Abstract
Gastroparesis is a motility disorder of the stomach causing delay in food emptying from the stomach without any evidence of mechanical obstruction. The majority of cases are idiopathic. Patients need to be diagnosed properly by formal testing, and the evaluation of the severity of the gastroparesis may assist in guiding therapy. Initially, dietary modifications are encouraged, which include frequent and small semisolid-based meals. Promotility medications, like erythromycin, and antiemetics, like prochlorperazine, are offered for symptom relief. In patients who are refractory to pharmacologic treatment, more invasive options, such as intrapyloric botulinum toxin injections, placement of a jejunostomy tube, or implantation of a gastric stimulator, can be considered. Hemin therapy and gastric electric stimulation are emerging treatment options that are still at different stages of research. Regenerative medicine and stem cell-based therapies also hold promise for gastroparesis in the near future.
Keywords: Gastroparesis, gastric emptying, gastric electrical stimulation, hemin
Introduction
Gastroparesis is a motility disorder of the stomach characterized by slowed emptying of food into the small bowel in the absence of mechanical obstruction.1 Diagnosis is usually established by evaluation of the gastric transit time with scintigraphy (gastric emptying study using solids labeled with technetium). The exact incidence of gastroparesis is not known, but it is estimated to affect about 4%–5% of the population.2 About 25%–55% of patients with insulin-dependent diabetes have diabetic gastroparesis, with a documented slightly higher incidence in patients with type 2 diabetes.3–6 Patients with gastroparesis present with variable symptoms, but the most frequently encountered symptoms include nausea, vomiting, bloating, and abdominal pain.7 Long-term gastroparesis is also associated with esophagitis, Mallory–Weiss tears, and severe peptic ulcer disease.8
Assessment of severity
The appropriate management of gastroparesis depends on the severity of the disease. There are multiple scoring systems available to access the severity of gastroparesis, but the two most commonly used systems are the Gastroparesis Cardinal Symptom Index (GCSI),9 which is a validated scoring system, and the Abell’s scoring system,10 which has yet to be validated. The GCSI score is a sum of three subscale scores (each ranging from 1–3), for the three main symptom complexes:
Postprandial fullness/early satiety
Nausea/vomiting
Bloating
The Abell Scoring system grades the severity of gastroparesis as follows:10
Grade 1 usually includes patients with mild intermittent symptoms that are controlled with diet modification and the avoidance of exacerbating agents.
Grade 2 patients have moderately severe symptoms but no weight loss and require prokinetic drugs plus antiemetic agents for control.
Grade 3 patients are refractory to medication, unable to maintain oral nutrition, and require frequent emergency room visits. These patients require intravenous fluids, medications, enteral or parenteral nutrition, and endoscopic or surgical therapy.
Treatment
General measures
Most patients with gastroparesis have dehydration and electrolyte disturbances on presentation. The objectives of treatment at this point include adequate hydration and correction of electrolyte imbalances, management of an underlying disorder (ie, diabetes mellitus), and alleviation of the presenting symptoms, such as nausea and vomiting, with medications. The patient’s current medications should be reviewed, and those that may precipitate gastric dysmotility should be discontinued. Hyperglycemia has been shown to exacerbate the symptoms of gastroparesis, so blood glucose should be optimized appropriately.11,12 Dietary modifications and symptom management with medications are recommended initially for patients with mild gastroparesis. Patients presenting with severe symptoms, such as pronounced dehydration or intractable vomiting, may need hospitalization, medications, or even more invasive interventions. These invasive interventions include intrapyloric botulinum toxin (BTX) (Botox®; Allergan Inc, Irvine, CA, USA) injections, placement of a feeding jejunostomy tube, or implantation of a gastric electrical stimulator. However, it must be mentioned that at this time, intrapyloric Botox injections and implantation of a gastric electrical stimulator remain controversial treatment options and offer varying results.
Dietary modifications
Dietary recommendations mainly involve adjustments to meal content and frequency. More liquid-based meals are recommended, as these patients usually have preserved gastric emptying with liquids. However, the intake of fats and nondigestible fibers should be discouraged as it is thought to worsen gastric emptying.13,14 Smaller and less frequent meals have also been found to be very helpful.15,16 Sometimes, patients may need enteral nutrition via a jejunostomy tube. Parenteral nutrition is usually reserved for patients who fail enteral feeding.17
Medications
Over the last decade, multiple research groups have been working towards the development of new medications that can improve gastric emptying and decrease the symptoms of gastroparesis. But no single agent has been proven to be effective in the management of gastroparesis, thereby making treatment of gastroparesis a challenging task for the health care provider.
Prokinetic medications
Prokinetic agents increase antral contractility, correct gastric dysrhythmias, and improve coordination between the antrum and duodenum, thereby promoting the movement of contents from the stomach.17 These medications have modest efficacy, and their response should be judged clinically.18
Motilin receptor agonists
The macrolide, erythromycin is a potent prokinetic, but it has the side effects associated with being an antibiotic. However, the doses required for its gastric emptying effect are much lower than the doses associated with its antibiotic properties. The development of tolerance to the medication is a major problem.
Mitemcinal is a macrolide-derived motilin receptor agonist with prokinetic properties. Research has shown that a dose of 10 mg twice daily of mitemcinal had significant effects on upper gastrointestinal symptoms in patients with types 1 and 2 diabetes.19
Atilmotin, another motilin receptor agonist, when given intravenously, has been shown to accelerate gastric emptying of liquids and solids in healthy subjects, without significant effects on colonic transit.20 No study has yet shown this effect on patients with gastroparesis.
Ghrelin is derived from the gastric mucosa and is similar in structure to motilin. It seems to play an important role in the regulation of appetite and body weight. Ghrelin has been shown to have prokinetic motility-stimulating properties in animals. It was also shown to accelerate gastric emptying after a test meal, in diabetic patients with slow gastric emptying,21 while another study showed that the administration of ghrelin in patients with idiopathic gastroparesis improved gastric emptying.22
Dopamine receptor antagonists
Metoclopramide is currently the only US Food and Drug Administration (FDA)-approved medication used in the treatment of gastroparesis. It is a benzamide derivative that is structurally similar to procainamide. It primarily acts as a dopamine D2 receptor antagonist but stimulates 5-hydroxytryptamine 4 (5-HT4) receptors. These effects result in the release of acetylcholine within the gut wall, leading in turn to increased lower esophageal sphincter tone, antral contractility, fundic tone, and antroduodenal tone.23 The resulting effect of accelerated gastric emptying has been demonstrated in several studies.24,25 Metoclopramide can cross the blood–brain barrier, leading to multiple neurological changes. Discontinuation of the drug should be strongly considered once a suspicion of this side effect arises. Metoclopramide has also been shown to cause or precipitate extrapyramidal movement disorders, such as Parkinsonism, tardive dyskinesia, and akathisia. Somnolence, anxiety, depression, and reduced mental acuity have also been reported.23,26,27
Domperidone, another dopamine receptor antagonist, is only approved as an investigational drug in the United States. It chiefly acts as a peripheral dopamine D2 receptor antagonist, with a mechanism of action similar to that of metoclopramide. It accelerates gastric emptying by inhibiting fundic relaxation while promoting antroduodenal coordination and is presently widely used in many countries outside the United States.
Sulpiride is another dopamine antagonist that is currently used for some psychotic disorders. Itopride is a new D2 antagonist with antiacetylcholinesterase effects. Many studies have shown the prokinetic properties of itopride in animals but so far, similar results are lacking in human subjects.28,29 One possible explanation for the effects of the D2 antagonists on gastrointestinal symptoms despite minimal effects on motility may be the action of these compounds on central emetic mechanisms.
5-HT4 agonists
Cisapride was formerly the treatment of choice for gastroparesis and gastroparesis-related symptoms. However, it has now been withdrawn from the market due to significant cardiac side effects. Presently, it is only available under compassionate care programs. No other 5-HT4 agonists have been approved for the treatment of gastroparesis.
The 5-HT4-agonist tegaserod has showed conflicting results in studies of gastric emptying in healthy subjects.30,31
Botulinum toxin
BTX has previously been used for the treatment of spasm in gastrointestinal sphincters, such as the lower esophageal sphincter, the sphincter of Oddi, and the anal sphincter. Recently, BTX has been injected intrapylorically for the treatment of gastroparesis. The BTX injections improve gastric emptying by decreasing the release of excitatory transmitter substances to the pyloric muscles. In recent research from Philadelphia on 63 patients with gastroparesis, 43% of the patients experienced a symptom response to BTX.32 The duration of the response was approximately 5 months, and the response rate was higher in male patients compared with female patients. However, a crossover, randomized study from Belgium of 23 patients with predominantly idiopathic gastroparesis found that BTX was not superior to a placebo injection with respect to effects on symptoms and on gastric emptying.33 The role of BTX remains controversial in the treatment of severe gastroparesis.
Gastric electrical stimulation
The frequency and direction of gastric peristalsis are determined by the gastric electrical slow wave rhythm. Many experiments in animals have shown that by increasing the electrical stimulation, the peristaltic pressure waves can be increased, resulting in improvement in nausea and vomiting.34 These results have led to the development of a fully implantable electronic device.
Surgical interventions
Refractory gastroparesis, defined as the failure of symptoms to respond to medical therapy, coupled with the inability to meet nutritional requirements can be encountered in some patients. In these patients with severe gastroparesis, endoscopic and surgical options should be considered. Surgical placement of a jejunostomy tube should be considered in patients requiring frequent hospitalizations for hydration, nutrition, and medications. Laparoscopic jejunostomy can be performed safely. Some major complications, such as displacement, obstruction, and aspiration pneumonia, may result after the procedure.35 In one retrospective study of patients with diabetic gastroparesis, 39% reported fewer symptoms of nausea and vomiting, 52% reported fewer hospitalizations, 56% reported better nutritional status, and 83% reported improved overall health after surgical intervention.36 Simultaneous placement of a gastric tube with the laparoscopic jejunostomy may be necessary, to facilitate abdominal decompression and symptom relief. If laparoscopy is difficult or impossible to perform because of altered intra-abdominal anatomy, the implantation can be performed by laparotomy. The latter technique prolongs postoperative hospital stay for most patients.37
Future directions
Advances in understanding the pathophysiology of gastroparesis have led to the development of many new potential treatment options and overall, the outlook is encouraging.38 Induction of the heme oxygenase-1 pathway has been shown to counter cellular changes related to the gastrointestinal complications of diabetes. It is believed that high levels of heme oxygenase-1 exert a protective effect on the interstitial cells of Cajal by decreasing oxidative stress.39 Currently, there is a pilot study going on that is investigating the efficacy of hemin, a therapy that induces heme oxygenase-1 expression in macrophages.39 Further research is aimed at studying macrolide derivatives that are motilin receptor agonists that do not have antimicrobial activity. Gastric electrical stimulation has shown promising results in improving gastrointestinal symptoms. Regarding the goal of achieving sustainable stimulation, alternative options include long-pulse high-energy, single-channel, and multichannel with long pulse gastric electrical stimulation.38 Other future treatment possibilities involve advances in regenerative medicine, particularly stem cell-based therapies. Stem cells are uncommitted cells characterized by their ability to undergo mitotic division and to cultivate into a variety of differentiated, specialized cells.40 Upon reprogramming, these stem cells would theoretically be able to provide an unlimited source of patient-specific replacement cells.40 Stem cell-based therapies would aim to restore tissue integrity, such as in the regeneration of interstitial cells of Cajal that are lost in diabetic gastroparesis or alleviation of the inflammatory changes seen in idiopathic gastroparesis.
Footnotes
Disclosure
The authors report no conflicts of interest in this work.
References
- 1.Parkman HP, Hasler WL, Fisher RS, American Gastroenterological Association American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology. 2004;127(5):1592–1622. doi: 10.1053/j.gastro.2004.09.055. [DOI] [PubMed] [Google Scholar]
- 2.Hasler WL. Gastroparesis: symptoms, evaluation, and treatment. Gastroenterol Clin North Am. 2007;36(3):619–647. doi: 10.1016/j.gtc.2007.07.004. ix. [DOI] [PubMed] [Google Scholar]
- 3.Kong MF, Horowitz M, Jones KL, Wishart JM, Harding PE. Natural history of diabetic gastroparesis. Diabetes Care. 1999;22(3):503–507. doi: 10.2337/diacare.22.3.503. [DOI] [PubMed] [Google Scholar]
- 4.Nowak TV, Johnson CP, Kalbfleisch JH, et al. Highly variable gastric emptying in patients with insulin dependent diabetes mellitus. Gut. 1995;37(1):23–29. doi: 10.1136/gut.37.1.23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Moldovan C, Dumitrascu DL, Demian L, Brisc C, Vatca L, Magheru S. Gastroparesis in diabetes mellitus: an ultrasonographic study. Rom J Gastroenterol. 2005;14(1):19–22. [PubMed] [Google Scholar]
- 6.Horowitz M, Su YC, Rayner CK, Jones KL. Gastroparesis: prevalence, clinical significance and treatment. Can J Gastroenterol. 2001;15(12):805–813. doi: 10.1155/2001/628102. [DOI] [PubMed] [Google Scholar]
- 7.Soykan I, Sivri B, Sarosiek I, Kiernan B, McCallum RW. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci. 1998;43(11):2398–2404. doi: 10.1023/a:1026665728213. [DOI] [PubMed] [Google Scholar]
- 8.Parkman HP, Schwartz SS. Esophagitis and gastroduodenal disorders associated with diabetic gastroparesis. Arch Intern Med. 1987;147(8):1477–1480. [PubMed] [Google Scholar]
- 9.Revicki DA, Rentz AM, Dubois D, et al. Development and validation of a patient-assessed gastroparesis symptom severity measure: the Gastroparesis Cardinal Symptom Index. Aliment Pharmacol Ther. 2003;18(1):141–150. doi: 10.1046/j.1365-2036.2003.01612.x. [DOI] [PubMed] [Google Scholar]
- 10.Abell TL, Bernstein RK, Cutts T, et al. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil. 2006;18(4):263–283. doi: 10.1111/j.1365-2982.2006.00760.x. [DOI] [PubMed] [Google Scholar]
- 11.Fraser RJ, Horowitz M, Maddox AF, Harding PE, Chatterton BE, Dent J. Hyperglycaemia slows gastric emptying in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1990;33(11):675–680. doi: 10.1007/BF00400569. [DOI] [PubMed] [Google Scholar]
- 12.Schvarcz E, Palmér M, Aman J, Horowitz M, Stridsberg M, Berne C. Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes mellitus. Gastroenterology. 1997;113(1):60–66. doi: 10.1016/s0016-5085(97)70080-5. [DOI] [PubMed] [Google Scholar]
- 13.Gentilcore D, Chaikomin R, Jones KL, et al. Effects of fat on gastric emptying of and the glycemic, insulin, and incretin responses to a carbohydrate meal in type 2 diabetes. J Clin Endocrinol Metab. 2006;91(6):2062–2067. doi: 10.1210/jc.2005-2644. [DOI] [PubMed] [Google Scholar]
- 14.Emerson AP. Foods high in fiber and phytobezoar formation. J Am Diet Assoc. 1987;87(12):1675–1677. [PubMed] [Google Scholar]
- 15.Moore JG, Christian PE, Brown JA, et al. Influence of meal weight and caloric content on gastric emptying of meals in man. Dig Dis Sci. 1984;29(6):513–519. doi: 10.1007/BF01296271. [DOI] [PubMed] [Google Scholar]
- 16.Moore JG, Christian PE, Coleman RE. Gastric emptying of varying meal weight and composition in man. Evaluation by dual liquid- and solid-phase isotopic method. Dig Dis Sci. 1981;26(1):16–22. doi: 10.1007/BF01307971. [DOI] [PubMed] [Google Scholar]
- 17.Parkman HP, Hasler WL, Fisher RS, American Gastroenterological Association American Gastroenterological Association medical position statement: diagnosis and treatment of gastroparesis. Gastroenterology. 2004;127(5):1589–1591. doi: 10.1053/j.gastro.2004.09.054. [DOI] [PubMed] [Google Scholar]
- 18.Talley NJ. Diabetic gastropathy and prokinetics. Am J Gastroenterol. 2003;98(2):264–271. doi: 10.1111/j.1572-0241.2003.07268.x. [DOI] [PubMed] [Google Scholar]
- 19.McCallum RW, Goldstein BJ. Diabetic gastroparesis: effect of metemcinal by subgroup analysis in a 12-week, randomized, multi-center, double blind, placebo-controlled phase 2b study. Gastroenterology. 2006;130(Suppl 2):A598. Abstract. [Google Scholar]
- 20.Park MI, Ferber I, Camilleri M, et al. Effect of atilmotin on gastrointestinal transit in healthy subjects: a randomized, placebo-controlled study. Neurogastroenterol Motil. 2006;18(1):28–36. doi: 10.1111/j.1365-2982.2005.00726.x. [DOI] [PubMed] [Google Scholar]
- 21.Murray CD, Martin NM, Patterson M, et al. Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut. 2005;54(12):1693–1698. doi: 10.1136/gut.2005.069088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Tack J, Depoortere I, Bisschops R, Verbeke K, Janssens J, Peeters T. Influence of ghrelin on gastric emptying and meal-related symptoms in idiopathic gastroparesis. Aliment Pharmacol Ther. 2005;22(9):847–853. doi: 10.1111/j.1365-2036.2005.02658.x. [DOI] [PubMed] [Google Scholar]
- 23.Rao AS, Camilleri M. Review article: metoclopramide and tardive dyskinesia. Aliment Pharmacol Ther. 2010;31(1):11–19. doi: 10.1111/j.1365-2036.2009.04189.x. [DOI] [PubMed] [Google Scholar]
- 24.Perkel MS, Moore C, Hersh T, Davidson ED. Metoclopramide therapy in patients with delayed gastric emptying: a randomized, double-blind study. Dig Dis Sci. 1979;24(9):662–666. doi: 10.1007/BF01314461. [DOI] [PubMed] [Google Scholar]
- 25.McCallum RW, Ricci DA, Rakatansky H, et al. A multicenter placebo-controlled clinical trial of oral metoclopramide in diabetic gastroparesis. Diabetes Care. 1983;6(5):463–467. doi: 10.2337/diacare.6.5.463. [DOI] [PubMed] [Google Scholar]
- 26.Miller LG, Jankovic J. Metoclopramide-induced movement disorders. Clinical findings with a review of the literature. Arch Intern Med. 1989;149(11):2486–2492. doi: 10.1001/archinte.149.11.2486. [DOI] [PubMed] [Google Scholar]
- 27.Ganzini L, Casey DE, Hoffman WF, McCall AL. The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Arch Intern Med. 1993;153(12):1469–1475. [PubMed] [Google Scholar]
- 28.Holtmann G, Talley NJ, Liebregts T, Adam B, Parow C. A placebo-controlled trial of itopride in functional dyspepsia. N Engl J Med. 2006;354(8):832–840. doi: 10.1056/NEJMoa052639. [DOI] [PubMed] [Google Scholar]
- 29.Choung RS, Talley NJ, Peterson J, et al. A double-blind, randomized, placebo-controlled trial of itopride (100 and 200 mg three times daily) on gastric motor and sensory function in healthy volunteers. Neurogastroenterol Motil. 2007;19(3):180–187. doi: 10.1111/j.1365-2982.2006.00869.x. [DOI] [PubMed] [Google Scholar]
- 30.Degen L, Petrig C, Studer D, Schroller S, Beglinger C. Effect of tegaserod on gut transit in male and female subjects. Neurogastroenterol Motil. 2005;17(6):821–826. doi: 10.1111/j.1365-2982.2005.00715.x. [DOI] [PubMed] [Google Scholar]
- 31.Talley NJ, Camilleri M, Burton D, et al. Double-blind, randomized, placebo-controlled study to evaluate the effects of tegaserod on gastric motor, sensory and myoelectric function in healthy volunteers. Aliment Pharmacol Ther. 2006;24(5):859–867. doi: 10.1111/j.1365-2036.2006.03049.x. [DOI] [PubMed] [Google Scholar]
- 32.Bromer MQ, Friedenberg F, Miller LS, Fisher RS, Swartz K, Parkman HP. Endoscopic pyloric injection of botulinum toxin A for the treatment of refractory gastroparesis. Gastrointest Endosc. 2005;61(7):833–839. doi: 10.1016/s0016-5107(05)00328-7. [DOI] [PubMed] [Google Scholar]
- 33.Arts J, Caenepeel P, Holvoet L, et al. A sham-controlled study of intrapyloric injection of botulinum toxin in gastroparesis. Gastroenterolog y. 2005;128(Suppl 2):A81. doi: 10.1111/j.1365-2036.2007.03467.x. Abstract. [DOI] [PubMed] [Google Scholar]
- 34.Familoni BO, Abell TL, Nemoto D, Voeller G, Johnson B. Efficacy of electrical stimulation at frequencies higher than basal rate in canine stomach. Dig Dis Sci. 1997;42(5):892–897. doi: 10.1023/a:1018804128695. [DOI] [PubMed] [Google Scholar]
- 35.Hotokezaka M, Adams RB, Miller AD, McCallum RW, Schirmer BD. Laparoscopic percutaneous jejunostomy for long term enteral access. Surg Endosc. 1996;10(10):1008–1011. doi: 10.1007/s004649900225. [DOI] [PubMed] [Google Scholar]
- 36.Fontana RJ, Barnett JL. Jejunostomy tube placement in refractory diabetic gastroparesis: a retrospective review. Am J Gastroenterol. 1996;91(10):2174–2178. [PubMed] [Google Scholar]
- 37.Al-Juburi A, Granger S, Barnes J, et al. Laparoscopy shortens length of stay in patients with gastric electrical stimulators. JSLS. 2005;9(3):305–310. [PMC free article] [PubMed] [Google Scholar]
- 38.Kashyap P, Farrugia G. Diabetic gastroparesis: what we have learned and had to unlearn in the past 5 years. Gut. 2010;59(12):1716–1726. doi: 10.1136/gut.2009.199703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Choi KM, Kashyap PC, Dutta N, et al. CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice. Gastroenterology. 2010;138(7):2399–2409. doi: 10.1053/j.gastro.2010.02.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Jaenisch R, Young R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell. 2008;132(4):5675–5682. doi: 10.1016/j.cell.2008.01.015. [DOI] [PMC free article] [PubMed] [Google Scholar]