ClinicalClinical presentation,presentation, diagnosis,diagnosis, andand managementmanagement ofof gastroesophagealgastroesophageal refluxreflux diseasedisease

Mitchell S. Cappell, MD, PhD, FACG

Med Clin N Am 89 (2005) 243–291 胃腸內科 陳青富 醫師

1 TerminologyTerminology

z GERD refers to the pathologic reflux of gastric fluid into the through the gastroesophageal junction. z Belching, which is reflux of air from the to the esophagus and beyond. z Vomiting, which is reflux of digested foods (primarily a semisolid solution). z Reflux have evident esophageal abnormalities at esophagogastroduodenoscopy (EGD) or at pathologic analysis of endoscopic biopsies.

2 TerminologyTerminology z Nonerosive reflux disease have reflux symptoms and abnormal acid exposure with no evident esophageal abnormalities at EGD or at pathologic evaluation of endoscopic biopsies. z Although gastroesophageal reflux has been defined as reflux of acid (pH<4), gastroesophageal reflux may incorporate reflux (regurgitation) of nonacid (neutral or alkaline) fluids. z GERD is also used as an all-inclusive term for any extraesophageal clinical consequences, symptomatic or anatomic, from reflux.

3 4 PathogenesisPathogenesis

5 PathogenesisPathogenesis

6 EpidemiologyEpidemiology IncidenceIncidence

z About 40% of US adults complain of monthly , about 20% complain of weekly heartburn, and about 7% complain of daily heartburn. z The prevalence of erosive esophagitis is, however, less, with estimates of 2% to 7% as determined by EGD. z About 0.25% of adults in the United States develop BE as a complication of GERD. z The prevalence of gastroesophageal reflux seems to have increased during the last 30 years.

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9 EpidemiologyEpidemiology RiskRisk factorsfactors

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13 ClinicalClinical presentationpresentation SymptomsSymptoms z Pyrosis is the cardinal symptom. Typically, a burning pain arises from the epigastrium and radiates retrosternally to the throat and neck; z exacerbated by meals, by recumbency, by bending over, and by ingesting acidic drinks; and is relieved by ingestion of antacids, milk, or other alkaline foods and by standing up. z Regurgitation: Patients may complain of bitter or acidic fluid in the oropharynx from regurgitation.

14 ClinicalClinical presentationpresentation SymptomsSymptoms z Nausea and vomiting is rare in GERD and suggests other diseases. Patients occasionally complain of atypical chest pain. Globus is an uncommon symptom that is usually caused by GERD. z Dysphagia suggests luminal obstruction from a reflux- induced stricture or from esophageal adenocarcinoma complicating BE, sometimes uncomplicated erosive esophagitis. z Involuntary weight loss with chronic reflux symptoms suggests possible esophageal adenocarcinoma, particularly when the patient is elderly and has dysphagia of recent origin.

15 ClinicalClinical presentationpresentation SymptomsSymptoms z Severe erosive esophagitis can occasionally cause odynophagia. z Ulcerative reflux esophagitis may present with acute gastrointestinal bleeding manifesting as hematemesis or melena.

16 ClinicalClinical presentationpresentation SignsSigns z GERD without esophageal complications and without extraesophageal symptoms rarely produces signs. z Signs may occur with esophageal complications or with extraesophageal disease. z Hemorrhagic esophagitis may produce pallor from acute GI bleeding, whereas esophageal ulcerations or adenocarcinoma may produce with chronic GI bleeding. z Esophageal adenocarcinoma from BE may cause cancer cachexia.

17 ClinicalClinical presentationpresentation LaboratoryLaboratory teststests z Routine blood tests are characteristically normal with uncomplicated GERD. z Complicated GERD can cause abnormal blood tests. Hemorrhagic reflux esophagitis may cause anemia. z Patients with esophageal adenocarcinoma may have hypoalbuminemia from malnutrition.

18 DifferentialDifferential diagnosisdiagnosis z The D/D of epigastric pain includes cholelithiasis, choledocholithiasis, acute viral hepatitis, alcoholic hepatitis, acute pancreatitis, PUD, gastritis, pyelonephritis, nephrolithiasis, shingles, and mesenteric ischemia. z The D/D of atypical chest pain includes angina, myocardial infarction, and diffuse esophageal spasm.

19 DifferentialDifferential diagnosisdiagnosis z Dysphagia may be caused by esophageal obstruction from esophageal s.c.c, large polyps, webs, radiation- induced stricture, foreign body ingestion, or lye ingestion; extrinsic compression, or paraesophageal . z Odynophagia suggests infectious esophagitis caused by Candida, herpes simplex, cytomegalovirus, or primary HIV infection; pill esophagitis or radiation- induced esophageal injury.

20 DiagnosisDiagnosis TrialTrial ofof empiricempiric therapytherapy z A 6-week trial of empiric acid-suppressive (PPI) therapy, without performing EGD, for patients who present with uncomplicated pyrosis or epigastric pain caused by suspected GERD. z Symptom resolution with therapy initiation and recurrence with therapy cessation provides presumptive evidence of GERD. z Sensitivity: 75% and specificity : 80% for GERD, using a 50% improvement in pyrosis as the therapeutic end point.

21 22 DiagnosisDiagnosis EsophagramEsophagram z Barium studies are used to evaluate a patient with suspected GERD to document the reflux; detect reflux- induced mucosal injury; identify an associated sliding hiatal hernia; exclude complications, such as BE, peptic stricture, or adenocarcinoma. z the sensitivity : 60% for single-contrast 90% for double-contrast studies for moderate to severe reflux esophagitis.

23 DiagnosisDiagnosis EsophagogastroduodenoscopyEsophagogastroduodenoscopy withwith endoscopicendoscopic biopsiesbiopsies z EGD is the standard clinical test for GERD, evaluates the severity and extent of mucosal injury, and detects the presence of complications from GERD. z Severity of esophagitis is endoscopically graded according to one of three systems. ( the Los Angeles, Savary-Miller grading system or the Hetzel classification ) z In the Los Angeles grading system, esophagitis is graded from A, where mucosal breaks are confined to folds and no longer than 5 mm, to D, where mucosal breaks are circumferential.

24 GradeGrade A,A, LALA classificationclassification

25 GradeGrade B,B, LALA classificationclassification

26 GradeGrade C,C, LALA classificationclassification

27 GradeGrade D,D, LALA classificationclassification

28 DiagnosisDiagnosis EsophagogastroduodenoscopyEsophagogastroduodenoscopy withwith endoscopicendoscopic biopsiesbiopsies z EGD cannot detect abnormal acid reflux without mucosal injury (nonerosive reflux disease). z It misses about 40% of acid reflux determined by pH monitoring, but such reflux tends to be mild and uncomplicated. z EGD often fails to diagnose clinically significant extraesophageal manifestations of GERD, which often occur without esophagitis. z When extraesophageal manifestations of GERD are suspected, normal findings at EGD should prompt 24- hour ambulatory pH monitoring.

29 DiagnosisDiagnosis EsophagogastroduodenoscopyEsophagogastroduodenoscopy withwith endoscopicendoscopic biopsiesbiopsies z GERD is associated with a sliding hiatal hernia. z EGD reveals a small pouch between the tubular esophagus and the baggy stomach; the pouch is lined by gastric mucosa and covered by gastric rugae that extend several centimeters above the diaphragmatic hiatus. z A stricture associated with reflux esophagitis may be benign from peptic injury, or malignant from adenocarcinoma, should be extensively biopsied.

30 HiatalHiatal herniahernia

31 EsophagealEsophageal PepticPeptic StricturesStrictures

32 EsophagealEsophageal CancerCancer

33 DiagnosisDiagnosis AmbulatoryAmbulatory pHpH monitoringmonitoring z 24-hour ambulatory pH monitoring is the most sensitive test, but cannot detect reflux of nonacidic fluids and cannot assess mucosal damage from the refluxate. z Indicated for pts with typical reflux symptoms refractory to conventional therapy who have nonerosive reflux disease; for pts presenting with extraesophageal symptoms of undetermined etiology and before antireflux surgery.

34 DiagnosisDiagnosis AmbulatoryAmbulatory pHpH monitoringmonitoring z The acid exposure time is defined as the percentage of time that the esophageal pH is less than 4. ( normal upper limit : 6.3% in the supine and 1.2% in the upright position). z Gastroesophageal reflux is most simply defined as an abnormally high acid exposure time. z An abnormal result at ambulatory 24-hour pH monitoring highly correlates with the diagnosis of reflux esophagitis at EGD. z Between 84% and 96% of patients with reflux esophagitis at EGD have abnormal esophageal acid exposure times.

35 36 MedicalMedical therapytherapy LifestyleLifestyle andand dietarydietary modificationsmodifications z Factors that promote or exacerbate gastroesophageal reflux should be avoided. z Obese patients should lose weight and avoid heavy or fatty meals. z Patients should avoid late night snacks and recumbency soon after eating. z The head of the bed should be elevated. z Patients should avoid midabdominal tight-fitting clothes or belts. z Patients should eliminate smoking and restrict alcohol intake.

37 MedicalMedical therapytherapy LifestyleLifestyle andand dietarydietary modificationsmodifications z Foods that exacerbate symptoms should be avoided; these foods often include citrus drinks, spicy foods, coffee, tea, cola beverages, and chocolate. z Medications known to lower the LES pressure, such as calcium channel blockers or nitrates, and that can exacerbate esophageal injury, such as NSAIDs, should be avoided if possible. z Avoidance of psychologic stress at home and work is advisable.

38 MedicalMedical therapytherapy MedicationsMedications

39 MedicalMedical therapytherapy γγ--AminobutyricAminobutyric acidacid agonistsagonists z A major current focus of research is to develop tLESR inhibitors that may effectively prevent GERD with minimal side effects. z γ -Aminobutyric acid is a powerful CNS inhibitory

neurotransmitter. Baclofen is a γ-aminobutyric acidB receptor agonist blocks tLESR relaxation in laboratory animals and in humans. z Baclofen reduced the frequency of reflux episodes and of tLESRs by 40- 60% as compared with placebo.

40 EndoscopicEndoscopic therapytherapy

41 SurgicalSurgical therapytherapy z The two most common antireflux operations are the Nissen and Toupet fundoplications. z Both procedures are most commonly performed laparoscopically. z Common indications include failed medical therapy despite adequate acid suppression; intolerance or noncompliance to PPI therapy in young patients with moderate to severe GERD; persistent extraesophageal symptoms; and reflux-induced regurgitation, aspiration, , or bronchiectasis not responding to PPI therapy.

42 SurgicalSurgical therapytherapy z Antireflux surgery is relatively contraindicated in elderly patients or in patients with significant comorbidity unrelated to GERD. z Both procedures are successful in more than 90% of patients, with relief of symptoms and prevention of recurrent strictures when performed by experienced surgeons at high-volume referralreferral centers.centers. z Postoperative complications include esophageal hemorrhage, esophageal perforation, crural disruption, paraesophageal herniation, and gastric volvulus. z The mortality of the is approximately 0.2%.

43 SpecialSpecial situationssituations ExtraesophagealExtraesophageal manifestationsmanifestations ofof GERDGERD

z Pulmonary manifestations of GERD may becaused by microaspiration of acid and pepsin into the tracheobronchial tree, or a bronchoconstrictive vagal reflex triggered by esophageal irritation. z Asthma is frequently associated with GERD. z The asthma is typically nocturnal because of the promotion of gastroesophageal reflux with recumbency, and the absence of food to buffer refluxed acid during overnight fasting.

44 SpecialSpecial situationssituations ExtraesophagealExtraesophageal manifestationsmanifestations ofof GERDGERD z GERD-associated asthma should be considered in patients who present with asthma in adulthood, lack a personal and family history of allergy, have heartburn, and respond poorly to traditional bronchodilator or steroid therapy. z Currently treated with PPI therapy. High dose, twice- daily, and long-term therapy is generally recommended. z Symptoms improved in 69% of patients receiving antireflux medications.

45 SpecialSpecial situationssituations ExtraesophagealExtraesophageal manifestationsmanifestations ofof GERDGERD z Reflux laryngitis is caused by microaspiration of acid. The most common symptom is hoarseness. Others include globus sensation, frequent throat clearing, halitosis, sore throats, and chronic . z 10% to 40% of patients with chronic cough have GERD. z Only a minority of patients have heartburn, and endoscopic evidence of esophagitis. z Esophageal pH monitoring is the best available diagnostic test, but is only moderately sensitive( 54%), and specific.

46 SpecialSpecial situationssituations ExtraesophagealExtraesophageal manifestationsmanifestations ofof GERDGERD z PPIs are the generally recommended therapy, with from 63% to 100% of patients experiencing significant improvement in laryngeal symptoms and laryngoscopic findings with therapy. z GERD is an important cause of nonbacterial dental erosions, in a prospective study, 47.5% of 181 patients with dental erosions had GERD, whereas only 12.5% of 72 healthy subjects had GERD.

47 SpecialSpecial situationssituations GERDGERD andand HelicobacterHelicobacter pyloripylori infectioninfection z An association between the decreasing prevalence of H pylori infection, caused by antibacterial therapy, and the increasing incidence of GERD and esophageal adenocarcinoma in Western countries. z A recent meta-analysis of 14 case-controlled studies reported that H pylori–negative status was significantly associated with GERD, and of 10 therapeutic clinical trials reported that anti–H pylori therapy was significantly associated with GERD. z Anti–H pylori therapy should not be withheld, when otherwise indicated, because of the quantitatively small increased risk of esophageal adenocarcinoma after H pylori eradication.

48 ComplicationsComplications BarrettBarrett’’ss esophagusesophagus andand esophagealesophageal adenocarcinomaadenocarcinoma z BE is defined as replacement of normal stratified squamous epithelium by metaplastic, specialized, intestinal epithelium that contains goblet cells. z BE is a premalignant lesion. z From 1/3-2/3 of esophageal adenocarcinoma contain foci of Barrett’s metaplasia. z About 10% of pts have esophageal adenocarcinoma at the time of diagnosis of BE. z The annual incidence of esophageal adenocarcinoma in pts with established BE is about 1 in 200. z The risk of developing esophageal adenocarcinoma is increased about 100-fold in patients with BE. 49 ComplicationsComplications BarrettBarrett’’ss esophagusesophagus andand esophagealesophageal adenocarcinomaadenocarcinoma z Demographic risk factors include male sex, older age, white race, lower socioeconomic status. and probably smoking tobacco. z Obesity is an important risk factor. z Patients with a hiatal hernia are more likely to have severe reflux esophagitis, BE, and esophageal cancer. z At EGD numerous biopsies should be taken to confirm the diagnosis of BE histologically and to exclude dysplasia or adenocarcinoma.

50 ComplicationsComplications BarrettBarrett’’ss esophagusesophagus andand esophagealesophageal adenocarcinomaadenocarcinoma z The surveillance interval for BE depends on the degree of dysplasia. BE without dysplasia :every 3 years; with mild dysplasia :every 6 months; with severe dysplasia, generally require . z PPIs are the mainstay of medical therapy for GERD complicated by BE. z Although intense PPI therapy usually effectively reverses severe erosive esophagitis, evidence for its effect on reversing Barrett’s metaplasia and on reducing the risk of esophageal adenocarcinoma is indirect and inconclusive. z 51 ComplicationsComplications HemorrhagicHemorrhagic esophagitisesophagitis z About 7% of patients with GERD have clinically significant acute hemorrhage. z Only about 40% of these patients report a history of heartburn. z Other risk factors for hemorrhagic reflux esophagitis include cirrhosis, coagulopathy, and anticoagulant therapy. z Focal lesions with stigmata of recent hemorrhage should receive endoscopic therapy at the time of endoscopic diagnosis. z Hemorrhagic reflux esophagitis is generally managed medically with intense PPI therapy.

52 ComplicationsComplications PepticPeptic stricturestricture z Risk factors include old age, a long history of GERD, a hypotensive LES, abnormalities in esophageal peristalsis, and a hiatal hernia. z Characteristically presents with progressive dysphagia, typically to solids and often with antecedent pyrosis. z Weight loss associated with an esophageal stricture suggests possible malignancy. z Barium esophagrams reliably detect peptic esophageal strictures.

53 ComplicationsComplications PepticPeptic stricturestricture z EGD is usually the choice to evaluate a suspected peptic stricture because of high sensitivity; high specificity; and the ability to perform endoscopic therapy. z Multiple biopsies are taken at EGD to exclude BE, esophageal adenocarcinoma, or other lesions. z Peptic strictures are usually treated with mechanical dilatation, especially strictures that are tight, severely symptomatic, or refractory to medical therapy.

54 ComplicationsComplications PepticPeptic stricturestricture z Patients with a peptic stricture should receive intense PPI therapy to reduce the mucosal inflammation from acid-induced injury. z Maintenance PPI therapy greatly decreases the need for repeated stricture dilatations.

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