Post on 26-Mar-2020
Disfunzione Autonomica GastroentericaLe possibili soluzioni per la diagnosi ed il trattamento prospettate dal gastroenterologo: Farmaci, GES, G-POEM ed altro
Gastroenterology Unit Department of Medicine and Surgery
University Federico II of Naples
G. Nardonenardone@unina.it
Neuropatia Diabetica Autonomica
Il Prof Gerardo Nardone dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche:
- Alfasigma- Sofar
Dichiara altresì il proprio impegno ad astenersi, nell’ambito dell’evento, dal nominare, in qualsivoglia modo o forma, aziende farmaceutiche e/o denominazione commerciale e di non fare pubblicità di qualsiasi tipo relativamente a specifici prodotti di interesse sanitario (farmaci, strumenti, dispositivi medico-chirurgici, ecc.).
Diabetic Autonomic Neuropathy is yet one of the most serious complications of Diabetes responsible for a significant increase of the mortality and morbidity
Diabetic Autonomic Neuropathy causes a constellation of symptoms and signs affecting various systems Cardiovascular Urogenital Gastrointestinal Pupillomotor Thermoregulatory Sudomotor
GASTROPARESIS is the most important disabling features of diabetic autonomic neuropathy affecting gastrointestinal system
Gastrointestinal Manifestations of Autonomic Neuropathy
Esophageal dysmotility
Gastroparesis
Constipation
Diarrhea
Fecal incontinence
Gastroparesis is a delay in gastric emptying in the absence of mechanical obstruction of the gastric outlet
Postprandial fullness
Early satiety
Nausea
Vomiting
Bloating
Abdominal pain
Abdominal pain is increasingly recognised to be one of the most common symptoms in this disease
Cardinal symptoms include
Camilleri , 2018 Nature
Causes of Gastroparesis
30% of patients with Gastroparesis had Diabetes1–5% of patients with Diabetes develop Gastroparesis
2.4 /100.000 Male / year 9.8 /100.000 Female / year
6.3 /100 000 person / years 10.5 /100 000 in patients 60 years of age or older
Blacks > White.Non-White versus White patients: worse symptoms, poorer QoL and healthcare utilisation
CRITICAL QUESTION
The vast majority of subjects with typical symptoms would never undergo Gastric Emptying tests
EPIDEMIOLOGY
Female-to-Male ratio 4:1
Incidence
Motor Activities
Meal
volume ↑↑↑pressure ↑
Reservoir function
Motor activities is triggered by a PACEMAKER placed along the great curvature 3 waves /min progressing towards the pylorus in a circumferential manner, increasing in amplitude and speed
The Interstitial Cells of Cajal and Platelet-Derived Growth Factor Receptor-α (PDGFRα)-positive cells, placed in the smooth muscle layer, are regarded as the gastric pacemakers that convey stimulation from extrinsic vagal fibres and intrinsic enteric nerves to stimulate the Smooth Muscle Cells.
Camilleri , 2018 Nature
Interstitial Cells of Cajal
ICC
Platelet-Derived Growth Factor Receptor-α PDGFRα
Ascendinginterneurons
Inhibitorymotoneurons
Sensoryneurons
V I PN O
Descendinginterneurons 5HT
Excitatorymotoneurons
AchSubstance P
− − −
Extrinsic afferent neurons
Contraction Relaxation
Mucosa layerMuscularis layer
Serosa layer
5HT1
Regulation of Motory function
Promoting contraction: Ach, Substance PInhibiting contraction: VIP, NO
NCS
Gastric Contractions allow food to be shreddedPeriodically, the pyloric sphincter opens “relaxation” to allow shredded food to pass through but immediately after it closes
1. Fundus accommodation
2. Body contraction
3. Pyloric sphincter relaxation
4. Pyloric sphincter contraction
Motor Activities
Loss of interstitial cells of Cajal has been reported in over half of the patients with diabetic gastroparesisICCs correlate with delayed gastric emptying
Pathogenesis of Diabetic Gastroparesis
Camilleri , 2018 Nature
Vittal H et al., Nat Clin Pract Gastroenterol Hepatol 2007
Experimental evidence suggests that the pathogenesis of gastroparesis might involve nerves and in particular those producing nitric oxide (NOS)
Pathogenesis of Diabetic Gastroparesis
Loss of Macrophages with anti-inflammatory phenotypeIncrease of proinflammatory Macrophages that through immune dysregulation and oxidative stress, appear to be driving injury to ICCs
Madhusudan Grover, Gut 2019
Pathogenesis of Diabetic Gastroparesis
Loss or injury to ICCs, the gastric pacemaker cells. Loss of Enteric Nerves and fibrosis in muscle layers Increase of proinflammatory Macrophages
Key points in Pathogenesis of Gastroparesis
Madhusudan Grover, Gut 2019
Diagnostic Algorythm of GASTROPARESIS
Diagnostic testing to exclude 1. Organic disease2. Mechanical obstruction
Gastric Emptying measurementby appropriate instruments
Cardinal GastroparesisSymptoms
Validated questionnairesGCSI based on the PAGI-SYM GCSI-Daily Diary score
Blood Tests
Upper Endoscopy
TEST METHOD
Fluoroscopy Liquid barium mealX ray scans measure wall movements and stomach emptying
Radiopaque markers 19 small indigestible markers in a standard mealX ray 6 hours after ingestion evaluates the markers remained in the stomach
Ultrasonography Liquid mealSerial evaluations measure changes in the volume remaining in the antrum
Magnetic Resonance GadoliniumSemi-solid gastric emptying and accomodationSequential transaxial abdominal scans
Single-photon emission CT 99-Tc pertechnetateAccumulation in gastric wall provides regional gastric volumes
Capsule telemetry Ingestible SmartPillMeasure pH, pressure and temperaturepH increase is the time point for the passage in duodedum
Manometry Water-perfused or solid-state manometric catheterMeasure gastroduodenal contractile activityFasting, interdigestive and post-prandial contractions recorded
Electrogastrography Serosal, mucosal or cutaneous electrodesMeasure gastric slow-wave myoelectrical activity
Scintigraphy 99-m technetiumLabeled low fat egg with mealScan at 1, 2, 4 hurs after meal ingestion
MAIN DIAGNOSTIC TESTS FOR THE STUDY OF GASTRIC EMPTYING
Liquid barium meal Wall movements emptying Qualitative analysis Better in obstructions or gastric stasis Easy to perform
Disadvantages
Radiation exposure
Old-fashioned, low reliability
Unphysiologic meal
Gastric Emptying measurement Fluoroscopy
Normal Delayed
Radiation exposureQualitative analysis
Easy to performPhysiological meal
10 markersTaken at mealtimeX-ray at 6 hours
Gastric Emptying measurement Radiopaque Markers
Disadvantages
02
4
6
8
10
12
14
Time (min)
Antr
al a
rea
(cm
2 )
Meal
Portincasa et al. Dig Liv Dis 2001, 2003
Min
Max
Intermediate
Residual
Easy to perform
Liquid meal
Operator-dependent
Gastric Emptying measurement Functional Ultrasonography
Carbone et al. European Journal of Radiology 75 (2010) 212–214
• Fasting from 6 h
• 400 ml of Vanillas pudding + 5ml of Gd-DTPA
• Acquisition every 5 min for 30 min
• T½ gastric volume assessment
• Speed of gastric waves
Gastric Emptying measurement Magnetic Resonance
Disadvantages
Expensive
Low availability
Dedicated personnel
Diagnostic accuracy 0.83 (ROC curve)
DisadvantageOffice-basedExpensiveLow availability
Gastric Emptying measurement Wireless pH Motility Capsule – Smart Pill
Approved by FDA
WMC provided new diagnosis in >50% of patients with suspected gastroparesis or slow intestinal transit
Cutoff time of 300 min
Non-invasive test to measure Gastric Emptying and intestinal transit
HRM evaluation for gastric motility is still embryonicHowever, HRM may be a useful tool due to its characteristics
Conventional manometry was not a widespread method to study gastric motility
Gastric Emptying measurement High-Resolution Manometry
The gold standard (MBq 0.5–1 mCi of 99mTc-sulphur colloid)
Gastric Emptying Scintigraphy Test
A non-invasive, physiologic, quantitative assessment of GE
Limitations:- ↓ Caloric intake (255 KCal) - ↓ Fat contents (2%) - Underestimation real prevalence
Due to radiation exposure, it should not be used in women of childbearing potential it should not be repeated to measure the clinical changes the effects of treatmentLow availability and Expensive
Bonfrate L et al, Gastroenterology Reports 2015
Gastric Emptying measurement 13C-Breath Test general principles
The technique is non-invasive, simple to perform, suitable for repeat it over time, and relatively cheap
repeatable
Substrates used for gastric emtying study by breath tests
Acetate 150mg of 13C acetate in water or juice
Octanoate One egg yolk labelled with 91–100mg 13C-octanoate
Muffin pre-labelled with 100mg 13C-octanoate
Liquid meal
Solid meal
3 small muffins + a capsule with 75mg 13C-octanoate
Spirulina 100–200mg 13C-spirulina incorporated into egg white
13C-OCT Breath Test
NORMAL DELAYEDACCELERATED
< 70 min
DELAYED
70-120 min >165 min120-165 min
13C breath-testing GE shows a strong correlation with Scintigraphyand has been approved by the US Food and Drug Administration (FDA)
88±29 min
146 min
179±50 min 151±20 min
131 healthy subjects8 diabetics with gastroparesis
11 untreated celiac patients
p≤0.001 vs controls
2010
Dietary Suggestion
Medical therapy
GES Botox
G-POEM
Treatment of GASTROPARESIS
First Line of Treatment
Dietary Suggestion generally suggested even if never validated
Eat small and frequent meals, 4-6 times/day Avoid high-caloric fatty meals Avoid indigestible fibres (delay gastric emptying) Consume homogenized, soups or liquids Avoid alcohol and carbonated beverage Maintain an adequate caloric intake
Anticholinergic Dopamine agonist Opioid analgesics Antidepressant
Avoid drugs that can impair Gastric Emptying
Calcium channel blockers Clonidine, Nicotine Progesterone Proton Pump Inhibitor
PROKINETICS
Increase Gastric Delivery
Prokinetics :
- Dopamine (D2) Receptor Antagonist Metoclopramide, Domperidone
- Serotonin 5-HT4 Receptor Agonist Cisapride, Mosapride, Prucalopride
- Serotonin 5HT‐3 receptor Antagonist Granisetron and Andansetron
- Cholinesterase inhibitor Neostigmine, Acotiamide
- Motilin-like agent Erythromycin
- Ghrelin-like agent Relamorelin
Prokinetics may be effective but with a very low quality of evidenceRapat Pittayanon, 2018
Not symptom-free or no symptom improvement
Gastrointestinal drugs withdrawnwith restricted use or black box
Drug Brand names
Year Reason for withdrawal or restriction of use
Alosetron LatronexTM 2000 Risk of fatal complications (i.e., ischemic colitisReintroduced in 2002 on a restricted basis
Cisapride PrepulsidTM
PropulsidTM2000 Risk of cardiac arrhythmia
Tegaserod ZelnomTM
ZelmarcTM2007 Imbalance of cardiovascular ischemic events
including hearth attack and strokeAvailable through a restricted access programuntill April 2008
Metoclopramide* ReglanTM
MaxolonTM20092013
Dose and duration of use should be restrictedto minimize the known risks of potentiallyserous neurological side effects (FDA & EMA)
Domperidone* MotiliumTM
PrimperanTM2013 Review started by EMA because the concerns
about cardiac adverse events, previouslyevaluated by the PhV Working Party
* Medications currently approved (although not in all countries)
Prucalopride significantly improved symptoms and quality of life and enhanced gastric emptying compared with placebo
Florencia Carbone, 2019
34 patients (28 idiopathic 6 diabetes) Prucalopride (2 mg x 4 wks)
Influence of Prucalopride and placebo on the Gastric Cardinal Symptom
Influence of Prucalopride or placebo on solid half emptying time
Placebo
Prucalopride
Prucalopride
Placebo
Serotonin 5-HT4 Receptor Agonist
Acotiamide can safely be administered continuously for 1 year. Rapid changes from baseline for the meal-related symptom severity, overall treatment evaluation, QoL and work productivity
OTE, Overall Treatment Evaluation;Gastroparesis Cardinal Symptom
Tack J 2017
Acotiamide a recent cholinesterase inhibitor
207 Patients with postprandial distress syndromeAcotiamide 100 mg tid for 1 year.
Acotiamide a recent Cholinesterase Inhibitor
Macrolide antibiotics are agonists at motilin receptors that induce a marked acceleration of GE.Erythromycin, Azithromycinare used in clinical practice,but their use is limited by side effects including Abdominal cramps, nausea, diarrhoea, QT prolongation
Motilin is an hormone secreted by the proximal GI tract that accelerate Gastric Empthying
In a large study no clinical benefit was obtained in patients with FD with or without gastroparesis.
5HT‐3 receptor antagonists
Granisetron and Ondansetronare effective in controlling chemotherapy‐induced nausea and vomiting and can be used in patients with dysmotility characterized by nausea and vomiting
NK1 receptor antagonists substance P antagonists Aprepitant and Tradipitant appear to be effective for at least some of the cardinal symptoms of gastroparesisThey act synergistically with serotonin type 3 (5-HT3) receptor blockers
Antiemetics
In a phase 2B randomized trial of patients with moderate to severe gastroparesis , RELAMORELIN, significantly reduced core symptoms, accelerated Gastric Empthying, and was generally safe and well tolerated.
393 patients with Gastroparesis
Michael Camilleri,, 2017
RELAMORELIN is a synthetic ghrelin receptor agonist that stimulates gastric contractions and accelerates gastric empthying of solids and improve nausea, fullness, bloating and pain in patients with gastroparesis and type 2 diabetes.
Levosulpiride (Neuromodulators) is an antipsychotic agent which accelerates gastric empthying by antidopaminergic and 5-HT4 agonistic activities
C. MANSI, 2000
Levosulpiride was signicantly more effective (p < 0.01) than cisapridein improving individual symptoms such as nausea, vomiting and early postprandial satiety
The GES assembly consists of two leads
that are placed in the muscularis
propria of greater curvature of the
stomach about 10 cm proximal
to the pylorus and a subcutaneously
placed pulse generator.
A temporary GES may be tried to
determine response before a permanent
device is placed.
ENDOSCOPIC AND SURGICAL TREATMENTGastric Electrical Stimulation
GES consists of low-energy stimulation applied in non-synchronized,high-frequency cycles of short pulses (330 to 450 µs).
33 symptomatic patients unresponsive to standard medical therapy
GES significantly decreased vomiting frequency and gastrointestinal symptoms and improved QoL in patients with severe gastroparesis
Weekly vomiting frequency (
GES has an immediate and potent anti-emetic effect. GES offers a safe and effective alternative for patients with intractable symptomatic gastroparesis
Abell T.L. 2002
38 symptomatic patients with drug-refractory gastroparesisMulticenter study,
Abell T.L. 2003
Patients with modified gastric empthyingafter a solid meal versus baseline Based on these two studies FDA approved
GES approach for gastroparesis
Adverse Effects after implantation of gastric electrical stimulators
Randomized trial (n.5): Score did not differ: 0.17 [95% CI: 0.06 -0.4] p = 0.15
Open label studies (n.16): Score decrease: 2.68 [95% CI: 2.04–3.32] p = 0.001
Total symptom severity score before and after GES
Follow up
Benefits of GES are reported in uncontrolled trials but not in RCTs
2016
Mearin et al made initial observations of pyloric dysfunction in a subset of patients with GastroparesisInjection of botulinum toxin, first used for achalasia, was extended to gastroparesis
A large open-labelled study of ~180 patients has suggested greater clinical response in such settings• Female patients • Patients with IG• Patients younger than 50 years of age• Using 200U in spite of 100U
ENDOSCOPIC TREATMENTBotulinum toxin injections
Madhusudan Grover, 2019
Two reviewers independently identified 15 relevant trials
13 NON–RANDOMIZED Trials significant improvement in subjective symptoms and objective gastric emptying study after botulinum toxin injection.
2 RANDOMIZED Controlled Trial NO IMPROVEMENT after botulinum toxin injection
Bai Y. 2019
Available high-quality trials showed no evidence torecommend botulinum toxin injection for the treatment of gastroparesis
Gastric Peroral Endoscopic Myotomy (G-POEM)A novel minimally invasive technique in endosurgery
By creating a submucosal tunnel, the pyloric musculature is accessedand a selective myotomy of the pyloric circular muscle is performed
The clinical response rate is 70-80%; GE improvement ranges from 4-to 64% Almost all studies showed improvement in nausea,vomiting and abdominal pain however, effects disappeared by 6 months
Gastric ulcer and related bleedingwere the most commonly reported complications followed by tension capno-peritoneum
Most of the studies originate from tertiary-care centres with endoscopic expertise
Danny J Avalos 2017
Retrospective study on 30 patients with refractory gastroparesis who underwent GPOEM from 2015 through 2017 at a tertiary center
G-POEM for refractory gastroparesis
- Improved symptoms
- Increased quality of life
- Reduced health care useBP, bodilypain; GH, general health; RE, role limitationdue to emotional problems; RP, role limitation owing tophysical health; SF, social functioning.
Improvement of QoL after GPOEM
Use of health care before and after GPOEMImprovement of GCSI after GPOEM
Parit Mekaroonkamol, 2019
G-POEM demonstrates clinical success in treating refractory gastroparesis
17 studies 10 outcomes with G-POEM
6 outcomes pyloroplasty surgery 1 outcome with both Babu P. Mohan 2019
Diabetic Autonomic Neuropathy continues to be a challenge for researchers and clinicians
A turning point in the pathogenesis of gastroparesis is the central role of pro inflammatory macrophages
13C-Octanoate Breath Test and Wireless Motility Capsule appear to be reliable non-invasive strategies for the assessment of gastric emptying
Aprepitant and Relamorelin could be a new potential treatment strategy for gastroparesis
G-POEM demonstrates clinical success in refractory gastroparesis
C O N C L U S I O N