New Evidence Defining the Pathology and Pathogenesis of Lower

review

Eur Surg (2019) 51:282–290 https://doi.org/10.1007/s10353-019-00616-0

New evidence deﬁning the pathology and pathogenesis of lower esophageal sphincter damage

Parakrama Chandrasoma

Received: 30 September 2019 / Accepted: 2 October 2019 / Published online: 6 November 2019 © The Author(s) 2019

Summary Conclusion The new understanding of the signifi- Background Present diagnosis and management of cance of cardiac mucosa provides a new and highly gastroesophageal reflux disease (GERD) has resulted accurate histologic method of assessment of LES dam- in a dramatic increase in the incidence of esophageal age, the primary cause of GERD. This opens a new adenocarcinoma. This is due to failure to identify door to complete histologic assessment of GERD from pathologic changes of early GERD; at present, pathol- its etiologic standpoint and to new research that per- ogy is limited to management of Barrett esophagus mit early diagnosis of GERD at its outset. Ultimately, (BE). such early diagnosis has the potential to reverse the Methods Convincing evidence have confirmed that increasing trend of esophageal adenocarcinoma. cardiac mucosa distal to the squamocolumnar junction in the endoscopically normal person is a meta- Keywords Gastroesophageal reflux disease · plastic GERD-induced esophageal epithelium, and Histopathologic diagnosis · Cardiac mucosa · Dilated not a normal proximal gastric epithelium. distal esophagus · Barrett esophagus Results When cardiac mucosa is recognized as a metaplastic esophageal epithelium, it becomes self- Introduction evident that the present endoscopic definition of the gastro-esophageal junction is incorrect, and there Gastroesophageal reflux disease (GERD) is a common exists a dilated distal esophagus (DDE) in what is human disease. In the Western world, it has a preva- incorrectly termed the “gastric cardia” presently mis- lence of 30% [1]. The cause of GERD is conceptually taken for proximal stomach. It also becomes clear that simple: it results when the mechanism that normally the length of the DDE correlates with the presence prevents reflux of gastric contents into the esopha- and severity of GERD and represents the pathology gus fails. That mechanism is the lower esophageal of the entire spectrum of GERD. Further, it allows sphincter (LES). In a patient with a competent LES, recognition that the DDE, measured as the gap be- reflux does not occur. tween esophageal squamous epithelium and gastric Despite this obvious etiology, present medical man- oxyntic mucosa that is composed of cardiac mucosa, agement is largely aimed at suppressing gastric acid represents the pathologic anatomy of damage to the secretion with a naïve and incorrect belief that the abdominal segment of the lower esophageal sphincter disease will be cured by making the refluxed gastric (LES). juice less acidic. In fact, the common name for GERD is “acid reflux disease.” No amount of acid in the stomach will cause GERD if the LES is competent. No P.Chandrasoma, M.D. () amount of acid suppression will cure reflux if the LES Keck School of Medicine, University of Southern California, is defective. Patients with GERD who are treated with Los Angeles, USA acid suppressive therapy continue to reflux gastric Los Angeles County, Los Angeles, USA contents of higher pH, i.e., weak acid reflux [2]. University of Southern California Medical Center, Los Acid-suppressive drugs, while healing erosive Angeles, USA esophagitis and controlling heartburn [3], have not [email protected] prevented progression of GERD to Barrett esopha-

282 New evidence deﬁning the pathology and pathogenesis of lower esophageal sphincter damage K review

gus (BE). Esophageal adenocarcinoma, which always resultsasacomplicationofGERD,increasedseven- fold in the Western world from 1973 to 2010 and it continues to increase [4]. If acid suppression can claim to heal erosive esophagitis and control heartburn, we must explain how and why it has failed to protect the progression of GERD to adenocarcinoma. The Pro-GERD study in Europe provides insight into the progression of GERD [5, 6]. Over a 5-year period of endoscopic surveillance, there was excellent control of erosive esophagitis. However, 9.7% of patients without BE at the index endoscopy had developed BE at 5 years. The incidence was significantly associated with the severity of erosive esophagitis at the index endoscopy and regular PPI (proton pump inhibitors) use compared to intermittent PPI use or use of H2 receptor antag- onists [6]. It has been suggested that the association with regular PPI use was the result of indication bias. However, indication bias is unlikely to be the full Fig. 1 Diagram of esophagus showing the presently ac- explanation because no significant association was cepted normal state. The entire esophagus is tubular and present between severity of symptoms in detailed lined by squamous epithelium (white). The stomach is lined questionnaires and the occurrence of BE. by columnar epithelium with rugal folds (blue), histologically of cardiac (proximal 30mm), oxyntic (body), and antral type. Whether or not PPI use is responsible, the fact that The lower esophageal sphincter surrounds the distal 50mm 10% of GERD patients under standard GERD therapy of the esophagus, including the entire abdominal esopha- in the primary care setting develop BE in 5 years can- gus. The circles show the biopsies taken in the DeMeester not be disputed. In a disease with a prevalence of 30% biopsy protocol in the endoscopically normal person. These in the population, the conversion to its premalignant include biopsies at the squamocolumnar junction (SCJ), biop- complication can explain the rapid increase in the in- sies within 10mm distal to the SCJ, and biopsies in the distal body and antrum cidence of esophageal adenocarcinoma over the past 30 years. With no changes in the way GERD is man- aged, the probability is that the increasing incidence esophagus are in the abdomen. When a sliding hiatal of esophageal adenocarcinoma will continue. hernia is present, the SCJ is above the diaphragm; in these patients, the gastroesophageal junction is de- Methods fined as the proximal limit of rugal folds. When a patient has BE, the SCJ is displaced cephalad and the GEJ This review updates recent evidence regarding the is defined as the point of flaring of the tubular esoph- pathogenesis, pathology, and pathophysiology of agus, which is concordant with the proximal limit of GERD, BE, and esophageal adenocarcinoma, using rugal folds (Fig. 2). PUBMED, Google scholar, Scropus, and Springer The distal 5cm of the esophagus is surrounded by Link. Statistics were not applied. the lower esophageal sphincter (Fig. 1), a high-pressure zone designed to prevent reflux along the pres- Review sure gradient that exists from the stomach (intraluminal pressure +5mmHg) to the mid-thoracic esophagus Present understanding of normal anatomy and (–5mmHg). histology The normal histology, as it is presently believed, is that the entire esophagus is lined by squamous ep- The present management of GERD is based on the ithelium and transitions to the stomach at the prox- present understanding of the normal anatomy and imal limit of rugal folds. It is believed that the prox- histology of the esophagus, LES, and proximal stom- imal stomach has a variable amount of cardiac mu- ach (Fig. 1). At endoscopy, the esophagus is a tube cosa distal to the endoscopic GEJ followed by gastric that is lined entirely by squamous epithelium. At the oxyntic epithelium. Hayward, in 1961 [7], stated with- end of the tube, the esophagus flares into what is be- out evidence that the proximal 30mm of the stomach lieved to be the saccular stomach. The stomach is was normally lined by cardiac mucosa. He suggested lined by columnar epithelium with longitudinal rugal that this mucus-secreting epithelium acted as a buffer folds. Normally, the rugal folds reach the horizon- zone that prevents squamous epithelial digestion by tal line of the squamocolumnar junction (SCJ) at the gastric acid. point of flaring of the esophagus. The normal SCJ is The present guidelines for endoscopy and biopsy below the diaphragm because the distal 2–4cm of the are based on this understanding of anatomy and his-

K New evidence deﬁning the pathology and pathogenesis of lower esophageal sphincter damage 283 review

In persons with normal endoscopy, sets of biopsies were taken from the SCJ, from within 10mm distal to the SCJ, and from the distal gastric body and antrum (Fig. 1). Over the next three decades, over 15000 patients undergoing endoscopy at the unit had histologic assessment based on specimens from this biopsy protocol. At the weekly clinicopathologic conferences of the unit, it quickly became apparent that the traditional belief that cardiac mucosa normally lined 30mm of the proximal stomach was incorrect. This was initially the result of two observations: (a) cardiac mucosa was sometimes absent in the two biopsies at and within 10mm distal to the endoscopic GEJ, and (b) when present, the amount of cardiac mucosa and inflammation within it correlated directly with the severity of GERD. These observations led to a clinical study that correlated cardiac mucosa to objective criteria for GERD. This resulted in an abstract in 1994 [9] followed by a larger study in 1997. In that study of 334 patients, Oberg et al. [10] showed that patients who had cardiac mucosa in the biopsies distal to a normal SCJ had a significantly higher probability of an abnormal 24- hour pH test and abnormalities in the LES compared to those who did not. The medical establishment resistance to the finding that cardiac mucosa was a GERD-related pathologic finding contrary to the traditional and universal view that it was normal proximal gastric mucosa Fig. 2 The present interpretation of the gross pathology and was intense. The finding was ignored by most, but endoscopy in a patient with long-segment Barrett esophagus stimulated numerous important studies over the next with adenocarcinoma. The esophagus is a tube that fares into the saccular stomach at a point that is concordant with two decades. Mainstream belief about cardiac mucosa the proximal limit of rugal folds, which defnes the gastroe- has evolved towards an acceptance of the concept. At sophageal junction. The esophagus is lined proximally by present, most pathologists still incorrectly believe that squamous epithelium and distally by Barrett-type columnar a small amount (less than 4mm) of cardiac mucosa epithelium. In such a patient, the DeMeester protocol will take normally lines the proximal stomach. However, there biopsies at 1–2cm intervals from the Barrett segment in addi- is evidence that the new concept is very close to main- tion to the biopsies taken in a person with normal endoscopy stream acceptance. In a review of Barrett esophagus in the August 2019 issue of Gastroenterology,Stuart tology. If the patient with GERD has no abnormality Spechler’s group writes [11]: “... thereisconsiderable at endoscopy, biopsies are not recommended because indirect evidence to support a hypothesis, proposed by the epithelium distal to the normal SCJ where it meets Chandrasoma in 1997, that cardiac mucosa is not nor- the proximal limit of rugal folds is gastric [3, 8]. Biopsy mal but an acquired, GERD-induced metaplasia, and is only indicated if there is a visible columnar-lined that cardiac mucosa is the precursor of intestinal meta- esophagus (CLE) [3, 8]; the objective of biopsy is to plasia in BE.” identify intestinal metaplasia, which defines BE and As soon as the fatal flaw that cardiac mucosa is is an indication for endoscopic surveillance because normal in the proximal stomach is corrected, the def- it is premalignant. The GERD patient who does not inition of the GEJ will change and the early changes of have BE has not been studied histologically because of GERD in the most distal abdominal esophagus will be the failure to take biopsies before BE has developed. recognized. These changes represent the pathologic changes associated with abdominal LES damage, the The basic flaw in the present understanding primary cause of GERD. At present, because of the incorrect definition of the GEJ at endoscopy as the In 1990, Dr. Tom DeMeester established a clinical pro- proximal limit of rugal folds, the critical early changes gram in foregut surgery at the University of Southern of GERD are mistaken for normal proximal stomach. California. A unique element of this program was an endoscopic biopsy protocol that he used for all patients undergoing upper gastrointestinal endoscopy.

284 New evidence deﬁning the pathology and pathogenesis of lower esophageal sphincter damage K review

Fig. 3 The zero squamo-oxyntic gap in a child with no gastroesophageal refux disease at autopsy. The esophageal squamous epithelium transitions at the squamocolumnar Fig. 4 A 2mm squamo-oxyntic gap in a resected specimen junction to gastric oxyntic mucosa with straight tubular glands of a patient with squamous carcinoma of the esophagus. The composed of parietal and chief cells. There is no cardiac mu- squamous epithelium has been displaced cephalad (to the left cosa in the picture) by cardiac and oxyntocardiac epithelium that separates it from the proximal limit of gastric oxyntic mucosa. Note the disorganized mucous cell containing glands in car- Evidence that cardiac mucosa is a metaplastic diac mucosa and the presence of infammation and reactive esophageal and not a normal proximal gastric changes in the foveolar region (“carditis”). CM cardiac mu- mucosa cosa, OCM oxyntocardiac mucosa, OM oxyntic mucosa

Cardiac mucosa is not present at the SCJ in all between the SCJ and gastric oxyntic mucosa (i.e., in persons the squamo-oxyntic gap) is therefore a GERD-induced In a study of autopsies in 18 persons without clinical metaplasia of squamous epithelium of the distal ab- GERD during life [12], we showed that pure cardiac dominal esophagus (Fig. 4). When found, cardiac mucosa was absent in 10/18 (56%). Oxyntocardiac mucosa always shows chronic inflammation (Fig. 4). mucosa (=cardiac mucosa with parietal cells in the Carditis is the earliest specific histologic manifestation glands) was present in all persons. However, both car- of GERD [16]. diac and oxyntocardiac mucosae were absent in some part of the circumference of the SCJ in 9/18 (50%). The length of cardiac mucosa distal to the endoscopic This proves that cardiac mucosa is absent in some per- GEJ correlates with severity of GERD sons in some part of the circumference of the GEJ. In Glickman et al. [17] showed that the presence of these persons, the esophageal squamous epithelium >1mm of cardiac mucosa in children was associ- transitions directly to gastric oxyntic mucosa (the zero ated with a significantly higher prevalence of reflux squamo-oxyntic gap [13]; Fig. 3). esophagitis in the squamous epithelium compared Studies from other centers have disputed the find- with patients with <1mm. Chandrasoma et al. [18] ing that cardiac mucosa can be absent. Kilgore et al. showed a significantly higher acid exposure in pa- [14], in an autopsy study, showed that cardiac mu- tients with >20mm of cardiac mucosa compared cosa was present in all persons to a length of 1–4mm. to patients with <20mm. Chandrasoma et al. [19] Marsman et al. [15], in an endoscopic study, re- showed, in esophagectomy specimens, that patients ported that cardiac mucosa was present at the normal with squamous carcinoma had lengths of cardiac squamocolumnar junction in 62% of patients; in the mucosa similar to the non-GERD autopsy popula- other 38%, the squamous epithelium transitioned to tion (<5mm), whereas patients with GERD-induced oxyntocardiac mucosa. No patient in these studies adenocarcinoma had lengths of 10–20mm. had a zero squamo-oxyntic gap. It should be understood that the absence of cardiac mucosa is not The pathogenesis of cardiac metaplasia has been proved by these findings. A single photograph (Fig. 3) elucidated of a zero squamo-oxyntic gap overrides claims that In two elegant studies of asymptomatic volunteers, cardiac mucosa is universal. Ayazi et al. [20] from our unit and Robertson et al. [21], from Professor McColl’s unit in Glasgow, showed that When present, cardiac mucosa correlates with gastric over-distension caused by air insufflation [20] presence of GERD or a heavy meal [21] resulted in a temporary shorten- The study of Oberg et al. [10] established the rela- ing of the LES that caused the squamous epithelium tionship of the presence of cardiac mucosa with ab- of the distal esophagus to become exposed to gas- normal reflux and LES abnormalities. Cardiac mucosa tric contents. With cumulative exposure, Derakhshan

K New evidence deﬁning the pathology and pathogenesis of lower esophageal sphincter damage 285 review

et al. [22] showed that the squamous epithelium un- diac and oxyntocardiac mucosa distal to the proximal derwent increasing expression of trefoil family factor 3 limit of rugal folds is esophageal. (TFF3) that triggered metaplasia into cardiac mucosa In that study, the anatomy of the region distal to [22]. This study also showed that the small amounts of the endoscopic GEJ that was lined by cardiac and cardiac mucosa found in these asymptomatic volun- oxyntocardiac mucosa was dilated and its mucosa was teers was similar to non-intestinalized columnar ep- lined by rugal folds. This was termed the dilated dis- ithelium in BE [22]. tal esophagus [26] and deﬁned as that area distal to Robertson et al. [21] also showed that the length of the end of the tubal esophagus that is dilated, lined cardiac mucosa was signiﬁcantly shorter (median of by cardiac and oxyntocardiac mucosa, and contains 1.75mm) in volunteers without central obesity than in rugal folds (Fig. 5). This exactly mimics the stomach obese persons (median 2.5mm). The correlation be- at gross examination and endoscopy; the error is only tween cardiac mucosal length and central obesity sug- revealed by the histologic presence of metaplastic car- gest that over-eating is a common etiology for these diac mucosa. two entities. Bu et al. [23] showed that there was Korn et al. [27] measured the circumference at the a dose-related relationship between the presence of anatomic GEJ, which is marked accurately by the peri- cardiac mucosa and body mass index. These conclusively show the mechanism whereby the most distal squamous epithelium of the abdominal esophagus in normal persons undergoes metaplasia into cardiac mucosa due to exposure to acid during gastric overdistention. The presence of a pathogenesis for the millimetric amounts of cardiac mucosa present at the SCJ conclusively proves that it is not a normal proximal gastric mucosa.

The deﬁnition of the gastroesophageal junction

When it is accepted that cardiac mucosa distal to the endoscopic GEJ (defined as the proximal limit of rugal folds) is a metaplastic esophageal epithelium de- rived from GERD-induced damage to the squamous epithelium, it must follow that the proximal limit of rugal folds is not the true GEJ. The evidence that the proximallimitofrugalfoldsisthetrueGEJisasin- gle unconvincing and flawed report by McClave et al. in 1987 [24]. It must be rejected in the light of presence evidence. The true GEJ is the junction between metaplastic cardiac and oxyntocardiac mucosa with gastric oxyntic epithelium [19]. It can be defined only by histology. The measured length of cardiac mucosa distal to the endoscopic GEJ in a limited number of resected and autopsy specimens is zero to 28 mm [12, 25]. When more studies are done, the length is likely to be greater. This length of cardiac mucosa is mistaken at endoscopy for proximal stomach because of the erro- neous use of the proximal limit of rugal folds to define the GEJ at endoscopy. In a study of resected specimens, Chandrasoma Fig. 5 Patient in Fig. 2 showing the distribution of metaplas- et al. [19] showed that the length of cardiac and tic columnar epithelium in the esophagus. The red line is the oxyntocardiac mucosa distal to the proximal limit of squamocolumnar junction; the yellow line is the distal extent of rugal folds was <5mm in two patients with squamous intestinal metaplasia. Cardiac and oxyntocardiac epithelia ex- carcinoma and between 10 and 20.5mm in 8 patients tend 20mm distal to the proximal limit of rugal folds (black line). with GERD-induced adenocarcinoma. Mapping of The black dots represent mapping of the submucosal glands in esophageal submucosal glands showed that the distal the specimen; their distribution is concordant with the extent of cardiac and oxyntocardiac epithelium, proving that the area extent of the submucosal glands was concordant with distal to the proximal limit of rugal folds is esophageal (“the the distal limit of cardiac and oxyntocardiac mucosa dilated distal esophagus”). The true GEJ (Gastro-esophageal (Fig. 5). Submucosal glands were never seen under junction) is defned histologically as the proximal limit of rugal gastric oxyntic mucosa. This finding proves that car- folds

286 New evidence deﬁning the pathology and pathogenesis of lower esophageal sphincter damage K review

Fig. 6 Diagram showing why the abdominal esophagus dilates when it loses the protection of the high-pressure zone by lower esophageal sphincter damage. The sphinc- terless abdominal esophagus can no longer re- sist the dilatory tendency of the positive intraluminal pressure which is ac- centuated with every meal. LES lower esophageal sphincter, CLE columnar lined esophagus toneal reflection, at surgery. They showed that the of the functioning LES. It is known that LES shorten- mean circumference in persons without GERD was ing occurs in GERD. However, without knowledge of 6.3, that of GERD patients without BE was 8.9cm, and its original length, manometric length of the abdomi- that of patients with BE was 13.8cm. This confirms nal LES cannot define LES shortening. Lee et al. [29] the increasing dilatation of the distal esophagus with showed that in patients with clinical GERD, the length increasing GERD severity. of the abdominal segment of the LES bears an inverse linear relationship to acid exposure by the 24-hour What causes dilatation of the esophagus when pH test. In that study, the length of the abdominal cardiac metaplasia of squamous epithelium occurs? segment of the LES decreased from 18 to 3mm with increasing reflux [29]. Zaninotto et al. [30]showed The entire abdominal esophagus is normally sur- that an abdominal LES length of <10mm is indicative rounded by the high-pressure zone of the abdominal of a defective LES and is associated with an abnormal segment of the LES. This high pressure is necessary 24-hour pH test. This criterion for an abnormal LES to withstand the dilatory force of the positive intra- is of value to identify an LES that needs to be sur- luminal pressure in the abdominal esophagus and gically repaired. There is no criterion of manometric maintain its tubular shape (Fig. 6). LES length or pressure that identifies early GERD prior Normal LES tone is likely maintained by a local re- to a defective LES. Surely, the change of a normal LES flex arc with the afferent nerve endings that are plen- to a defective LES is not an acute and sudden event. It tiful in the squamous epithelium [28], a central relay in the ganglion cells of the submucosal and myenteric plexus, and the efferent nerves passing to the smooth muscle to maintain tonic contraction. When cardiac metaplasia occurs in the esophagus, the nerve endings in the squamous epithelium are lost, the afferent arc of the local reflex is disrupted, and the high-pressure of LES tone disappears. With loss of LES tone, the abdominal esophagus that has undergone cardiac metaplasia dilates because of the positive intraluminal pressure and the fact that it distends with every gastric over-distension (Fig. 6). It essentially becomes “gastricized,” behaving physiologically like the stomach, distending and collapsing in the full and fasting state, respectively. This results in the development of rugal folds which are a feature of all reservoir organs.

Conclusion

Result of this new understanding Fig. 7 Multi-level biopsy protocol for assessment of the length of cardiac and oxyntocardiac mucosa distal to the endoscopic gastroesophageal junction (= squamocolumnar The abdominal esophagus surrounded by the abdom- junction [SCJ] in the endoscopically normal person). Five sets inal segment of the LES is the critical barrier that of biopsies are at 5mm intervals at and distal to the SCJ and prevents reﬂux of gastric juice from the esophagus. submitted in separate jars (red dots). Though unoriented, The only recognized measurement of the LES that is these biopsies provide reasonable assessment of the length presently used for diagnosis is the manometric length of cardiac mucosa

K New evidence deﬁning the pathology and pathogenesis of lower esophageal sphincter damage 287 review

is highly likely that there is a chronic progressive loss damage. This new pathologic test measures the criti- of LES length before the defective state is reached. cal causative factor in determining the absence, pres- The chronic progression is likely to be chronic repeti- ence, and severity of GERD. It is analogous to coro- tive gastric over-distension due to chronic over-eating nary artery narrowing as a more accurate assessment over a long period. Kahrilas et al. [31] showed that of ischemic heart disease than symptoms of ischemia. the temporary LES shortening associated with gastric Accurate measurement of the length of cardiac mu- over-distension by air insufﬂation was identical irre- cosa cannot be made with present biopsy technology. spective of baseline length of the LES. This points to Biopsy forceps in use can access an unoriented pinch the probability of a linear progression of LES shorten- sample of the mucosa measuring a maximum of 8 ing. mm [21]. Multilevel biopsies distal to the endoscopic The relationship between metaplastic cardiac mu- GEJ (Fig. 7), though they may lack precision of mea- cosa distal to the endoscopic GEJ and concordant di- surement, provide the best possible measurement of latation of the esophagus in the area of the damaged the length of the dilated distal esophagus with present LES enables a simple formula to be developed regard- biopsy technology [32]. A quantitative biopsy device ing the abdominal esophagus: that can remove a 20–25mm longitudinal piece of mucosa vertically on the lesser curvature distal to the en- Length of abdominal esophagus doscopic GEJ (the SCJ in a patient without BE) needs (= length of abdominal segment of the LES) to be developed. This will provide an accurate mea- = Length of the tubular abdominal esophagus surement of abdominal LES damage. The available data suggest that a length of dilated (= manometric length of the functional distal esophagus <15mm represents a competent LES abdominal segment of the LES) and absence of GERD. This minimal level of abdomi- + Length of the dilated distal esophagus/cardiac nal LES damage is almost universal, producing small mucosa distal to endoscopic GEJ amounts of cardiac metaplasia. Such minimal damage is within the reserve capacity of the LES and does = ( length of damaged/shortened abdominal not result in LES failure or reﬂux. The changes of segment of the LES) GERD are limited to the area of the damaged distal abdominal LES (intrasphincteric GERD). Measurement of the length of cardiac and oxyn- When LES damage (cardiac mucosal length) reaches tocardiac mucosa in the dilated distal esophagus is a length >15mm, clinical evidence of early postpran- an accurate pathologic assessment of abdominal LES dial GERD becomes appears. With a further progres-

Fig. 8 Diagram showing the correlation between damage to tal end, there is progression from postprandial refux to fully the lower esophageal sphincter and newly understood stages established refux disease with a defective lower esophageal of gastroesophageal refux disease. The frst stage, where sphincter. GERD gastroesophageal refux disease, NERD non- LES damage is within its reserve capacity, is not associated erosive refux disease, CE cardiac epithelium, CLE columnar with refux because the LES is competent. As LES dam- lined esophagus, LES lower esophageal sphincter, DDE di- age progressively shortens the abdominal LES from its dis- lated distal esophagus

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sive increase of LES damage, the severity of GERD 7. Hayward J. The lower end of the oesophagus. Thorax. progressively increases [29] until the LES becomes 1961;16:36–41. defective and associated with an abnormal pH test at 8. Sharma P,McQuaid K, Dent J, et al. A critical review of the diagnosisandmanagementofBarrett’sesophagus: theAGA a<10mm length of the abdominal LES, to the end- ChicagoWorkshop. Gastroenterology. 2004;127:310–30. point of destruction of the entire abdominal segment 9. Clark GWB, Ireland AP,Chandrasoma P,et al. Inflammation of the LES when reflux is severe, impossible to control andmetaplasiainthetransitionalmucosaoftheepithelium with medical therapy, and likely to be associated with ofthegastroesophagealjunction: anewmarkerforgastroe- BE ([33]; Fig. 8). sophagealrefluxdisease. Gastroenterology. 1994;106:A63. The measurement of abdominal LES damage by 10. Oberg S, Peters JH, DeMeester TR, et al. Inflammation histology is possible in the asymptomatic person. If and specialized intestinal metaplasia of cardiac mucosa is a manifestation of gastroesophageal reflux disease. Ann abdominal LES damage has a linear progression, this Surg. 1997;226:522–32. information may allow prediction of GERD and its 11. Que J, Garman KS, Souza RF,Spechler SJ. Pathogenesis and severity in the person’s future, allowing development cells of origin of Barrett’s esophagus. Gastroenterology. of new methods to prevent progression of LES damage 2019;157:349–64. in selected persons [34]. 12. Chandrasoma PT, Der R, Ma Y, et al. Histology of the I (the author), who have no symptoms of GERD, gastroesophageal junction: an autopsy study. Am J Surg Pathol. 2000;24:402–9. have had multiple biopsies taken at and distal to my 13. Chandrasoma PT, Wijetunge S, DeMeester SR, Ha- normal SCJ at intervals of 5 to 25mm distal to the gen JA, DeMeester TR. The histologic squamo-oxyntic SCJ. Only the biopsy at the SCJ had metaplastic car- gap: an accurate and reproducible diagnostic marker diac mucosa; the remainder had normal gastric oxyn- of gastroesophageal reflux disease. Am J Surg Pathol. tic mucosa. My measured dilated distal esophagus 2010;34:1574–81. was 4mm with <1mm of cardiac mucosa and 4mm of 14. Kilgore SP, Ormsby AH, Gramlich TL, et al. The gastric oxyntocardiac mucosa. If it is correct that abdominal cardia: factorfiction? AmJGastroenterol. 2000;95:921–4. 15.MarsmanWA,vanSandyckJW,TytgatGNJ,etal. The LES shortening has a linear progression, I have calcu- presenceandmucinhistochemistryofcardiactypemucosa lated that my LES will remain competent until I reach at the esophagogastric junction. Am J Gastroenterol. an age of 250 years! 2004;99:212–7. 16. Der R, Tsao-Wei DD, DeMeester T,et al. Carditis: a manifes- Conflict of interest P. Chandrasoma declares that he has no tation of gastroesophageal reflux disease. 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