William L. Hasler, MD

Disclosures

Medscape J Med. 2008;10(1):16 

In This Article

Etiology

Gastroparesis has many causes. In a case series of 146 gastroparesis patients seen at a large US tertiary medical center, 29% had underlying diabetes, 13% developed symptoms after gastric surgery, and 36% were idiopathic.[4] The mean age of onset for gastroparesis is 34 years. Eighty-two percent of cases occur in women.[4]

Epidemiology. The systemic disease most often complicated by development of gastroparesis is diabetes mellitus. In one population-based survey,[12] 18% of diabetic patients reported upper gastrointestinal symptoms, a greater proportion than reported by nondiabetic controls. The prevalence of delayed emptying in those patients with long-standing type 1 diabetes ranges from 27% to 58%.[13] Likewise, gastroparesis is present in up to 30% of patients with type 2 diabetes.[14] Diabetes more profoundly affects gastric motor function than small bowel transit, indicating an increased sensitivity of the stomach to diabetic injury. In diabetic patients on hemodialysis, development of gastroparesis correlates with the presence of orthostatic hypotension, prior myocardial infarction or cerebrovascular accident, and gangrene of the extremities.[15] Patients with diabetes secondary to chronic pancreatitis also may develop gastroparesis.

Pathogenesis. Delayed emptying of solids in diabetic gastroparesis traditionally is believed to result from impaired phasic antral contractions, but other factors contribute to impaired gastric evacuation. Increased postprandial antral diameter on ultrasonography suggests defects in tone. Increased liquid retention in the fundus and prolonged solid food retention in both the proximal and distal stomach occur in diabetic patients with gastroparesis, demonstrating altered intragastric distribution. Improperly timed pyloric contractions of abnormal intensity (> 10 mm Hg) and duration (> 3 minutes) leading to pylorospasm are observed in some patients with diabetes.[16] Others exhibit abnormal postprandial jejunal burst contractions which retard gastric outflow.[17]

Autonomic neuropathy is a likely contributor to the pathogenesis of delayed emptying in patients with long-standing diabetes. Gastric acid output in response to sham feeding is reduced by two thirds in diabetic patients, indicating vagal neuropathy.[18] Histologic study of vagus nerves from affected patients with diabetes reveals variable degrees of myelin degeneration.[19] Other measures of dysautonomia, including postural hypotension and loss of vagotonic cardiac reflexes, are prominent in diabetic patients with gastroparesis. In type 1 diabetes, delays in emptying correlate with the degree of cardiovascular autonomic neuropathy but not peripheral neuropathy.[20]

Nonneuropathic factors lead to delayed emptying in diabetes as well. In a longitudinal study of patients with type 1 and type 2 diabetes, the prevalence of autonomic neuropathy increased from 35% to 80% over 12 years, but emptying rates did not worsen, indicating that progressive neuropathy did not promote development of gastroparesis.[21] Diabetic animals show impaired contractility at the smooth muscle level.[22] Histopathologic examination of gastric specimens from 4 diabetic patients with gastroparesis who underwent gastric resection revealed smooth muscle degeneration and fibrosis with eosinophilic inclusion bodies.[23] Impaired smooth muscle contractile responses in type 1 diabetes may also occur because of circulating antibodies to L-type calcium channels.[24] Interstitial cells of Cajal (ICCs), in concert with smooth muscle and nerves, play a crucial role in regulating gastric motor function. One subset of ICCs in the circular muscle relays and amplifies information from enteric neurons to smooth muscle cells, while another population in the myenteric plexus generates rhythmic electrical depolarizations (slow waves) that control the frequency and direction of gastric contractions. Depletion of myenteric and smooth muscle ICCs was observed in one insulin-dependent diabetic patient with severe gastroenteropathy.[25] In another study of diabetic patients undergoing gastric surgery, disruption of gastric ICC networks correlated with loss of normal slow wave cycling on preoperative testing.[26] Tissues from patients with type 2 diabetes show ICC losses that are more prominent in circular muscle than in the myenteric plexus.[27] One unpublished observation suggests that the histopathology of diabetic gastroparesis is highly variable, even between individuals with similar degrees of gastric stasis. Gastric tissue from one individual with an abrupt symptom onset and well-controlled diabetes showed no morphologic abnormalities, whereas tissue from another with long-standing, poorly controlled diabetes exhibited muscle fibrosis, loss of myenteric neurons, and reduced staining for many neurotransmitter and ICC markers.[28] Some histologic deficits may be linked to single pathogenic defects. In a murine model, decreased insulin and insulin-like growth factor-I signaling reduced stem cell factor production and led to muscle atrophy that in turn promoted ICC depletion.[29] The observation that the mitochondrial DNA mutation 3243 predisposes to gastroparesis in type 2 diabetes suggests that genetic factors also contribute to disease development.[30]

Metabolic factors participate in the control of gastric emptying. Hyperglycemia in the absence of neuropathy or myopathy disrupts normal antral motor complexes at plasma glucose levels as low as 140 mg/dL in healthy humans.[31] In type 1 and type 2 diabetes, gastric emptying of liquids is delayed when blood glucose levels exceed 270 mg/dL.[14] Likewise, in type 1 diabetes, delays in solid emptying are observed during hyperglycemia which improve during euglycemia. Hyperglycemia also blunts motor responses to prokinetic drug treatment of diabetic gastroparesis.[32,33]

Epidemiology. Idiopathic gastroparesis is at least as common as diabetic gastroparesis in most case series.[4] Patients typically are young or middle-aged and up to 90% are women. Although many individuals report an insidious clinical course with no obvious trigger, one fourth present with an acute onset of symptoms in association with acute gastroenteritis or with viral prodromal symptoms such as diarrhea, fever, myalgias, and headache.[34] Postinfectious idiopathic gastroparesis has a relatively good prognosis, with symptom resolution over several years in many cases. In most instances, the offending organism is not characterized. However, 8 of 11 children with acute-onset gastroparesis in one study tested positive for rotavirus infection.[35] Transient slowing of gastric emptying also develops after infection with parvovirus-like agents and with Lyme disease. In immunosuppressed individuals, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, and herpes simplex virus may be implicated.[36,37] In one case, postinfectious gastroparesis occurred as part of a larger dysautonomic syndrome also involving cardiac conduction and bladder function.[38] Furthermore, gastroparesis has been observed after vaccination for tetanus, anthrax, and hepatitis.[39]

Pathogenesis. The pathogenic basis of idiopathic gastroparesis is less well studied than that for diabetic gastroparesis. Most patients do not exhibit underlying neuropathy. Pre- and postprandial gastric pH levels measured by a radiotelemetry capsule are higher in diabetic patients with gastroparesis than in those with idiopathic gastroparesis, suggesting a lesser degree of vagal neuropathy in individuals with idiopathic disease.[40] Similarly, plasma pancreatic polypeptide responses to sham feeding are normal in patients with idiopathic gastroparesis but are markedly blunted in diabetic patients with gastric stasis, indicative of greater vagal damage secondary to diabetes.[41] As in patients with diabetes, histologic examination of gastric tissue from patients with idiopathic gastroparesis may reveal loss of ICCs and myenteric neurons.[26,42] Isolated gastric myopathy also has been described as a cause of idiopathic gastroparesis.[43] Inflammatory mechanisms may play a role in some cases. Prominent eosinophilic infiltrates were noted in the smooth muscle layers and around nerve fibers in the gastric wall in tissues from 2 gastroparesis patients undergoing gastrectomy.[44] Another patient with idiopathic gastroparesis exhibited increases in CD4+ and CD8+ T lymphocytes in the gastric myenteric plexus and reductions in myenteric neuronal staining for tachykinins.[45]

Epidemiology. Gastroparesis may complicate surgery performed on the stomach. Approximately 5% of patients who undergo vagotomy and drainage for ulcer disease or malignancy experience nausea, vomiting, and early satiety due to postoperative gastric stasis.[46] Roux-en-Y gastrojejunostomies may be complicated by the Roux stasis syndrome, which presents with nausea, vomiting, abdominal pain, and delayed gastric emptying resulting from either spastic or retroperistaltic Roux limb contractions.[47] Esophagectomy with gastric pull-through or with colonic interposition may cure esophageal neoplasm but can lead to gastroparesis. Half of patients undergoing pylorus-preserving Whipple procedures for pancreatic cancer or chronic pancreatitis develop delayed emptying. Gastroparesis commonly occurs after lung and heart-lung transplantation and may cause microaspiration into the transplanted lung.[48] Gastric bypass and gastroplasty performed for morbid obesity delay gastric emptying of solids and promote fundic distention, leading to early satiety, anorexia, and weight loss. However, some individuals exhibit rapid emptying of caloric liquids which may limit the degree of weight loss.[49] Numerous recent cases of postsurgical gastroparesis have developed after fundoplication for gastroesophageal reflux disease.[50] In many instances, it is uncertain whether gastric motor impairments were present preoperatively or whether they occurred as a consequence of the surgery. It is estimated that 4% to 40% of patients undergoing laparoscopic fundoplication develop intraoperative vagal damage to some degree.[50] Some centers have advocated preoperative gastric scintigraphy in those being considered for fundoplication to detect individuals at risk for gastroparesis.

Pathogenesis. Abnormal antral peristalsis and fundic tone are demonstrable in patients with postsurgical gastroparesis. In one study, 8 of 9 patients with gastroparesis had no fasting motor cycles.[51] Increases in intragastric volumes, impaired fundic responses to meals and balloon inflation, and heightened perception of gastric distention are also observed after vagotomy, documenting combined motor and afferent defects in this condition.[52] Gastroparesis occurring after fundoplication likely results from operative compression or severing of the vagus nerves. As evidence of this, one study reported reductions in antral postprandial phasic contractions after fundoplication.[53]

Approximately 25% to 30% of cases of gastroparesis are not idiopathic and are not secondary to diabetes or postoperative gastric motor dysfunction. Etiologies in such instances include disorders with isolated gastric dysmotility, conditions with diffuse motor dysfunction involving most or all of the gastrointestinal tract, and nongastrointestinal diseases with associated emptying delays.

Other disorders with isolated gastric motor dysfunction. Some disorders present with isolated impaired gastric motor function. Delayed emptying of liquids, solids, or mixed meals has been reported in up to 57% of patients with gastroesophageal reflux, while other studies have demonstrated no abnormalities.[54] Delays in emptying in patients with gastroesophageal reflux disease correlate poorly with symptoms, lower esophageal sphincter pressure, and esophageal acid exposure.[55] Gastric stasis is observed in up to 60% of individuals with nonobstructing pancreatic carcinoma and in smaller numbers of patients with other malignancies.[56,57] Severe nausea, vomiting, and impaired gastric evacuation are common after abdominal irradiation.[58] Delayed solid emptying is noted in atrophic gastritis with or without pernicious anemia.[59] In this condition, reductions in gastric secretion increase the time needed to fragment solid foods to tiny particles. The median arcuate ligament syndrome is an entity caused by compression of the celiac axis by a fibrous band that presents with postprandial pain, nausea, vomiting, weight loss, and delayed gastric emptying and can be relieved by surgical decompression.[60] Ischemic gastroparesis results from celiac arterial occlusion.[61] Some patients with inactive Crohn's disease and no radiographic evidence of obstruction may present with markedly delayed gastric emptying and severe symptoms of gastroparesis.[62]

Disorders of diffuse gastrointestinal dysfunction with associated gastroparesis. Gastroparesis frequently occurs in patients with diffuse disorders of gut motility, such as chronic intestinal pseudo-obstruction. These individuals may also present with small intestinal bacterial overgrowth, nutritional deficiencies, bowel habit abnormalities, and pneumatosis intestinalis. The prevalence of delayed emptying in scleroderma ranges from 40% to 67%, whereas rates in polymyositis-dermatomyositis and systemic lupus erythematosus are lower.[63] Gastric stasis is described in smooth muscle disorders such as myotonic dystrophy and progressive muscular dystrophy. Primary or secondary amyloidosis can cause neuropathic or myopathic intestinal pseudo-obstruction.[64,65,66,67] Gastric stasis is found in 19% to 64% of patients with chronic constipation, irritable bowel syndrome with constipation, and idiopathic megarectum.[68] Other cases of intestinal pseudo-obstruction are familial, occur after a viral prodrome, or present as a paraneoplastic phenomenon, usually with small-cell lung carcinoma.[69] Serologic markers in paraneoplastic gastroparesis or intestinal pseudo-obstruction include type 1 antineuronal nuclear antibody, anti-Purkinje cell cytoplasmic antibody, and ganglionic nicotinic acetylcholine receptor antibody.[70] Such antineuronal antibodies are also detected in some patients with idiopathic gastrointestinal dysmotility syndromes with an autoimmune basis.[71] In addition to producing an achalasia-like picture, Chagas disease may cause gastroparesis, megaduodenum, and chronic intestinal pseudo-obstruction. Other infectious agents that produce generalized gut dysmotility include varicella zoster, Epstein-Barr virus, Clostridium botulinum, and HIV.[37,72,73]

Nongastrointestinal disorders with associated delays in gastric emptying. Neurologic diseases may present with delayed gastric emptying. More than 7% of a large series of gastroparesis patients had underlying Parkinson's disease.[4] Drugs used to treat Parkinson's disease may exacerbate gastric stasis in this condition. Disturbed gastric motility is also observed with cerebrovascular accident, migraine headaches, high cervical spine injury, and peripheral nerve disorders such as stiff-man syndrome and Charcot-Marie-Tooth syndrome.[74] Some patients with familial dysautonomia, Shy-Drager syndrome, Guillain-Barré syndrome, multiple sclerosis, and other demyelinating disease may exhibit gastric stasis or intestinal pseudo-obstruction.[74]

Gastroparesis is rarely found in eating disorders. Retarded gastric emptying and reduced antral contractions are observed in some patients with anorexia nervosa.[75] It is possible that these motor disturbances are consequences of the disorder, as malnutrition itself impairs gastric evacuation and improved nutrition promotes accelerated solid emptying.[76] In rare instances, patients with bulimia nervosa exhibit delayed gastric emptying. Rumination syndrome usually is not associated with gastric stasis.[77] Characteristic simultaneous contractions on antroduodenal manometry are detected in many cases, which reflects increases in abdominal wall tone. However, one study reported small reductions in postprandial antral contractions in patients with rumination.[78]

Other conditions affect gastric emptying and can produce gastroparesis symptoms. Studies of gastric emptying during nausea of pregnancy using nonradioactive methods have reported variable results, with some studies showing delays and others observing normal emptying.[79] Cyclic vomiting syndrome is characterized by intermittent attacks of relentless nausea and vomiting with prolonged intervening asymptomatic periods.[80] Most investigations observe acceleration rather than delay of emptying in adults with cyclic vomiting syndrome.[81] However, one study reported reduced antral motor activity after eating in 5 of 8 cyclic vomiting patients.[82] Gastroparesis or intestinal pseudo-obstruction may complicate severe hypothyroidism as well as hyper- and hypoparathyroidism. Other diseases associated with gastroparesis include chronic pancreatitis, cystic fibrosis, cirrhosis, and chronic renal insufficiency. Genetic disorders such as Turner's syndrome may predispose to delays in gastric emptying. Many prescription medications delay emptying, as can tobacco, excess ethanol, or cannabis.[83,84,85] Total parenteral nutrition impairs gastric evacuation. This effect correlates with increases in serum glucose and is minimized by replacement of half of the amino acid content with branched-chain amino acids.[86]

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