Clinical presentations of gastroparesis

Introduction

Gastroparesis is a chronic gastric motility disorder, characterized by delays in the emptying of food contents from the stomach into the small bowel in the absence of a mechanical obstruction . The most frequently reported symptoms of gastroparesis include early satiety, nausea, vomiting, bloating, abdominal discomfort, and postprandial fullness . However, these symptoms of gastroparesis can also be seen when gastric emptying is even normal or rapid and are not specific to the degree of gastric emptying delay . This finding has led some researchers to identify patients who suffer from many of the symptoms of gastroparesis but who exhibit normal or rapid gastric emptying to have a gastroparesis-like syndrome or chronic nausea and vomiting syndrome as designated by ROME IV criteria .

However, this lack of association between delayed gastric emptying and the other characteristics of gastroparesis may also stem from sub-optimal methods in measuring gastric transit, gastric accommodation and gastric motility as not one test measures all these important gastric functions. For example, a meta-analysis of associations between delayed gastric emptying and the symptoms of gastroparesis as measured by scintigraphy and gastric emptying breath test (GEBT) initially documented only weak associations between delayed gastric emptying and gastroparesis symptoms . Nevertheless, that same study, when the analysis focused only on optimal measures of assessing gastric emptying, found significant associations between delayed gastric emptying and other symptoms of gastroparesis, although the findings were limited in diabetics with gastroparesis . Others have found that amongst subjects with chronic undifferentiated nausea and vomiting (CUNV) evaluated by a standardized scintigraphy, that the degree of delay does not correlate with symptom severity. Interestingly. those with diabetes were less likely to have a normal gastric scintigraphy .

Clinical presentations of gastroparesis may thus vary according to its primary underlying etiology, which can be grouped into three major and multiple less common etiologies of gastroparesis, many of which are frequently overlooked in the diagnosis and management of gastroparesis. This chapter first addresses the three major etiologies of gastroparesis—idiopathic, diabetic, and postsurgical gastroparesis —then the minor etiologies, while covering the different clinical presentations of gastroparesis across etiologies. This chapter will also review overlap with functional dyspepsia, a more common gastrointestinal syndrome than gastroparesis. Furthermore, the chapter will differentiate symptoms common to gastroparesis and other conditions which also exhibit upper gastrointestinal symptoms with vomiting as a main manifestation, including cyclic vomiting syndrome, cannabinoid-induced hyperemesis and chronic nausea and vomiting syndrome, designated by ROME IV criteria.

Idiopathic gastroparesis accounts for the largest percentage of documented cases—an estimated 49.4%; with diabetic gastroparesis accounting for approximately 25.3% of cases; medications including narcotics, for 22.9%; connective tissue diseases and autoimmune disorders, for 10.8%; and postsurgical, 7.2% . Less common etiologies of gastroparesis include Parkinson Disease , paraneoplastic syndrome , connective tissue disorders, including Ehlers-Danlos Syndrome , scleroderma , scleroderma and lupus , cystic fibrosis , and chronic intestinal pseudoobstruction .

Primary measures of gastroparesis symptoms

Three of the best means of evaluating the severity of gastroparesis symptoms are via patient-based assessments, including the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM), Gastroparesis Cardinal Symptoms Index (GCSI), and the American Neurogastroenterology and Motility Society’s Gastroparesis Cardinal Symptom Index-Daily Diary (ANMS GCSI-DD) developed in concert with the Food and Drug Administration to provide patient-reported outcome (PRO) endpoints for pharmacologic therapies of and clinical trials performed on patients with gastroparesis.

PAGI-SYM

The PAGI-SYM covers the main symptoms for upper GI disorders, including dyspepsia and chronic nausea and vomiting syndrome, as well as gastroparesis. The PAGI-SYM uses six sub-scales, ranging from 0 for no symptoms to 5 for “very severe” symptoms, across 20 questions. Questions address symptoms of nausea, upper abdominal discomfort or pain, stomach fullness, lower abdominal discomfort or pain, visible abdominal distention, retching, vomiting, early satiety, and postprandial fullness . The well-validated and commonly utilized PAGI-SYM has established that abdominal pain is a common clinical presentation of gastroparesis across its two most common etiologies—idiopathic and diabetic gastroparesis—occurring in nearly 90% of patients, with nausea present in over 94% of patients, despite poor correlations with the severity of the delayed gastric emptying . Nevertheless, gastric emptying has been consistently associated with nausea and vomiting, as well as with postprandial fullness and early satiety .

GCSI

The GCSI uses three sub-scales from the PAGI-SYM to assess gastroparesis symptoms with a 6-point Likert scale that measures symptoms from 0 to 5 precisely as the PAC-SYM does. At nine questions, the GCSI is brief and easily completed by patients, assessing patients’ nausea, retching, vomiting, early satiety, postprandial fullness, loss of appetite, bloating, and visible abdominal distention. In addition, the GCSI also addresses patients simply feeling that their stomach is full, symptoms also seen in functional dyspepsia thought to be related to a lack of gastric accommodation . Unfortunately, the GCSI leaves out abdominal pain, a symptom commonly seen in patients with gastroparesis. In initial validation studies of the GCSI, factor analysis of a large US-based population survey identified bloating as a significant symptom of gastroparesis, although bloating had previously not been considered a common symptom . The GCSI score is the sum of three sub-scale scores across postprandial fullness/early satiety, pain/bloating, and nausea/vomiting. Consistently, across all symptoms, higher mean GCSI scores were highly associated with clinician ratings of increased symptom severity. In addition, the GCSI also proved sensitive to changes in patients’ gastroparesis status, with higher scores, indicative of increased severity in symptoms, being highly correlated with patients’ bed disability or restricted activity days . Abell Scoring uses the GCSI to assess the overall severity of gastroparesis symptoms by using mean scores across the three main sub-scales, assigning a score of 1–3 for symptom severity. Grade 1 patients have mild, or intermittent symptoms controllable with modification of diet and avoidance of exacerbating agents or habits (such as eating meals immediately before bedtime). Grade 2 patients experience moderately severe symptoms without weight loss but require prokinetic medications, usually with antiemetic agents for control. In contrast, Grade 3 patients are refractory to medications, unable to maintain oral nutrition and require intravenous fluids, plus medications, enteral or parenteral nutrition, and endoscopic or surgical therapy. Grade 3 patients frequently have weight loss with malnutrition, require frequent emergency room visits and some hospitalization .

ANMS GSCI-DD

Both the PAGI-SYM and GCSI ask patients to rate the severity of their gastroparesis symptoms over the two weeks preceding the administration of the questionnaire(s). Because the ANMS GCSI-DD measures the efficacy of therapeutic treatments of gastroparesis, this questionnaire relies on a 24-hour recall period, assessing patients’ symptom severity across five different symptoms: nausea, early satiety, post-prandial fullness, upper abdominal pain , and vomiting ( Table 3.1 contains a representative sample of responses) . All symptoms, excluding vomiting, rely on a 5-point scale to assess severity, with responses including none, mild, moderate, severe, or very severe. Patients are also asked to record the number of vomiting episodes over the last 24 hours . Although the original GCSI included bloating, research using the GCSI, prior to the development of the ANMS GCSI-DD, identified significant overlap between bloating and postprandial fullness, resulting in the ANMS GCSI-DD removing bloating as a symptom . Moreover, fewer than half the patients in the study that validated the ANMS GCSI-DD endorsed the inclusion of bloating as a distinct symptom of gastroparesis .

Table 3.1

Gastrointestinal symptoms and their descriptions as reported by patients with gastroparesis.

From Revicki DA, Lavoie S, Speck RM, et al. (2018). The content validity of the ANMS GCSI-DD in patients with idiopathic or diabetic gastroparesis. Journal of patient-reported outcomes 2: 61. Used under permission of Open Source Creative Commons License: https://creativecommons.org/licenses/by/4.0/ .

Abdominal pain	“Yeah so for me it’s in my upper left quadrant, like right underneath my rib cage. It’s constant. It’s always there and there’s some days where it’s worse and there’s some days where it’s less and then there’s some days where I also get pain on like my mid-right abdomen.” “And the abdominal pain that comes either they come in cramps or they come in stabbing pains.”
Nausea	“I have a low level of nausea all day, like pretty much all day I could throw up and I’m keeping myself from throwing up.”
Vomiting	“... it’s almost like a fire hydrant sometimes when I go to throw up to where it’s just spewing right out and to where sometimes...I can feel like the muscles straining from trying to open up to get it to come out to where it hurts a lot > “Non-stop throwing up for a few minutes, being unable to hold it—the stomach is unable to hold anything in, and even the smell of the breath would be bad. You experience fever, sweat, things like that.”
Bloating	“It’s just my whole abdomen area, my whole stomach area that pretty much gets bloated... it just get big, like a beer belly.”
Early satiety	“Feeling full all the time even if I’d only taken a bite or two of food” (003-001) “Not being able to finish half of a meal. It’s frustrating to me not being able to finish um even half of what everybody else is eating.”
Post-prandial fullness	“Feeling like you can’t possibly put another bite into your mouth.” “You’re just stuffed full”

The different symptoms covered by the PAGI-SYM and GCSI, as well as the different duration assessed by the ANMS GCSI-DD, enable clinicians to capture accurate evaluations of patients’ symptoms and severity that are well correlated with clinician observations of patients’ symptoms of gastroparesis—but not pan-enteric dysmotility. These instruments can provide robust criteria for assessing patients’ symptoms of gastroparesis, especially when augmented with other modalities for assessing delays in gastric emptying that include gastric emptying scintigraphy, wireless capsule motility studies ( Chapter 12 ), GEBT ( Chapter 13 ), antroduodenal manometry ( Chapter 16 ), and barostat and satiety testing ( Chapter 17 ).

Symptoms presentations according to pathophysiology of gastroparesis

Symptoms of diabetic gastroparesis

The term Gastroparesis Diabeticorum was first coined by Kassander et al. in 1958 describing minimal symptoms but finding of “asymptomatic” gastric retention on Upper GI Series . Symptoms of diabetic gastroparesis may vary, attributed to the patients’ glycemic control or of their type of diabetes or duration after diagnosis with Type 1 or Type 2 diabetes. In one community-based study of Olmsted County, Minnesota, patients with Type 1 or Type 2 diabetes reported the same rates of nausea and vomiting as controls . However, another community-based study in Australia documented severe bloating, abdominal discomfort or pain, early satiety, and post-prandial fullness, along with nausea and vomiting in a sample of patients with predominantly Type 2 diabetes . Some patients with diabetes though may present instead with accelerated gastric emptying , while others may report symptoms consistent with rumination syndrome—daily, early post-prandial, effortless regurgitation of food within 10–30 minutes of ingestion . Postprandial fullness, nausea with vomiting 1 hour after food intake are symptoms more suggestive of a delayed gastric emptying, according to some studies .

Because standards for assessing delayed gastric emptying vary widely (see Chapter 10, Chapter 11, Chapter 12, Chapter 13, Chapter 14, Chapter 15, Chapter 16, Chapter 17, Chapter 18 ), and studies have used a variety of methods in assessing rates of gastric emptying, associations between delayed gastric emptying and severity of other symptoms associated with gastroparesis are also absent in some studies while strong in others . These limitations may be responsible for findings in some studies that treatments that improved gastric emptying times failed to impact patients’ symptoms of nausea, bloating, abdominal discomfort, early satiety, and postprandial fullness . Conversely, these same limitations may also account for patients in some studies reporting significant symptom improvement using the GCSI , despite their gastric emptying remaining significantly delayed . Since glucose control impacts the rate of gastric emptying, blood glucose levels less than 275 mg are required prior to undergoing any gastric emptying studies in order to prevent a false diagnosis.

Across studies, only limited evidence indicates associations between increased glycemic control and decreases in severity of gastroparesis symptoms, including nausea, pain, bloating, abdominal discomfort, postprandial fullness, early satiety, and delayed gastric emptying . Despite variations in testing modalities and standards, patients generally experience accelerated gastric emptying during hypoglycemia and delayed gastric emptying during hyperglycemia . Nevertheless, even in diabetics without delayed gastric emptying or significant symptoms characteristic of gastroparesis, the loss of good glycemic control should prompt clinicians to administer the PAGI-SYM or GCSI and consider gastric emptying delay as a cause. Clinicians should also assess patients’ gastric emptying, as gastroparesis may lead to postprandial hypoglycemia or hyperglycemia, since gastric dysmotility can impair absorption of nutrients, as well as of oral hypoglycemic medications . For patients with Type 1 diabetes, severe delays in gastric emptying may be an indication for the use of insulin-pump therapy . In addition, diabetic retinopathy in diabetic patients can be correlated with delays in gastric emptying .

Other factors may impact patients’ reporting of the nature and severity of their gastroparesis symptoms, including some differences in presentations of symptoms between Type 1 and Type 2 diabetes, as well as autonomic and enteric neuropathy stemming from long-term loss of glycemic control . For example, in one 48-week study of patients with both Type 1 and Type 2 diabetes, symptoms on the GCSI at baseline were remarkably similar between both groups, including nausea and postprandial fullness . However, patients with Type 1 diabetes reported increased gastroesophageal reflux disease (GERD) possibly due to more severe delays in gastric emptying due to longer duration of diabetes. In contrast, patients with Type 2 diabetes displayed more severe bloating or distention . Over time, patients with poor glycemic control exhibit severe nausea and vomiting, as well as significantly delayed gastric emptying with some possible explanations being a blunted pancreatic polypeptide response, reducing gastric secretions and stimulation of the vagus nerve responsible for gastric motility .

Symptoms of idiopathic gastroparesis

Idiopathic gastroparesis accounts for an estimated 49.4% of documented cases . Of these cases, in many the onset of symptoms may be due to a viral etiology . An NIDDK Gastroparesis Consortium study found approximately 19% of patients with idiopathic gastroparesis, as well as 28% of patients with both Type 1 and Type 2 diabetic gastroparesis had features indicative of past viral infection, including elevated antibody titers against cytomegalovirus and Epstein-Barr . A study of patients enrolled in the NIDDK Gastroparesis Registry also found significant differences between symptoms reported by patients with idiopathic gastroparesis and those in patients with diabetic gastroparesis. Patients with idiopathic gastroparesis reported the same levels of nausea, but higher rates of upper abdominal pain but decreased instances of vomiting or retching, compared with diabetic patients with gastroparesis . However, given the overlap of infectious gastroparesis in patients with idiopathic and diabetic gastroparesis, increased vomiting could be indicative of either vagal neuropathy in diabetic patients or of post-infectious gastroparesis .

Symptoms of post-infectious gastroparesis

Post-infectious gastroparesis may account for the majority of cases of idiopathic gastroparesis, especially since so few studies have tested for infectious Enteroviruses (EV), many of which cannot even be identified. To date, studies have established that EV involves at least 71 viruses, including Coxsackievirus Groups A & B , Echovirus , and Parechovirus . EV numbers among the most common viruses infecting humans world-wide . Few patients infected with EV likely receive clinical attention for lingering GI symptoms. Additionally, few patients with symptoms of gastroparesis receive testing for EV from gastric biopsies taken during an upper endoscopy done to evaluate symptoms of nausea and vomiting . This finding is similar to outcomes from two other studies, where as many as 82% of patients presenting with symptoms of dyspepsia tested positive for EV . For example, in a small pilot study of 11 patients referred for symptoms of gastroparesis with idiopathic gastroparesis, 82% were positive for gastric EV by qualitative immune staining of gastric mucosa . Significantly, over half of these patients had autonomic dysfunction confirmed by tilt-table testing . These patients were also likeliest to require total parenteral nutrition—Grade 3 gastroparesis, according to Abell scoring on the GCSI . Unsurprisingly, patients with autonomic dysfunction, a common finding in patients with gastroparesis, are the least likely to experience remission of their symptoms following treatment for EV .

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