Functional Dyspepsia and GastroparesisFunctional Dyspepsia and Gastroparesis David J. Levinthal, MD,...
Transcript of Functional Dyspepsia and GastroparesisFunctional Dyspepsia and Gastroparesis David J. Levinthal, MD,...
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