Introduction

The most common etiologies of gastroparesis are typically understood to be post-infectious, post-operative, diabetic, and idiopathic (the latter often overlapping with post-infectious gastroparesis, which can be difficult to identify confidently by clinical history). Case series often frame idiopathic gastroparesis as the single most common etiologic category . There are, however, a variety of less common pathophysiologic mechanisms by which gastric motor function can be disturbed and that can likewise be difficult to identify discretely ( Table 21.1 ). This chapter will provide a review of these entities, which should be borne in mind when confronted with a patient with ostensibly idiopathic gastroparesis, not least because mechanistic clarity can hold promise for a more targeted approach to therapy.

Medications

Numerous common medications can affect gastrointestinal motility at various segments, including the stomach ( Table 21.2 ). Indeed, discontinuing such agents prior to formal measurements of gastric transit is deemed judicious in order to mitigate the likelihood of spurious results . Recognizing the potential role of such medications in driving or exacerbating gastroparesis symptoms suggests a relatively straightforward mode of partial or complete symptom reversal.

Opioid analgesics are perhaps the most classic example of a pharmaceutical class with deleterious effects on gastrointestinal motility. In recent years, progressive scrutiny has been placed on these agents in accordance with increasing awareness of associated substance use disorders and deaths, though the use of opioids in medical contexts remains significant . Chronic opioid use is also common among patients with pain-predominant gastroparesis given the paucity of other treatment options, which can sometimes make it difficult to separate cause and effect .

Opioids target a number of receptors in humans, including the mu-opioid receptor (MOR), delta-opioid receptor (DOR), kappa-opioid receptor (KOR), and the nociceptin/orphanin FQ receptor (NOR). Among these, MOR is the best studied, with expression in the enteric nervous system at both submucosal and myenteric ganglia. Most clinically utilized opioids act as agonists at the MOR, leading to inhibition of motility via diminished luminal secretion (due to effects at the submucosal plexus) as well as diminished smooth muscle peristalsis (due to effects at the myenteric plexus) . Opioid-mediated dysmotility has been demonstrated in all segments of the gastrointestinal tract, but with specific attention to the stomach, opioids have been shown to increase pyloric tone and inhibit antral contractions . Independent of motor delays, opioids can also provoke symptoms of nausea and vomiting centrally through activation of the brain’s chemoreceptor trigger zone .

Predictably, the effects of opioids on gastric emptying are more pronounced with more potent agents (e.g. morphine) and less so with less potent agents (e.g. tramadol), though still detectable . Delays in gastric emptying have also been seen with novel opioid agents like tapentadol, designed to mitigate the risk of gastrointestinal side effects by reducing colonic transit delays . Likewise predictably, based on their direct effects on the enteric nervous system, the impact of opioids on gastrointestinal motility has been shown to be dose-dependent . A class of medications called peripherally-acting mu-opioid receptor antagonists (PAMORAs) has been devised to block the adverse impact of opioids on the gut while preserving their central analgesic effects. Agents like naldemedine, naloxegol, and methylnaltrexone have been studied rigorously and shown to be effective for the specific indication of opioid-induced constipation, but their role in more proximal opioid-mediated dysmotility, including gastroparesis, is not yet clear .

Anticholinergic medications comprise another broad pharmacologic class with deleterious effects on gastric motility. The presumptive mechanism of these effects is parasympathetic inhibition via blockage of acetylcholine, a neurotransmitter with excitatory effects in the gastrointestinal tract. Common anticholinergic agents include antipsychotic medications, tricyclic antidepressants, first-generation antihistamines, and antispasmodic medications (e.g. dicyclomine, hyoscyamine). Notably, the anticholinergic class includes several medications that are used for empiric nausea therapy (e.g. meclizine, scopolamine) . Certain antipsychotic medications like clozapine are more frequently tied to severe motility disturbances, including overt gastric transit delays, due to their high binding affinities for muscarinic receptors . While other anticholinergic agents may have milder effects independently (e.g. dicyclomine up to 20 mg three times daily with comparatively little risk of dysmotility symptoms), these medications are often used in combination, particularly in the management of complex disorders of gut-brain interaction, which can lead to compounding effects on gastrointestinal transit.

Cannabinoids constitute a therapeutic paradigm of increasing professional relevance (alongside a long history of complementary use among patients with chronic gastrointestinal symptoms). Recent attention to the motility effects of cannabinoids has demonstrated that tetrahydrocannabinol (THC) slows gastric motility but exerts antinauseant effects via central agonism of type 1 cannabinoid receptors (CB ₁ ). Gastric transit delay has also been demonstrated with the synthetic derivative dronabinol . Other cannabinoids have more complicated symptomatic effects, mitigating nausea at lower doses and promoting it at higher doses . As distinct from gastroparesis, cannabinoid hyperemesis syndrome, characterized by episodic nausea and vomiting resulting from sustained (typically a few years or longer) daily cannabinoid use, resolves with cannabinoid cessation and merits a high degree of clinical suspicion in contemporary practice, given the reasonably high proportion of patients with gastroparesis who use cannabis for therapeutic purposes, with or without a formal prescription .

Constipation and distal obstruction

Animal studies from the early 20th century demonstrated that rectal balloon distension led to inhibition of muscle activity in the stomach and proximal small bowel . These early observations have served as the foundation for an enduring interest in neurohormonal mechanisms whereby gastric emptying might be slowed as a function of constipation (a so-called cologastric reflex or brake). There are some clinical data to support this hypothesis; for example, a small study in children with dyspepsia noted longer gastric emptying times in subjects with concomitant constipation and improved dyspeptic symptoms and gastric emptying times after initiation of a daily osmotic laxative . Relatively higher rates of delayed gastric emptying have been demonstrated often in patients with disorders of gut-brain interaction primarily manifesting with lower gastrointestinal symptoms, e.g. functional constipation or irritable bowel syndrome with constipation. It is often difficult to parse the true implications of these associations, however, as the pathophysiology of these disorders is complex and incompletely understood. For instance, it may be that simultaneous slow transit constipation and delayed gastric emptying reflect the presence of a diffuse dysmotility process rather than secondary proximal transit delays caused by constipation . Obstructing lesions in the small intestine may also be associated with gastric emptying delays and should be excluded in the appropriate clinical context .

Connective tissue disorders

A number of connective tissue disorders are associated with gastrointestinal dysmotility, including systemic sclerosis, systemic lupus erythematosus, Sjogren’s syndrome, polymyositis, and dermatomyositis. Screening for these disorders may be reasonable in patients with dysmotility symptoms, particularly when extraintestinal symptoms are present that raise additional suspicion for an underlying rheumatologic process. Among these entities, systemic sclerosis is generally regarded to have the highest rate of associated dysmotility, with esophageal involvement being the most commonly affected gut segment, though gastroparesis is also noted at a prevalence of 38–50% .

Several potential explanations have been put forward regarding the pathophysiology of gastrointestinal dysmotility in systemic sclerosis, including progressive vasculopathy leading to smooth muscle damage, autonomic dysfunction mediated by parasympathetic denervation, and immune damage by circulating autoantibodies. It may be that gastrointestinal dysmotility in systemic sclerosis is mechanistically heterogeneous, which raises the question of whether targeted therapeutic interventions might eventually be developed for relevant clinical subpopulations . Given the frequency of multisegment transit delays in systemic sclerosis, there may be a special role for diffusely acting prokinetic agents .

Progressive clinical awareness of joint hypermobility syndromes, including Ehlers-Danlos syndrome (EDS), suggests another potential link between gastrointestinal dysmotility and connective tissue abnormalities. According to the most recent classification scheme, EDS includes 13 subcategories, all characterized by different genotypes and phenotypes. Genetically defined subtypes with discrete and well-defined collagen defects are generally much less prevalent than the hypermobility type of EDS (EDS-HT), which hitherto has no known genetic association and is therefore defined according to clinical criteria .

Manifestations of EDS-HT vary from asymptomatic joint hypermobility to a variety of secondary complaints, including a range of gastrointestinal symptoms. Foregut complaints including heartburn, early satiety, abdominal pain, and bloating tend to be more common in patients with joint hypermobility syndromes . Available data incorporating formal transit testing are sparse and vulnerable to selection bias, but rates of delayed gastric emptying appear to be increased in patients with joint hypermobility and upper gastrointestinal symptoms . The pathophysiology of gastrointestinal dysmotility in EDS-HT is unclear, but speculation has included ligamentous laxity in the gut’s supportive structures, predisposing to positionally dependent visceral torsion and prolapse; and putative deficits in the extracellular matrix, leading to molecular-level alterations in the gut’s mechanical properties, including distensibility .

Autoimmune and paraneoplastic phenomena

Recent attention has also been paid to the possibility of autoimmune-mediated neuropathy underlying certain cases of gastrointestinal dysmotility, including gastroparesis. Autoimmune autonomic neuropathy (AAN) and the slightly narrower autoimmune gastrointestinal dysmotility (AGID) are two descriptors for this phenomenon, which may or may not include more diffuse manifestations of autonomic dysfunction, such as orthostatic intolerance, thermoregulatory disturbances, and urinary retention . Gastrointestinal dysfunction is thought to be quite common in cases of AAN, though AGID may not necessarily manifest with widespread dysautonomia. In the latter case, it can be difficult to know when to suspect an autoimmune etiology, though the typical history of symptom onset in AGID is thought to be sudden and severe . High rates of symptomatic response to intravenous immunoglobulin (IVIG) have been reported in AGID, leading some investigators to propose empiric IVIG administration as a simultaneous diagnostic and therapeutic strategy in cases of gastroparesis otherwise refractory to medical and device-based therapy, though data for such an approach are as yet limited to small case series .

Various autoantibodies have been associated with AAN and AGID, which can be assayed when such entities are suspected clinically, though seropositivity with respect to these ad hoc panel assays is neither mandatory for diagnosis nor indicative of any specific pathology . Several of these autoantibodies (e.g. anti-Hu, anti-neuronal nuclear antibodies type 1 and 2 [ANNA-1, ANNA-2], ganglionic acetylcholine receptor antibody, voltage-gated calcium channel antibodies, etc.) have been previously identified in cases of paraneoplastic dysautonomia manifesting as gastrointestinal dysmotility. Paraneoplastic AGID is classically associated with small cell lung cancer, though it has also been reported in the context of non-small cell lung cancer, leiomyosarcoma, pancreatic cancer, and carcinoid tumors . Histologic studies in paraneoplastic dysmotility have suggested that symptoms are mechanistically driven by inflammatory destruction of interstitial cells of Cajal in the myenteric plexus and in the circular and longitudinal muscle layers related to antibodies against the enteric ganglia .

Malignancy

Malignancy may be associated with gastroparesis independent of paraneoplastic syndromes . Tumors affecting or adjacent to the upper gastrointestinal tract, including esophageal, gastric, pancreaticobiliary, breast and lung tumors, can lead to gastroparesis through vagal or celiac plexus infiltration. A small case series suggested that 60% of patients with pancreatic carcinoma had objective evidence of delayed gastric emptying, though nausea was only present in 20% of these patients, suggesting that gastroparesis in this context may be symptomatically variant or subclinical . Certain cancer therapies may also be associated with gastroparesis. Bone marrow transplantation, for example, is frequently complicated by nausea and vomiting with higher than usual rates of delayed gastric emptying on objective testing, independent of conditioning regimen, cytomegalovirus antigemia, or the presence of graft-versus-host disease . Gastroparesis has also been infrequently reported as occurring after abdominal radiation therapy .

Infiltrative disorders

Amyloidosis, an infiltrative disorder involving the extracellular deposition of abnormal protein in various organ systems, can lead to motor disturbances of the gastrointestinal tract through neuronal as well as muscular dysfunction . While systemic amyloidosis involves the stomach in less than 10% of cases, delayed gastric emptying is more common in patients with histologically confirmed gastric amyloidosis . Gastroparesis has also been reported in the context of sarcoidosis, another infiltrative disorder that can affect a variety of organ systems, often in conjunction with extraintestinal neuropathic symptoms .

Neurologic disorders

Gastroparesis can occur in a background of global, progressive neurologic disorders. Recent research has centralized the potential role of the gut in the pathogenesis of Parkinson’s disease, with specific attention to interactions between the enteric nervous system, intestinal microbiota, and immune activation pathways. In addition to autonomic neurodegeneration, intestinal permeability has been suggested as a mechanism for increased alpha-synuclein deposition in the gastrointestinal tracts of individuals with Parkinson’s disease . While a unified mechanistic model remains elusive, the implication of the enteric nervous system in disease pathogenesis correlates with the relatively high frequency of gastrointestinal symptoms observed in Parkinson’s disease, including dysphagia, nausea, and constipation, which may precede the onset of more typical motor manifestations .

Gastric emptying delays tend to be associated with progressively severe motor symptoms in Parkinson’s disease . That said, while symptoms of nausea are present in about 25% of patients with Parkinson’s disease and symptoms of bloating in about 45%, the true prevalence of gastroparesis in Parkinson’s disease is difficult to determine, in part due to methodological heterogeneity in gastric transit measurement and in part due to a number of native confounding variables, including the effects of medications like levodopa, which can itself slow gastric emptying. Because of the temporal sensitivity of levodopa dosing in patients with Parkinson’s disease, significant gastroparesis can present a therapeutic challenge by leading to unpredictable drug absorption. Potential mitigating strategies include post-pyloric medication administration via enteral tubes versus the use of prokinetic agents, including dopamine antagonists that do not cross the blood-brain barrier .

Multiple sclerosis, an autoimmune demyelinating disease of variable course, has been intermittently tied to gastroparesis in the context of case reports. Symptom onset may be acute or chronic and is typically attributed to autonomic disruption secondary to central disease foci . While rare, this association merits early recognition, as immunomodulatory therapy is likely to offer more benefit than traditional symptomatic measures . Neuromyelitis optica, a similar but distinct demyelinating disease, has been associated with gastroparesis as well . Gastric motor abnormalities also may be observed in other rare diffuse neurologic disorders, including Shy-Drager syndrome, Guillain-Barré syndrome, and stiff person syndrome .

Pancreatitis

Gastroparesis can be associated with various forms of pancreatic pathology, including pancreatic tumors and their subsequent treatment, including, for example, after pancreaticoduodenectomy . Gastroparesis has also been reported as a complication of celiac plexus block, a procedure sometimes performed for the relief of chronic pain related to pancreatic disease . Furthermore, chronic pancreatitis, and specifically idiopathic cases of small-duct or minimal change chronic pancreatitis, has been associated with a relatively high prevalence of gastric transit delay (though high background rates of opioid use tend to compound this association). Reasons remain uncertain, though one proposed mechanism is increased levels of cholecystokinin, a neurohormone that inhibits gastric emptying and that may be mediated by pancreatic insufficiency . This same association is reinforced by an increased prevalence of gastroparesis observed in advanced cases of cystic fibrosis complicated by pancreatic insufficiency . Querying gastroparesis merits consideration in clinically refractory cases of chronic pancreatitis, particularly given the significant overlap in typical symptoms between these two entities, including severe nausea, vomiting, and abdominal pain. Indeed, it may be the case that identifying and treating a comorbid gastric transit delay renders chronic pancreatitis therapy more effective .

Ischemia

Rarely, gastroparesis can be the primary manifestation of chronic mesenteric ischemia. Descriptions of this entity are limited to case reports involving either insufficiency of all three major mesenteric arteries or focal severe compromise of the celiac axis, including in the context of median arcuate ligament compression . When performed, electrogastrography in the setting of ischemic gastroparesis has suggested the disruption of normal slow wave activity. Transit delays and symptoms of ischemic gastroparesis have been noted to reverse with successful revascularization, underscoring the utility of considering this diagnosis in individuals with a history of vasculopathy or relevant risk factors .

Other medical comorbidities

While diabetes is certainly the most common endocrinopathy associated with gastroparesis, hypothyroidism has also been associated with a predisposition toward delayed gastric emptying . Associations between gastroparesis and hypocortisolism and panhypopituitarism have also been reported . Additionally, chronic renal failure and hemodialysis have been scrutinized as risk factors for gastroparesis, including in individuals without diabetes. A series investigating gastric emptying in patients with renal failure found that transit delays were more frequent prior to initiation of hemodialysis than after, raising the possibility of uremic autonomic neuropathy as the driving mechanism for these findings . In a later case series, however, over half of patients on hemodialysis who reported dyspeptic symptoms were found to have delayed gastric emptying, suggesting a persistent predisposition toward gastroparesis even after initiation of therapy .

Conclusion

Beyond the major categories of idiopathic, post-infectious, diabetic, and post-surgical gastroparesis, there are several other etiologies for gastric transit delay whose recognition may offer distinct opportunities for further high-yield diagnostic evaluation, counseling, and intervention. Some common themes emerge among those causes of gastroparesis that represent independent chronic disease entities, including the fact that an unmanaged gastric transit delay can undermine appropriate pharmacologic management of the primary process. Several of these less common causes of gastroparesis remain incompletely understood, leading to a number of opportunities for further research into pathophysiology and treatment.