DISEASES OF THE ESOPHAGUS Prof Ferenc Szalay MD

DISEASES OF THE ESOPHAGUS Prof. Ferenc Szalay MD, Ph. D 1 st Department of Medicine of Semmelweis University Budapest, Hungary 1 Budapest, 03. 02. 2003 lecture for students

Diseases of the esophagus GERD Motility disorders Esophagitis (infection, chemicals, pills) Neurological disorders Skeletal muscle disorders Varices Mallory-Weiss sy. Barrett’s Tumors 2 Common complains Wide range of symptoms

Swallowing Many muscle 5 nerves : V, VII, IX, X, XII Stages oral - voluntary pharyngeal - involuntary esophageal - LES relaxed 1 second 5 steps 3

5 steps within 1 second 1. Soft palate is elevated + retracted to prevent nasopharingeal reflux 2. Vocal cords are closed Epiglottis swings backward closure the larynx 3. UES relaxes 4. Larynx is pulled upward streching, opening E and UES 5. Contractions of pharyngeal muscle 4

Anatomy 5

Anatomy 6

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Motility disorders of oropharynx • Dysfunction of the UES Zenker’s diverticulum, Cricopharingeal bar • Neurologic disorders (stroke) Cerebrovascular diseases, Poliomyelitis Amyotrophic lateral sclerosis, Multiple sclerosis, Brain stem tumor • Skeletal musclular disorders Myastenia gravis, Metabolic myopathy (T 4 toxicosis, myxedema, steroid) Muscular dystrophies • Local structural lesions Neoplasms, extinsic compression (Thyroid, cervical spur), Surgery 8 Common problem in the elderly patients and frequently associated with poor prognosis owing to a high incidence of aspiration

Zenker’s diverticulum 9

Motility disorders of the esophagus Smooth muscle diseases (scleroderma) Intrinsic nervous system Achalasia, Chagas disease loss of ganglion cells in Auerbach plexus LES no peristalsis Diffuse esophagus spasm and its variants 10

Esophagus motility disorder: scleroderma 11

Achalasia: Chagas’ disease Cause: Tripanosoma Cruzi inf. 12

Diffuse esophageal spasms 13

Rings and Webs 14 Schatzki’s ring - proximal or distal - congenital or secondary to GERD Plummer Vinson syndrome - upper E web - dysphagia - irondeficiency anemia Symptoms if diameter < 13 mm - intermittent dysphagia for solid food - sudden: “steak house syndrome” Treatment - mechanical dilators

Schatzki’s ring 15

16 Endoscopic image of the narrow area in mid-esophagus

Post-mortem specimen from a similar case of esophageal narrowing in a young boxer. 17

18 Map of lymph nodes near the oesophagus

Radiographic evaluation in suspected esophageal cancer 19

Gastroesophageal junction type II tumors 20

Esophageal cancer 21

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AJCC Staging of Esophagus: TNM Staging Regional lymph nodes (N) Nx Regional lymph nodes cannot be assassed N 0 No regional lymph node metastasis N 1 Regional lymph node metastasis Distant metastasis (M) Mx Distant metastasis cannot be assassed M 0 No distant metastasis M 1 Distant metastasis Tumors of lower or upper esophagus M 1 a Metastasis in nonregional lymph node M 1 b Distant metastasis (eg: liver, bone, brain) Tumors of middle esophagus M 1 a Not applicable M 1 b Metastasis in nonregional lymph node or distant metastasis (eg: liver, 23 bone, brain)

AJCC Staging of Esophagus: TNM Staging Stage Tumor Node Metastasis Stage 0 Stage I Tis T 1 T 2 T 3 T 4 Any T N 0 N 0 N 1 N 1 Any N M 0 M 0 M 1 a M 1 b Stage IIA Stage IIB Stage III Stage IV A Stage IV B 24

Resected esophageal specimen 25

Other esophageal disorders 26

Coin in upper oesophagus 27

INFECTIONS OF THE OESOPHAGUS Viral Fungal herpes, CMV Candida Most common in immuncompromized patients: AIDS Immunosuppressive treatment Immune defects Antibiotic os steroid treatment 28

Candida oesophagitis 29

Acid-related diseases of the oesophagus GERD / GORD 30

Definitions Heartburn: • Burning retrosternal pain radiating upward due to exposure of the oesophagus to acid Oesophagitis: • Endoscopically demonstrated damage to the oesophageal mucosa Gastro-oesophageal reflux disease (GORD): • Pathological reflux ranges from simple to erosive to Barrett’s Non-erosive reflux disease (NERD): • Reflux disease in which erosion does not occur 31 Talley et al. , BMJ 2001; 323: 1294– 7. de Caestecker, BMJ 2001; 323: 736– 9. Nathoo, Int J Clin Pract 2001; 55: 465– 9. Quigley, Eur J Gastroenterol Hepatol 2001; 13(Suppl 1): S 13– 18.

Pathophysiology of GORD salivary HCO 3 Impaired mucosal defence oesophageal clearance of acid (lying flat, alcohol, coffee) Impaired LOS Hiatus hernia (smoking, fat, alcohol) – – transient LOS relaxations basal tone Bile and pancreatic enzymes H+ Pepsin acid output (smoking, coffee) intragastric pressure (obesity, lying flat) bile reflux 32 gastric emptying (fat) de Caestecker, BMJ 2001; 323: 736– 9. Johanson, Am J Med 2000; 108(Suppl 4 A): S 99– 103.

Diagnosis of GORD • History 1. Does reflux exist? 2. Is acid R responsible for symptoms? 3. Has R led to esophagus damage? • • • 33 Barium swallow Radionuclide scintigraphy (99 m. Tc sulfur colloid) E. manometry Bernstein test p. H monitoring Endoscopy

Bernstein test Retrosternal pain for 0. 1 N HCl 34

Los Angeles classification system for oesophagitis Grade A One or more mucosal breaks, no longer than 5 mm, that do not extend between the tops of two mucosal folds One or more mucosal breaks, more than 5 mm long, that do not extend between the tops of two mucosal folds Grade C Grade D One or more mucosal breaks, that are continuous between the tops of two or more mucosal folds, but which involve less than 75% of the circumference 35 Grade B One or more mucosal breaks, that involve at least 75% of the oesophageal circumference Lundell et al. , Gut 1999; 45: 172– 80.

Savary-Miller classification of oesophagitis Grade I One or several erosions in one mucosal fold Grade II Several erosions in several mucosal folds, the erosions can merge Grade III Grade IV I-V Erosions surrounding the oesophageal circumference Ulcer(s), strictures, shortening of the oesophagus Grade V 36 Barrett’s epithelium Savary & Miller. The Esophagus. In: Handbook & Atlas of Endoscopy. Solothurn, Switzerland: Verlag Gassman AG, 1978: 119– 205.

Grade I oesophagitis Savary-Miller classification One or several erosions in one mucosal fold 37 Quigley, Eur J Gastroenterol Hepatol 2001; 13(Suppl 1): S 13– 18. Nathoo, Int J Clin Pract 2001; 55: 465– 9. www. gastrolab. net

Grade II oesophagitis Savary-Miller classification Several erosions in several mucosal folds, the erosions can merge 38 www. gastrolab. net

Grade III oesophagitis Savary-Miller classification Erosions surrounding the oesophageal circumference 39 Freytag et al. , Atlas of gastrointestinal endoscopy. www. home. t-online. de/home/afreytag/indexe. htm

Grade IV oesophagitis Savary-Miller classification Ulcer(s), shortening of the oesophagus 40 Freytag et al. , Atlas of gastrointestinal endoscopy. www. home. t-online. de/home/afreytag/indexe. htm

Grade IV oesophagitis Savary-Miller classification Stricture 41 Nadel, UCHC

Grade V oesophagitis Savary-Miller classification Moderate Barrett’s oesophagus 42 Freytag et al. , Atlas of gastrointestinal endoscopy. www. home. t-online. de/home/afreytag/indexe. htm

Grade V oesophagitis Savary-Miller classification Moderate Barrett’s oesophagus Chromoendoscopic picture 43 Freytag et al. , Atlas of gastrointestinal endoscopy. www. home. t-online. de/home/afreytag/indexe. htm

Barrett’s dysplasia 44 Columnar cells instead of squamous cells

Grade V oesophagitis Savary-Miller classification Severe Barrett’s oesophagus 45 Freytag et al. , Atlas of gastrointestinal endoscopy. www. home. t-online. de/home/afreytag/indexe. htm

Adenocarcinoma of the oesophagus 46 Nadel/Saint Francis Hospital. In: Gastrointestinal Pathology. Fenoglio-Preiser, New York: Raven Press, 1989: 96– 100.

Range of presentations of GORD Typical symptoms (Heartburn/regurgitation) With oesophagitis Chest pain (visceral hyperalgesia) Without oesophagitis Complications Atypical symptoms Oesophageal erosions and/or ulcers Stricture Hoarseness (‘reflux laryngitis’) Asthma, chronic cough, wheezing Dental erosions 47 Barrett’s oesophagus Oesophageal adenocarcinoma Nathoo, Int J Clin Pract 2001; 55: 465– 9.

Prevalence of heartburn or acid regurgitation % Women: at least weekly episodes 40 Prevalence (%) Men: at least weekly episodes 0 25– 34 35– 44 45– 54 55– 64 65– 74 Age (years) 48 Locke et al. , Gastroenterology 1997; 112: 1448– 56.

Asthma patients experiencing GORD symptoms (%) GORD can be a trigger for asthma 100 80 72 77 65 60 40 20 0 Perrin-Fayolle et al. (n=150) O’Connell et al. (n=189) Field et al. (n=109) Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S 23– 32.

Correlation of respiratory and oesophageal symptoms with oesophageal acid events Asthmatic patients with GORD (n=118) Wheezing or shortness of breath 65 Cough 98 Chest pain 60 Heartburn 83 Regurgitation 87 Nausea 91 0 20 40 60 80 100 Respiratory and oesophageal symptoms associated with oesophageal acid events (%) 50 Harding et al. , Chest 1999; 115: 654– 9.

Mechanism of asthma symptoms on exposure to oesophageal acid Asthma symptoms plus oesophageal acid Oesophageal acid-induced bronchoconstriction: vagally mediated oesophageal bronchial reflex heightened bronchial reactivity microaspiration Increase: minute ventilation respiratory rate Evidence of airway inflammation: Substance P and tachykinin release 51 Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S 23– 32.

Chronic cough and GORD VN N 52 Receptors Cough centre Vagus nerve Cortical input Irwin & Madison, Am J Med 2000; 108(Suppl 4 A): S 126– 30.

Effect of PPI on pulmonary and GI symptoms in asthma patients 14 Pulmonary symptoms score Symptom score 12 Gastric symptom score 10 8 6 4 2 0 0 1 2 3 4 5 Placebo 53 6 7 8 9 10 11 12 13 14 15 16 17 18 Weeks PPI Kiljander et al. , Chest 1999; 16: 1257– 64.

Consequences of severe and prolonged GORD Savary-Miller Grade IV and above Oesophageal stricture • Oesophageal stricture Barrett’s oesophagus • Barrett’s OE Oesophageal adenocarcinoma Anaemia • OE Adenocarcinoma • Anemia 54 Nathoo, Int J Clin Pract 2001; 55: 465– 9.

Differential diagnosis of oesophageal stricture Oesophageal cancer Oesophageal spasm GORD Globus hystericus Epiglottitis Ingestion of caustic substances Pharyngitis Peritonsillar abscess Foreign body Oesophageal candidiasis 55

Prevalence and risks of Barrett’s oesophagus in Europe/USA Barrett’s found at endoscopy: 0. 5– 2%1 Barrett’s found while investigating GORD: 10– 15%2, 3 Barrett’s is common in white males 4 Prevalence of adult heartburn: 20– 40%3 Barrett’s increases the risk of oesophageal cancer 50– 100 fold 4 56 1. Jankowski et al. , The Lancet 2000; 356: 2079– 85. 2. Gore et al. , Aliment Pharmacol Ther 1993; 7: 623– 8. 3. Spechler. Digestion 1992; 51(Suppl 1): 24– 9. 4. Peters et al. , Gut 1999; 45: 489– 94.

Mortality due to oesophageal adenocarcinoma in England Wales 4000 Mortality 3500 3000 2500 2000 1500 1000 500 0 79 84 89 94 97 Year 57 Office of National Statistics, 1999.

Heartburn as a risk factor for oesophageal adenocarcinoma Frequency and duration of symptoms 20 Frequency 16. 7 16. 4 Odds ratio Chronicity 7. 5 6. 3 5. 2 5. 1 1 1 0 None 1 2– 3 >3 Heartburn episodes/week 58 0 <12 12– 20 >20 Duration of symptoms (years) Lagergren et al. , N Engl J Med 1999; 340: 825– 31.

Management of upper GI symptoms in primary care Clinical history Heartburn (GORD) Upper abdominal pain/dyspepsia Alarm features Manage with antisecretory agents Early endoscopy Appropriate treatment 59 Age >45 Test-and-treat for H. pylori Treat empirically

Alarm features for GORD Odynophagia Dysphagia Bleeding Alarm features Vomiting 60 Weight loss Nathoo, Int J Clin Pract 2001; 55: 465– 9.

European practice guidelines: GORD Careful analysis of symptoms and history is key to diagnosis Diagnosis based on symptoms can be aided by a trial of treatment Clear endoscopic abnormalities are found in <50% of patients Treatment should start with a proton pump inhibitor (PPI) Most patients will require long-term treatment; anti-reflux surgery may be as effective as PPIs, but is less predictable 61 Summary of conclusions from a multidisciplinary workshop held in Genval, Belgium in 1999. Dent et al. , BMJ 2001; 322: 344– 7.

When should endoscopy be considered in patients with GORD? Alarm symptoms (e. g. dysphagia, weight loss, bleeding, abdominal mass) Diagnostic problems (e. g. atypical symptoms) Heartburn for 5 years or longer Failure to respond to initial treatment Pre-operative assessment 62 Dent et al. , BMJ 2001; 322: 344– 7.

Differential diagnosis of GORD Hiatus hernia Oesophageal stricture Oesophageal cancer Chest pain of cardiac origin Functional dyspepsia 63 Nathoo, Int J Clin Pract 2001; 55: 465– 9.

Treatment options in GORD • Simple (lifestyle) measures • Medical treatment antacids acid secretion suppressors PPI, H 2 RAs, H. p. erad. prokinetics • Surgery (laparascopic) 64

Lifestyle modifications for the management of GORD Reduce weight Elevate head of bed Stop smoking Modifications Avoid reflux-promoting agents (e. g. alcohol, coffee, some foods) (not evidence based) 65 Eat small meals, no late meals, reduce fat Consider alternatives to reflux-promoting drugs (e. g. theophylline, anticholinergics)

Antacids Increase the p. H of gastric refluxate Reduce the erosive effect and hence reduce symptoms Suitable for quick relief of mild symptoms Most antacids are not suitable therapies for established GORD or oesophagitis Less effective than H 2 RAs or PPIs for treatment of GORD Adverse effects include: 66 Accumulation in patients with renal impairment Milk-alkali syndrome with high doses Constipation Sonnenberg A, Pharmacoeconomics 2000; 17: 391– 401. Diarrhoea de Caestecker, BMJ 2001; 323: 736– 9. Hatlebakk & Berstad, Clin Pharmacokinet 1996; 31: 386– 406. Scott & Gelhot, Am Fam Physic 1999; 59: 1161– 9.

H 2 -receptor antagonists (H 2 RAs) Inhibit histamine stimulation of gastric parietal cell, resulting in reduced gastric acid secretion Slower onset but longer duration of action than antacids Cimetidine is associated with more drug interactions than other H 2 RAs, such as ranitidine H 2 RAs are generally not as effective as PPIs for symptom relief or healing 68 de Caestecker, BMJ 2001; 323: 736– 9. Sonnenberg, Pharmacoeconomics 2000; 17: 391– 401.

Available PPIs in Europe in 2002 Omeprazole Lansoprazole Pantoprazole Rabeprazole Esomeprazole But are they all the same? 69

PPI bioavailability after the first dose Bioavailability (%) 90 80 70 60 50 40 30 80 77 64 52 40 20 10 0 Lansoprazole Pantoprazole Esomeprazole 70 Rabeprazole Omeprazole Tolman et al, J Clin Gastroenterol 1997; 24: 65– 70. Fitton & Wiseman, Drugs 1996; 51: 460– 82. Hassan-Alin et al, Gastroenterology 2000; 118: A 16. Swan et al. , Aliment Pharmacol Ther 1999; 13(Suppl 3): 11– 7. Howden, Clin Pharmacokinet 1991; 20: 38– 49.

Lansoprazole metabolism is unaltered with repeated dosing LAN LANSOPRAZOLE CYP 3 A 4 CYP 2 C 19 Lansoprazole sulphone Hydroxy lansoprazole Liver enzymes unaffected LAN 71 Tolman et al. , J Clin Gastroenterol 1997; 24: 65– 70. Welage & Berardi, J Am Pharm Assoc 2000; 40: 52– 62.

Healing rates for various PPIs in GORD L = lansoprazole P = pantoprazole O = omeprazole R = rabeprazole 30 = 30 mg/day, 20 = 20 mg/day, 40 = 40 mg/day Petite et al. L 30/O 20 Castell et al. L 30/O 20 Mee et al. L 30/O 20 Mulder et al. L 30/O 40 Mossneret al. P 40/O 20 Corinaldesi et al. P 40/O 20 Hotz et al. P 40/O 20 Vicari et al. P 40/O 20 Thjodleifsson et al. R 20/O 20 Dekkers et al. R 20/O 20 0 20 40 60 80 100 Patients healed at 8 weeks (%) 72 Thomson, Curr Gastroenterol Rep 2000; 2: 482– 93.

Nissen’s fundoplication for GORD 73

Clinical management of Barrett’s oesophagus Acid suppression therapy with PPIs 1 Surveillance endoscopy with biopsies Mucosal ablation (electrocautery, laser or photodynamic therapy) combined with high -dose acid suppression Oesophageal resection 74 1. de Caestecker, BMJ 2001; 323: 736– 9.

Conclusions Reflux symptoms are frequent throughout life Incidence of oesophageal adenocarcinoma is rising: Associated with increasing incidence of reflux and decreasing incidence of H. pylori Heartburn is a risk factor for oesophageal adenocarcinoma: 75 Frequency Duration Severity Hennessy, Postgrad Med J 1996; 72: 458– 63. Malfertheiner & Gerards, Baillière’s Clin Gastroenterol 2000; 14: 731– 41.

Key points Long-term GORD can result in serious complications, which may prove fatal Early treatment of GORD is associated with excellent outcomes Late treatment is associated with an increased risk of complications and potentially poor outcomes Early intervention relieves symptoms and helps prevent serious complications 76

Mallory-Weiss syndrome Bleeding from rupture of esophageal mucosa 77

Pill induced esophageal mucosal lesion 78

Portal hypertension – Esophageal varices 79

Esophageal varices 80