Gastroparesis: Pathophysiology and management

Preceptor: Dr. Govind MakhariaSpeaker: Dr. Moka Praneeth

Definition Epidemiology Pathophysiology Clinical Manifestations Diagnosis Treatment

Gastroparesis-Overview

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

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

Gastroparesis: Etiology

Kendall and McCallum. Gastroenterology 1993.Soykan et al. Dig Dis Sci 1998.

Electrophysiologic basis of gastric peristaltic waves

Gastric neuromuscular work after ingestion of a solid meal

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

Gastric neuromuscular disorders

Diabetic gastroparesis-pathophysiology

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. 1997 Nov

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. 1997 Nov

Watkins CC et al. J Clin Invest. 2000

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

Gastroparesis

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

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

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. 2011 May

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. 2011 May

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. 2012 July

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. 2012 July

Nausea 92% Vomiting 84% Bloating 75% Early Satiety 60% Abdominal pain 45-90% Rule out rumination syndrome

Clinical Manifestations

Soykan et al. Dig Dis Sci. 1998 Nov; 43(11):2398-404.

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 FD1

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 1993.2. Kusano M et al. J Gastroenterol Hepatol. 2011 Apr

Grade 1: Mild gastroparesisSymptoms relatively easily controlledAble to maintain weight and nutrition on a regular dietor minor dietary modifications

Grade 2: Compensated gastroparesisModerate symptoms with partial control withpharmacological agentsAble to maintain nutrition with dietary and lifestyleadjustmentsRare hospital admissions

Grade 3: Gastroparesis with gastric failureRefractory symptoms despite medical therapyInability to maintain nutrition via oral routeFrequent emergency room visits or hospitalizations

Gastroparesis: a proposed classification

Abell et al. Neurogastroenterol Motil (2006) 18, 263–283

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)

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

Mean blood glucose (17.0 +/- 5.6 mmol/L vs. 13.8 +/- 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

Between 1984-89, 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

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

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

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

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

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

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

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

Gastric emptying scintigraphy

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

Time 1.5 hrs liquid, up to 3-4 hrs solidBaseline 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 30-120 ml of water.

Encourage patient to eat quickly

Procedure

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 60-90 minutes. Patient remain motionless under camera

Supine is good for checking esophageal reflux

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)

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

Liquid (e.g., radiolabeled water or orange juice ) t1/2 (50%) at

10-15 minutes ) or 80% in 1 hour

Solid (Type and size of meals and population varies): t1/2

(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

Wireless motility capsule

Farmer A D et al. United European Gastroenterology Journal 2013;2050640613510161

Farmer A D et al. United European Gastroenterology Journal 2013;2050640613510161

Comparison of the various techniques, currently utilized, indicating their relative advantageous and disadvantageous features.

Farmer A D et al. United European Gastroenterology Journal 2013;2050640613510161

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

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

Treatment algorithm

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

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

No evidence from controlled trials Phenothiazines

Prochlorperazine (Stemetil) Promethazine (Phenergan)

Serotonin 5-HT3 antagonists Ondansetron (Zofran)

Muscarinic antagonisits Butylscopolamine (Buscopan)

Antiemetics

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

Pasricha et al. J Neurogastroenterol Motil, Vol.19

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

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

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

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

Energy

Fre

quen

cyGastric 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

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

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

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

Date of download: 1/30/2014Copyright © 2014 American Medical Association.

All rights reserved.

From: Gastric Electrical Stimulation:  An Alternative Surgical Therapy for Patients With Gastroparesis

Arch Surg. 2005;140(9):841-848. doi:10.1001/archsurg.140.9.841

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:

Hasler, W. L. (2011) Gastroparesis: pathogenesis, diagnosis and management Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2011.116

Figure 4 Vomiting frequency in patients with diabetic gastroparesis after implantation of a gastric electrical stimulator device

Permission obtained from Elsevier © McCallum, R. W. et al. Clin. Gastroenterol. Hepatol. 11, 947–954 (2010)

Hasler, W. L. (2011) Gastroparesis: pathogenesis, diagnosis and management Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2011.116

Vomiting frequency in patients with diabetic gastroparesis after implantation of a gastric electrical stimulator device

GES for the Treatment of Gastroparesis: A Meta-Analysis

O’Grady G, et al. World J Surg 2009; 33:1693-1701

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

O’Grady G, et al. World J Surg 2009; 33:1693-1701

Complications 8.3 % (22/265 patients, 10/13 studies)

Infection 8 Skin erosion 6 Pain at site 4 Gastric perforation 2 Device migration 1 Volvulus 1

GES for the Treatment of Gastroparesis: A Meta-Analysis

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 < 0.00001) and gastric retention at 2 h (P = 0.003) and 4 h (P < 0.0001) 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. 2012

GES for the Treatment of Gastroparesis: A Meta-Analysis

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): 690-695

•Lin et al: Treatment of Diabetic Gastroparesis by High-Frequency Gastric Electrical Stimulation. Diabetes Care 2004; 27(5), 1071-1076.

•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

6.0%

7.0%

8.0%

9.0%

10.0%

Forster 2003 Lin 2004 Van der Voort2005

Baseline 8.6%

Baseline 9.4%

Baseline 9.8%

At 6 mths

At 12 mths8.5%

At 12 mths8.4%

At 12 mths6.5%

At 6 mths

At 6 mths

HbA1c Reduction at 6 and 12 months vs. Baseline

Lin et al: Treatment of Diabetic Gastroparesis by High-Frequency Gastric Electrical Stimulation. Diabetes Care 2004; 27(5), 1071-1076

Nutritional Support

Nutritional Support Reduction

13

9

5*0

5

10

15

20

25

Baseline 12 mths

Pat

ien

t N

um

ber

TPN

J-tubes

48 28 n

* p < 0.05

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

Thank you

Baseline

ON

Implant

1/2

1/2

OFF

Random

1 20 Months6 12

WAVESS*: Study DesignMulticenter double blind crossover

* Worldwide Anti-Vomiting Electrical Stimulation Study

Phase I Phase II

N= 33 33 33 27 24 Patients17 diabetic16 idiopathic

Gastric Electrical Stimulation Enterra System (Medtronic)

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

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

The History of Gastric Stimulation

Surgery

Laparoscopy - 3 Ports Left upper quadrant port becomes

stimulator pocket Length of stay: 2-3 days Evaluate neurostimulator parameters

before discharge

Lead Location

Greater curvature Leads placed

10cm from pylorus Utilize measuring

tape or 10cm suture length

Leads 1cm apart

Lead Placement

One centimeter electrode length in

stomach wall

Proximal anchoring point utilizing

winged/trumpet anchor

Lead Fixation

Disc sutured to stomach wall

1-2 sutures Lead suture wire

clipped to disc 1-2 clips

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

Comparison of methods used to assess gastric emptying

Parkman et al. Neurogastroenterol Motil. 2010 Feb

Excessive relaxation

Abnormal duodenal motility

Poorantro-pyloro-duodenal

synchronisation

Antral hypomotility

Gastroparesis: Pathophysiology