Gastroparesis from other causes

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 .