Gastroparesis

Etiology

Gastroparesis is most frequently idiopathic. Other common etiologies include diabetic, postsurgical, and postinfectious causes.[3] Various neurologic disorders can also affect gastrointestinal motility by altering the parasympathetic or sympathetic nerve supply to the gastrointestinal (GI) tract. Etiologic categories of gastroparesis include but are not limited to:[5][6][7][8][9]

• Idiopathic: the etiology is approximately 50% of cases
• Diabetes mellitus (DM): diabetic gastroparesis is more frequent and more severe in patients with type 1 DM but is seen in patients with type 2 DM
• Postsurgical: iatrogenic vagal nerve injury and altered stomach anatomy affect gastric emptying
• Viral infections: particularly Norwalk virus, rotavirus, and Epstein-Barr virus
• Rheumatological diseases: amyloid neuropathy and systemic sclerosis (scleroderma)
• Autoimmune: may benefit from plasmapheresis of autoantibodies
• Neurological conditions
• Traumatic spinal cord injury
• Medications: opioids, cyclosporine, phenothiazines, dopamine agonists, octreotide, alpha-2-adrenergic agonists, tricyclic antidepressants, calcium channel blockers, GLP-1 agonists or analogs, lithium, and progesterone.

Patients with idiopathic gastroparesis are more likely to be women, White, and have symptoms of abdominal pain and early satiety than patients with diabetic gastroparesis. Similar to diabetic gastroparesis, episodes can be episodic or cyclical.[10]

Patients with diabetes at increased risk of developing gastroparesis usually have a combination of the following: long duration of the disease, poorly controlled blood sugars, and other autonomic neuropathic complications. Patients with type 1 diabetes are more likely to have gastroparesis than those with type 2, and up to 50% of patients with diabetes and suboptimal glucose control will have gastroparesis.[11] However, optimal glucose control is not always associated with improved gastric motility, especially in the short term. Gastroparesis can also affect glucose control, and hyperglycemia decreases gastric motility, even in nondiabetic patients.[12]

Gastroparesis is common following surgery involving the esophagus, stomach, duodenum, or pancreas and procedures that risk injury to the vagal nerve. Postsurgical gastroparesis may develop immediately or months to years following the procedure. Surgical procedures associated with postoperative gastroparesis include Nissen fundoplication, gastrectomy, pancreatic cancer cryoablation, and pancreatoduodenectomy. Gastroparesis has been reported in gynecological surgeries performed in the lower abdominopelvic cavity. Uncomplicated fundoplication and sleeve gastrectomy can prolong gastric emptying time due to reduced stomach capacity, as can fluid-filled balloon bariatric surgery.[13][14][15]

Postinfectious is common and typically self-limited; full recovery is usual. Norwalk virus and rotavirus are the most commonly identified etiologic viral pathogens. However, Epstein-Barr virus, cytomegalovirus, and Varicella Zoster virus have also been implicated in gastroparesis due to their potential to cause long-term autonomic dysfunction.[9]

Epidemiology

The epidemiology of gastroparesis is difficult to estimate due to the relatively weak correlation of symptoms with gastric emptying, resulting in a high rate of underdiagnosis.[16] In one of the largest population-based studies, 3604 cases of possible gastroparesis were evaluated, of which 83 patients classified as definite gastroparesis and 127 patients as probable gastroparesis. A 2022 systematic review of 13 studies from 1994 to 2019 found a prevalence of gastroparesis in the general population between 13.8 to 267.7 per 100,000 adults and an incidence of 1.9 to 6.3 per 100,000 person-years.[17] The incidence of gastroparesis in women is quadruple that in men and increases with increasing age in both sexes.[18][19] The overall incidence of hospitalizations for gastroparesis increased by 300% between 1997 to 2013.[20]

Pathophysiology

The initial step for digesting solids is gastric expansion of the fundus and proximal stomach, followed by antral contraction. Peristaltic waves cause ingested food to be triturated into smaller particles. Coordinated antral motor function is crucial for grinding, mixing, and gastric emptying of solids; abnormal motor function results in accumulated indigestible food and eventual bezoar formation. Once a particular force is reached, pyloric contraction allows particles smaller than 2 mm to proceed to the duodenum; larger particles are returned to the stomach body to allow further trituration. Decreases in antral contraction and pyloric relaxation are the primary mechanisms of gastroparesis. Antral hypomotility is defined as fewer than one contraction per minute in the first postprandial hour.[1]

Neuromuscular control is exerted at several levels, including intrinsic and extrinsic neurons, smooth muscle cells, and interstitial cells of Cajal. Interactions among smooth muscle cells, interstitial cells of Cajal located between the circular and longitudinal muscle layers, and fibroblast-like PGFRα-positive cells regulate the contraction and relaxation involved in peristalsis. The enteric nervous system is complex and comprises over 100 million neurons. Interstitial cells of Cajal also have a pacemaker function to generate and propagate gastric and intestinal slow waves; they also initiate pyloric contraction and relaxation. In gastroparesis, decreased nitrous oxide levels may contribute to increased pyloric tone.[1] Increased localized inflammatory cell infiltration is notable, and one possibility is that gastric stasis is associated with macrophage and CD8 T-cell infiltration of the lamina propria, an infiltration unseen in patients with functional dyspepsia but no gastroparesis.[3]

Both the parasympathetic and sympathetic nervous systems regulate gastric motility. The vagal nerve is essential, innervating over 70% of myenteric nerves. Vagus nerve motor pathways control muscle contraction of the stomach, and sensory pathways relay information to coordinate the forward propulsion of gastric contents.[12]

Idiopathic and diabetic gastroparesis are associated with antral hypomotility. In contrast, infiltrative disorders like systemic sclerosis are associated with a normal number of antral contractions but a decreased contraction strength (amplitude). Higher postprandial gastric volume is also associated with delayed gastric emptying.[1][21] In postvagotomy and post-gastric resection patients, phasic contractility and the accommodation response of the stomach are impaired.[22]

Histopathology

Histopathologically, gastroparesis is associated with a reduced number of autonomic ganglia and inflammatory changes resulting in abnormal gastric myoelectric motor functions.[11] A study in patients with refractory gastroparesis evaluated gastric neuromuscular histopathology revealed lymphocytic infiltration of the myenteric plexus, fibrosis in the inner circular and outer longitudinal layers, and decreased interstitial cells of Cajal.[23] Gastric biopsies of patients with idiopathic and diabetic gastroparesis show loss of Cajal cells and enteric neurons and increased inflammatory infiltrates.[12][19]

History and Physical

History

Gastroparesis is a heterogeneous disorder. Symptoms do not always correlate with the degree of delayed gastric emptying, and some patients positive for gastroparesis on diagnostic testing are asymptomatic. Nausea and vomiting are the most common clinical symptoms and correlate with the degree of gastric emptying delay.[4] Other symptoms include postprandial fullness and bloating; weight loss is common in severe and persistent cases. Vomitus may contain food ingested several hours prior.[24][25] There are similarities and differences in the clinical characteristics of diabetic and idiopathic gastroparesis. Patients with idiopathic gastroparesis report more symptoms of early satiety, postprandial fullness, and abdominal pain as compared with patients with diabetic gastroparesis. Patients with diabetic gastroparesis have more severe nausea and vomiting.[10] 

Even though abdominal pain is a frequent complaint in patients with gastroparesis, it is rarely the predominant symptom. In patients whose principal symptom is abdominal pain, etiologies other than gastroparesis merit consideration.[26] Functional dyspepsia has many overlapping symptoms with gastroparesis and can occur in the same cohort of patients. Gastric emptying studies are often needed to differentiate the two conditions. Symptoms of gastroparesis may also be quantifiable via the gastroparesis cardinal symptom index, a questionnaire based on the severity of symptoms of postprandial fullness: early satiety, nausea, vomiting, and bloating.[27][28] 

Physical Examination

The physical examination of a patient with gastroparesis may reveal epigastric distention or tenderness but no guarding or rigidity suggestive of peritonitis. Patients may have signs of the underlying disorder causing gastroparesis, such as a parkinsonian tremor, diminished sensation in diabetic neuropathy, or surgical scars in cases of postsurgical gastroparesis.

Evaluation

Gastroparesis should be suspected in patients with chronic nausea, vomiting, early satiety, postprandial fullness, abdominal pain, or bloating. After obtaining a thorough history and performing a physical examination, most patients in whom gastroparesis is suspected will undergo basic laboratory testing with a metabolic panel, liver function testing, complete blood count, and lipase. Abdominal imaging often involves computed tomography (CT) scans or magnetic resonance imaging (MRI) to rule out other causes of pain and vomiting. Imaging can help exclude a mechanical obstruction, such as from malignancy. Upper GI endoscopy can also assist in ruling out obstructive etiology.

Scintigraphic gastric emptying studies (GES) are the gold standard for detecting gastroparesis. A solid or liquid radioisotope-containing meal may be used to measure gastric emptying.[29] Based on the scintigraphic gastric retention of contents after 4 postprandial hours, gastroparesis is graded as mild (< 15% retention), moderate (15% to 35% retention), and severe (> 35% retention). Some centers perform testing after 2 postprandial hours; 4-hour testing is more accurate. Adding a liquid GES study can further increase sensitivity in patients with normal gastric emptying of solids.[30]

The gastric emptying breath test (GEBT) is also used for evaluating gastroparesis. In this test, a stable isotope, ¹³C, is incorporated into a substrate, usually spirulina, and measured from the patient's breath by spectroscopy. This test is noninvasive and avoids radiation exposure. Correlation with scintigraphy is estimated at 73% to 95%. The use of GEBT is limited in patients with liver or lung disease.[4][31]

The wireless motility capsule (WMC) is another FDA-approved method for evaluating gastroparesis. The utility of WMC is limited by cost, availability, and a poor correlation with gastric emptying of food; the capsule is an indigestible solid. The WMC has an estimated sensitivity of 59% to 86% and a specificity of 64% to 81% for gastroparesis.[4][31]

Gastric ultrasonography has been utilized to assess antral wall motion, image transpyloric flow patterns, and estimate gastric emptying based on measurements of the gastric antrum. Gastric ultrasonography is limited by the lack of image detail, the need for an experienced technician, and its impracticality for prolonged examinations. However, ultrasonography is noninvasive and does not involve radiation, so it is sometimes used in children and pregnant patients.[4][31]

Treatment / Management

A holistic approach is recommended when treating patients with gastroparesis. Treatment should comprise assessment of nutritional status, measures to correct fluid, electrolyte, and nutritional deficiencies, relief of symptoms of gastroparesis, improvement of gastric emptying, and treatment of the underlying cause to prevent disease progression.[32]

Dietary Modifications

Given the importance of dietary modification, formal nutrition and dietetic consults are recommended. Small meals limit emptying time and can alleviate symptoms. Patients may need to eat 4 or 5 times daily to compensate for the small meal size. Meals composed of low-fat, low-fiber, and small-particle foods are also recommended.[33] Liquids are more easily absorbed than solids. Carbonated drinks release carbon dioxide that aggravates gastric distention. Tobacco and alcohol decrease antral contractility and impair gastric emptying.[32] Despite the prevalence of obesity in this cohort, malnutrition is common, and vitamin supplements are often required. If oral intake is inadequate, enteral nutrition via jejunostomy tube should be considered. Parenteral nutrition is rarely needed.(A1)

Pharmacological Treatment

Antiemetics such as prochlorperazine (5 to 10 mg up to 3 times daily), diphenhydramine (12.5 to 25 mg up to 4 times daily), and ondansetron (4 or 8 mg up to 3 times daily) can provide symptomatic relief in gastroparesis. The prokinetic medication metoclopramide is the only drug approved by the United States Food and Drug Administration (FDA) for gastroparesis and is usually administered 15 minutes before meals. The initial dosage is 5 mg 3 times daily. The total dose may be increased to 40 mg daily; this dose requires close monitoring for adverse reactions. The duration of treatment approved by the FDA is 12 weeks due to the possibility of severe side effects, including anxiety, restlessness, dystonia, hyperprolactinemia, and QT prolongation. Metoclopramide has a black box warning for extrapyramidal symptoms like dystonia and tardive dyskinesia, which can occur in up to 1% of patients.[34] 

Other off-label medications aimed at symptom relief include domperidone, centrally-acting antidepressants, and the serotonin type 4 (5-HT4) partial agonist tegaserod.[32] Domperidone is a dopamine-D2 antagonist that works similarly to metoclopramide to improve gastric emptying and decrease nausea and vomiting. The FDA restricts domperidone use in the United States; it is currently under review as an investigational drug. The initial dosage of domperidone is usually 10mg 3 times daily but can be increased to 20 mg per dose. Significant adverse effects of domperidone include cardiac arrhythmias and hyperprolactinemia; drug reactions are prevalent. Monitoring the QTc interval in patients taking domperidone is recommended; avoid or discontinue use if the QTc exceeds 450 ms.

Patients who cannot tolerate metoclopramide or domperidone may benefit from erythromycin, a macrolide antibiotic and motilin agonist that stimulates high-amplitude gastric fundal peristaltic contractions, thereby improving symptoms during acute exacerbations. Erythromycin can be given intravenously (3 g/kg every 8 hours) in acute cases and orally (250 to 500 mg 3 times daily) for maintenance. Patients exhibit tachyphylaxis, a decrease in response quickly due to desensitization, to erythromycin; its use is restricted to 4 weeks of continuous administration. Common side effects of erythromycin include GI toxicity, ototoxicity, bacterial resistance, and QTc prolongation. Erythromycin is the best-studied of this medication class, but clarithromycin and azithromycin have similar therapeutic and adverse effects.[31]

Nonpharmacological Therapies

Gastric electrical stimulation (GES) decreases the frequency of vomiting and the need for nutrition supplementation.[35] In patients with symptoms refractory to pharmacologic measures, GES is considered a compassionate treatment approved for diabetic and idiopathic gastroparesis. Patients with diabetic gastroparesis respond more effectively than other groups. Implantation of a GES stimulator is a surgical procedure via laparotomy or laparoscopic approach. The device consists of a pair of leads implanted in the muscularis propria 10 cm proximal to the pylorus, then connected to a pulse generator. Risks of GES placement include infection, lead migration, and perforation. The devices require battery replacement every 10 years. 

Other less studied interventions include venting gastrostomy, feeding jejunostomy, partial gastrectomy, pyloroplasty, and intrapyloric botulinum toxin injection; botulinum toxin has not been shown effective in randomized control trials. 

Investigational Therapies

Multiple prospective treatments for gastroparesis are under investigation. Granisetron, a 5-HT3 antagonist administered as a transdermal patch, appears to improve gastroparesis-related nausea and vomiting.[36] Similarly, a randomized control trial of aprepitant, a neurokinin-1 receptor antagonist, showed symptom improvement in gastroparesis patients.[37] Cannabinoids, such as dronabinol, have been considered in the treatment of gastroparesis symptoms but have not been studied in clinical trials. However, cannabinoids can also delay gastric emptying. Acupuncture has proven effective for diabetic gastroparesis in randomized control trials.[31] Other investigational therapies undergoing evaluation include elamorelin, a pentapeptide ghrelin-receptor agonist; the 5HT-4 receptor agonists prucalopride and velusetrag; and metoclopramide nasal spray.[31][38][39](B3)

Differential Diagnosis

The clinician should consider a wide differential diagnosis list in patients with symptoms of nausea and vomiting. The following conditions can present similarly to gastroparesis:

• Functional dyspepsia: very similar symptoms to gastroparesis, and a functional test is often required to differentiate these processes.[20]
• Gastric outlet obstruction: a similar presentation but with underlying mechanical obstruction. 
• Cyclical vomiting syndrome: recurrent episodes of intractable nausea and vomiting lasting hours to days.
• Rumination syndrome: a behavioral disorder that consists of daily, effortless regurgitation of undigested food after ingestion of a meal. In contrast to gastroparesis, it is not preceded by nausea or vomiting.[40][41]
• Cannabinoid hyperemesis syndrome: prolonged cannabis use can cause episodic vomiting, accompanied by a tendency for hot showers to aid symptom relief; symptoms improve with the cessation of cannabis.
• Psychiatric disorders: including anxiety neurosis, anorexia nervosa, or bulimia, could have persistent upper GI symptoms confused with gastroparesis.

Prognosis

Patients with gastroparesis may have a relatively poor quality of life due to persistent symptoms and poor nutrition.[18] In a study of 20 patients with diabetes followed for 12 years, gastric emptying symptoms were reasonably stable.[42] In another study of 86 patients with diabetes, after adjusting for comorbidities, gastroparesis symptoms did not correlate with mortality.[43] In contrast, results from a study done at a tertiary center revealed that 7% of gastroparesis patients died, and 22% of patients needed long-term enteral or parenteral nutrition after 6 years of follow-up.[25] Controlled community studies for the prognosis of gastroparesis are needed, and data from tertiary care hospitals may not accurately represent the disease outcomes in the general population. Postviral gastroparesis often improves within 12 months.[7][8]

Complications

The incidence of complications from gastroparesis will vary according to underlying etiology. Patients with longstanding gastroparesis may have the following complications:

• Severe protein-calorie malnourishment
• Bezoar formation requiring surgical resection
• Mallory-Weiss tears
• Procedure-related complications
• Recurrent hospitalizations
• Significant healthcare burden.