HM is a 34 year old woman sent for a third opinion in gastroenterology. Her symptoms include near daily nausea, epigastric fullness, early satiety and bloating. Symptoms started two years ago after she, and the rest of the family, all developed a severe gastroenteritis. She was well before that without any significant medical, surgical, family or psychological history. Initial symptoms included daily nausea and vomiting with significant epigastric pain and early satiety. Vomiting has slowly resolved with time and her abdominal pain has transitioned to symptoms of epigastric fullness and burning. She continues to have symptoms of early satiety. Her weight has remained stable during this period. Eighteen months ago she underwent a battery of laboratory tests (complete blood count (CBC), liver chemistries, C-reactive protein (CRP), thyroid stimulating hormone (TSH), anti-nuclear antibody), upper endoscopy and an abdominal ultrasound. All of these were normal, including random duodenal and gastric biopsies. She was treated with twice daily ondansetron without benefit. She was then referred to a local gastroenterologist for further evaluation. An upper endoscopy, with duodenal and gastric biopsies, was repeated and was normal. A 4 hour gastric emptying scan using a standardized meal revealed 83% emptying at 4 hours (normal≥85% emptying at 4 hours). The patient was diagnosed with idiopathic gastroparesis and started on metoclopramide; however, 10 mg taken by mouth three times daily made her anxious and “jittery.” She was then started on a liquid form of erythromycin but this caused stomach cramps and did not improve any of her GI symptoms. Domperidone was recommended, but her insurance company would not approve it and she could not afford the out-of-pocket costs. Her local GI provider told her there were no other options available so she sought out a second opinion from another gastroenterologist to discuss other treatment options. A repeat abdominal ultrasound was normal, as were repeat laboratory studies (CBC, liver chemistries, TSH, CRP). A second 4-hoursolid phase GES was read as normal as it demonstrated 86% emptying at 4 hours (normal≥85% emptying at 4 hours). The patient was told that she has functional dyspepsia and was started on a daily proton pump inhibitor (PPI). After 8 weeks she did not notice any improvement in symptoms. She returned to her PCP asking for advice, as she was confused by the two diagnoses. She has done some research and comes in with a list of questions. What is my diagnosis? Why did I develop my symptoms? Do I need any other tests? What is the natural history of my disease? What can be done to improve my symptoms?
Functional dyspepsia is the most common sensorimotor disorder of the upper gastrointestinal tract; gastroparesis is the second most common disorder . Apart from gastroesophageal reflux disease, these two upper gastrointestinal disorders are some of the most frequent reasons patients are referred to a gastroenterologist . Historically, these two disorders have been thought of as completely separate disorders with regard to etiology, pathophysiology, symptom expression and diagnosis. Health care providers have been taught that patients should be diagnosed with either functional dyspepsia (FD) or gastroparesis (GP) based on symptoms of epigastric pain, early satiety, nausea, vomiting and bloating, and that the treatment for these two disorders was distinct. However, research over the last decade has shown that there is significant overlap in these two sensorimotor disorders of the upper gastrointestinal tract . These disorders frequently cause chronic symptoms that are disabling to many patients. Both disorders dramatically reduce patients’ quality of life and impose a significant negative impact to the health care system. At present, the treatment for both disorders remains suboptimal. In the sections that follow we will review the epidemiology, etiology, pathophysiology and diagnosis of these two disorders, highlighting important similarities and differences. Treatment options will be briefly reviewed, although the reader is referred to chapter 23, chapter 24, chapter 25, chapter 26, chapter 27, chapter 28, chapter 29, chapter 30, chapter 31 for a comprehensive review of treatment options for gastroparesis.
Patients can be diagnosed with FD using the Rome IV criteria . Functional dyspepsia is defined by symptoms of dyspepsia that have been present for at least 6 months without evidence of an underlying organic disorder to explain them (see Table 36.1 ). In the last two versions of the Rome criteria, FD has been categorized into two distinct subtypes: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) (see Fig. 36.1 ). Symptoms of functional dyspepsia (FD) are relatively non-specific and include epigastric pain or burning, postprandial fullness, early satiety, and in some studies, other symptoms including postprandial nausea and upper abdominal bloating (see Table 36.2 ).
|Loss of appetite||+||++|
Gastroparesis is defined using a combination of subjective symptoms and objective measures . First, patients should report symptoms thought to represent a delay in gastric emptying. These symptoms, which are relatively non-specific, include epigastric pain, nausea, vomiting, early satiety, bloating and weight loss . Second, a mechanical obstruction should be ruled out; this is typically performed using upper endoscopy, although a careful upper gastrointestinal series with small bowel follow-through is sufficient for patients without ready access to upper endoscopy. Third, a delay in gastric emptying needs to be documented. The 4-hour solid phase scintigraphic emptying scan is considered the most valid method to objectively measure gastric emptying .
In summary, the current definitions of FD and GP highlight their many similarities. The considerable overlap in symptom expression was recently demonstrated in a prospective study of FD patients meeting Rome III criteria . Using the gastroparesis cardinal symptom index (GCSI), a validated measure to assess symptoms in patients with gastroparesis, the authors found that there were few differences in GCSI scores in FD patients compared to historical controls. Both disorders are also similar in that upper endoscopy is often a requirement for diagnosis. The utility of performing a gastric emptying scan will be addressed in the diagnosis section.
Epidemiology and natural history
The epidemiology of FD is not as well understood as other functional gastrointestinal disorders such as IBS, as most epidemiologic research has focused on the broader topic of dyspepsia in general, rather than FD. Multiple studies, however, have shown that the majority of patients with dyspepsia (approximately 75–80%), once studied, are diagnosed with FD rather than an organic process . Thus, inferences can be safely made from a number of studies regarding the incidence and prevalence of FD.
The incidence of dyspepsia has been studied in 3 large studies. In a Swedish study of more than 1000 individuals from the community, the incidence of new-onset dyspepsia over 1 and 7 years was 1% and 3%, respectively . A study from the United Kingdom that followed patients over a 10-year period found a slightly higher incidence of new-onset dyspepsia of nearly 3% per year . A large, prospective survey study in Olmstead County (n=1365) over a 12-year period identified a new onset of FD symptoms of 5% . The prevalence of FD, based on an analysis of 22 separate studies, is estimated at approximately 10% . The natural history of FD was nicely described in a study by Olafsdottir and colleagues . A population-based survey study was performed in a large group of Icelandic adults (ages 18–75) over two time points, spaced 10 years apart (1996 and 2006). The prevalence of FD was 13.9% in the 1996 survey and 16.7% in the 2006 survey. Interestingly, women were more likely to be diagnosed with FD than men in the 2006 survey (20.2% vs. 12.3%), but not in the 1996 survey. The relative constancy in the overall prevalence rate of FD occurred because some patients noted a resolution of their symptoms over time, while others developed new symptoms. The natural history of FD was also investigated in a survey study of 253 patients with FD (Rome II criteria). Kindt and colleagues found that, over a mean follow-up of 68 months, 17% of patients reported resolution of symptoms while 38% reported an improvement in symptoms . No study has found that FD confers an increased risk for malignancy (e.g. gastric cancer) or reduces lifespan.
The epidemiology of gastroparesis is more difficult to tease out since many patients are categorized using inappropriate or less specific ICD-10 codes, such as the code for nausea and vomiting. One carefully performed study found that the observed prevalence of gastroparesis in Olmsted County was 37.8 in women and 9.6 in men per 100,000 persons . Using prevalence rates for the most common known cause of gastroparesis (diabetes), and data from other epidemiologic studies, it can be estimated that approximately 5–10 million US adults suffer from symptoms of gastroparesis. The natural history of GP has not been well-studied. Experienced clinicians who are experts in the evaluation and treatment of patients with GP report that a reasonable percentage of patients – approximately one-third – who develop GP after an infection will note a significant improvement or resolution of their symptoms over time (months to years). In contrast, patients with GP secondary to an underlying disorder (e.g., type 1 diabetes, scleroderma, prior gastric surgery, a malignancy), and those on opioids, may recognize symptom improvement with a combination of diet and medications – however, symptoms typically do not resolve. The reader is also referred to Chapter 4 for further details.
In summary, FD is a more prevalent disorder than is GP. This difference is important to highlight because when patients present with non-specific symptoms of upper abdominal pain, early satiety, nausea and bloating, it is 3–6 times more likely that, in the absence of warning signs, the diagnosis is that of FD, rather than GP.
Impact of FD and GP on patients
Functional dyspepsia is a chronic condition for many patients. Similar to other chronic disorders, FD has a significant negative impact to our patients and to our health care system. The impact on patients can be measured using standardized questionnaires to assess quality of life, such as the Nepean Dyspepsia Index (NDI) and the Short-Form 36. In a study of 864 US patients with FD (Rome II criteria) quality of life, measured by both the SF-36 and the NDI was significantly lower than historical controls . Both the mean physical component score (PCS) and the mental component score (MCS) of the SF-36 were reduced. Female sex, increasing age and elevated symptom scores for epigastric pain and nausea were associated with reduced PCS scores and impaired NDI scores. The extent of delay in gastric emptying was not associated with reduced quality of life scores. A recent study evaluated quality of life scores using the NDI from 289 adults who participated in the NIH funded Functional Dyspepsia Treatment Trial . This study confirmed the validity of the NDI and demonstrated a significant reduction in patient’s quality of life, confirming other studies . The negative economic impact of FD on our health care system is impressive. Recent studies estimate an annual direct health care cost of over 9.5 billion US dollars . These substantial costs are a composite reflecting office visits, emergency room visits, diagnostic tests and medication trials.
Similarly, a number of studies have evaluated the substantial negative impact that gastroparesis imposes on patients and the health care system. Using the well-validated SF-36 to assess quality of life, a recently published study reported that mean SF-36 scores for mental health and social functioning in patients with gastroparesis were analogous to scores for patients with serious chronic medical disorders and depression . Another study found that SF-36 subscale scores were lower in gastroparesis patients compared to the US mean general population norm for every sub-scale except mental health . The economic impact of gastroparesis is also substantial. A questionnaire study of 228 gastroparesis patients found that gastroparesis symptoms reduced annual income in 28.5% and resulted in disability in 11% . Using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS) to evaluate charges in gastroparesis-related hospitalizations over a 10-year period Wang and colleagues reported that in 2004, gastroparesis as either the primary or secondary diagnosis accounted for a total of 3500 million dollars in hospital charges and 911,963 hospital days . A more recent found that there has been a significant rise in ER visits for patients with GP . These facts highlight the need to identify better treatment options for patients with gastroparesis in order to improve quality of life and reduce the economic burden of this bothersome disorder.
The etiology of FD is diverse, complex and incompletely understood. A genetic predisposition may play a role in the development of FD in some patients . Stressful life events, home life environment, diet, medications (e.g., anti-inflammatory agents), tobacco use, disturbances in the gut microbiome and female gender are also risk factors . Helicobacter pylori is a known risk factor, as are other gastrointestinal infections such as Salmonella, Shigella and E. coli . A number of studies have shown that duodenal inflammation, with an abundance of mast cells and eosinophils, may be associated with the development of FD symptoms .
The etiology of gastroparesis is similarly diverse, although somewhat better understood. Long-standing diabetes with associated peripheral neuropathy, connective tissue disorders, prior gastric surgery, ischemia, and a variety of inflammatory or neurologic disorders are well-identified risk factors for the development of gastroparesis . In regard to the impact of diabetes on the development of gastroparesis, it is estimated that up to 50% of type I (insulin-dependent) diabetics and 30% of type 2 (noninsulin dependent) diabetics have symptoms consistent with gastroparesis . In the largest group of patients, an underlying cause cannot be confidently identified, however, and these patients are categorized as having idiopathic gastroparesis. Many of these patients likely develop symptoms of gastroparesis after a preceding viral or bacterial infection .
The sections above highlight the etiologic overlap for FD and gastroparesis. For example, patients may develop symptoms of epigastric pain, pressure, fullness, early satiety and nausea after a preceding infection or after an inflammatory insult. However, a number of etiologic differences exist. A genetic predisposition for FD exists in some patients, although similar data for GP has not been published. Prior gastric surgery, ischemia, connective tissue disorders and/or a known malignancy are well documented risk factors for GP, although by definition they cannot be considered etiologic agents for FD, which excludes organic causes . A proposed schema for the development of FD and GP is outlined in Fig. 36.2 .
It is critical to understand that both FD and GP are pathophysiologically heterogeneous disorders. The complex pathophysiology of each disorder readily explains the similarities, differences, and overlap in symptom presentation and response to therapy (see Fig. 36.3 ). Gastroparesis is defined, in part, by a documented delay in gastric emptying. On a macro scale, this is generally thought to reflect abnormalities in the amplitude or frequency of antral contractions (i.e., a weak “antral pump”). However, delayed gastric emptying can also occur for a number of other reasons including abnormalities in fundic tone, antroduodenal dyscoordination, gastric dysrhythmias and abnormal duodenal feedback . On a microscopic scale, delays in gastric emptying may reflect loss of interstitial cells of Cajal, damage to the enteric nervous system (ENS), loss of nitric oxide synthase, and alterations in fibroblasts . Although less well studied, symptoms of gastroparesis may also reflect abnormalities in gastric sensory function, which can arise due to alterations in intrinsic primary afferent neurons, the enteric nervous system (ENS), ascending pathways, or the vagus nerve . Finally, although prospective controlled studies evaluating this theory have not yet been performed, it has been hypothesized that symptoms of GP may reflect, in part, abnormal CNS processing of visceral sensations or even a learned response .
Functional dyspepsia is similarly a pathophysiologically diverse disorder. Barostat studies from the Leuven research group have shown that approximately 30% of FD patients have abnormal fundic accommodation . These same researchers found that symptoms of early satiety were closely associated with impaired gastric accommodation. Delayed gastric emptying is present in 20–30% of patients with FD . This point is worth emphasizing since one of the key diagnostic criteria for gastroparesis is that of delayed gastric emptying; however, the identical endpoint is present in a large percentage of FD patients, highlighting the similarities of FD with GP. Hypersensitivity to gastric distension is thought to account for FD symptoms in approximately 30% of individuals . Other patients may have symptoms that arise due to abnormal duodeno-gastric feedback, gastric acid or bile salt hypersensitivity, or alterations in neurotransmitters or hormones (e.g., serotonin, cholecystokinin, substance P) . Still in its infancy, functional brain imaging has demonstrated abnormal sensory processing in some FD patients, compared to healthy controls .
In summary, the pathophysiology of FD and GP is similar in many ways. For example, a defining and, to some clinicians, a distinct characteristic for the diagnosis of gastroparesis is a delay in gastric emptying; however, this is also present in at least 30% of patients with FD . Generally, the delay in gastric emptying in patients with FD is less severe than those with GP. Abnormalities in fundic accommodation are common in FD patients and present in some patients with gastroparesis . However, this pathophysiologic process has been less well studied in GP patients compared to FD patients. Disorders of sensation likely occur in both patient groups, although the majority of research in this area has focused on FD patients. Further research into the field of visceral sensation in gastroparesis patients is needed, as these abnormalities may explain why many patients with GP do not respond to prokinetic agents. Lastly, and somewhat frustratingly, there is a poor relationship between underlying pathophysiology and symptom generation in both FD and GP. For example, symptoms can not accurately discriminate the epigastric pain subtype (EPS) of FD from the post-prandial distress subtype (PDS) .
One of the difficulties clinicians face in diagnosing neuromuscular/sensorimotor disorders of the upper gastrointestinal tract is the fact that symptoms are not specific to the underlying disorder. The stomach plays a critical role in the health and well-being of all humans. Unfortunately, however, the stomach has a limited vocabulary to represent the multitude of diseases and disorders that can affect the stomach. Symptoms of FD include epigastric pain, epigastric burning, early satiety, post-prandial fullness or pressure, bloating, nausea, vomiting and even weight loss (see Table 36.2 ). Vomiting can occur in FD patients, although it is usually mild and intermittent. Persistent, intractable vomiting signifies another diagnosis. Weight loss of up to 5% of body weight is not uncommon in FD patients. Significant weight loss, or evidence of nutritional compromise, warrants a thorough investigation ( Tables 36.3 and 36.4 ).