abnormal structure and function of the …. kugener; journal club 21.05.2014: abnormal structure and...

A. Kugener; Journal Club 21.05.2014: Abnormal Structure and Function of the Esophagogastric Junction and Proximal Stomach in Gastroesophageal Reflux Disease 1

Universitätsklinik für viszerale Chirurgie und Medizin. Abteilung für Gastroenterologie

Abnormal Structure and Function of the Esophagogastric Junction and

Proximal Stomach in Gastroesophageal Reflux Disease

Curcic J, Fox M, et al

The American Journal of GASTROENTEROLOGY VOLUME 109 | MAY 2014



Background •  esophagogastric junction (EGJ) plays major role preventing reflux

•  lower esophageal sphincter (LES), crural diaphragm together with the clasp and sling fibers of the gastric cardia, form an integrated sphincter complex.

•  Most reflux events occur during spontaneous relaxations of the EGJ, called “transient LES relaxations” (TLESRs), triggered by gastric distension.

•  Observation & manometric studies in patients with mild-to-moderate gastroesophageal reflux disease (GERD) showed that TLESR frequency is similar compared to healthy controls

•  Other factors must contribute to the occurrence of gastroesophageal reflux

•  Structural factors including a “flap valve” at the EGJ may protect against reflux during TLESRs



WHAT IS CURRENT KNOWLEDGE

• The esophagogastric junction (EGJ) is a key defense against reflux.

• Most reflux in healthy subjects and in patients with mild-moderate gastroesophageal reflux disease (GERD) occurs during transient lower esophageal sphincter relaxations (TLESRs).

• TLESR frequency is not necessarily increased in GERD, rather it is the likelihood of reflux occurring during TLESRs that is increased.

• Structural factors including a “flap valve” at the EGJ may protect against reflux during TLESRs; however, this is difficult to assess with the current, invasive methodology that alters EGJ structure and function.



Hypothesis „flap valve“ •  Several studies evaluated flap valve-theory of EGJ (animal models, surgical

preparations, invasive methodology...)

•  limitation esophagogastroscopy, manometry, video fluoroscopy, CT

•  No adequate description of the mechanism of reflux protection

•  Magnetic resonance imaging (MRI) and high-resolution manometry (HRM) offer new possibilities in assessing the 3D “functional anatomy” of the EGJ

•  Aim of this study:

-  To test the hypothesis, by MRI & HRM, that structural factors, in particular the acute esophagogastric insertion angle, are involved in reflux protection and are altered in patients with mild-to-moderate GERD (primary endpoint: insertion angle of the esophagus into the stomach)

-  Secondary endpoint: gastric morphology (EGJ-opening, esophagogstric insertion point), orientation within the abdomen, reflux events



•  Prospective design

•  2 study groups (1 GERD, 2 healthy control) -  GERD diagnosis: endoscopy and/or pathologic acid exposure on 24h-

pH-monitoring.

-  Healthy subjects: no symptoms suggestive of reflux, dyspepsia or other digestive problems; no medication that could alter gastrointestinal function (endoscopy and pH studies were not performed)

•  Exclusion criteria: hiatus hernia (>3cm), history of other digestive diseases, abdominal surgery

Study design



Participants were studied in the right decubitus position to reduce TLESR inhibition that occurs on lying down



Results

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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EGJ Structure and Function

protect against gastroesophageal refl ux (GER) despite a variety of challenges, including large meals, abdominal straining, and recumbent posture ( 1,2 ). Most refl ux events occur during spon-taneous relaxations of the EGJ, called “ transient LES relaxations ” (TLESRs), which are triggered by gastric distension, whose func-tion in health is to vent air swallowed with the meal (belching) ( 3,4 ). A key observation in patients with mild-to-moderate gas-troesophageal refl ux disease (GERD) is that TLESR frequency is not greatly elevated compared with that in healthy controls ( 5,6 ); rather it is the likelihood of acid refl ux occurring during TLESR that is a marker of disease ( 5 ). Further , manometry studies have revealed no diff erences in the functional characteristics of TLESR between healthy and GERD subjects (e.g., nadir pressure, dura-tion of relaxation) ( 7,8 ). Th is indicates that other factors must contribute to the occurrence of gastroesophageal refl ux.

Several authors have proposed that the “ functional anatomy ” of the EGJ, in particular a “ fl ap valve ” at the entry of the esopha-gus into the stomach, may provide additional protection against refl ux ( 1,9,10 ); however, the data used to support this view were acquired in anesthetized animals, in surgical preparations, or by using invasive methodology that alter EGJ structure and function ( 11 – 14 ). Furthermore, these studies did not provide an adequate description of the mechanism of refl ux protection: endoscopy off ers a semi-qualitative assessment of EGJ morphology in the fasted and gas-distended stomach, manometry delivers only an indirect assessment of EGJ structure based on pressure (e.g., LES length and position), and video fl uoroscopy suff ers from a lack of soft -tissue contrast and exposes patients to ionizing radiation that precludes prolonged or repeated measurements. Computed tom-ography (CT) has been used to assess EGJ anatomy, including the “ angle of His ” , with measurements obtained from 2D image slices aft er ingestion of barium liquid ( 15 ). However, previous work has shown that measurements of a complex 3D object such as the EGJ on the basis of one 2D image do not provide reliable results because any rotation of the object in the abdomen or selection of any other slice plane would change the measurement outcome ( 16 ).

To overcome these diffi culties, we have developed and validated concurrent magnetic resonance imaging (MRI) and high-resolu-tion manometry (HRM) to obtain a comprehensive assessment of the 3D “ functional anatomy ” of the EGJ in the fasted state and aft er ingestion of a large test meal ( 16 ). Th ree-dimensional models of the distal esophagus and proximal stomach were reconstructed from stacks of 2D image slices from which objective measure-ments were made including the insertion angle of the esophagus into the stomach, gastric morphology, and orientation within the abdomen ( 16,17 ). In addition, refl ux events were imaged in real time by cine-magnetic resonance imaging (MRI) with concurrent HRM providing a continuous assessment of EGJ function includ-ing LES pressure and occurrence of TLESRs ( 16 ). Previously, based on biophysical analysis of these data in healthy subjects, we pro-posed a “ fl ap valve ” mechanism by which proximal gastric disten-sion compresses the distal esophagus aft er a meal, a mechanism that, if present, would increase resistance to gastroesophageal refl ux and would protect the esophagus from refl ux even when the EGJ is relaxed during TLESRs ( 17 ).

Th is study applies concurrent MRI and HRM to test the hypothesis that structural factors thought to be involved in refl ux protection, in particular the acute esophagogastric insertion angle, are altered in patients with mild-to-moderate GERD.

METHODS Study population A total of 24 GERD patients (10 female, mean age 39 ± 14 years, mean body mass index (BMI) 25.2 ± 3.5 kg / m 2 ) and 24 healthy volun-teers (11 female, mean age 27 ± 5 years, mean BMI 22.6 ± 2.3 kg / m 2 ) participated in the study. GERD diagnosis was established by the presence of refl ux esophagitis on endoscopy on the basis of LA classifi cation and / or pathologic acid exposure on 24 h pH moni-toring. Patients with a hiatus hernia ( > 3 cm), indicative of gross EGJ disruption ( 18 ), were excluded as were those with a history of other digestive diseases, abdominal surgery (except appendec-tomy), or any condition that required active medical management. Healthy subjects had no symptoms suggestive of refl ux, dyspepsia, or other digestive problems and were not taking any medication that could alter gastrointestinal function (endoscopy and pH studies were not performed). Table 1 describes the study population. Th is prospective clinical study was approved by the Ethics Committee of Canton Zurich, Switzerland (EK 1631) and registered on www.ClinicalTrials.gov (NCT01053585). Written informed consent was obtained from all participants. All coauthors had access to the study data and have reviewed and approved the fi nal manuscript.

Study design GERD patients discontinued PPI treatment at least 3 days prior to the study. Alginate or antacid preparations were provided for breakthrough symptoms. All participants attended the depart-ment aft er a minimum 4 h of fasting. Th e structure and func-tion of the proximal stomach and EGJ were assessed by validated

Table 1 . Demographic and clinical characteristics of the study population

Characteristic Healthy sub-jects ( n =24) GERD patients ( n =24)

Male / female 13 / 11 14 / 10

Age (range), years 27 ± 5 (20 – 35) 39 ± 14 (19 – 62)

BMI (kg / m 2 ) 22.6 ± 2.3 25.2 ± 3.5

GERD grade A (male / female) and / or pH > 6

— 14 (6 / 8)

GERD grade B — 3 (2 / 1)

GERD grade C — 7 (6 / 1)

Hiatus hernia ( < 3 cm) — 3 (3 / 0)

Duration of GERD symptoms a — 6 years (1 year – 20 years)

Duration of GERD diagnosis a — 1 year (1 month – 5 years)

Duration of GERD treatment a — 1 year (1 month – 5 years)

BMI, body mass index; GERD, gastroesophageal refl ux disease. a Before the inclusion in the study.

•  No significant effects of age or BMI were detected in either study group on the esophagogastric insertion angle or secondary parameters

•  All reflux events detected during cine-MRI were detected also on HRM recordings.

•  Number of reflux events after the meal was similar in healthy volunteers and GERD patients




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events (95 % CI: 2.5 – 4.6) during a total observation time of ~ 20 min ( P = 0.092). Refl ux duration was longer in GERD patients by 6 s, being on average 26.8 s (95 % CI: 23.9 – 30.2 s) in healthy subjects and 32.8 s (95 % CI: 29.2 – 37.0 s) in GERD patients ( P = 0.002). EGJ opening during refl ux was larger in GERD patients than in healthy subjects. Th e EGJ diameter during refl ux averaged 16.8 mm (95 % CI: 15.1 – 18.6 mm) in healthy subjects and 19.3 mm (95 % CI: 17.6 – 21.1 mm) in GERD patients ( P = 0.04).

Magnetic resonance imaging Measurements of EGJ structure and function are summarized in Table 3 .

Esophagogastric insertion angle and proximal gastric disten-sion . Th e insertion angle of the esophagus into the proximal stomach was 55 ± 2.5 ° in the healthy group aft er meal intake and during expiration. Th e insertion angle was wider (more obtuse) in GERD patients by 7 ± 3 ° ( P = 0.03) ( Figure 5 , with animated im-ages in Supplementary Videos 1 and 2 ). Gastric fi lling did not alter this parameter. Respiration modulated the insertion angle in both groups, being more obtuse (wider) during inspiration than during expiration ( + 3 ± 1 ° ; P = 0.00001). Proximal gastric curvature (i.e. distension) was 74 ± 4 ° in healthy group and was similar in healthy controls and GERD patients ( + 2 ± 4 ° , P = 0.56). As expected, this measurement increased with gastric fi lling from the fasted to the postprandial phase ( + 18 ± 4 ° , P < 0.0001) and increased further aft er feeding to maximum full-ness ( + 8 ± 5 ° ). It did not change with respiration ( P = 0.32).

Gastric content volume and intra-gastric air volume . Gastric con-tent volume directly aft er meal intake was similar in healthy controls and GERD patients; however, intra-gastric air volume aft er the meal was larger in healthy subjects than in the GERD group by 64 ± 29 ml ( P < 0.03). Gastric emptying during the 30-min emptying phase was 3.8 ± 0.4 ml / min in healthy volunteers, which was 1.6 ± 0.6 ml / min faster compared with that in GERD patients ( P = 0.009).

Stomach orientation and esophagogastric insertion point . Th e angle of orientation of the proximal stomach within the abdomen relative to the central abdominal axis ( Figure 2 ) in the healthy group aft er meal intake and during expiration was 60 ± 5 ° . Th is an-gle was smaller in GERD patients by − 17 ± 7 ° ( P = 0.01), implying that the proximal stomach is in a more anterior-posterior orienta-tion in GERD ( Figure 6 ). Gastric orientation in the abdomen did not change with gastric fi lling / study phase. Th e insertion point of the esophagus relative to the major (long) axis of the proximal stomach ( Figure 2 ) in the healthy group aft er meal intake and during expiration was 31 ± 5 ° . Th e insertion point was displaced further away from the major axis in GERD patients by 12 ± 6 ° ( P = 0.05) ( Figure 6 ). Gastric fi lling had no eff ect on this parameter. Measurements of gastric orientation within the abdomen and the position of insertion of the esophagus into the stomach are strongly correlated during respiration, as the anatomical relation-ship between the esophagus and proximal stomach is fi xed (Pear-son correlation coeffi cient r = 0.8). Th us, during inspiration, as the stomach rotated into a more antero-posterior position within the

Table 2 . Summary of observation times and of refl ux events detected

HRM MRI

Observation time [h]

Number of detected refl ux

events Median number of refl ux

events / h (interquartile range) Observation

time (h) Number of detected

refl ux events

HV 21 161 7.06 (3.48 – 9.98) 8.4 38

GERD 26 236 9.53 (5.56 – 15.0) 9.8 97

GERD, gastroesophageal refl ux disease; HRM, high-resolution manometry; HV, healthy volunteers; MRI, magnetic resonance imaging. HRM measurements were acquired continuously. Concurrent MRI measurements were acquired for about 40 % of the study duration. Agreement between the two modali-ties was perfect.

Table 3 . Biomarkers of esophageal and gastric structure and function.

Esophagogastric junction Gastric volumes Gastric morphology HRM measurement

Parameter

Esophagogastric insertion angle

Proximal gastric curvature / distension

Content (ml)

Air (ml)

Stomach orientation within abdomen

Esophago-gastric insertion point

LES pressure (mm Hg)

Intra-abdominal LES length (cm)

HV 55 74 723 165 60 31 20 1.9

GERD 62 76 662 101 43 43 8 0.9

Difference + 7 ( ± 3) 2 ( ± 4) − 61 ( ± 56) − 64 ( ± 29) − 17 ( ± 7) 12 ( ± 6) − 12 ( ± 2) − 1.0 ( ± 0.3)

P value 0.03 0.56 0.3 < 0.03 < 0.01 0.05 0.0001 0.0006

GERD, gastroesophageal refl ux disease; HRM, high-resolution manometry; HV, healthy volunteers; LES, lower esophageal sphincter. All measurements acquired in the “ after meal ” phase during expiration.

•  Healthy volunteers in average 2 reflux after meal, GERD 3 reflux •  Reflux duration was longer in GERD patients by 6 s, -  healthy subjects 26.8s (95 % CI: 23.9 – 30.2s) -  GERD patients 32.8s (95 % CI: 29.2 – 37.0s) (p=0.002)

•  EGJ opening during reflux was larger in GERD patients than in healthy subjects. •  The EGJ diameter during reflux averaged 16.8mm (95% CI: 15.1–18.6mm) in healthy

subjects and 19.3mm (95% CI: 17.6–21.1mm) in GERD patients (p=0.04)




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events (95 % CI: 2.5 – 4.6) during a total observation time of ~ 20 min ( P = 0.092). Refl ux duration was longer in GERD patients by 6 s, being on average 26.8 s (95 % CI: 23.9 – 30.2 s) in healthy subjects and 32.8 s (95 % CI: 29.2 – 37.0 s) in GERD patients ( P = 0.002). EGJ opening during refl ux was larger in GERD patients than in healthy subjects. Th e EGJ diameter during refl ux averaged 16.8 mm (95 % CI: 15.1 – 18.6 mm) in healthy subjects and 19.3 mm (95 % CI: 17.6 – 21.1 mm) in GERD patients ( P = 0.04).

Magnetic resonance imaging Measurements of EGJ structure and function are summarized in Table 3 .

Esophagogastric insertion angle and proximal gastric disten-sion . Th e insertion angle of the esophagus into the proximal stomach was 55 ± 2.5 ° in the healthy group aft er meal intake and during expiration. Th e insertion angle was wider (more obtuse) in GERD patients by 7 ± 3 ° ( P = 0.03) ( Figure 5 , with animated im-ages in Supplementary Videos 1 and 2 ). Gastric fi lling did not alter this parameter. Respiration modulated the insertion angle in both groups, being more obtuse (wider) during inspiration than during expiration ( + 3 ± 1 ° ; P = 0.00001). Proximal gastric curvature (i.e. distension) was 74 ± 4 ° in healthy group and was similar in healthy controls and GERD patients ( + 2 ± 4 ° , P = 0.56). As expected, this measurement increased with gastric fi lling from the fasted to the postprandial phase ( + 18 ± 4 ° , P < 0.0001) and increased further aft er feeding to maximum full-ness ( + 8 ± 5 ° ). It did not change with respiration ( P = 0.32).

Gastric content volume and intra-gastric air volume . Gastric con-tent volume directly aft er meal intake was similar in healthy controls and GERD patients; however, intra-gastric air volume aft er the meal was larger in healthy subjects than in the GERD group by 64 ± 29 ml ( P < 0.03). Gastric emptying during the 30-min emptying phase was 3.8 ± 0.4 ml / min in healthy volunteers, which was 1.6 ± 0.6 ml / min faster compared with that in GERD patients ( P = 0.009).

Stomach orientation and esophagogastric insertion point . Th e angle of orientation of the proximal stomach within the abdomen relative to the central abdominal axis ( Figure 2 ) in the healthy group aft er meal intake and during expiration was 60 ± 5 ° . Th is an-gle was smaller in GERD patients by − 17 ± 7 ° ( P = 0.01), implying that the proximal stomach is in a more anterior-posterior orienta-tion in GERD ( Figure 6 ). Gastric orientation in the abdomen did not change with gastric fi lling / study phase. Th e insertion point of the esophagus relative to the major (long) axis of the proximal stomach ( Figure 2 ) in the healthy group aft er meal intake and during expiration was 31 ± 5 ° . Th e insertion point was displaced further away from the major axis in GERD patients by 12 ± 6 ° ( P = 0.05) ( Figure 6 ). Gastric fi lling had no eff ect on this parameter. Measurements of gastric orientation within the abdomen and the position of insertion of the esophagus into the stomach are strongly correlated during respiration, as the anatomical relation-ship between the esophagus and proximal stomach is fi xed (Pear-son correlation coeffi cient r = 0.8). Th us, during inspiration, as the stomach rotated into a more antero-posterior position within the

Table 2 . Summary of observation times and of refl ux events detected

HRM MRI

Observation time [h]

Number of detected refl ux

events Median number of refl ux

events / h (interquartile range) Observation

time (h) Number of detected

refl ux events

HV 21 161 7.06 (3.48 – 9.98) 8.4 38

GERD 26 236 9.53 (5.56 – 15.0) 9.8 97

GERD, gastroesophageal refl ux disease; HRM, high-resolution manometry; HV, healthy volunteers; MRI, magnetic resonance imaging. HRM measurements were acquired continuously. Concurrent MRI measurements were acquired for about 40 % of the study duration. Agreement between the two modali-ties was perfect.

Table 3 . Biomarkers of esophageal and gastric structure and function.

Esophagogastric junction Gastric volumes Gastric morphology HRM measurement

Parameter

Esophagogastric insertion angle

Proximal gastric curvature / distension

Content (ml)

Air (ml)

Stomach orientation within abdomen

Esophago-gastric insertion point

LES pressure (mm Hg)

Intra-abdominal LES length (cm)

HV 55 74 723 165 60 31 20 1.9

GERD 62 76 662 101 43 43 8 0.9

Difference + 7 ( ± 3) 2 ( ± 4) − 61 ( ± 56) − 64 ( ± 29) − 17 ( ± 7) 12 ( ± 6) − 12 ( ± 2) − 1.0 ( ± 0.3)

P value 0.03 0.56 0.3 < 0.03 < 0.01 0.05 0.0001 0.0006

GERD, gastroesophageal refl ux disease; HRM, high-resolution manometry; HV, healthy volunteers; LES, lower esophageal sphincter. All measurements acquired in the “ after meal ” phase during expiration.

•  Gastric emptying 40% slower in GERD



Discussion / Conclusion •  “functional anatomy” of reflux barrier is altered in patients with mild-moderate

GERD

•  Insertion angle of the esophagus into the stomach is wider in GERD patients than in healthy subjects after ingestion of a large test meal.

•  Wider EGJ opening during reflux in GERD allows greater volume of reflux events (75%)

•  An acute esophagogastric insertion angle is essential for the proposed “flap valve” mechanism of reflux protection by compressing the intra-abdominal esophagus by the proximal stomach after distension/meal ingestion.

•  Minimally invasive technology that combines MRI and HRM provides assessment of esophagogastric structure and function

•  Abnormal gastric anatomy on magnetic resonance imaging could identify GERD patients with pathological acid exposure, not responding being well controlled on PPI.



Limitations

•  neither designed nor powered to confirm a causal association between measurements of EGJ structure/function and clinical measurements

•  patient group 12 years older and heavier (BMI+2.5 kg/m2)

•  MRI protocols do not resolve the gastric muscle layers, including the clasp and sling fibers of the cardia, which must be quantified for a full biophysical description of reflux protection

•  Position during examination affects orientation of stomach.



WHAT IS NEW HERE

•  Minimally invasive technology that combines magnetic resonance imaging (MRI) and high-resolution manometry (HRM), and provides a comprehensive assessment of esophagogastric structure and function after a large test meal.

•  Compared with healthy subjects, GERD patients have a wider esophagogastric insertion angle and other abnormalities of gastric anatomy that can compromise reflux protection by the “flap valve” mechanism.

•  GERD patients also have wider EGJ opening during reflux events after meals, allowing greater volume of reflux events.

•  Abnormal gastric anatomy on magnetic resonance imaging could identify GERD patients with pathological acid exposure.

abnormal structure and function of the …. kugener; journal club 21.05.2014: abnormal structure and...

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