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Gastroparesis: Pathophysiology and management Preceptor: Dr. Govind Makharia Speaker: Dr. Moka Praneeth.

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Presentation on theme: "Gastroparesis: Pathophysiology and management Preceptor: Dr. Govind Makharia Speaker: Dr. Moka Praneeth."— Presentation transcript:

1 Gastroparesis: Pathophysiology and management Preceptor: Dr. Govind Makharia Speaker: Dr. Moka Praneeth

2  Definition  Epidemiology  Pathophysiology  Clinical Manifestations  Diagnosis  Treatment Gastroparesis-Overview

3 The diagnosis of gastroparesis is based on the combination of  symptoms of gastroparesis,  absence of gastric outlet obstruction or ulceration (documneted on UGIE or Barium swallow),  and documentation of delay in gastric emptying. Definition Michael Camilleri et al. Clinical Guideline: Management of Gastroparesis. Am J Gastroenterol 2013

4  The age-adjusted prevalence of definite gastroparesis per 100,000 person was 9.6 (95% CI, 1.8–17.4) for men and 37.8 (95% CI, 23.2–52.4) for women.  Incidence & prevalence of gastroparesis in India: ? Gastroparesis in Olmsted County, 1996–2006 Incidence Jung HK et al. J Neurogastroenterol Motil. 2010

5 Gastroparesis: Etiology Kendall and McCallum. Gastroenterology Soykan et al. Dig Dis Sci 1998.


7 Electrophysiologic basis of gastric peristaltic waves

8 Gastric neuromuscular work after ingestion of a solid meal

9  The proximal stomach serves as the reservoir of food, and the distal stomach as the grinder  Solids are initially retained in the stomach and undergo churning while antral contractions propel particles toward the closed pylorus.  Food particles are emptied once they have been broken down to approximately 2 mm in diameter Normal gastric emptying

10 Gastric neuromuscular disorders

11 Diabetic gastroparesis-pathophysiology

12  Gastric myenteric plexus of spontaneously diabetic biobreeding /Worcester (BB/W) rats was studied  NANC relaxation in gastric muscle preparations in response to transmural stimulation obtained from diabetic BB/W rats was significantly impaired NOS – impaired expression Takahashi T et al. Gastroenterology Nov

13  The number of NOS-immunoreactive cells in the gastric myenteric plexus and the NOS activity were significantly reduced in diabetic BB/W rats.  Northern blot analysis showed that the density of NOS messenger RNA bands at 9.5 kilobases was significantly reduced in the gastric tissues of diabetic BB/W rats. NOS – impaired expression Takahashi T et al. Gastroenterology Nov

14 Watkins CC et al. J Clin Invest. 2000

15 Patterns of Gastric Emptying in Healthy People and in Patients with Diabetic Gastroparesis

16  13 normal subjects, 9 patients of DG, 10 patients of IG, 5 patients of postsurgical gastroparesis  There were significantly decreased fasting levels of pancreatic polypeptide and ghrelin in the diabetic (79±26pg/ml) and postsurgical gastroparesis groups (51±11 pg/ml) compared to the normal subjects (315±76 pg/ml) and the idiopathic gastroparesis group (161±53 pg/ml). Idiopathic gastroparesis/IG – intact vagal function Gaddipati KV et al. Dig Dis Sci. 2006

17  Sham feeding was characterized by an increase in pancreatic polypeptide levels in normal controls and patients with idiopathic gastroparesis, with no change in diabetic and postsurgical gastroparesis.  Meal ingestion resulted in an increase in pancreatic polypeptide concentration in the normal subjects groups and idiopathic gastroparesis group. IG – intact vagal function Gaddipati KV et al. Dig Dis Sci. 2006

18  Full-thickness gastric body biopsy specimens were obtained from 40 patients with gastroparesis (20 diabetic) and matched controls.  Sections were stained for H&E and trichrome and immunolabeled with antibodies against PGP 9.5, nNOS, VIP, substance P, and tyrosine hydroxylase to quantify nerves, S100β for glia, Kit for ICCs, CD45 and CD68 for immune cells, and smoothelin for smooth muscle cells. IG & DG-cellular changes Grover M et al. Gastroenterology May

19  Histologic abnormalities were found in 83% of patients.  The most common defects were loss of ICC with remaining ICC showing injury, an abnormal immune infiltrate containing macrophages, and decreased nerve fibers.  On light microscopy, no significant differences were found between DG and IG with the exception of nNOS expression, which was decreased in more patients with IG (40%) compared with DG patients (20%) by visual grading. IG vs DG-cellular changes Grover M et al. Gastroenterology May

20  Tissue was collected from anterior aspect of stomach, midway between GC and LC where the gastroepiploic vessels meet, at ~ 9 cm proximal to pylorus, from 20 DG, 20 IG and 20 patients undergoing gastric bypass for obesity  4 tissue strips for each patient 1 mm × 10 mm long and containing the muscularis propria plus a small portion of the tunica submucosa, were immediately cut after the full thickness biopsy was obtained and processed for electron microscopy IG vs DG- Ultrastructural differences The NIDDK GpCRC J Cell Mol Med July

21  ICC were affected in both diabetic and idiopathic gastroparesis.  19/20 DG patients had a thickened basal lamina around smooth muscle cells and nerves.  In contrast, tissues from 18/20 patients with IG did not have the thickened basal lamina around smooth muscle cells and nerves but had more intense fibrosis than those from DG  Nerve damage was much more prominent in IG with both nerve cell bodies and nerve fibers affected to a greater degree.  Unlike in DG, glial cells were also abnormal in IG IG vs DG- Ultrastructural differences The NIDDK GpCRC J Cell Mol Med July

22  Nausea 92%  Vomiting 84%  Bloating75%  Early Satiety 60%  Abdominal pain 45-90%  Rule out rumination syndrome Clinical Manifestations Soykan et al. Dig Dis Sci Nov; 43(11):

23  In a meta analysis of 17 studies involving 868 dyspeptic patients and 397 controls, significant delay of solid gastric emptying was present in 40% of patients of FD 1  Severity of delay does not correlate with symptoms  Rapid gastric emptying, rather than delayed gastric emptying, might provoke functional dyspepsia. 2 Dyspepsia & gastric emptying 1. Perri F et al. Am J Gastroenterol Kusano M et al. J Gastroenterol Hepatol Apr

24 Grade 1: Mild gastroparesis Symptoms relatively easily controlled Able to maintain weight and nutrition on a regular diet or minor dietary modifications Grade 2: Compensated gastroparesis Moderate symptoms with partial control with pharmacological agents Able to maintain nutrition with dietary and lifestyle adjustments Rare hospital admissions Grade 3: Gastroparesis with gastric failure Refractory symptoms despite medical therapy Inability to maintain nutrition via oral route Frequent emergency room visits or hospitalizations Gastroparesis: a proposed classification Abell et al. Neurogastroenterol Motil (2006) 18, 263–283

25  Prevalence of delayed emptying in longstanding Type-1 and 2 Diabetics: 27-58% and 30% respectively  Diabetic gastroparesis typically develops after DM has been established for ≥10 years, and patients with type 1 diabetes might have triopathy Diabetic Gastroparesis (DG)

26  20 patients (6 men and 14 women) of diabetes mellitus (16 with type-1 DM, 4 with Type-2 DM)  No differences in mean gastric emptying of the solid component (retention at 100 minutes at baseline: 56% +/- 19% vs. follow-up: 51% +/- 21%, P = 0.23) or the liquid component (time for 50% to empty at baseline: 33 +/- 11 minutes vs. follow-up: 31 +/- 12 minutes, P = 0.71) during follow-up DG-natural history Jones KL et al. Am J Med 2002

27  Mean blood glucose (17.0 +/- 5.6 mmol/L vs /- 4.9 mmol/L, P = 0.007) and HbA(1c) (8.4% +/- 2.3% vs. 7.6% +/- 1.3%, P = 0.03) levels were lower at follow-up.  There was no difference in symptom score (baseline: 3.9 +/- 2.7 vs. follow-up: 4.2 +/- 4.0, P = 0.78).  There was evidence of autonomic neuropathy in 7 patients (35%) at baseline and 16 (80%) at follow-up. DG-natural history Jones KL et al. Am J Med 2002

28  Between , 86 patients of DM underwent assessment  Solid gastric emptying percentage of retention at 100 min) was delayed in 48 (56%) patients and liquid emptying (50% emptying time) was delayed in 24 (28%) patients.  At follow-up in 1998, 62 patients were known to be alive, 21 had died, and 3 were lost to follow-up. DG-natural history 1.Kong MF et al. Diabetes Care 1999

29  In the group who had died, duration of diabetes (P = 0.048), score for autonomic neuropathy (P = 0.046), and esophageal transit (P = 0.032) were greater than in those patients who were alive, but there were no differences in gastric emptying between the two groups.  Of the 83 patients who could be followed up, 32 of the 45 patients (71%) with delayed solid emptying and 18 of the 24 patients (75%) with delay in liquid emptying were alive  Gastroparesis was not associated with a poor prognosis DG-natural history Kong MF et al. Diabetes Care 1999

30  Out of 416 patients, 254 patients of IG, 137 with DG and 25 with other causes  More likely to be female (89% vs 71%-T1 vs 76%-T2), Caucasians (90% vs 77% vs 76%)  Mean Age at enrollment: T2DM (53 ± 11) > IG (41 ± 14) > T1 DM (39 ± 11 years)  Obesity in: T2 DM (71%) vs 28% (T1DM) vs IG (26%) IG vs DG - Differences The NIDDK GpCRC. Clin Gastroenterol Hepatol. 2011

31  Nausea and vomitings are the most common symptoms prompting evaluation for DG  Abdominal pain was more often a symptom prompting evaluation for IG (76% IG, 60% T1DM, 70% T2DM; p=0.01). IG vs DG - Differences The NIDDK GpCRC. Clin Gastroenterol Hepatol. 2011

32  20% having chronic but stable symptoms, 33% having chronic but worsening symptoms, 33% having chronic symptoms with periodic exacerbation, and 10% having a cyclic pattern.  Patients with T1DM were more likely to have grade 3 gastroparesis severity (29% IG, 49% T1DM, 39% T2DM) and had greater frequency of hospitalisations due to dehydration IG vs DG - Differences The NIDDK GpCRC. Clin Gastroenterol Hepatol. 2011

33  The symptoms with highest severity at enrollment were stomach fullness and postprandial fullness for IG, nausea for T1DM, and stomach fullness for T2DM.  DG had more severe retching and T1DM had more severe vomiting than IG  Severity of postprandial fullness and upper abdominal pain in: IG > DG IG vs DG - Differences The NIDDK GpCRC. Clin Gastroenterol Hepatol. 2011

34  Gastric retention in: T1 DM (47 ± 27% at 4 hours) > T2 DM (33 ± 24) > IG (28 ± 19)  IG had an increase in endometriosis and migraine headaches, whereas T2DM had an increase in coronary artery disease.  An acute onset of symptoms was reported in approximately half of the patients in each of the IG, T1DM, and T2DM.  An initial prodrome was present at the start of symptoms in a minority, approximately 15% of cases, without significant differences among the three groups. IG vs DG - Differences The NIDDK GpCRC. Clin Gastroenterol Hepatol. 2011

35  Clinical Evaluation  Evaluate Volume Status  Abdominal distention, Succussion splash  Clues to other etiologies  Malar rash, sclerodactyly  Cachexia, lymphadenopathy  Lab  Electrolytes  Protein/albumin  Glucose  Thyroid/parathyroid  If suspected, autoantibodies for scleroderma, SLE, polymyositis Evaluation

36 Gastric emptying scintigraphy

37 Patient Preparation  NPO at least 3 hours prior to the procedure  No smoking for 3 hours prior to the procedure  Ensure that diabetics receive orange juice 4-12 hrs before examination Briefly explain to the patient:  The oral administration of the radiotracer  Positioning and immobilization during the imaging

38 Time 1.5 hrs liquid, up to 3-4 hrs solid Baseline solid Study:  Prepare one or two eggs/chicken liver/idli (in AIIMS) and mixed in radiotracer  Stir and scramble  Or prepare choice of gastronomic vehicle with radiotracer  Administer to patient PO with ml of water. Encourage patient to eat quickly Procedure

39 Procedure (cont) Patient Supine  Place patient in supine position. Acquisition should be started as quickly as possible after ingestion of food  Position camera anterior or LAO  Instruct patient to remain motionless during imaging  Obtain Patient images every 5 minutes up to 30 minutes, then every 15 minutes thereafter, allowing the patient to ambulate between images  Or preset dynamic images for minutes. Patient remain motionless under camera  Supine is good for checking esophageal reflux

40 Patient standing  Position patient standing or sitting, one image facing camera. Optional :one image with back to camera  Obtain immediate images, then every 10 minutes  Standing, sitting, then standing uses normal movement and gravity to aid realism in study Procedure (cont)

41 Procedure Liquid Study  Baseline Liquid Study  Add 500 uci of 99mTc-DPA TO 120 ml, of water or orange juice  Administer to patient PO, encourage patient to drink quickly.  Images same as solid study, although only imaged for 1.5 hours

42  Liquid (e.g., radiolabeled water or orange juice ) t 1/2 (50%) at minutes ) or 80% in 1 hour  Solid (Type and size of meals and population varies): t 1/2 (50%) movement out the stomach within a lower limit of 32 minutes to an upper limit of 120 min with and adult mean of 90 min.  Delayed GE (gastric retention) was determined to be >90% at 1 h, >60% at 2 h and>10% gastric retention at 4 h.  Terminate study before 60 min if gastric emptying becomes > 95% Normal Results

43 Wireless motility capsule

44 Farmer A D et al. United European Gastroenterology Journal 2013;



47 Comparison of the various techniques, currently utilized, indicating their relative advantageous and disadvantageous features. Farmer A D et al. United European Gastroenterology Journal 2013;

48  The association of delayed emptying with specific symptoms is relatively weak  Gastric emptying tests do not yield a high diagnostic specificity  With few exceptions, most studies have failed to demonstrate a correlation between the severity of delayed emptying and response to prokinetics  An initial treatment approach should be required before performing gastric emptying test  In refractory patients or in those with symptoms that impair nutritional status or the ability to function normally, assessment of gastric emptying may play a pivotal role Clinical impact Tack J et al. Best Pract Res Clin Gastroenterol. 2009

49  Gastroparesis can be associated with and may aggravate GERD.  Evaluation for the presence of gastroparesis should be considered in patients with GERD that is refractory to acid- suppressive treatment. GERD-Gastric emptying study Michael Camilleri et al. Clinical Guideline: Management of Gastroparesis. Am J Gastroenterol 2013

50 Treatment algorithm


52  Poor evidence -  Multiple small meals  Liquid instead of solid meals  Low fat, Reduce indigestible fiber  Discontinue medications that slow emptying if possible Dietary/Non-medical

53 If oral intake is insuffi cient, then enteral alimentation by jejunostomy tube feeding should be pursued (after a trial of nasoenteric tube feeding). Indications for enteral nutrition include : unintentional loss of 10 % or more of the usual body weight during a period of 3 – 6 months repeated hospitalizations for refractory symptoms. Nutrition Michael Camilleri et al. Clinical Guideline: Management of Gastroparesis. Am J Gastroenterol 2013

54  No evidence from controlled trials  Phenothiazines  Prochlorperazine (Stemetil)  Promethazine (Phenergan)  Serotonin 5-HT3 antagonists  Ondansetron (Zofran)  Muscarinic antagonisits  Butylscopolamine (Buscopan) Antiemetics

55  Metoclopramide (Maxalon)  Only FDA approved drug for gastroparesis  Erythromycin  Domperidone (Motilium/Vomidon)  Not FDA approved in US  Cisapride (Prepulsid)  Removed from market 2000  Cardiac toxicity Prokinetics-algorithm

56 Pasricha et al. J Neurogastroenterol Motil, Vol.19

57  Venting PEG  Botox injection – Pylorus  Pyloric Balloon Dilation (No published evidence)  Temporary placement of stimulation leads in stomach to predict response to more permanent stimulator Endoscopic Therapy

58  23 patients (5 males, 19 idiopathic) underwent 2 UGIEs with 4 week interval  Injection of saline (in 11 as first injection) or botox 4×25 U (in 12 patients) in a cross-over RCT  Before the start of the study and 4 weeks after each treatment, they underwent a solid and liquid gastric emptying breath test with measurement of meal-related symptom scores, and filled out the GCSI Intrapyloric injection of Botox Arts J et al. Aliment Pharmacol Ther. 2007

59  Significant improvement in emptying and GCSI was seen after initial injection of saline or botox.  No further improvement occurred after the second injection  No significant difference in improvements of solid t(1/2) and liquid t(1/2), meal-related symptom scores or GCSI Intrapyloric injection of Botox Arts J et al. Aliment Pharmacol Ther. 2007

60  Gastrostomy for venting and jejunostomy for feeding  Completion gastrectomy in markedly symptomatic PSG  Pyloroplasty (± jejunal feeding tube placement)  Subtotal gastrectomy + Roux-Y reconstruction for gastric atony due to PSG)  Gastric Electrical Stimulation Surgical

61 Energy Frequency Gastric Electric Stimulation 3 bpm 12 bpm Gastric Pacing: Gastric Neurostimulation (Enterra)  High Frequency (~ 4 x Slow Wave Freq) Low Energy with short pulse  Low Frequency (~ Slow Wave Freq) High Energy with long pulse

62  Unknown  Gastric emptying not consistently improved  Gastric dysrhythmias not normalised  Increased gastric accommodation  Increased vagal afferent activity  Increased thalamic activity Mechanisms of action of gastric electrical stimulation McCallum RW et al. Neurogastroenterol Motil 2013

63  Enterra therapy was granted approval as a Humanitarian Use Device (HUD) to be used in patients with refractory diabetic or idiopathic gastroparesis, restricted to institutions where Institutional review board approval has been obtained Enterra therapy: Humanitarian device exemption FDA 2000

64  Enterra therapy is indicated for the treatment of patients with chronic intractable (drug refractory) nausea and vomitings secondary to gastroparesis Enterra therapy CE mark Indication

65 Date of download: 1/30/2014 Copyright © 2014 American Medical Association. All rights reserved. From: Gastric Electrical Stimulation: An Alternative Surgical Therapy for Patients With Gastroparesis Arch Surg. 2005;140(9): doi: /archsurg Diagrammatic representation of the laparoscopic placement technique showing trocar placement, lead placement in the stomach wall, and position of the subcutaneous pocket for the neurostimulator. Figure Legend :


67 GES for the Treatment of Gastroparesis: A Meta-Analysis O’Grady G, et al. World J Surg 2009; 33: Total Symptom Severity Score Requirement for Enteral or Parenteral Nutritional Support Change in Weight (kg) Vomiting Symptom Severity Score Nausea Symptom Severity Score 13 papers

68 O’Grady G, et al. World J Surg 2009; 33: Complications 8.3 % (22/265 patients, 10/13 studies) Infection8 Skin erosion6 Pain at site4 Gastric perforation2 Device migration1 Volvulus1 GES for the Treatment of Gastroparesis: A Meta-Analysis

69  A meta-analysis of 10 studies (n = 601) using high-frequency GES to treat patients with gastroparesis from January 1995 to January 2011  GES significantly improved both TSS (P < ) and gastric retention at 2 h (P = 0.003) and 4 h (P < ) in patients with diabetic gastroparesis (DG), while gastric retention at 2 h (P = 0.18) in idiopathic gastroparesis (IG) patients, and gastric retention at 4 h (P = 0.23) in postsurgical gastroparesis (PSG) patients, did not reach significance. Chu H et al. J Gastroenterol Hepatol GES for the Treatment of Gastroparesis: A Meta-Analysis

70 Glucose Control in Diabetic gastroparesis Patients Forster et al: Further experience with gastric stimulation to treat drug refractory gastroparesis. Am J Surgery 2003; 186(6): Lin et al: Treatment of Diabetic Gastroparesis by High- Frequency Gastric Electrical Stimulation. Diabetes Care 2004; 27(5), Van Der Voort et al: Gastric Electrical Stimulation Results in Improved Metabolic Control in Diabetic Patients Suffering From Gastroparesis. Exp Clin Endocrinol Diabetes 2005; 113:38-42 Baseline 8.6% Baseline 9.4% Baseline 9.8% At 6 mths At 12 mths 8.5% At 12 mths 8.4% At 12 mths 6.5% At 6 mths HbA1c Reduction at 6 and 12 months vs. Baseline

71 Lin et al: Treatment of Diabetic Gastroparesis by High-Frequency Gastric Electrical Stimulation. Diabetes Care 2004; 27(5), Nutritional Support

72  More studies on gastroparesis are warranted in India  WMC is as good and has advantages compared to gastric emptying scintigraphy, the gold standard  GES is a good choice for refractory gastroparesis  Treatment options are likely to improve after the pathophysiology of gastroparesis is better understood. Conclusion

73 Thank you

74 Baseline ON Implant 1/2 OFF RandomRandom 120 Months 6 12 WAVESS*: Study Design Multicenter double blind crossover * Worldwide Anti-Vomiting Electrical Stimulation Study Phase IPhase II N= Patients 17diabetic 16idiopathic

75  Gastric Electrical Stimulation  Enterra System (Medtronic)

76  1972: Kelly and Laforce at Mayo Clinic induced antegrade and retrograde conduction of slow waves in canines with gastric stimulation.  1988: McCallum et al at University of Virginia showed increased gastric emptying in canines with vagotomy  1997: Familoni et al reported improved peristalsis in canines with GES  1998: The WAVESS study group demonstrated the feasibility of GES, leading to Enterra therapy. The History of Gastric Stimulation

77 1963 – Bilgutay et al.: Gastric stimulation was practiced for the treatment of postoperative ileus. The History of Gastric Stimulation

78 Surgery  Laparoscopy - 3 Ports  Left upper quadrant port becomes stimulator pocket  Length of stay: 2-3 days  Evaluate neurostimulator parameters before discharge

79 Lead Location  Greater curvature  Leads placed 10cm from pylorus  Utilize measuring tape or 10cm suture length  Leads 1cm apart

80 Lead Placement One centimeter electrode length in stomach wall Proximal anchoring point utilizing winged/trumpet anchor

81 Lead Fixation  Disc sutured to stomach wall  1-2 sutures  Lead suture wire clipped to disc  1-2 clips

82 Switch on and interrogation  Device is initiated remotely  A system check is performed and impedance is checked  Power setting is programmed and rechecked on discharge

83 Comparison of methods used to assess gastric emptying Parkman et al. Neurogastroenterol Motil Feb

84 Excessive relaxation Abnormal duodenal motility Poor antro-pyloro-duodenal synchronisation Antral hypomotility Gastroparesis: Pathophysiology

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