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