Post on 21-Jan-2020
Functional Dyspepsia and Gastroparesis
David J. Levinthal, MD, PhDDirector, Neurogastroenterology and Motility Center
Assistant Professor, Department of MedicineDivision of Gastroenterology, Hepatology, and Nutrition
University of Pittsburgh Medical Center
Overview
• Functional dyspepsia (FD) and gastroparesis (GP)• Epidemiology and Definitions
• Pathophysiological Mechanisms in Dyspepsia• FD/GP overlap – spectrum of gastric sensorimotor dysfunction
• Treatment options• Diet• Medications • Cognitive / Mind-Body interventions• Devices / Surgical Interventions (last resort)
“Dyspepsia” – what do patients say?
• Early satiety and/or post-prandial fullness (often several hours)
• Bloating
• Abdominal pain / burning / intense discomfort (upper abdomen)
• Nausea +/- vomiting
• Loss of Appetite
FD vs GP: Epidemiology
Functional Dyspepsia
10-20%
F ≥ M
All adults
~33%
Anxiety / DepressionEarly-life adversity
Other chronic pain disorders
Prevalence (general population)
Gender
Age
Delayed Gastric Emptying
Associated Conditions
Gastroparesis
0.2 - 1%
3:1 F>M
All adults
100%
Diabetes Parkinson’s
Scleroderma (>50% idiopathic)
Functional Dyspepsia: Rome IV Criteria
1 or more: post-prandial fullness, early satiation, epigastric pain or burning ANDNo evidence of structural disease (i.e. normal EGD; negative H. pylori)
Symptom persistence – last 3 months, onset at least 6 months priorSymptom frequency – must meet either EPS or PDS criteria
Comment: Nausea +/- vomiting “warrants consideration of another disorder”
Functional Dyspepsia: EPS vs. PDS
• Epigastric Pain Syndrome (EPS)• At least 1 day / week: epigastric pain and/or burning• Severe enough to impact “usual activities”
• Post-prandial Distress Syndrome (PDS)• At least 3 days / week: postprandial fullness and/or early satiation • Severe enough to prevent finishing a “regular-size meal”
• Imprecise distinctions (significant symptom overlaps in FD)• 61% PDS, 18% EPS, 21% both1
1 Lancet Gastroenterol Hepatol. 2018 Apr;3(4):252-262.2 Dtsch Arztebl Int 2018; 115: 222-232.
Defining Gastroparesis
• Symptoms: Dyspepsia (PDS>EPS-like), often with some nausea/vomiting
• Presence of significantly delayed gastric emptying • Typically via a solid-phase, 4 hour gastric emptying test
• Absence of mechanical obstruction (often via normal EGD)
Gastroenterology 2009;136:1526–1543Gastroenterology 2016;150:1380–1392
Blurred Lines in FD and GP: Are they really distinct disorders?
Normal Gastric Motor Physiology Potential Pathophysiological Mechanisms
Gastroenterology 2001;121:526–535.
Measuring Visceral (gastric) HypersensitivityGastric “balloon” inflated (fundus)
Shaded region = “normal range” (+/- 2 SD)
“Left shift” of the distention pressure-sensation curve in FD patients = “Hypersensitivity”
~35% of FD patients show “allodynia” (presumably mostly EPS subtype)
Clinical Phenotype: “Within 30 seconds, I have pain after I eat anything”
Gastroenterology 2001;121:526–535.
Measuring Fundic Accommodation
Gastric barostat (research tool)
FD patients have impaired meal-induced fundic accommodation
Impaired fundic accommodation is independent of gastric sensitivity (pathophysiologic dissociation)
Clinical Phenotype: “I feel full after swallowing just a few bites of a sandwich.”
Mind Influences the Stomach: normal physiology
Geeraerts et al. (2005) Gastroenterology 129:1437-1444.
Neutral Face (Visual)Neutral Story (Audio)
Fearful Face (Visual)Scary Story (Audio)
Gastroenterology 2009;136:1526 –1543
4 hour solid-phase GES: 99mTc-infused egg sandwich
NORMAL: <10% retention @ 4 hrs
~1/3 FD pts have mild GE delay
Poor correlation of GE delay with symptom severity
Clinical Phenotype: “I just feel like a boulder is sitting in my stomach for hours after a meal”
Lag Phase
Emptying Phase
Measuring Gastric Emptying
“FD” w/ mild GE delay
GP w/ severe GE delay
Am J Gastroenterol 2017; 112:1689-1699
1,287 pts with “functional upper GI symptoms”
Mixed FD/GP population, partially investigated (only ~40% had an EGD)
Limitation: No precise measure of sensitivity (likely present in those w/ “normal GE and GA”)
FD vs. GP – Can one make the distinction?
GE = gastric emptyingGA = gastric accommodation
Current Opinion in Pharmacology 2018, 43:111–117
CBT / Mind-Body Therapies
Pyloric Botox Injection
Personalized Medicine for FD/GP?
Gastric Electrical Simulation
Personalized Medicine for FD/GP?Symptom-Directed Therapy
• “PDS-dominant”: likely impaired accommodation, possibly delayed gastric emptying
• “EPS-dominant”: likely visceral hypersensitivity
• “N/V-dominant”: consider gastric emptying, but likely central mechanisms + visceral hypersensitivity
• Smaller, more frequent meals (snacking/grazing, rather than 3 meals/day)
• Decrease fat content (avoid fried, greasy foods)
• Avoid highly fibrous foods (raw vegetables)• Cooked vegetables may be tolerated
• Nutritive soft/liquid diet for severe dyspeptic symptoms (with weight loss)
Dietary Approaches for Dyspepsia
• Visceral Hypersensitivity • PPI • TCAs• Neuromodulators (SNRIs, gabapentanoids)
• Impaired Fundic Accommodation • Buspirone• Mirtazapine
• Impaired Gastric Emptying • Prokinetics
• Nausea Dominance• Anti-emetics
Tailored Pharmacotherapy for Dyspepsia
PPI for Dyspepsia
Meta-analysis
15 RCTs; n=5,853 FD pts
RR = 0.87 [0.82-0.94] w/ PPI
ACG and CAG Clinical Guideline: Management of Dyspepsia.Am J Gastroenterol. 2017 Jul;112(7):988-1013.
Talley et al. Gastroenterology 2015;149:340–349
Neuromodulators for Dyspepsia“EPS”
“PDS”
292 FD Patients
12-week RCT: 1:1:1
PlaceboAmitriptyline (50 mg)Escitalopram (20 mg)
~12% withdrawal in all armsITT Analysis
NORIG (Nortriptyline for Idiopathic GP)
15 week double-blind RCT: n=130
1:1 – Placebo: 75 mg Nortriptyline (dose-escalation)
NO EVIDENCE OF EFFICACY
JAMA. 2013 Dec 25;310(24):2640-9.
Neuromodulators for Gastroparesis
Talley et al. Gastroenterology 2015;149:340–349
Neuromodulators for Dyspepsia
Gabapentin (low dose, 50 to 300 mg PO TID)
Open Label, Retrospective Cohort StudyN=62 “Treatment Refractory” FD Pts
2/3 with anxiety and or depression1/2 of cohort on TCA/SSRI/SNRI prior to tx
50% responder rate(Using minimal clinical significant cutoff of 0.3 on total symptom score)
(Pain)
J Clin Gastroenterol. 2019 May/Jun;53(5):379-384.
Clin Gastroenterol Hepatol 2012;10:1243
“Fundus Relaxants” for Dyspepsia5-HT1a Receptor Agonists: Buspirone (5-15 mg PO TID)
Clinical Gastroenterology and Hepatology 2016;14:385–392
Mirtazapine for Dyspepsia34 patients with FD and >10% wt loss from baseline(15% delayed GE; 50% impaired accommodation; 44% hypersensitivity)
RCT: 8 weeks placebo vs. mirtazapine 15 mg qhs
Prokinetics for Dyspepsia
Meta-Analysis: Cisapride for FD
567 FD pts (mixed population)
Random-effects model
Conclusion: Improvement in ~25% of patients
Risk Ratio [95% CI]
Am J Gastroenterol. 2017 Jul;112(7):988-1013.
Prokinetics for Gastroparesis
Am J Gastroenterol 2013; 108:1382 – 1391
Improvements in Gastric Emptying Do NOT clearly correlate with symptom improvement!!
Anti-Emetics for Nausea-Dominant Dyspepsia
Standard Medications:• Promethazine, prochlorperazine, ondansetron (the “big 3”)• Anti-histamines (meclizine)• Anti-cholinergics (scopolamine patch)
Emerging use:• Mirtazapine • Dronabinol• Aprepitant
CAM therapies:• Aromatherapy• Accupuncture / Accupressure
Psychological Interventions for Dyspepsia
Favors Treatment Favors Control
RR 0.56 [0.48-0.67]
RR 0.44 [0.26-0.75]
RR 0.53 [0.44-0.65]
“Psychotherapy”2 trials; n=250
CBT2 trials; n=144
Total psych therapy4 trials; n=394
Am J Gastroenterol. 2017 Jul;112(7):988-1013.
Psychological therapies – NNT ~2
High placebo rates in FD and GP trials
CAM / Mind-Body Medicine- Need for high quality trials!
Devices/Surgery for Gastroparesis
Often considered when nutritional status is impaired
Nutrition-support:1) Nasojejunal tube 2) Venting gastrostomy + jejunostomy (or combined G-J tube)3) TPN (rare)
Non-pharmacological treatments 1) Pyloric Botox injection (failed placebo-RCTs)2) Gastric electrical stimulation (GES) (failed placebo-RCTs)3) Pyloroplasty (surgical vs. G-POEM) (no sham-RCTs) 4) Partial gastrectomy / Roux-en-Y (no formal studies)
Favors treatment Favors control
Meta-Analysis of GES for Gastroparesis
Autonomic Neuroscience: Basic and Clinical 202 (2017) 45–55