Learning points

1. Explain the symptoms associated with the gastroparesis syndrome and the relationship with functional dyspepsia.
2. Discuss the physiology of gastric emptying and the methods used to assess this.
3. Explain the pharmacological management of gastroparesis.

Case history

A 33-year old woman presented with a 6-month history of epigastric pain, usually worse after eating, a feeling of fullness after eating and sometimes an inability to finish her meal. These symptoms were associated with a consistent feeling of nausea, loss of appetite and she reported vomiting about once every 2 weeks. She had lost about 5 kg in weight over this period, although her body mass index was within the normal range (22.9 kg/m²). The symptoms seemed to have begun after a bout of presumed gastroenteritis. Previous tests by her general practitioner including full blood count, renal, liver and bone profiles and Helicobacter pylori faecal antigen were all normal. A direct access upper GI endoscopy was normal, without any food reside retained in the stomach after an overnight fast. She had a progesterone-releasing intrauterine device in situ (inserted 3-years previously). She had had treatment with lansoprazole, famotidine, domperidone and cyclizine without any appreciable benefit.

She was referred for further assessment. Clinical examination was normal.

Diagnoses of functional dyspepsia and gastroparesis were considered.

What is gastroparesis?

Gastroparesis is defined as a chronic syndrome characterised by upper GI symptoms and objective evidence of delayed gastric emptying of solids in the absence of mechanical obstruction (1). The symptoms of gastroparesis overlap considerably with those of functional dyspepsia (particularly the post-prandial distress subtype) and at this point in the presentation post-prandial distress is probably the most likely diagnosis given that it is much commoner than gastroparesis.   A recent study reported that the diagnoses of gastroparesis and functional dyspepsia and the associated gastric emptying are not stable with time and that over 12 months up to 40% of patients can be reclassified as the alternative diagnosis (2).

Nausea is the single commonest symptom in gastroparesis (at least 80% of cases), followed by vomiting (70% or more) (3), all the other symptoms are also seen with gastroparesis but it is the emphasis on nausea and vomiting symptoms that are most suggestive of gastroparesis. It has been proposed that impaired gastric emptying should be best regarded as a phenotypic marker of subsets of the syndromes of functional nausea and vomiting and functional dyspepsia, rather than a separate syndrome (4).

Assessment of gastric emptying

The motility and sensory disorders in gastroparesis are complex and although gastric emptying is relatively easy to assess it is important to appreciate that other mechanisms contribute to the symptomatology and there is an inconsistent relationship between improvements in symptoms and objective gastric emptying (1,5,6). Liquids normally leave the stomach passively, under gravity. Solids are not passed out the of stomach by bolus transit (as is typically seen and measured in the oesophagus) but instead are degraded into smaller solids by the process of trituration (1). This is the grinding action of the antral contractions against the mostly closed pylorus. With time this allows the degraded solids to spill over the partially opened pylorus into the duodenum.

As gastric emptying of liquids is generally preserved in gastroparesis, methods measuring predominantly the liquid phase (barium meal, ultrasound, MRI and absorption of paracetamol) are not reliable. There are two well validated methods to assess gastric emptying of solids; ⁹⁹Tc labelled meals and the ¹³C Spirulina breath test (1,7). The latter is non-radioactive but requires calculation of the gastric passage half-life. In areas such as the UK and Europe, where the ⁹⁹Tc study is available, this is regarded as the most appropriate test. It is important to study gastric emptying for 3 to 4 hours to obtain a reliable result. In practice, retention of more than 10% of the label after 4 hours is indicative of gastroparesis (8).

The wireless motility capsule is passed from the stomach by the force of the phase 3 migrating motor complex, in the inter-meal phase. Although there is reasonable correlation between results from the motility capsule and other validated methods, it must be appreciated that this measures a somewhat different process (1).

The presence of food-residue in the stomach at endoscopy is an unreliable indicator of gastroparesis; approximately 3% of upper GI endoscopies may show intragastric residue and overall, the positive and negative predictive values of food-residue in the stomach for gastroparesis are 55% and 72% respectively (9).

As there is considerable overlap between gastroparesis and functional dyspepsia, it can be argued that in many cases assessment of gastric emptying does not alter initial management pathways (4). However, for those with refractory symptoms assessment of gastric emptying may help phenotype the disease and plan treatments (7).

Treatment

The evidence base for pharmacological treatments is poor with few high-quality trials specifically in gastroparesis populations, plus considerable extrapolation from either surrogate end points, or studies in related but different populations, such as functional dyspepsia. It is important to give medicines in an oral liquid form (or another form not relying on enteric absorption) to enhance reliable effects (1).

Opiates further delay gastric emptying and should be avoided for the treatment of pain in gastroparesis (1,7). It does not seem that the gastric effects of opiates can be antagonised by peripherally acting opiate-antagonists such as naloxegol (13). Cannabinoids also delay gastric emptying (14). Cannabis use is prevalent in the gastroparesis population and patients should generally be dissuaded from the use (1). Recently cannabidiol (a cannabinoid receptor 2 inverse agonist with central effects) has been shown in small trial to reduce symptoms associated with delayed gastric emptying, despite further delaying gastric emptying (15). Further studies with this class of agent will be informative.

Although there is some relationship between improvements in measured gastric emptying and symptoms (6), this is not universal and for some agents, maximal improvement in symptoms occurs at a much lower dose than improvement in gastric emptying (1,5,6). So-called prokinetic agents (with very different modes of action) are widely used (10). The dopamine antagonists domperidone and metoclopramide do reduce symptoms (16) but because of concerns about adverse cardiovascular events, it is often recommended that short courses of a few weeks are used rather than maintenance (1,7). The macrolide antibiotics such as erythromycin and azithromycin have subsidiary actions as motilin agonists. Although they enhance gastric emptying when given acutely, tachyphylaxis with loss of response is rapidly seen and these are probably not suitable for longer term therapy (1,7). Prokinetics, acting as 5HT₄ receptor agonists appear to be useful and safe for longer term therapy (1,7,16). In the UK, prucalopride is used off licence (10). Efficacy in idiopathic gastroparesis with 2 mg daily was demonstrated (17), although 4 mg daily was ineffective in diabetic or connective-tissue disease associated gastroparesis (18).

Although drugs with antimuscarinic effects, such as hyoscine, the non-selective histamine antagonists and tricyclic antidepressants theoretically may impair gastric emptying, in practice these are not contraindicated and may be useful for symptomatic treatments (7). The 5HT₃ antagonists, such as transdermal granisetron appear safe and have some useful effect in gastroparesis (1,5,19). Mirtazepine, a neuromodulator with a variety of pharmacological targets including  5HT₃, 5HT_2a 5HT_2c, H₁ and a2 receptors. was effective in small trial in gastroparesis (20). NK1 antagonists, such as apreptitant have small but useful effects against nausea and vomiting symptoms (1,5,21,22).

Case progress

A⁹⁹Tc-low fat egg white meal showed 22% retention at 4 hours consistent with delayed gastric emptying (retention of < 10% at 4 hours is usually regarded as normal (6). Haemoglobin A_1c was normal excluding diabetes mellitus. With dietetic support she transitioned to a low particle size diet and was treated with prucalopride and mirtazapine, with an additional 4-week course of metoclopramide for a particularly bad symptomatic period. After 12 months her symptoms are minimal.

Conclusion

Gastroparesis is a rare condition, with considerable overlap with functional dyspepsia. Impaired gastric emptying of solids is the pathological prerequisite, although other sensory and motor disturbances contribute to the symptoms. Measuring gastric emptying of solids after at least 3 hours is the key diagnostic step. Treatments should be focused on the symptoms of concern rather than trying to simply improve gastric emptying. Most cases can be satisfactorily managed by diet and pharmacological means, although in selected refractory cases, intense nutritional support, gastric electric stimulation, botulinum toxin, surgery or endoscopic myotomy (G-POEM) may all have a role (1,5).

Author Biography

Dr Beales is Clinical Associate Professor in Gastrointestinal Pharmacology, University of East Anglia and Consultant Gastroenterologist, Norfolk & Norwich University Hospital. He is currently Director of the Norwich GI Physiology Service, Director of the Norwich Endoscopy Training Centre, Chair of the BSG Gastroduodenal Section and Chair of the Examination Board and Head of Question writing for the ESEGH examination.

After qualifying from Barts in London, he completed Gastroenterology training in London, Cambridge, Norwich and undertook a period of research at University or Michigan. His initial original research for his MD was on the pathogenesis of H pylori infection and gastric secretory function. He has expanded these interests and maintains broad clinical and research interests in all aspects of GI physiology and pharmacology, as well as education and training. He has authored over 160 original papers. He is Chief and Principal investigator in a portfolio of academic and commercial clinical trials.