REVIEW ARTICLE

The Pathophysiology of Gastroesophageal Refiux Disease

Bradley Jimmy Waleleng, Marcellus Simadibrata, Ari Fahrial Syam * Division of Gastroentero-, Department of Internal Medicine Faculty of Medicine, University of Sam Ratulangie, Prof. Dr. RD Kandou Hospital, Manado ** Division of , Department of Internal Medicine, Faculty of Medicine University of Indonesia/Dr. Cipto Mangunkusumo General National Hospital, Jakarta

ABSTRACT The incidence of Gastroesophageal Reflux Disease (GERD), especially in Indonesia, is increas- ing with the change of community life-style. Also, the doctors’ perception in understanding clinical manifestation of GERD is alike in addition to the development of diagnostic facilities such as in Indonesia. The GERD incidence in Indonesia is as high as the incidence in developed countries. Esophageal reflux develops in physiological condition, which may be found in normal individual. GERD development is caused by anatomical and physiological disorders such as hereditary or acquired factor; and other factors that may be categorized into offensive factors such as , pepsin, bile acid, trypsin and disturbance in defensive factors such as hypotensive Lower Esophageal Sphinc- ter (LES), Transient Lower Esophageal Sphincter Relaxations (TLESR), hiatal , disrupted saliva production, esophageal peristaltic disorder; as well as other factors such as genetic, diet, or certain drugs. Imbalance of such factors may cause pathological repeated esophageal refiux which may damage esophageal mucosa and lead to GERD development including all of complications.

Keywords: esophageal refiux, GERD, LES

INTRODUCTION 13.4-16.3% patients with GERD in Taiwan, Malaysia Gastroesophageal Reflux Disease (GERD) is and Japan. At the Faculty of Medicine, Cipto Man- a condition of gastric content refiux into the gunkusumo hospital, Syam AF et al, reported that there and causes clinical manifestations.1 This disease is was increased GERD prevalence from 5.7% in 1997 a consequence of various physiological and into 25.18% in 2002 (approximately 13.13%).3,4 anatomical disorders which may have important Heartburn and acid regurgitation are reported role of anti-refiux mechanism in the and once weekly by 20% of Americans, and the annual esophagus. Basically, gastrointestinal reflux is prevalence is more than 59%. Traditionally, refiux a physiological process which normally occurs for treatment is aimed to deal with aggressive substance approximately one hour daily in normal individual. of gastric acid. However, we found other factors which Such refiux may not occur continuously due to ana- have important roles in GERD development and tomical barriers, i.e. lower esophageal sphincter (LES), esophageal mucosa damage.5 diaphragm crural and phrenoesophageal ligament.2 Noxious substances that may damage esopha- The incidence of GERD is high in Western geal mucosa include gastric-derived substances, i.e. countries and recently, the experts are getting more gastric acid and pepsin and duodenal-derived curios about GERD. It is reported that there are substances, i.e. conjugated and unconjugated bile acid as well as trypsin. Injury induced by such substances Correspondence: BJ Waleleng may cross esophagogastric junction and moisten Division of Gastroentero-hepatology esophageal mucosa. To prevent such condition, LES Department of Internal Medicine Prof. Dr. RD Kandou Hospital together with diaphragm crural have a major role Jl. Raya Tanawangko Manado, Indonesia in protecting structures from noxious substances of E-mail: [email protected] gastroduodenal refiux. Gastroesophageal junction may

84 The Indonesian Journal of Gastroenterology, Hepatology, and The Pathophysiology of Gastroesophageal Reflux Disease be pass due to transient lower esophageal relaxations that , including the Barrett’s esophagus, (TLESR), hypotensive LES (HLES), or by other cause increases with frequency and contact duration associated with .5 The mucosa is exposed of esophagus and the refiuxate at pH < 4.5,8,9 It is to noxious gastroduodenal substance, therefore interesting that GERD may occur even when esophagus lumen is protected by esophageal clearance the patient’s gastric acid production does not increase. mechanism through peristaltic and acid neutraliza- This is found by Hirschowitz et al, who reveal that tion process which is also part of defense mechanism stimulation of basal pentagastrin gastric acid secretion and epithelial cell recovery. Hence, it is important in and pepsin is similar in GERD patients and normal preventing mucosa damage.5 Normally, there is control subjects. Therefore, esophageal disturbance due a balance between aggressive factors and defense to acid exposure in GERD case may be identi›ed by mechanism.5,6 When the protection mechanism fails, ambulatory pH monitoring, which shows that the most it may cause GERD complication including frequent cause is esophageal barrier failure and poor esophagitis, stricture, or Barrett’s esophagus,5,7 or even esophageal clearance.5 A small number of patients with esophageal .7 In some individuals, genetic Zollinger-Ellison syndrome and acid hypersecretion factor may also have a role as predisposition factor that cause increased gastroesophageal refiux.5 Frequen- of GERD.5 cy and duration of acid exposure on esophageal are not always reliable in predicting the severity of esophageal PATHOPHYSIOLOGY mucosa injury. Other factors may also play a role Gastroduodenal Factors including duodenogastroesophageal refiux, mechanism Gastric substances that most frequently cause of esophageal lumen clearance and epithelial recovery 5 injury are gastric acid produced by parietal cells and and protection. Pepsin, bile acid, trypsin and hyper- pepsin produced by gastric chief cells. In endos- osmolar diet increase the sensitivity of esophageal 6 copy, usually gastric substances may be mixed with mucosa to acid-induced injury. Locke et al, found that duodenal substances which contain bile acid and 72% of 2,118 participants who had body mass index of 2 trypsin. Therefore, when there is a refiux of gastric con- > 30 kg/m , family history of heartburn, or symptoms tent into esophagus, it is a combination of gastric and of esophageal or gastric disorder, smoking history, duodenal substances which contribute to pathogenesis alcohol consumption more than 7 times weekly and of GERD.5 Other gastric factor contributes to such obvious psychosomatic symptoms are associated with 9 pathogenesis is , which has a role frequent heartburn. in acid secretion.5 Duodenal Substances Gastric Substances Duodenogastric reflux is a condition with Experimental findings and clinical evidences regurgitation of duodenal content (bile acid and support the important role of gastric acid and pepsin pancreas secretion) into the stomach. This condition in GERD. An experimental animal study demonstrates normally occurs especially after meal (post pran- 8 that the gastric acid itself may cause esophageal dial) and at night. If the duodenogastric refiux reach mucosa injury in a very low pH (pH 1-2).5 Acid refiux esophagus, it is referred as duodenal gastroesopha- may become pathological when the esophagus is geal refiux or it may be mentioned as bile refiux or exposed to acid condition (pH < 4) for more than 5.8% alkaline refiux (because of esophageal pH that > 7). of 24 hours pH-metry.7 Combination of acid and slight The high esophageal pH is also infiuenced by saliva concentrated pepsin will cause esophageal injury, bicarbonate.8 Bile acid and pancreatic enzymes may either macroscopic or microscopic.5,8,9 At pH 2, migrate from to gastric pylorus and cause pepsin disrupts the histological integrity of mucosa a mixture with gastric secretion. The role of duodenal barriers which increases the permeability of hydrogen content, especially bile acid and trypsin the pancreatic ion and produces bleeding. In contrast, esophageal enzyme in the development of esophageal mucosa contact with pepsin at pH 7.5 followed by solution injury is still controversial.5 Some studies propose contact at pH 2 without any pepsin demonstrate that the esophageal mucosa damage is depend on minimal mucosa disruption or permeability change. conjugation state of bile acid. Conjugated bile acid Hence, pepsin may produce mucosa injury depend on may bring damage at acid pH, while unconjugated pH with maximal enzyme activity at pH 3.6 In acid form may cause damage at alkaline pH. Little has been condition (pH < 4), pepsin may produce esophageal known of how bile acid may cause esophageal mucosa damage due to proteolytic characteristic and it is injury. The proposed mechanism is cell damage due to inactive at pH > 4.5,8 Several studies that measure dissolved lipid membrane of the mucosa and intra distal esophageal to acid exposure demonstrate that mucosa damage after bile acid infiux into the cells.5,8 there is a correlation between heartburn symptom and Trypsin, akin to pepsin, bring damage through prote- exposure of refiux substance at pH < 4. It is also found olysis mechanism and it frequently causes damage at

Volume 8, Number 3, December 2007 85 Bradley Jimmy Waleleng, Marcellus Simadibrata, Ari Fahrial Syam pH 5-8.5,8 It seems that gastric acid itself only cause Gastric Emptying least mucosa damage. However, when it is combined The loose of gastric cardia is a main factor with pepsin or conjugated bile acid, it will cause in GERD development. Prolonged distention of a signi›cant mucosa damage.8 Clinical evidences on proximal gastric part increases the number of post- noxious effect of duodenogastroesophageal refiux on prandial TLESR and refiux episode. Sustained diet esophageal mucosa is still controversial. Nevertheless, accumulation in stomach body is found in GERD Vaezi and Richter study5 that utilized a monitor of patients. It is assumed that prolonged diet bilirubin ambulatory instrument (bilitec) suggest that accumulation at the stomach body (fundus) will induce duodenogastroesophageal refiux is parallel to acid increased TLESR.5 In spite of contradictory result in refiux in clinical spectrum of GERD with the high- a study evaluating the correlation of gastric emptying est spectrum in patients with Barrett’s esophagus. and refiux, it is suggested that gastric emptying rate Moreover, it is found that esophageal exposure acid of upper stomach has more signi›cant effect com- and duodenogastroesophageal refiux are the most pared to the refiux. Stracher et al, measured gastric common refiux and it occurs in 95% patients with Bar- emptying of semi-solid diet and conducted 24 hours rett’s esophagus, 79% patients with GERD.5 Hence, pH monitoring in 71 patients with slow gastric the study supports the possibility of a synergy be- emptying symptoms and refiux. It was found that tween gastric acid and bile acid in the development of gastric emptying is slow at the proximal and not at esophagitis and Barrett’s esophagus.5,8 The role of the distal part and gastric emptying is correlated to duodenogastroesophageal refiux in bringing damage increased acid exposure to esophagus, either in 24 hour to esophageal mucosa without any of acid refiux has or after meal.5 not been known. A study by Marshall et al, utilizing extended pH and bilirubin monitoring in 38 patients Helicobacter pylori Microorganism with GERD found that duodenogastroesophageal Helicobacter pylori, known as a risk factor of refiux without acid refiux is rarely occur (7%) in pa- peptic ulcer in stomach and duodenum, may pre- tients without previous gastric operation.5 Sears et al, vent GERD because corpus caused by such who studied partial gastrectomy in 13 patients with microorganism may decrease the production of refiux symptoms found that there was an increase of gastric acid.5,9 On the contrary, H. pylori eradica- duodenogastroesophagal refiux by bilitec monitoring tion shows increased basal gastric acidity.5,9 A large in 77% patients. Endoscopic esophagitis was only epidemiological study found that between 1975 and found in patients who had concomitant acid refiux.5,8 1995, the number of patients hospitalized due to GERD Furthermore, Vaezi et al, observed and found that and esophageal adenocarcinoma increased signi›cantly there was only 24% patients with upper gastrointesti- in the United States; while patients hospitalized due nal tract symptoms who had partial gastrectomy due to peptic ulcer and gastric cancer decrease. Such to duodenogastroesophageal refiux without any acid tendency occurs because of reduced infection rate of H. reflux. The study demonstrates that duodeno- pylori in Western population. In another study Labenz gastroesophageal refiux without any excessive acid et al, explained that in 450 patients with duodenal refiux may cause refiux symptom without produc- ulcer and treated with H. pylori treatment and 3 years ing esophagitis.5 Thus, so far it is suggested that following the therapy, the incidence of esophagitis acid and pepsin are the main etiologies of mucosa refiux was found 2 times higher in the subject group injury.5 Duodenal content may exaggerate mucosa that had successful eradication treatment (26%) damage due to acid and pepsin and without acid and compared to the group with persistent infection pepsin it will not cause mucosa injury.5,8 In non-acidic (13%). Moreover, they suggested that H. pylori has reflux, gastroduodenal content may be taken into protecting effect against refiux.5,9 account in persistent symptoms of some patients treat- Another study gives different result about ed with acid-blocking agents. Using pH and bilirubin the correlation between H. pylori and GERD. monitoring, Koek et al, demonstrated that in Vakil et al, studied 242 patients with duodenal ulcer 15 symptomatic patients treated with proton pump who received treatment for H. pylori infection in four inhibitor (PPI), bile acid refiux will cause GERD randomized control studies and they found no increased symptoms. Vela et al, reported that in a group with incidence of GERD in patients who had successful frequent heartburn symptom after meal, omeprazole H. pylori eradication treatment. Eight double-blinded significantly decrease the number of acid reflux prospective study of H. pylori treatment in episode, but the non-acid reflux may persist and 1.165 patients with duodenal ulcer found that responsible for symptoms.5 Esophagitis reflux is eradication of such microorganism may not in- rarely found in achlorhydria patients such as secondary crease the development of esophagitis or exacerbate gastric atrophy due to perniciosa or post symptoms in patients who previously had GERD.5 8 gastrectomy. However, the clinical signi›cance of H. pylori role

86 The Indonesian Journal of Gastroenterology, Hepatology, and The Pathophysiology of Gastroesophageal Reflux Disease on GERD is still being disputed. In some patients during spontaneous TLESR associated with acid who had corpus gastritis due to H. pylori strain cyto- gastroesophageal refiux.12 toxin associated gen A (cagA), it may have protecting A study evaluated mechanisms responsible for effect against reflux through reduced gastric acid reflux episode of more than 24 hours duration in production.5 patients with and without hiatal hernia. It demonstrated that in patients with moderate to severe hiatal hernia, Gastroesophageal Junction Factor the contribution of TLESR against refiux is relatively Increased abdominal and gastric pressure is small. However, there was signi›cant number of normally occur in some of physiologic condition.10 refiux caused by hypotensive LES.5 Pharmacological Discrepancy between abdominal and thoracic pressure inhibition of TLESR provides new alternative for push the gastric content continuously into esophagus,5,7 GERD treatment through acid inhibition.5 Experimental and the pressure increase during inspiration and studies in animal and human reported that it found strained abdominal muscle. Hence, the pressure at reduced bile acid reflux and symptoms following boundary which is able to compensate intragastric treatment with GABA-B agonist, i.e. baclofen, which pressure is important to prevent esophageal refiux. The may reduce gastroesophageal refiux through TLESR border of such dynamic pressure is gastroesophageal inhibition, and it was suggested as a novel treatment junction.5,7,10 Lower esophageal sphincter and crural for GERD patients.6,7 A study of postprandial refiux diaphragma are part of sphincter complex which in patients with heartburn demonstrated that baclofen provide protection against gastroesophageal refiux.7 may reduce acid and non-acid refiux associated with LES is an internal sphincter, which is part of circu- symptoms in postprandial period.5 lar smooth muscle at distal esophagus. The healthy volunteers have sphincter complex with tonus Hypotensive Lower Esophageal Sphincters pressure 15-30 mmHg above the intragastric pres- (HLES) sure. Refiux is mainly occur when the LES pressure The length of LES segment is 3-4 cm. It has below 5 mmHg.7 Crural diaphragma prevents stress smooth muscles with tonic contraction at distal part of refiux and it may also prevent refiux when the LES esophageal end. The tonic contraction of LES has pressure ceased. This indicates the signi›cance of ex- two characteristics, i.e. from the muscle itself and ternal sphincter complex in maintaining effective anti- extrinsic innervations. Normal LES tonus at rest refiux barrier.7 GERD develops as a consequence of is varried, i.e. 10 -30 mmHg.6 There is only a small the incompetence of gastroesophageal junction against number of GERD patients who have a very low LES gastric secretion reflux. It may be overstated by pressure (< 10 mmHg). Some factors may reduce LES some of anatomical and physiological disorder of pressure: stomach distension, cholecystokinin, some gastroesophageal junction.11 diet (fat, chocolate, caffeine, alcohol), smoking and some drugs.5,6 Gastroesophageal refiux occurs due to Transient Lower Esophageal Sphincter low basal LES pressure which is incompetent to main- Relaxation (TLESR) tain the effective anti-refiux barrier.10 However, relax- The TLESR is a physiologic response of stomach ation of transient LES is a main mechanism of refiux distention due to food or gas and it is a mechanism development, low LES pressure is also an impor- that responsible in stomach gas expulsion. Some stud- tant mechanism of reflux in patients with severe ies reported that it was found in all of refiux state in GERD. HLES (basal pressure < 10 mmHg) facilitates individual with normal LES pressure during the refiux the gastric content to freely enter the esophagus which occur.6,7,10,12 TLESR occurs spontaneously, prolonged lead to esophagitis or GERD symptoms. Mechanism relaxation is not depend on the swallowing process.5,7,10 causing low LES pressure in reflux has not been During TLESR, the activity of crural diaphragma is known yet. The possible combination of hypotensive also inhibited,5,7 in the presence of crural diaphragma LES and hiatal hernia is necessary in development of relaxation, this condition may be induced by stomach erosive esophagitis. The degree of hernia severity, the distention through the pathways mediated by the va- width of esophagus hiatus, and the incompetent cru- gal nerve that integrate stimulation and inhibition of ral diaphragma component of sphincter affect GERD such factors. When excitation threshold is reached, it development.5 The severity of injury, which can be will give signal to LES and crural diaphragma to be observed through endoscopy, is correlated to LES relaxed.5 Relaxation of transient LES is the most pressure. For example, patients with scleroderma who common mechanism of refiux in healthy subjects and frequently have severe esophagitis may also have patients with GERD. It is reported that there is more a very low LES pressure. Myogenic and neurogenic than 90% refiux episodes in a healthy individual.5 failure, either primary or secondary due to acid injury In patients with reflux, the progression of lower are suggested to explain the low LES pressure, but esophageal contraction is frequently disrupted the mechanism which responsible for such condition

Volume 8, Number 3, December 2007 87 Bradley Jimmy Waleleng, Marcellus Simadibrata, Ari Fahrial Syam has not been clear.10 clearance, the rate of TLESR increase. Combination of such factors may explain the increased incidence in Hiatal hernia patients with refiux.5 Hiatal hernia derived from herniation of abdomi- nal organ at the abdominal cavity through esophagus Phrenoesophageal Ligament hiatus of the diaphragm. There are 4 types of hiatal It is a component of anatomical barrier which hernia, the most common type is sliding hernia (type separates the abdomen from the thorax. Hence, it is I) with prevalence of 10-80%. Type II, III, and IV are a border between intra abdominal part and variations of hernia paraesophageal which are rarely the esophagus. Integrity of phrenoesophageal ligament found.5 Patients with hiatal hernia will have refiux and its insertion into distal esophagus is an important only when the basal LES pressure is low. In severe factor in controlling reflux. Disruption of caudal GERD, basal LES pressure is frequently found low.10,11 insertion of such ligament into esophagus wall is likely In patients with severe GERD such as erosive to cause shortening and straightening of intraabdominal esophagitis and Barrett’s metaplasia, hiatal hernia esophageal segment. Therefore, it will increase is common because it is exposed to higher degree the possibility of refiux.10 of esophageal acid.11 It has been known that all pa- tients with severe GERD (erosive esophagitis, Bar- Esophageal Factor rett’s esophagus, or ) have basal Anti-refiux mechanism is the ›rst-line defense hypotensive LES of 0 – 5 mmHg. Nevertheless, not mechanism against refiux which may cause injury due all of patients with reflux have hypotensive LES to gastroduodenal content. Such mechanism appears which suggests there is another factor that may affect to restrict refiuxate frequency and volume. Once the the pathogenesis of GERD.10 LES pressure recording ›rst mechanism is retrieved, there is a second-line usually increase during inspiration due to contraction defense mechanism which includes esophageal crus of diaphragm surrounding the LES. Observation clearance, esophageal protection by gastric emptying on anti-refiux mechanism during certain maneuver through peristaltic process and neutralization of acid such as raising leg and compressing abdomen may residue in the lumen by saliva bicarbonate and other bring on crural contraction which will enhance the anti- secretion. Each factor may start performing clearance refiux barrier. Crural diaphragm is a component of pres- to prevent mucosa damage.5 sure at the gastroesophageal and it is very relevant in Esophageal Clearance patients with hiatal hernia, who may have disturbance In normal condition, gastroesophageal refiux occurs 6 of such component. Patients with hernial hiatal may approximately one hour daily in asymptomatic sub- have progressive sphincter diaphragm disorder which jects who have 24 hours continuous pH examination. depend on the extent of herniation. A lot of patients Although refiux phenomenon occurs regularly; but with moderate to severe gastroesophageal reflux it does not occur in esophagitis. Esophagitis may de- may also have type I hiatal hernia. Furthermore, in a velop due to some factors including duration of gastric study of 66 GERD patients and 16 controlled subjects contents which contact to esophageal mucosa, po- who had experienced endoscopy, manometry and pH tency of gastric contents and neutralization capac- monitoring, we found that the size of hiatal hernia ity, and refiuxate clearance from the esophagus. Fast correlated to the severity of esophagitis.5,6 Hiatal clearance of refiuxate contents which have a potency hernia is correlated to decreased LES pressure which to injure esophagus is the main role in preventing lead to accumulation of gastric contents at the hiatal mucosa damage. Successful clearance depends on sac which facilitates the development of refiux dur- esophageal motoric activity and sufficient saliva ing swallowing process and induces LES relaxation. drainage.10 After the refiux occurs, a period when Hiatal hernia may also disturb the esophageal esophageal pH still reach < 4 is known as acid peristaltic and consequently it will reduce esopha- clearance period.6 When gastric contents have ex- geal clearance.7 Regarding the correlation between ceed gastroesophageal junction, exposure period in the function and anatomy associated with reflux, esophageal epithelial should be limited because i.e. TLESR and hiatal hernia, Kharilas et al, demonstrated that in patients with hiatal hernia had the mucosa is not able to bear prolonged exposure of more signi›cant TLESR compared to the patients gastric acid, pepsin and bile acid. During the refiux, without hiatal hernia.7 Moreover, they indicated one or two peristaltic movement will empty the a positive correlation between the distance of distal esophagus, and only a little part of refiuxate intra-squamocollumnar junction and the centre of will be left. However, the pH remains low following hiatus and TLESR rate which are induced by stomach the peristaltic movement. The esophageal pH will be distention. Hence, in a the condition of big-size hernia, maintained after one has frequent swallowing and due 7 loss of basal LES pressure, diminished compensa- to the buffer ability of saliva. Prolonged clearance tion function of the crural diaphragm, and disrupted period of esophageal acid is found in 50% patients

88 The Indonesian Journal of Gastroenterology, Hepatology, and The Pathophysiology of Gastroesophageal Reflux Disease with esophagitis. A quite large-scale study report with enter the esophagus, administration of acid bolus will 24 hour esophageal monitoring suggested that induced persistent low pH in the esophagus although individuals with known hiatal hernia tend to have the esophageal clearance is effective. This shows that prolonged acid clearance period when lying down. saliva has important function as a buffer in neutral- Two main causes of such problem are disturbance of izing acid. Intra-esophageal acid perfusion stimulates esophageal emptying and saliva function.6 There are saliva secretion.10 Reduced saliva secretion or reduced two steps of esophageal acid clearance which involve neutralization capacity of the saliva may also pro- esophageal refiuxate emptying through gravitation long acid clearance.6 Saliva contains growth factor, and peristaltic pressure (primary and secondary) fol- including skin growth factor which has a potency to lowed by acid neutralization at esophageal lumen by increase mucosa repair and acts as cytoprotection bicarbonate in saliva and secreted by esophageal against irritant and reduce the esophageal mucosa submucosa gland.5 permeability against hydrogen ion.5 In a condition disturbing saliva production, it may cause a defect on Abnormal Peristaltic Movement esophageal acid neutralization. For example, prolonged Anterograde peristaltic movement of esophagus acid exposure has been demonstrated in patients with drives solid and liquid bolus into the stomach and chronic xerostomia.5 A study indicated that smok- removes the irritating gastric contents out from ing may exaggerate GERD thorough anticholinergic esophagus.10 Although peristaltic movement is usu- effect reducing saliva production and cause signi›- ally a primary condition induced by swallowing pro- cant increase of acid clearance period compared to cess, but it may also occur without being induced by the non-smoker. In contrast, stop smoking may be swallowing due to secondary peristaltic movement. associated with significant improvement of Esophageal distention due to gastric refiux may also bicarbonate saliva secretion.5,6 act as a stimulation of secondary peristaltic move- At cellular level, esophagitis may occur in patients ment which is an important component of esophageal with GERD due to diffusion of hydrogen ion into clearance.5,10 the mucosa which causes cellular acidity and In patients with peristaltic disorder such as necrosis. Refiux, esophageal emptying disorder and Scleroderma, gravitation is very important for reduced saliva function may worsen esophageal esophageal clearance. Loss of esophageal motoric 6 function may because reduced esophageal clearance exposure against hydrogen ion. in lying down position. Contraction force is also Epithelial Defense and Repair important in esophageal clearance. A study on Esophageal mucosa has several morphologic esophageal motility suggested that there is and physiologic defense against cellular acidity.6 a correlation between the stage of esophagitis and The surface of esophagus epithelial is a defense peristaltic dysfunction. An individual with severe structure against acid and pepsin diffusion because esophagitis may have low-amplitude esophageal there are tight junction and intracellular glycoprotein contraction and primary peristaltic failure. Such matrix which mutually produce a high-resistance alteration is more apparent at the distal esophagus.10 electric epithelial that prevent acid influx into A defect in primary peristaltic (which is also known the tissue.5 GERD may develop when the acid refiux as ineffective esophageal motility) characterized by of gastroduodenal contents damages intracellular low-amplitude contraction (< 30 mmHg) at distal relationship of esophageal mucosa, which finally esophagus may cause esophageal clearance disorder. facilitate hydrogen ion infiux and cause afferent nerves Moreover, ineffective esophageal motility is a main contanct in the esophagus epithelial and produce abnormal motility disorder in patients with GERD. heartburn symptom in patients with GERD.4,5,6 When Peristaltic dysfunction more frequently exaggerates hydrogen ions entering cells, phosphate, protein and esophagitis stage, i.e. it is found in 50% patients with carbonic anhydrase derived from bicarbonate will 5,6 severe esophagitis. Acute dysfunction is correlated react as a buffer system, but if the intracellular buffer to active esophagitis which is partly reversible, while is fail and saturated, esophagus epithelial cells may chronic dysfunction is associated with extensive prevent acid by two transmembrane pumps: Na/H stricture or ›brosis.6 exchanger and sodium dependent Cl/HCO3 ex- Acid Neutralization changer. If the epithelial ›nally has exceeding acid, Saliva plays an important role in neutralization of the intracellular pH will be reduced, causing cell injury, gastric content. Recovery of esophageal intraluminal disturbance in volume control, and defense mechanism neutralization process requires not only esophageal disorder resulting increased permeability against acid peristaltic movement but also saliva production. and lead to cell death and necrosis. Repeated acid Normal pH saliva varies of 6-7 due to bicarbonate. exposure will cause continued cell death and If saliva is suck from the mouth or it is prevented to subsequently cause mucosa erosion which appears

Volume 8, Number 3, December 2007 89 Bradley Jimmy Waleleng, Marcellus Simadibrata, Ari Fahrial Syam as erosive GERD by endoscopy examination.5 depend on the severity of disease. The refiux may be Furthermore, if there is severe and uncontrolled found in normal condition. However, if it is prolonged mucosa injury and high acid exposure, epithelial then it may cause pathological condition. repair will occur through cell replication and subse- Factors that have a role in GERD development quently migrates into the injured area. Depending on includes aggressive factors such as gastric acid and the maintenance stage of germinativum layer, cell pepsin derived from the stomach, bile acid and trypsin proliferation occur through epithelial repair which is derived from duodenum which has a potency to cause histologically characterized by basal cell hyperplasia esophagus mucosa injury and disturbed defensive that may cause epithelial to re-growth or get back into factor such as TLESR, hypotensive LES, crural normal condition and it may also cause pathological diaphragm, weak phrenoesophageal ligaments and condition such as stricture or Barrett’s esophagus.5 other factors i.e. Helicobacter pylori and genetic factor. Normally, there is a balance between Genetic Factor aggressive and defensive factors. Nevertheless, when It is suggested that genetic factor may have a role in there is imbalance of such factors, GERD will be GERD development and some of its complications.5,9 developed. Some case reports in families with GERD and Bar- rett’s esophagus by Romero and Lock explained that of REFERENCES 88 siblings, 28% had Barrett’s esophagus and 42% had esophagitis or heartburn symptom.5 1. Manan C. Penyakit refiuks gastroesofageal-esofagitis refiuks pengobatan masa kini. Dalam: Setiati S, Alwi I, Kasjmir YI, Three case-control studies evaluating reflux Atmakusuma D, Lydia A, Syam AF (Eds). Current diagnosis symptoms in the families of GERD patients by and treatment in Internal Medicine 2001. Pusat Informasi dan Romereo et al, found that there was no increase Penerbitan FKUI Jakarta 2001.h.1-7. prevalence of reflux symptoms in the families of 2. Ogorek CP. Gastroesophageal reflux disease. In: Fauci 5 AS, Braunwald E, Isselbacher KJ, et al (Eds). Harrison’s GERD patients compared to subject control. In con- Principles of Internal Medicine. 15th ed. Mc Graw-Hill, New trast, Trudgill et al, studied on prevalence of refiux York 2001.p.1642-9. symptoms in the ›rst degree family with a variation 3. Julius, Zubir N, Tarigan P, dkk. Konsensus Nasional Penata- of GERD severity (positive symptom, abnormal acid laksanaan Penyakit Refiuks Gastroesofageal. Kelompok Studi exposure in pH assessment, peptic stricture, and GERD Indonesia 2004. 4. Rani AA. Gastroesophageal Refiuks Disease (GERD) dan Barrett’s esophagus) using patients with and without Non Erosive Refiux Disease (NERD). Dalam: Setiati S, Alwi dyspepsia symptoms as the control. It is found that I, Simadibrata M, Sari NK (Eds). Pertemuan Ilmiah Tahunan the frequency of refiux symptoms is signi›cantly Ilmu Penyakit Dalam 2004. Pusat Informasi dan Penerbitan higher in patient’s family with abnormal pH, or Bar- FKUI Jakarta 2004.h.1-8. 5,9 5. Vela MF, Vaezi MF. The pathophysiology of gastro- rett’s esofagus. Moreover, Chak et al, found that esophageal refiuks disease. In: Fass R. GERD/Dyspepsia: Hot individuals with Barrett’s esophagus and esophagus Topics. Hanley & Belfus, USA 2004.p.23-40. adenocarcinoma are more likely have positive family 6. Kahrilas PJ. Pathophysiology of reflux esophagitis. history compared to control subjects without Bar- UpTo Date 2004. rett’s esophagus or adenocarcinoma. Further study is 7. Hirsch DP, Tytgat GN. Boeckxstaens GE. Review ar- ticle: Transient lower oesophageal sphincter relaxations - required to confirm the role of genetic factors in a pharmacological target for gastroesophageal refiux disease? GERD.5 Aliment Pharmacol Ther 2002;16;17-26. Cameron et al, conducted a study in twin siblings 8. Katz PO. Review article: the role of non-acid reflux in evaluating refiux symptoms. They performed telephone gastro-esophageal refiux disease. Aliment Pharmacol Ther 2000;14;1539-51. interview in 8,401 twin siblings and they found high 9. Rai AM, Orlando RC. Gastroesophageal refiux disease. Curr similarity rate of refiux symptoms for monozygotic Opi Gastroenterol 2000:16;351-9. twin (31%) compared to dizygotic twin (14%) in equal 10. Ogorek CP. Gastroesophageal refiux disease. In: Haubrich sexual category. Although it was performed only by WS, Schaffner F, Berk JE (Eds). Bockus Gastroenterology. th telephone interview but this study supported the role 5 ed. WB Saunders Co, Philadelphia 1995.p.445-64. 11. Pandolfino JE, Shi G, Curry J, et al. Esophagogastric 5 genetic factors as etiology of refiux. junction distensibility: A factor contributing to sphincter A study which is designed to find genetic lo- incompetence. Am J Physiol Gastrointest Liver Physiol cus in severe childhood GERD in 5 families found 2002;282:G1052-8. that there are genes maps of chromosome 13q14 in 12. Sifrim D, Janssens J, Vantrappen G. Transient lower esophageal sphincter relaxation and esophageal body the childhood GERD.5

CONCLUSION Gastroesophageal refiux disorder is a condition with refiux of gastric and duodenal contents into esophagus resulting disruption and varied clinical symptoms that

90 The Indonesian Journal of Gastroenterology, Hepatology, and