Gastroparesis for the Nongastroenterologist (Part I)

Note: This article is reprinted from the Cleveland Clinic Journal of Medicine (2024;91[6]:373-383). The first portion of the published journal article provides an overview of the condition and its primary symptoms. Part II focuses on the diagnosis and management of gastroparesis.

Written by Jorge Araujo-Duran, MD, Arjun Chatterjee, MD, and Samita Garg, MD

Gastroparesis is a chronic motility disorder and a heterogeneous syndrome with significant variability in its symptoms, causes, severity and response to treatment. It is defined by symptoms such as nausea, vomiting, postprandial fullness and upper abdominal discomfort; objective documentation of delayed gastric emptying of solid food; and exclusion of mechanical obstruction.¹

Delayed gastric emptying was first reported in patients with diabetes by Boas² in 1925, and the term “gastroparesis diabeticorum” was used by Kassander³ in 1958 to describe asymptomatic gastric retention in patients with diabetes. Although diabetes mellitus accounts for more than one-third of all cases of gastroparesis,⁴ other risk factors include gastrointestinal surgery, medications and neurologic and autoimmune disorders. Moreover, in many patients no underlying cause is found,⁵ making this condition even more variable.

Regardless of the cause and despite advances in understanding of the pathogenesis (which has unresolved questions), gastroparesis poses a challenge in diagnosis and management for gastroenterologists and nongastroenterologists alike.

This review focuses on the most relevant challenges encountered when approaching patients with this condition, current recommendations for diagnosis and treatment and how nongastroenterologists, such as primary care clinicians, can use these to help manage patients.

Prevalence varies in different studies and countries

A 2023 systematic review reported that the overall standardized prevalence of gastroparesis ranged widely (from 13.8 to 267.7 per 100,000 adults) in studies from 1994 to 2019.⁶ However, many of these studies used a broad definition of gastroparesis (“probable and/or possible gastroparesis”) solely based on diagnosis codes and without objective evidence of delayed gastric emptying.

Community-based studies with a strict case definition (objective evidence of delayed gastric emptying, typical symptoms and absence of mechanical obstruction)¹ appear to offer a more accurate estimate. For instance, two U.S. studies using community-based databases reported a prevalence of 21.5 per 100,000 adults⁷ and 24.2 per 100,000 adults.⁸ In contrast, a study conducted using a community database from the United Kingdom and a strict case definition reported a prevalence of 13.8 per 100,000 persons.⁹ Similarly, a study from Israel showed a crude prevalence of 13.6 per 100,000 persons.¹⁰ The incidence has been reported to be around 6.3 per 100,000 person-years in the United States⁸ and 1.9 per 100,000 person-years in the United Kingdom.⁹

The difference in prevalence in different studies and countries can be attributed to several factors. First, epidemiologic studies classify gastroparesis inconsistently: some rely solely on diagnosis codes while others consider specific diagnostic criteria. Second, the diagnosis of gastroparesis may vary among regions and countries, influenced in part by differences in the methodology of gastric emptying studies and variations in clinical practice.⁶ Lastly, diabetes mellitus is a major contributor to gastroparesis, and its prevalence is notably higher in the United States (11.6%)¹¹ than in the United Kingdom (7%)¹² and Israel (2.6%),¹³ potentially contributing to the overall higher prevalence of gastroparesis in the United States.

The mean age of patients with gastroparesis has been reported as between 45.4 and 58.9 years and the proportion who are white from 46.7% to 90.1%.⁶ In several reports, most patients (63.7% to 76.4%) were female,⁶ with an age-adjusted female-to-male ratio of 3.9:1.⁸ Although this female predominance has been attributed to factors such as sex hormones, it has not been accurately described or researched.⁶

The mortality rate is higher in patients with gastroparesis than in the general population, the most common causes of death being cardiovascular disease, respiratory failure and malignancy, although some studies reported that inpatient mortality rates have been falling over time.⁶

The most common comorbidities also differ among regions and countries. For instance, in the United States, the most common comorbidities were hypertension, smoking history, obesity, chronic pulmonary disease and cerebrovascular disease, regardless of the cause of gastroparesis, while in the United Kingdom chronic pulmonary disease was most common, followed by renal disease and malignancy.^7,9

Diabetes and other causes

Diabetes and idiopathic disease are the most common causes of gastroparesis. However, the etiology differs among studies and populations.

A large national claims database study from the United States (N = 82,574,650) reported diabetes mellitus as the most common cause, involving 57.4% of all cases, with Type 2 diabetes (51.7%) being more prevalent than Type 1 (5.7%).⁷ Second was surgery (15%), mostly esophageal, gastric and duodenal surgeries, although there are anecdotal cases involving cardiothoracic surgery, mainly vagus nerve resection.⁷ Third (11.8%) were drugs that can impair gastric emptying (opioids, anti-cholinergic agents, calcium channel blockers, glucagon-like peptide 1 [GLP-1] receptor agonists, cyclosporine). Unknown causes came fourth (11.3%).⁷ Other causes such as autoimmune diseases (scleroderma, systemic lupus erythematosus), hypothyroidism, Parkinson's disease, cerebral palsy and multiple sclerosis account for less than 5% of all cases.

Other studies had different findings. For instance, another U.S. study found that the most common causes were idiopathic (49.4%), diabetes mellitus (25.3%), drugs (22.9%) and surgery (7.2%).⁸ In another large population-based study in the United States (N = 43,827,910), diabetes was the most common cause (71.7%), followed by idiopathic (28.3%).¹⁴ However, the investigators relied solely on diagnosis codes from medical records for gastroparesis classification.

Interestingly, the etiology varies in other countries and regions. For instance, in the U.K. study, idiopathic disease was the most common cause of gastroparesis (39.4%), followed by diabetes (37.5%)⁹; in the study in Israel,¹⁰ diabetes accounted for 17.2% of all cases and the rest (82.8%) were classified as idiopathic (the authors excluded cases due to other causes).

Differences in the etiology of gastroparesis across countries can be partly explained by differences in the prevalence of diabetes mellitus, which is probably the most common cause where its prevalence is higher. Additionally, in some studies, the differentiation of the etiology is poor, with subgroup analyses that classify all nondiabetic gastroparesis cases (postsurgical, drug-induced) as idiopathic.⁶

Evidence regarding certain risk factors or causes of gastroparesis lacks consensus. For example, hypothyroidism has been reported to be associated with 4.0% of cases.⁷ Some studies suggest hypothyroidism may affect esophageal and gastric motor activity, leading to upper gastrointestinal symptoms that can be improved with thyroid hormone replacement.^15,16 However, a group of experts from European gastroenterology societies could not reach consensus on hypothyroidism as a cause of gastroparesis.⁵ Similarly, this group did not reach consensus on whether viral infections can cause gastroparesis.⁵ Nonetheless, gastroparesis has been (rarely) associated with viruses such as Epstein-Barr, norovirus, herpes and cytomegalovirus and viral illness has been linked to poor prognosis if there is evidence of autonomic dysfunction, such as postural hypotension.⁴

Recent findings highlight that gastrointestinal motility disorders presenting with gastroparesis symptoms can occur in patients with generalized autoimmune dysautonomia.¹⁷ Several antibodies have been associated with autoimmune disorders that manifest gastroparesis-like symptoms, including antibodies targeting ganglionic nicotinic acetylcholine receptors containing alpha 3 subunits or antibodies against calcium channels.¹⁷

For instance, autoimmune gastrointestinal dysmotility is a limited form of autoimmune dysautonomia that can occur as an idiopathic or paraneoplastic phenomenon. It has various presentations: hypermotility or hypomotility, such as colonic inertia, pyloric obstruction, anal spasm and gastroparesis.¹⁷ It is believed that an unknown number of “idiopathic” gastroparesis cases may fall within this category, leading to consideration of immunotherapy as a treatment option.¹⁷ However, stronger evidence regarding the immune profiles and response to immunotherapy of this group of patients is needed. The latest American College of Gastroenterology guideline does not recommend routine clinical use of autoimmune therapy in the management of gastroparesis.¹

Gastroparesis often persists despite treatment

More than two-thirds of patients receiving treatment for gastroparesis do not have significant symptom improvement during one year of follow-up.^18,19

Gastroparesis is associated with increased emergency department visits and hospitalizations due to exacerbation of symptoms such as vomiting, electrolyte abnormalities, abdominal pain and malnutrition. Higher healthcare resource utilization has been shown within two years of gastroparesis diagnosis.¹⁰

Gastroparesis predominantly affects women, who are more likely to have idiopathic gastroparesis with more severe symptoms of postprandial fullness, early satiety, bloating and upper abdominal pain, and are less likely to improve after 48 weeks of follow-up.^18,19

Some predictors of improvement over 48 weeks include age 50 and older, moderate or severe gastroparesis (> 20% gastric retention at 4 hours) and onset of gastroparesis following an infectious prodrome. Predictors associated with lack of improvement include being overweight or obese, severe abdominal pain, concomitant gastroesophageal reflux (e.g., pyrosis, dysphagia, chest pain, chronic cough) and depression.^18,19

Gastroparesis in patients with Type 1 diabetes mellitus is associated with higher hemoglobin A1c levels, longer duration of gastrointestinal symptoms, greater gastric retention and more hospitalizations due to gastroparesis. Patients with Type 2 diabetes mellitus and gastroparesis are older and heavier and have more comorbidities. More than 40% of patients with Type 2 diabetes who require insulin therapy have delayed gastric emptying.¹⁸

Improvement in glycemic control is associated with a decreased incidence of microvascular complications, and it is expected to be associated with a lower incidence of diabetic gastroparesis.⁴ Indeed, diabetic gastroparesis seems to be associated with poor glycemic control and vascular and neurogenic complications.²⁰ But once delayed gastric emptying is established, it may persist for up to 25 years despite improved glycemic control.²¹

Gastric emptying is complex, and so is gastroparesis

In diabetic and idiopathic gastroparesis, the main alterations that lead to delayed gastric emptying and symptoms are impaired accommodation of the gastric fundus and body, antral hypomotility, impaired pyloric relaxation and dysmotility in the small intestine.¹⁸

Emptying a meal from the stomach into the small bowel requires complex coordination involving the fundus, antrum and pylorus. Swallowing induces relaxation of the gastric fundus, allowing it to accommodate the food. Then, steady increases in fundic tone propel gastric contents toward the pylorus, where phasic contractions facilitate the grinding of digestible solids.¹⁸ The antral contractions are regulated by the interstitial cells of Cajal, generating a basal electrical rhythm. This process reduces digestible solids to particles 2 mm or smaller, forming the chyme. Small bowel function is also crucial to complete gastric emptying, as emptying requires coordination between the antrum and pylorus, and inhibitory signals from the small bowel modulate emptying rates based on chyme composition.¹⁸

Fewer inhibitory neurons expressing nitric oxide synthase (nitrergic neurons) may play an important role in impaired accommodation and pyloric relaxation.^4,18 The interstitial cells of Cajal and cells positive for platelet-derived growth factor receptor-alpha (fibroblast-like) in the gastric smooth muscle layer are considered the pacemakers that convey the stimulation from extrinsic vagal fibers and intrinsic enteric nerves to the gastric smooth muscle cells (multicellular electrical syncytium), resulting in coordinated contractions towards the antropyloric region.⁴ Reduced numbers of interstitial cells of Cajal and fibroblast-like cells and altered expression of smooth muscle cell contractile protein have been found in patients with gastroparesis, and this may explain the antral hypomotility that interferes with peristalsis, trituration and gastric emptying.⁴

Immune alterations seem to play an important role in the mechanism of injury. Injury and loss of the interstitial cells of Cajal, smooth muscle cells and fibroblast-like cells, comprising the electrical syncytium of the gut, have been associated with reduced numbers of anti-inflammatory M2 macrophages, which mediate cell repair.^4,18 Losing M2 macrophages reduces the protection of neural tissue from oxidative stress and inflammation—both involved in diseases such as diabetes mellitus.⁴

Nausea, vomiting, early satiety

The main symptoms of gastroparesis are nausea, vomiting, early satiety, postprandial fullness, bloating, belching and upper abdominal discomfort.⁴ These cardinal symptoms are usually present in clusters or combinations, e.g., abdominal pain with early satiety and heartburn; heartburn with bloating, early satiety, nausea and vomiting; and regurgitation with bloating, nausea and vomiting.^4,22

Severe early satiety and postprandial fullness are reported by 50% to 60% of patients, and 95% experience nausea, which is the predominant symptom in 29% of cases.¹⁸ Nausea is related to food intake in at least three-quarters of patients; in 40% of cases, nausea lasts most of the day.¹⁸

Vomiting and early satiety are often the initial symptoms in diabetic gastroparesis. Patients with diabetic gastroparesis may experience greater nausea and longer periods of vomiting than those with idiopathic gastroparesis.^18,23

Abdominal pain is often the initial presentation of idiopathic gastroparesis.²³ Two-thirds of patients report it, and it is associated with nonacute onset of gastroparesis, bowel disturbances and opiate and antiemetic use. In addition, patients in whom pain is the predominant symptom have greater impairment in quality of life than those in whom nausea and vomiting predominate.¹⁸

Bloating is more significant in women, individuals who are overweight and those using probiotics, regardless of the etiology.

REFERENCES

1. Camilleri M, Kuo B, Nguyen L, et al. ACG clinical guideline: gastroparesis. Am J Gastroenterol 2022; 117(8):1197–1220.
2. Boas T. Disease of the Stomach, 9th ed. Leipzig; Georg Thieme, 1925.
3. Kassander P. Asymptomatic gastric retention in diabetics (gastroparesis diabeticorum). Ann Intern Med 1958; 48(4):797–812. doi:10.7326/0003-4819-48-4-797.
4. Camilleri M, Chedid V, Ford AC, et al. Gastroparesis. Nat Rev Dis Primers 2018; 4(1):41.
5. Schol J, Wauters L, Dickman R, et al. United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis [published correction appears in United European Gastroenterol J 2021; 9(7):883–884]. United European Gastroenterol J 2021; 9(3):287–306.
6. Dilmaghani S, Zheng T, Camilleri M. Epidemiology and healthcare utilization in patients with gastroparesis: a systematic review. Clin Gastroenterol Hepatol 2023; 21(9):2239–2251.e2.
7. Ye Y, Yin Y, Huh SY, Almansa C, Bennett D, Camilleri M. Epidemiology, etiology, and treatment of gastroparesis: real-world evidence from a large US national claims database. Gastroenterology 2022; 162(1):109–121.e5.
8. Jung HK, Choung RS, Locke GR 3rd., et al. The incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006. Gastroenterology 2009; 136(4):1225–1233.
9. Ye Y, Jiang B, Manne S, et al. Epidemiology and outcomes of gastroparesis, as documented in general practice records, in the United Kingdom. Gut 2021; 70(4):644–653.
10. Yekutiel N, Chodick G, Knop J, et al. The epidemiology and burden of gastroparesis: real-world data from a large healthcare provider in Israel. Neurogastroenterol Motil 2023; 35(4):e14522.
11. Centers for Disease Control and Prevention. National diabetes statistics report. Updated November 29, 2023. www.cdc.gov/diabetes/data/statistics-report/index.html. Accessed May 15, 2024.
12. Whicher CA, O’Neill S, Holt RIG. Diabetes in the UK: 2019. Diabet Med 2020; 37(2):242–247.
13. Chodick G, Heymann AD, Shalev V, Kookia E. The epidemiology of diabetes in a large Israeli HMO. Eur J Epidemiol 2003; 18(12): 1143–1146.
14. Syed AR, Wolfe MM, Calles-Escandon J. Epidemiology and diagnosis of gastroparesis in the United States: a population-based study. J Clin Gastroenterol 2020; 54(1):50–54.
15. Canpolat AG, Kav T, Sivri B, Yildiz BO. Effects of L-thyroxine on gastric motility and ghrelin in subclinical hypothyroidism: a prospective study. J Clin Endocrinol Metab 2013; 98(11):E1775–E1779.
16. Yaylali O, Kirac S, Yilmaz M, et al. Does hypothyroidism affect gastrointestinal motility? Gastroenterol Res Pract 2009; 2009:529802.
17. Flanagan EP, Saito YA, Lennon VA, et al. Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility. Neurogastroenterol Motil 2014; 26(9):1285–1297.
18. Grover M, Farrugia G, Stanghellini V. Gastroparesis: a turning point in understanding and treatment. Gut 2019; 68(12):2238–2250.
19. Pasricha PJ, Yates KP, Nguyen L, et al. Outcomes and factors associated with reduced symptoms in patients with gastroparesis. Gastroenterology 2015; 149(7):1762–1774.e4.
20. Kofod-Andersen K, Tarnow L. Prevalence of gastroparesis-related symptoms in an unselected cohort of patients with type 1 diabetes. J Diabetes Complications 2012; 26(2):89–93.
21. Chang J, Rayner CK, Jones KL, Horowitz M. Prognosis of diabetic gastroparesis—a 25-year evaluation. Diabet Med 2013; 30(5): e185–e188.
22. Ricci JA, Siddique R, Stewart WF, Sandler RS, Sloan S, Farup CE. Upper gastrointestinal symptoms in a US national sample of adults with diabetes. Scand J Gastroenterol 2000; 35(2):152–159.
23. Parkman HP, Yates K, Hasler WL, et al. Similarities and differences between diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol 2011; 9(12):1056–1064.