Impaired upper esophageal sphincter reflexes in patients with supraesophageal reflux disease

Abstract

Background & aims: Normal responses of the upper esophageal sphincter (UES) and esophageal body to liquid reflux events prevent esophagopharyngeal reflux and its complications, however, abnormal responses have not been characterized. We investigated whether patients with supraesophageal reflux disease (SERD) have impaired UES and esophageal body responses to simulated reflux events.

Methods: We performed a prospective study of 25 patients with SERD (age, 19-82 y; 13 women) and complaints of regurgitation and supraesophageal manifestations of reflux. We also included 10 patients with gastroesophageal reflux disease (GERD; age, 32-60 y; 7 women) without troublesome regurgitation and supraesophageal symptoms and 24 healthy asymptomatic individuals (controls: age, 19-49 y; 13 women). UES and esophageal body pressure responses, along with luminal distribution of infusate during esophageal rapid and slow infusion of air or liquid, were monitored by concurrent high-resolution manometry and intraluminal impedance.

Results: A significantly smaller proportion of patients with SERD had UES contractile reflexes in response to slow esophageal infusion of acid than controls or patients with GERD. Only patients with SERD had abnormal UES relaxation responses to rapid distension with saline. Diminished esophageal peristaltic contractions resulted in esophageal stasis in patients with GERD or SERD.

Conclusions: Patients with SERD and complaints of regurgitation have impaired UES and esophageal responses to simulated liquid reflux events. These patterns could predispose them to esophagopharyngeal reflux.

Keywords: Cervical; EUCR; EURR; Extraesophageal Reflux; Laryngopharyngeal Reflux; Striated Esophagus.

Figure-1. Distal esophageal rapid saline infusion elicits different responses in healthy controls (A), GERD (B–C) and SERD (D–F) patients

A and B) Extension of infusate into the cervical esophagus is followed by strong esophago-UES contractile reflex (EUCR), and a secondary peristaltic wave transporting the infusate away from UES into the stomach. C) Rapid distal esophageal saline injection is followed by esophago-UES contractile reflex (EUCR), and a simultaneous esophageal contraction without esophageal clearance. D) Extension of the infusate into the cervical esophagus of a SERD patient elicits transient UES relaxation and results in immediate esophagopharyngeal reflux (EPR), and repetitive defensive swallows to clear hypopharynx from the infusate. E and F) shortly after saline injection, saline reaches the lower border of UES in SERD patients. Non-peristaltic esophageal contraction coupled with a transient incomplete UES relaxation results in EPR evidenced by retrograde hypopharyngeal impedance drop.

Figure-2. Frequency of elicitation and temporal characteristics of UES and esophageal contractile response, along with esophageal clearance after distal esophageal rapid saline injection in healthy controls (n=18), GERD (n=8) and SERD (n=19) subjects

A) Esophago-UES contractile reflex (EUCR) was the predominant response in majority of healthy controls and GERD patients. SERD subjects exhibited a transient UES relaxation response that was never observed in healthy controls and GERD patients. SERD patients also showed significantly less EUCR compared to healthy controls (* p< 0.05). B) Bolus saline injection in overwhelming majority of healthy controls was cleared by a peristaltic wave (secondary or primary). GERD and SERD patients though often demonstrated non-peristaltic contractions while healthy controls showed them rarely (* p< 0.05). C) Time lag from onset of esophageal rapid saline injection to elicitation of EUCR, transient relaxation and initial esophageal contractile response. Esophageal contractile response occurred later than UES response, and was significantly delayed in GERD and SERD subjects compared to healthy controls (* p< 0.05 and ^# p< 0.01). D) Quantitative analysis of esophageal stasis following saline infusion in GERD and SERD patients (N=27). Non-peristaltic esophageal contractions and lack of early esophageal contractile activity are similarly associated with delayed luminal clearance and resultant esophageal stasis. (# p< 0.01, n=number of infusion trials demonstrating response in each group).

Figure-2. Frequency of elicitation and temporal characteristics of UES and esophageal contractile response, along with esophageal clearance after distal esophageal rapid saline injection in healthy controls (n=18), GERD (n=8) and SERD (n=19) subjects

A) Esophago-UES contractile reflex (EUCR) was the predominant response in majority of healthy controls and GERD patients. SERD subjects exhibited a transient UES relaxation response that was never observed in healthy controls and GERD patients. SERD patients also showed significantly less EUCR compared to healthy controls (* p< 0.05). B) Bolus saline injection in overwhelming majority of healthy controls was cleared by a peristaltic wave (secondary or primary). GERD and SERD patients though often demonstrated non-peristaltic contractions while healthy controls showed them rarely (* p< 0.05). C) Time lag from onset of esophageal rapid saline injection to elicitation of EUCR, transient relaxation and initial esophageal contractile response. Esophageal contractile response occurred later than UES response, and was significantly delayed in GERD and SERD subjects compared to healthy controls (* p< 0.05 and ^# p< 0.01). D) Quantitative analysis of esophageal stasis following saline infusion in GERD and SERD patients (N=27). Non-peristaltic esophageal contractions and lack of early esophageal contractile activity are similarly associated with delayed luminal clearance and resultant esophageal stasis. (# p< 0.01, n=number of infusion trials demonstrating response in each group).

Figure-2. Frequency of elicitation and temporal characteristics of UES and esophageal contractile response, along with esophageal clearance after distal esophageal rapid saline injection in healthy controls (n=18), GERD (n=8) and SERD (n=19) subjects

A) Esophago-UES contractile reflex (EUCR) was the predominant response in majority of healthy controls and GERD patients. SERD subjects exhibited a transient UES relaxation response that was never observed in healthy controls and GERD patients. SERD patients also showed significantly less EUCR compared to healthy controls (* p< 0.05). B) Bolus saline injection in overwhelming majority of healthy controls was cleared by a peristaltic wave (secondary or primary). GERD and SERD patients though often demonstrated non-peristaltic contractions while healthy controls showed them rarely (* p< 0.05). C) Time lag from onset of esophageal rapid saline injection to elicitation of EUCR, transient relaxation and initial esophageal contractile response. Esophageal contractile response occurred later than UES response, and was significantly delayed in GERD and SERD subjects compared to healthy controls (* p< 0.05 and ^# p< 0.01). D) Quantitative analysis of esophageal stasis following saline infusion in GERD and SERD patients (N=27). Non-peristaltic esophageal contractions and lack of early esophageal contractile activity are similarly associated with delayed luminal clearance and resultant esophageal stasis. (# p< 0.01, n=number of infusion trials demonstrating response in each group).

Figure-3. Slow esophageal acid infusion elicits distinctive response in healthy controls (A–B), GERD (C–D) and SERD (E–F) patients

Healthy controls show persistent esophago-UES contractile response (EUCR) associated with repetitive peristaltic waves (A). A unique pattern of persistent EUCR associated with peristaltic waves limited to the striated-muscle segment of esophagus while distal smooth-muscle esophagus is inhibited was observed in healthy control (B) and GERD patients (C). Slow acid infusion is often followed by rhythmic UES contractions (robust EUCR) accompanied by repetitive non-peristaltic esophageal contractions in GERD (D) and SERD (F) patients. E) Repetitive swallows associated primary peristalsis follow slow acid infusion in a SERD patient. Impaired EUCR and brief episodes of UES relaxation are observed before and after the third swallow.

Figure-4. Frequency of elicitation, rate and temporal characteristics of UES and esophageal contractile response during slow esophageal acid infusion in healthy controls (n=12), GERD (n=9) and SERD (n=15) patients

A) Overwhelming majority of healthy controls and GERD patients showed esophago-UES contractile response (EUCR). In contrast, SERD patients frequently demonstrated no discernable UES response (* p< 0.01 and ^# p< 0.001 compared to GERD and healthy respectively). While healthy controls universally responded by esophageal peristaltic contraction following slow acid infusion, GERD and SERD patients often exhibited non-peristaltic esophageal contractions (^# p< 0.001 compared to healthy). C) Non-peristaltic esophageal contractions in GERD and SERD patients were significantly delayed compared to peristaltic contraction counterparts in healthy controls (* p< 0.05, n=number of infusion trials demonstrating response in each group). D) Rate of esophageal contractile activity during total 180 seconds of ongoing acid infusion over three trials was measured. Striated peristaltic waves were predominantly seen in healthy controls, while in contrast esophageal non-peristaltic contractions were significantly more common in GERD and SERD patients (* p< 0.05). E) Duration from termination of acid infusion till complete esophageal clearance from infusate was measured up to 180 seconds. Both GERD and SERD patients showed longer duration of esophageal stasis compared to healthy controls (^#p< 0.001, n=number of infusion trials demonstrating response in each group).

Figure-4. Frequency of elicitation, rate and temporal characteristics of UES and esophageal contractile response during slow esophageal acid infusion in healthy controls (n=12), GERD (n=9) and SERD (n=15) patients

A) Overwhelming majority of healthy controls and GERD patients showed esophago-UES contractile response (EUCR). In contrast, SERD patients frequently demonstrated no discernable UES response (* p< 0.01 and ^# p< 0.001 compared to GERD and healthy respectively). While healthy controls universally responded by esophageal peristaltic contraction following slow acid infusion, GERD and SERD patients often exhibited non-peristaltic esophageal contractions (^# p< 0.001 compared to healthy). C) Non-peristaltic esophageal contractions in GERD and SERD patients were significantly delayed compared to peristaltic contraction counterparts in healthy controls (* p< 0.05, n=number of infusion trials demonstrating response in each group). D) Rate of esophageal contractile activity during total 180 seconds of ongoing acid infusion over three trials was measured. Striated peristaltic waves were predominantly seen in healthy controls, while in contrast esophageal non-peristaltic contractions were significantly more common in GERD and SERD patients (* p< 0.05). E) Duration from termination of acid infusion till complete esophageal clearance from infusate was measured up to 180 seconds. Both GERD and SERD patients showed longer duration of esophageal stasis compared to healthy controls (^#p< 0.001, n=number of infusion trials demonstrating response in each group).

Figure-4. Frequency of elicitation, rate and temporal characteristics of UES and esophageal contractile response during slow esophageal acid infusion in healthy controls (n=12), GERD (n=9) and SERD (n=15) patients

A) Overwhelming majority of healthy controls and GERD patients showed esophago-UES contractile response (EUCR). In contrast, SERD patients frequently demonstrated no discernable UES response (* p< 0.01 and ^# p< 0.001 compared to GERD and healthy respectively). While healthy controls universally responded by esophageal peristaltic contraction following slow acid infusion, GERD and SERD patients often exhibited non-peristaltic esophageal contractions (^# p< 0.001 compared to healthy). C) Non-peristaltic esophageal contractions in GERD and SERD patients were significantly delayed compared to peristaltic contraction counterparts in healthy controls (* p< 0.05, n=number of infusion trials demonstrating response in each group). D) Rate of esophageal contractile activity during total 180 seconds of ongoing acid infusion over three trials was measured. Striated peristaltic waves were predominantly seen in healthy controls, while in contrast esophageal non-peristaltic contractions were significantly more common in GERD and SERD patients (* p< 0.05). E) Duration from termination of acid infusion till complete esophageal clearance from infusate was measured up to 180 seconds. Both GERD and SERD patients showed longer duration of esophageal stasis compared to healthy controls (^#p< 0.001, n=number of infusion trials demonstrating response in each group).

Figure-4. Frequency of elicitation, rate and temporal characteristics of UES and esophageal contractile response during slow esophageal acid infusion in healthy controls (n=12), GERD (n=9) and SERD (n=15) patients

A) Overwhelming majority of healthy controls and GERD patients showed esophago-UES contractile response (EUCR). In contrast, SERD patients frequently demonstrated no discernable UES response (* p< 0.01 and ^# p< 0.001 compared to GERD and healthy respectively). While healthy controls universally responded by esophageal peristaltic contraction following slow acid infusion, GERD and SERD patients often exhibited non-peristaltic esophageal contractions (^# p< 0.001 compared to healthy). C) Non-peristaltic esophageal contractions in GERD and SERD patients were significantly delayed compared to peristaltic contraction counterparts in healthy controls (* p< 0.05, n=number of infusion trials demonstrating response in each group). D) Rate of esophageal contractile activity during total 180 seconds of ongoing acid infusion over three trials was measured. Striated peristaltic waves were predominantly seen in healthy controls, while in contrast esophageal non-peristaltic contractions were significantly more common in GERD and SERD patients (* p< 0.05). E) Duration from termination of acid infusion till complete esophageal clearance from infusate was measured up to 180 seconds. Both GERD and SERD patients showed longer duration of esophageal stasis compared to healthy controls (^#p< 0.001, n=number of infusion trials demonstrating response in each group).

Figure-5. Healthy controls distinctively demonstrate a unique pattern of striated-muscle peristaltic waves while distal smooth-muscle esophagus is quiescent

A–B) In healthy controls, when the infusate reaches proximal esophagus a robust esophago-UES contractile reflex (EUCR), and sometimes a unique pattern of striated peristaltic waves sweep the infusate away from UES. Perhaps more importantly, when infusate is in close proximity of the lower border of UES, striated-muscle activity is universally present prior to any swallow-related UES relaxation. C–D) SERD patients frequently show impaired EUCR and non-peristaltic esophageal contractions. They frequently do not mount any esophageal striated activity prior to swallow-related UES relaxation despite exposure of the lower border of UES to infusate.

Figure-6. Distal esophageal rapid air injection elicits predominantly esophago-UES relaxation reflex (EURR) in healthy controls (A–B), GERD (C–D) and SERD (E–F) patients

Distal esophageal simultaneous contraction was observed shortly after onset of UES relaxation (A,C,D,E) in all groups. Occasionally a secondary peristaltic wave was triggered in healthy controls and GERD patients (B,D) or no discernable esophageal contractile activity could be recognized after air injection (F). The reported air-induced simultaneous contraction as shown was distinctly after termination of air infusion and not consistent with esophageal isobaric pressurization (E).

Figure-7. Frequency of elicitation and temporal characteristics of UES and esophageal response to distal esophageal rapid air injection (10, 20, 30 and 50 ml) in healthy controls (n=18), GERD (n=8) and SERD (n=19) subjects

A) Esophago-UES relaxation reflex (EURR) was the predominant response in majority of participants. B) Initial esophageal contractile response to bolus air injection was either a non-peristaltic distal esophageal contraction, or a peristaltic response during analysis window. SERD patients never showed peristaltic response to air injection (*compared to healthy and ^#compared to GERD, p< 0.05). C) Time lag from onset of esophageal rapid air injection to elicitation of EURR, esophago-UES contractile reflex (EUCR) and esophageal contractile response. Esophageal contractile response occurred universally later than onset of UES response. Peristaltic contraction was significantly delayed compared to non-peristaltic contractions (^*p< 0.05 and ^#p< 0.01 compared to UES response and non-peristaltic contraction, n=number of infusion trials demonstrating response in each group).

Figure-7. Frequency of elicitation and temporal characteristics of UES and esophageal response to distal esophageal rapid air injection (10, 20, 30 and 50 ml) in healthy controls (n=18), GERD (n=8) and SERD (n=19) subjects

A) Esophago-UES relaxation reflex (EURR) was the predominant response in majority of participants. B) Initial esophageal contractile response to bolus air injection was either a non-peristaltic distal esophageal contraction, or a peristaltic response during analysis window. SERD patients never showed peristaltic response to air injection (*compared to healthy and ^#compared to GERD, p< 0.05). C) Time lag from onset of esophageal rapid air injection to elicitation of EURR, esophago-UES contractile reflex (EUCR) and esophageal contractile response. Esophageal contractile response occurred universally later than onset of UES response. Peristaltic contraction was significantly delayed compared to non-peristaltic contractions (^*p< 0.05 and ^#p< 0.01 compared to UES response and non-peristaltic contraction, n=number of infusion trials demonstrating response in each group).