more than doubled in the US [32].

Long-term outcomes – morbidity and mortality

Recent data from the NIDDK consortium indicate that the outcome for those with gastroparesis is not good; over a median follow-up period of 2.1 y, only 28% of 262 patients treated for gastroparesis at centers of expertise experienced a reduction of their gastroparesis-related symptoms [33]. Male sex, age over 50 years, initial infectious prodrome, antidepressant use, and a four-hour gastric retention in excess of 20% on a gastric emptying study were the factors predictive of symptom reduction whereas being overweight or obese, a history of smoking, use of pain modulators and the presence of moderate to severe abdominal pain, severe gastroesophageal reflex or moderate to severe depression predicted a failure to improve [33].

Reported mortality rates related to gastroparesis in the literature are highly variable, ranging from as low as 4% to as high as 40% [34,35]. Several studies support an association between gastroparesis and increased long-term mortality [19,34,35]. For example, in the Olmsted county study the estimated 5-year survival for those with gastroparesis was only 67% in comparison to an expected 81% survival. Predictors of mortality included older age at diagnosis and diabetes as the cause of gastroparesis [12]. In their review, Camilleri and colleagues concluded that patients with type 1 or 2 diabetes with symptoms of gastroparesis (including bloating, early satiety, nausea, vomiting, retching and postprandial fullness) and in whom there was a documented delay in gastric emptying were more likely to suffer co-morbid cardiovascular disease, hypertension, and retinopathy [19]. These complications are most likely due to poor diabetic control rather than to gastroparesis per se. This conclusion is supported by admission data collected from the Nationwide Inpatient Sample of the Agency for Healthcare Research and Quality and Nationwide Emergency Department Sample - inpatient deaths among patients with a primary or secondary diagnosis of gastroparesis were more often due to a co-morbid condition, rather than gastroparesis itself [36]. Among diabetics, short and longer term outlook, in terms of symptoms, morbidity and mortality are worse for those with type 1 than type 2 disease [37].

Global or regional variations

Data on global or regional variations in regard to any aspect of gastroparesis are very scarce. In a study in the US, Blielefeldt noted very dramatic variations between states in relation to care for, and outcomes from, gastroparesis [38]. For example, admission rates for gastroparesis were four-fold higher in Maryland compared to Utah with mortality rates varying to a similar extent from 0.5 ± 0.1/100,000 in Colorado to 2.3 ± 0.1/100,000 in Florida. Similarly dramatic rates were noted for interventions such as endoscopy, gastrostomy and nutritional support. A variety of demographic, health care delivery and insurance status factors influenced these variations [38].

Conclusions

Gastroparesis, a diagnosis that rests on the combination of certain (though non-specific symptoms), a demonstrated delay in gastric emptying and the absence of any obstructing lesion in the gastrointestinal tract will inevitably pose challenges for the epidemiologist. Not surprisingly, therefore, truly accurate population estimates of incidence and prevalence are lacking. Available data does permit some conclusions, however: gastroparesis, though not common, is increasing in prevalence and incidence, is especially common among females and contributes disproportionately to impaired quality of life, health care utilization and costs [39]. The latter alone should prompt research into its true incidence and prevalence, facilitated, one hopes, by the advent of diagnostic approaches that could be applied accurately to large numbers of the general population.

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