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Esophageal and Gastric Conflicts of Interest:

Motility Disorders: A case • None based approach

Gokul Balasubramanian, MD Assistant Professor Director of Gastrointestinal Motility Lab Division of , Hepatology and Nutrition The Ohio State University Wexner Medical Center

Overview

• Esophageal anatomy • -case based approach • Reflux disease-case based approach Dysphagia-Case • Gastric physiology based approach • -case based approach

1 : Anatomy Terminology

• 25 cm muscular tube. • Dysphagia: derived from the Greek word dys (difficulty, disordered) and phagia (to eat). • Extends from upper esophageal sphincter to . • : painful swallowing. • Proximal 1/3rd consist of striated muscles while distal • Globus Sensation: Sensation of lump in throat 2/3rd is formed by smooth muscles. between meals. • Lined squamous epithelium.

History Dysphagia Assessment

Oropharyngeal Esophageal Fluoroscopic • Oral: • Food stuck in examination ‒ Drooling of saliva suprasternal notch or ‒ Food spillage retrosternal region ‒ Sialorrhea ‒ Piecemeal swallows • Motility: ‒ Associated dysarthria ‒ dysphagia to solids and liquids • Pharyngeal: ‒ Associated with ‒ Choking/cough during or chest . swallow • Mechanical: ‒ Associated dysphonia Endoscopic Manometric ‒ progressive dysphagia to examination examination solids; may involve liquids at later stages

2 Case Study 1: Case Study 1: 78-year-old female with no significant medical history presenting with: ‒ Dysphagia to both solids and liquids ‒ ‒ Denies any heartburn • Mean DCI:2380 ‒ 50 lb weight loss • Mean LES IRP:32 mm Hg • Mean DL: 3.8 sec

• Epiphrenic diverticulum • Epiphrenic diverticulum • Resistance at GEJ • Beaking at GEJ

Case Study 1: Achalasia

• Post extended myotomy and diverticulectomy • Rare esophageal motility • Fairly doing disorder • Esophageal aperistalsis • Impaired LES relaxation

Loss of inhibitory neurons secreting VIP and NO leads to unopposed excitatory activity and failure of LES relaxation

DA Patel. An Overview of Achalasia and Its Subtypes. Gastroenterology & Hepatology. Volume 13, Issue 7 July 2017

3 Achalasia: Subtypes Achalasia: Treatment Algorithm

Type I is characterized by a quiescent esophageal body, type II has pan-esophageal pressurization, and type III is characterized by simultaneous contractions.

DA Patel. An Overview of Achalasia and Its Subtypes. DA Patel. An Overview of Achalasia and Its Subtypes. Gastroenterology & Hepatology. Volume 13, Issue 7 July 2017 Gastroenterology & Hepatology. Volume 13, Issue 7 July 2017

Achalasia: Treatment Options Case Study 2: Treatment Options Pros Cons • On Demand Medications(CaCB/Nitrate • Minimal risk • Least effective 24-year-old s) • For non-operative • Not durable female presented candidates • Good option for with dysphagia to nonoperative • Durability of 6–12 solids and Botulinum toxin injection candidates months liquids. • Short procedure time • Most effective • Mean DCI:NA nonsurgical option • Mean LES IRP:24 mm Hg • Short recovery time • Perforation (1%– Pneumatic dilation • Mean DL: NA • Durability 2–5 years 5%) • Procedure time <30 Diagnosis?? minutes • General anesthesia • Durability 5–7 years required Surgical myotomy • Procedure time 90 ∼ • Hospital stay of 1–2 minutes days Type 2 Achalasia. Patient • High morbidity and Esophagectomy • For end-stage disease mortality sent for myotomy

4 Case Study 3: Opioid-induced esophageal dysfunction 64-year-old female with CAD, chronic backache on morphine is presenting dysphagia Opioid-induced esophageal and spasmodic pain in dysfunction is often characterized the neck and chest. by EGJ outflow obstruction and type III achalasia pattern. • Mean DCI:2765 • Mean LES IRP:18 mm Hg • Mean DL: 3.8s

Diagnosis?? Opioid induced esophageal dysfunction Ratuapli S, et al.Opioid-Induced Esophageal Dysfunction (OIED) in Patients on Chronic Opioids. Am J Gastroenterol 2015; 110:979–984;

Achalasia syndromes beyond the CC v3.0

GERD-Case based approach

Kahrilas, P. J. et al. (2017) Advances in the management of oesophageal motility disorders. in the era of high-resolution manometry: a focus on achalasia syndromes. Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2017.132

5 Gastroesophageal Reflux Risk factors: Disease Definition • Obesity GERD is a condition that develops • Family history for GERD when the reflux of gastric content • Tobacco smoking causes troublesome symptoms or • Alcohol consumption complications. • Associated psychosomatic complaints

• Mild symptoms once in > 2 days/week • Moderate/Severe once in >1 day/week

Vakil N, van Zanten SV, Kahrilas P, et al. Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Locke GR, et al. The American Journal of Medicine. 1999;106(6):642-649 Gastroenterol. 2006;101:1900–1920. Hampel H. Ann Intern Med. 2005;143(3):199-211.

Impact of Gastroesophageal Reflux Disease

Gastroesophageal Reflux Disease

Esophagitis Extra-esophageal Non-erosive GERD GERD (EGD negative)

Stricture ENT

Impairs quality Barrett’s metaplasia Asthma of life & Adenocarcinoma Dental

Irvine EJ, Hunt RH. Evidence-Based Gastroenterol. BC Decker Inc. Hamilton and London. 2001.

6 Goals for Treatment of GERD Life-Style Modifications include:

• Eliminate symptoms • Elevate the head of the bed on 4" to 6" blocks. • Advise weight loss for obese patients. • Heal erosive • Avoid recumbency for 3 hours after meals. • Avoid bedtime snacks. • Prevent the relapse of erosive • Avoid fatty foods, chocolate, peppermint, onions, and esophagitis and complications from garlic. GERD • Avoid cigarettes and alcohol. • Avoid drugs that decrease LES pressure and delay gastric emptying.

Medical treatment options: Maintenance of Healing Erosive Esophagitis Proton Pump Inhibitors: • Higher healing rates in mild to moderately severe reflux esophagitis(80% to 100%). 100 Esomeprazole 40 mg 80 20 mg • Improves dysphagia. 10 mg 60 Placebo • Decreases the need for esophageal dilation in patients 40

who have peptic esophageal strictures. Remission In (%) 20

• About 70% may have nocturnal acid breakthrough that 0 0123 4 5 6 requires H2RA. Months

Pooled from Johnson DA, et al., Am J Gastroenterol, 2001;96:27-34 and Vakil NB, et al., Aliment Pharmacol Ther, 2001;15:927-935.

7 GERD Is a Chronic Condition Appropriateness of PPI use Likely to Relapse

100 No mucosal breaks

LA Grade A 80 LA Grade B

60 LA Grade C (%) 40

20

Patients in Symptomatic Remission 0 0123456 Time After Cessation of Therapy (Months)

Lundell LR, et al. Gut. 1999;45:172-180.

Yadlapati and Kahrilas BMC Medicine (2017) 15:36

Medical treatment options:

• Antacids and Alginic Acid: ‒ Temporarily relieve episodic heartburn ‒ Useful add on therapy

• Histamine H2-Receptor Blocking Agents: ‒ Safe and effective in mild esophagitis Decisions to start, properly dose, ‒ Not useful in severe esophagitis continue, or discontinue PPI ‒ Useful for breakthrough symptoms therapy should be personalized ‒ Concern for tachyphylaxis based on indication, effectiveness, • Prokinetic Agents: patient preferences, and risk ‒ Limited efficacy and side effects in up to 30% assessment. • TLESR Inhibitors: ‒ As addon for non-acid reflux/post prandial reflux Yadlapati and Kahrilas BMC Medicine (2017) 15:36

8 Indications for anti-reflux Case Study 4:

• Unwillingness to remain on medical therapy • Intolerance of medical therapy 42-year-old female with • Medically refractory symptoms with objective prior history of evidence of GERD scleroderma is presenting • GERD in the setting of a large hiatal with persistent reflux inspite of twice daily PPI, referred for fundoplication.

• Mean DCI:NA • Mean LES IRP:2mm Hg • Mean DL: NA

Badillo R, Francis D. Diagnosis and treatment of gastroesophageal reflux disease. World J Gastrointest Pharmacol Ther. 2014;5(3):105-12.

Case Study 4: Case Study 4:

• Acid exposure: • Total AET:14.5% • Reflux events:112 • Educated on lifestyle measures. • Reflux symptom analysis: • SI:54 • Added H2B at bedtime. • SAP: 98 • Was doing much better.

What would be the next step?

9 Case Study 5: Case Study 5:

• 28 yr old female • Acid exposure: with anxiety • Total AET:10.5% presenting with • Reflux events:119 • Reflux symptom analysis: persistent • SI:50 heartburn inspite • SAP: 96 of PPI twice daily • EGD: normal What would be the esophagus with next step? biopsy

DDx to PPI-Refractory GERD Effect of DBT on belching and GERD • Refractory reflux • Refractory reflux symptoms with symptoms with normal esophagitis esophagus • Eosinophilic esophagitis • Eosinophilic esophagitis • Pill induced esophagitis • Achalasia • Skin disorders like • Gastroparesis Lichen planus • and • Hypersecretory Belching disorder condition like ZES • Rumination syndrome • Genotypic differences in • Functional heartburn CYP450 2C19

Ong et al.Diaphragmatic Breathing Reduces Belching and Proton Pump Inhibitor Refractory Gastroesophageal Reflux Symptoms. Clinical Gastroenterology and Hepatology 2018;16:407–416

10 Case Study 5:

• Continued PPI, • Started on behavioral therapy and Gastroparesis-Case anti-anxiety medication, • Educated on DBT based approach

Physiology of stomach

Normal Velocities of emptying of solid and liquid chyme.

11 Definition: Etiology of Gastroparesis

Gastroparesis Gastroparesis is defined as a delay

in the emptying of ingested food in Idiopathic Diabetic Post-surgical the absence of mechanical gastroparesis gastroparesis gastroparesis (30-35%) obstruction of the stomach or Vagotomy . Nissen fundoplication Partial gastrectomy Obesity related Pancreatectomy (5-10%)

Camilleri M, Parkman H, Shafi M, et al. Clinical guideline: management of gastroparesis. Am J Gastroenterol 2013;108:18–37.

Pathophysiology Clinical Presentation: • • • Early satiety • • Postprandial fullness • Abdominal pain • Weight loss/weight gain • and/or • Wide glycemic fluctuations

Grover, M et al. Gut. 2019 Dec;68(12):2238-2250.

12 Pair-wise P valuea Treatment Algorithm for Characteristic IG (n 254) T1DM (n 78) T2DM (n 59) IG vs all DM IG vs T1DM IG vs T2DM N (% or mean)b N (% or mean)b N (% or mean)b Symptoms Suspected Gastroparesis prompting evaluation for gastroparesis Suspected Gastroparesis

Nausea 214 (84.3) 66 (84.6) 56 (94.9) .19 .94 .03

Vomiting 152 (59.8) 69 (88.5) 54 (91.5) <.001 <.001 <.001 Confirm Diagnosis Testing for Cause Bloating 146 (57.5) 44 (56.4) 37 (62.7) .75 .87 .46 Early satiety 146 (57.5) 37 (47.4) 44 (74.6) .75 .12 .02 Postprandial 136 (53.5) 44 (56.4) 39 (66.1) .18 .66 .08 fullness Restoration of Fluids and Abdominal pain 193 (76.0) 47 (60.3) 41 (69.5) .01 .007 .30 Dietary Diarrhea 98 (35.6) 35 (44.9) 30 (50.9) .09 .32 .08 Modifications Glucose Control Constipation 112 (44.1) 32 (41.0) 34 (57.6) .44 63 .06 Anorexia 32 (12.6) 12 (15.4) 17 (28.8) .03 .53 .02 Weight loss 118 (46.5) 41 (52.6) 31 (52.5) .25 .35 .40 Weight gain 45 (17.7) 14 (18.0) 14 (23.7) .57 .96 .24 Prokinetic Therapy qac Anti-emetics prn Gastroesophageal 137 (53.9) 43 (55.1) 35 (59.3) . 57 .85 .45 reflux Problems with 0 (0.0) 39 (50.0) 27 (45.8) <.001 <.001 <.001 diabetes control Consider Feeding Jejunostomy, Decompressive Gastrostomy, In 416 patients from the NIH Gastroparesis Registry, symptoms prompting evaluation more often included Gastric Electrical Stimulation vomiting for diabetic gastroparesis and abdominal OR Surgical Therapy pain for idiopathic gastroparesis. Camilleri, et al. Clinical Guideline: Management of Gastroparesis. Source: Parkman HP, Yates K, Hasler WL, et al. Similarities and differences between diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol. 2011;9(12):1056–e134. Am J Gastroenterol 2013; 108:18–37

Diagnostic Testing for Gastroparesis: Radionuclide Gastric Emptying Scintigraphy TABLE 2. Diagnostic Testing for Gastroparesis Modality Advantages Disadvantages • Best current test for measuring gastric emptying Gastric scintigraphy because it is sensitive, quantitative, and physiological. 4-hour solid phase Widely available Radiation exposure • 99mTc sulfur colloid-labeled low-fat egg white meal as a Considered the “gold False positives with liquid test meal. standard” for diagnosis phase only studies • Imaging is performed in the anterior and posterior Wireless motility capsule projections at least at four time points (0, 1, 2, and 4 h). Smart Pill, given imaging Avoids radiation exposure Less validated than scintigraphy • The 1 h image is used to help detect rapid gastric FDA approved for Cannot be used in those emptying. diagnosis with pacemaker or • The 2 and 4 h images are used to evaluate for delayed defibrillator gastric emptying. Radiolabeled carbon • Hyperglycemia (glucose level > 270 mg/dL) delays breath test gastric emptying in diabetic patients. 13C-labeled octanoic acid Low cost Lack of standardization or Sprirulina platensis Has primarily been used as a research tool Parkman H.P. (2018) Gastric Emptying Studies. In: Bardan E., Shaker R. (eds) Gastroparesis: A Review of Current Diagnosis and Treatment Options. Stein, Benjamin; Everhart, Kelly; Lacy, Brian. Journal of Clinical Gastroenterology. 49(7):550‐558, August 2015. Gastrointestinal Motility Disorders. Springer, Cham

13 Radionuclide Gastric Emptying Scintigraphy

Keller, J. et al. (2018) Advances in the diagnosis and classification of Gastroparesis: A Review of Current Diagnosis and Treatment Options. Stein, Benjamin; Everhart, gastric and intestinal motility disorders. Nat. Rev. Gastroenterol. Hepatol. Kelly; Lacy, Brian. Journal of Clinical Gastroenterology. 49(7):550‐558, August 2015.

Pro-kinetics: Anti-emetics: Medications MOA Pros Cons Medications Mechanism Pros Con Diphenhydramine Antihistamines Useful in mild • Sedative effect. Improves gastric emptying. Black box warning:>12 nausea/vomiting. • Anticholinergic Metaclopramide D2 Antagonist Lowest possible dose (5 mg TID weeks use of tardive S/E. before meals). dyskinesia Hyoscine Anti-cholinergics Cheap and widely • Anti-cholinergic No long term study available. Acute dystonias available. side effects(dry Efficacy:29‐53%. Parkinsonism type Useful in mild cases. mouth, Comparable to Domperidone movements glaucoma,etc). Associated with QTc Phenothiazines/ D1/D2 Useful in severe • EKG changes interval prochlorperazine Antagonist nausea and vomiting. • Psychomotor issues in elderly D2 Antagonist Improvement in symptoms Less CNS effcts • Dystonia/Parkinson Domperidone (54% to 79%). Drug Associated with QTc ism interaction. interval. Increases Prolactin levels. Ondansetron 5HT3 antagonists Widely available. • QT prolongation. Requires IND for approval. Useful in mild • Serotonin vomiting. syndrome. Motilin agonist Useful during acute Tachyphylaxis. • Constipation. exacerbation. IV better than Associated with QTc Transdermal 5HT3 antagonists Not widely • QT prolongation. PO. prolongation. granisetron available/cost. • Serotonin Significant improvement in cardiac arrhythmias and Useful in those who syndrome. Cisapride 5-HT4 symptoms. death cannot tolerate oral • Constipation. agonist Requires IND meds. Aprepitant NK1 receptor Not widely • Fatigue. Improves gastric emptying and Diarrhea and suicidal antagonists available/cost. • Neutropenia. 5-HT4 colon transit times. ideations. Useful in reducing agonist FDA approved for chronic Avoidance in ESRD. N/V. constipation. No cardiac toxicity Dronabinol Agonist of CB1 Helpful for N/V when • Delays gastric document. and CB2 other therapies have emptying. failed.

14 Neuromodulators: Gastric electric stimulation

Medications MOA Pros Con • Patient Selection: Diabetic gastroparesis with refractory N/V even after 1 year of pro-kinetics. Nortriptyline/ TCA Modest Worsens gastric • Response to therapy: Amitriptyline improvement in emptying. ‒ Diabetics. N/V and abdominal Anti‐cholinergic side pain effects. ‒ Not on narcotics. Constipation. ‒ Predominant nausea/vomiting. Mirtazapine/ SNRI/SSRI Improves appetite. Suicidal thoughts. • Response was modest with 43% over a period of Improves fundic EKG changes. a year and half. accommodation. Serotonin syndrome.

Heckert, J., Sankineni, A., Hughes, W. B., Harbison, S., & Parkman, H. (2016). Gastric Electric Stimulation for Refractory Gastroparesis: A Prospective Analysis of 151 Patients at a Single Center. Digestive Diseases and Sciences, 61(1), 168-175.

Final Case Study

• 42-year-old gentleman with type 2 (HgbA1c:9) on exenatide presenting with recurrent vomiting and nausea for the last 6 months? What would be the next step?

Normal upper with moderate food retention in the stomach. Bx: negative for H. pylori. 4-hour GES: 43%. What do we do next?

Switch exenatide to insulin+CGM. Nutrition consult for gastroparesis.

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