2012 SSAT OTHER

Gastroparesis: What is the Current State-of-the-Artfor Evaluation and Medical Management? Whatare the Results?

Allen Lee

Received: 24 April 2013 /Accepted: 10 June 2013 /Published online: 26 June 2013# 2013 The Society for Surgery of the Alimentary Tract

Abstract Gastroparesis is a chronic motility disorder that leads to delayed gastric emptying and negatively impactsmorbidity, mortality, and quality of life. This paper provides an overview of the pathophysiology leading to symptoms ingastroparesis, discusses tests for diagnosis, and examines the evidence behind different treatment options forgastroparesis. Although delayed gastric emptying is the cardinal finding in gastroparesis, other physiologic abnormalitiesmay contribute to the pathogenesis of symptoms. Gastric emptying scintigraphy is considered the gold standard for thediagnosis of gastroparesis but novel tests are currently available. Although metoclopramide is the only FDA approvedmedication to treat gastroparesis, alternative therapeutic options are available and should be tailored according tosymptoms as well as physiologic abnormalities.

Keywords Gastroparesis . Idiopathic gastroparesis .

Diabetic gastroparesis . Post-surgical gastroparesis

Background

Gastroparesis is a chronic disorder characterized by impairedgastric emptying in the absence of obstruction in the proximalGI tract. It is estimated to affect up to five million persons in theUSA with a large female predominance and an age-adjustedprevalence of 37.8 per 100,000 persons.1 Typical symptomsinclude nausea, vomiting, postprandial fullness, bloating, earlysatiation, and abdominal pain. The most common identifiableetiologies are diabetes mellitus in 30% and postsurgical causesin 19 %, but 36 % are classified as idiopathic.2

Although delayed gastric emptying is considered the car-dinal finding in gastroparesis, it is clear that the pathogenesisof symptoms is complex and involves other physiologic ab-normalities. Impaired accommodation may play a role ingastroparesis. Nitric oxide (NO) released from the gastricmyenteric plexus via a vagovagal reflex is required for gastric

relaxation. Animal models as well as human patients haveshown loss of gastric inhibitory neurons that contain NOsynthase in diabetic gastroparesis.3,4 This may explain thedefective accommodation process seen in gastroparesis withsubsequent symptoms of early satiation, bloating, and abdom-inal fullness.

There may also be neuropathic changes involving themyenteric plexus. Full-thickness gastric biopsy samples fromgastroparetic patients have shown loss of interstitial cells ofCajal.4 This may explain defective antral contractions leadingto delayed gastric emptying.

Abdominal pain may be present in gastroparesis and canbe the predominant symptom in up to 19 % of patients.Sensory nerve dysfunction may be responsible for abdomi-nal pain symptoms in gastroparesis. Barostat studies haverevealed increased symptoms of pain, nausea, and bloatingin gastroparesis.5 Histologically, full-thickness biopsy sam-ples have shown immune infiltrates within the myentericplexus suggesting a sensory neuropathy within the myentericplexus.4

Gastric dysrhythmias may also play a role in the patho-genesis of symptoms in gastroparesis. Ectopic pacemakerswithin the stomach may generate gastric dysrhythmias. Thiselectrical activity generally cannot generate normal peristal-tic activity but may precipitate symptoms of nausea andvomiting.6

A. Lee (*)University of Vermont, 111 Colchester Ave, MS 320FL4,Burlington, VT 05401, USAe-mail: allen.lee@vtmednet.org

J Gastrointest Surg (2013) 17:1553–1556DOI 10.1007/s11605-013-2254-x

Diagnosis

Currently, the diagnosis of gastroparesis largely revolvesaround testing for delayed gastric emptying. Gastricemptying scintigraphy remains the most widely utilizedtest to measure gastric emptying. However, there are stillconcerns about the standardization of the test includingthe test meal utilized, duration of imaging (2 vs. 4 h),and quantitative data (e.g., half time of emptying vs.percentage of meal emptied) that are reported. To addressthese concerns, a consensus recommendation from theAmerican Neurogastroenterology and Motility Societyand the Society of Nuclear Medicine was issued in2007. They recommended the use of a low-fat, egg-white sandwich meal with images acquired at 0, 1, 2,and 4 h after meal ingestion based on normative datafrom a large multicenter study.7 Despite these recommen-dations, there still remains a lack of standardization atsome centers which can make interpretation of the testchallenging.

Wireless motility capsule (WMC) has emerged as a novelnoninvasive method to test gastric function in an outpatientsetting. The capsule houses sensors that measures pH,temperature, and pressure. This can be utilized to measureregional transit (gastric, small bowel, and colon) times,whole-gut transit time, and pressure parameters throughoutthe gut. WMC has shown a good correlation (r=0.73) to 4-hgastric emptying scintigraphy in both healthy controls andgastroparetic patients. A gastric emptying time <5 h is able todifferentiate between normal and delayed emptying.8 However,WMCmay not be appropriate in all patient populations as thereis a small risk for capsule retention.

Treatment

Patients should be counseled on lifestyle modifications.This includes dietary changes, such as eating smaller,more frequent meals throughout the day. A diet low infat and fiber should also be emphasized as these tend toempty later in the gastric emptying process. Liquid meals,such as protein shakes or low-fat nutritional drinks, maybe helpful as liquid emptying is often preserved even incases of severe gastroparesis. Glycemic control in diabeticpatients and smoking cessation should also be emphasizedas this may worsen gastric function.2

Prokinetic agents can be used, but it is important to realizethat correlation between improvement in gastric emptyingand symptoms is poor. Metoclopramide, a D2-antagonist and5-HT4-agonist, is the only medication currently FDA ap-proved for treatment of gastroparesis. Studies have shownimprovement in symptoms and gastric emptying withmetoclopramide over placebo.9,10 However, evidence for

long-term efficacy of metoclopramide is lacking.11 There isalso the possibility of adverse reactions which may be seen inup to 40 % of subjects. Potential adverse reactions includedrowsiness, fatigue, depression, and extrapyramidal reactions,such as dystonia, akathisia, and Parkinsonian-type symptoms.The most feared complication of the medication is tardivedyskinesia which may be potentially irreversible. Nationalguidelines state that the risk may be as high as 15 % althoughprescription database studies suggest the risk is likely muchlower.12 As a result, the Food and Drug Administration re-cently issued a black box warning against chronic use ofmetoclopramide. If metoclopramide is prescribed, the risksshould be discussed and documented with the patients. Thesmallest possible dose should be initiated and titrated asneeded. Drug holidays should be considered to minimize totaldrug exposure. Alternative formulations of the drug, e.g.,liquid or sublingual, may provide more consistent absorptionand potentially allow for a lower dosage of medication.

Domperidone also acts as a D2-antagonist but has poorpenetration beyond the blood–brain barrier. It has antiemeticeffects by blockade of dopamine receptors in the area postremaand chemoreceptor trigger zone. It appears to have similarefficacy to metoclopramide but with a better side effectprofile.13 However, trials investigating domperidone have beenunderpowered, methodologically heterogeneous, and some-times uncontrolled, so results should be interpreted cautiously.Domperidone may also cause side effects including gyneco-mastia from elevated prolactin levels as well as QTprolongation.14 Although domperidone is available from cer-tain compounding pharmacies, it is not approved for use by theFDA and an investigational new drug application is recom-mended prior to starting the medication. Electrocardiogram(ECG) and electrolyte panel should be obtained prior tostarting and should be followed on an annual basis.

Erythromycin is a macrolide antibiotic that acts as amotilin receptor agonist and brings about pro-motilityeffects by inducing phase III of the migrating motor com-plex. Although studies have shown erythromycin to be apotent pro-motility agent, there is limited data available onthe efficacy of the drug for symptomatic relief ofgastroparesis.15 Prolonged use of erythromycin will bringabout downregulation of the motilin receptors and subse-quent tachyphylaxis. In addition, erythromycin may causeQT prolongation and cardiac arrhythmias. Smaller dosesof erythromycin (50 mg tid or qid) may provide a morecoordinated contractile pattern between the stomach andsmall bowel.16 Liquid formulation may allow for morerapid and consistent absorption. Drug holidays can beutilized to mitigate against tachyphylaxis with long-termuse. ECG should be obtained prior to starting the medica-tion and can be followed on an annual basis.

Botulinum toxin (Botox) injection into the pylorus has alsobeen evaluated as a potential treatment for gastroparesis. Initial

1554 J Gastrointest Surg (2013) 17:1553–1556

observational studies showed promise as Botox injectionsimproved symptoms and gastric emptying. However, random-ized, controlled studies did not show a significant benefitcompared with placebo.17 A retrospective review of 179 pa-tients with gastroparesis suggests that certain factors mightpredict a more favorable response with Botox injections, in-cluding higher dose of medication (200 units), female gender,age<50 years, and idiopathic etiology for gastroparesis.18

Although this study is intriguing, larger, controlled trials areneeded to confirm these findings.

Antiemetic therapy including 5-HT3-antagonists, suchas ondansetron; cannabinoids, including Marinol; benzo-diazepines, such as lorazepam; and H1-antagonists, suchas promethazine, can be useful in relieving symptoms ofnausea.

Pain can be a difficult symptom to treat in gastroparesis andis largely based on observational or anecdotal evidence.Selective serotonin and/or norepinephrine reuptake inhibitors,such as citalopram or duloxetine, as well as gamma aminobutyric acid analogs, such as gabapentin or pregabalin, havebeen used with varying success in gastroparesis. Tricyclicantidepressants may also be considered but should not befirst-line agents as they may cause inhibitory effects on GImotility.19 Narcotics should largely be avoided because oftheir deleterious actions on gut motility as well as potentialfor abuse.

Novel agents for treatment of gastroparesis are also beingdeveloped. Ghrelin is a gut-derived peptide that plays animportant role in the regulation of appetite and energy ho-meostasis. Dysregulation of ghrelin synthesis may be in-volved in the pathogenesis of gastroparesis, while adminis-tration of ghrelin can improve gastric motility. Ghrelin islimited by its short half-life, so synthetic ghrelin analogs,such as TZP-101, have been developed which are morestable and show high affinity for the ghrelin receptor. PhaseII trials have shown promise in improving symptoms andgastric emptying compared with placebo.20 Acotiamide, anM1 and M2 muscarinic receptor antagonist, is another novelagent that leads to enhanced acetylcholine release. It hasbeen shown to improve gastric emptying as well as accom-modation. A recent phase III trial showed that acotiamidesignificantly improved symptoms compared with placebo insubjects with functional dyspepsia.21

In conclusion, the pathogenesis of symptoms in gas-troparesis is complex, and not all symptoms are related todelays in gastric emptying. Other physiologic abnormali-ties may be present including impaired accommodation,gastric dysrhythmias, and sensory neuropathy. Althoughthere is poor correlation between improvement in gastricemptying and symptomatic improvement, the diagnosis ofgastroparesis still largely rests on testing for delays ingastric emptying. Novel testing methods may allow forthe discovery of additional abnormalities in the future that

are more difficult to diagnose currently. Finally, treatmentshould be targeted towards symptoms as well as specificphysiologic abnormalities. Novel medications are current-ly being developed to address these abnormalities, butfurther investigation is required.

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