Gastro Hep Advances 2024;3:109–121

NARRATIVE REVIEWS
Why so Many Patients With Dysphagia Have Normal
Esophageal Function Testing
Ravinder K. Mittal and Ali Zifan

Division of Gastroenterology, Department of Medicine, University of California San Diego, San Diego, California

Esophageal peristalsis involves a sequential process of initial symptom to be either “quite a bit” or “very severe”. Drinking
inhibition (relaxation) and excitation (contraction), both liquids to help with dysphagia was reported by 86% and tak-
occurring from the cranial to caudal direction. The bolus ing longer time to finish eating by 77%. Dysphagia prevalence
induces luminal distension during initial inhibition (recep- increases with age and other comorbidities such as gastro-
tive relaxation) that facilitates smooth propulsion by
esophageal reflux disease (30.9%), eosinophilic esophagitis
contraction travelling behind the bolus. Luminal distension
(EOE) (8.0%), and esophageal stricture (4.5%). Interestingly,
during peristalsis in normal subjects exhibits unique char-
acteristics that are influenced by bolus volume, bolus vis- only half of individuals with dysphagia sought medical care
cosity, and posture, suggesting a potential interaction for their difficulty swallowing. An earlier study found the
between distension and contraction. Examining distension- dysphagia incidence to be 7.8% in the US.2 A similar study in
contraction plots in dysphagia patients with normal bolus Australia and Argentina reported prevalence rates of 16%3
clearance, ie, high-amplitude esophageal peristaltic con- and 13%,4 respectively. Therefore, similar to the heartburn
tractions, esophagogastric junction outflow obstruction, and and reflux disease, dysphagia is highly prevalent in the west-
functional dysphagia, reveal 2 important findings. Firstly, ern world. On the other hand, dysphagia rate was reported
patients with type 3 achalasia and nonobstructive dysphagia to be lower in the Asian population,5 only 1.7% in China.
show luminal occlusion distal to the bolus during peristalsis.
Secondly, patients with high-amplitude esophageal peri-
staltic contractions, esophagogastric junction outflow Etiology of Dysphagia
obstruction, and functional dysphagia exhibit a narrow
Dysphagia generally can be categorized into oropha-
esophageal lumen through which the bolus travels during
peristalsis. These findings indicate a relative dynamic ryngeal and esophageal. The focus of this article is on
obstruction to bolus flow and reduced distensibility of the esophageal dysphagia, which can be due to structures
esophageal wall in patients with several primary esophageal extrinsic and/or intrinsic to the esophagus. Mediastinal
motility disorders. We speculate that the dysphagia sensa- structures such as blood vessels, heart, and mediastinal
tion experienced by many patients may result from a normal tumors may compress the esophagus resulting in obstruc-
or supernormal contraction wave pushing the bolus against tion to the passage of swallowed contents. Dysphagia, due to
resistance. Integrating representations of distension and the pathology intrinsic to the esophagus, may be further
contraction, along with objective assessments of flow timing divided into mucosal and neuromuscular. Rings and web in
and distensibility, complements the current classification of the esophagus, e.g., Schatzki ring is a common cause of
esophageal motility disorders that are based on the
dysphagia and one can diagnose it with a well-done barium
contraction characteristics only. A deeper understanding of
swallow and endoscopy exam. Inflammation of the esoph-
the distensibility of the bolus-containing esophageal
segment during peristalsis holds promise for the develop- ageal mucosa related to viral (herpes) and fungal (candida)
ment of innovative medical and surgical therapies to effec- infection may cause dysphagia and odynophagia, and these
tively address dysphagia in a substantial number of patients. are easily diagnosed with endoscopy and biopsy, and
treated with antiviral and antifungal agents, respectively.
Reflux disease and esophagitis resulting in mucosal
Keywords: Dysphagia; Distension Contration Plot; Esophageal inflammation and strictures is a common cause of dysphagia
Peristalsis; Functional Dysphagia

See editorial on page 136. Abbreviations used in this paper: CSA, cross-sectional area; EGJOO,
esophagogastric junction outflow obstruction; EOE, eosinophilic esoph-
agitis; FD, functional dysphagia; HRMZ, high resolution manometry
impedance; LES, lower esophageal sphincter.
Epidemiology of Dysphagia Symptom Most current article

A cross-sectional study of the US population found a

dysphagia prevalence of 16% in the general popula-
tion, with 92% experiencing symptoms in the previous
Copyright © 2024 The Authors. Published by Elsevier Inc. on behalf of the
AGA Institute. This is an open access article under the CC BY-NC-ND li-
cense (http://creativecommons.org/licenses/by-nc-nd/4.0/).
2772-5723
week.1 Sixteen percent of the respondents described their https://doi.org/10.1016/j.gastha.2023.08.021
110 Mittal and Zifan Gastro Hep Advances Vol. 3, Iss. 1

and reflux disease; it can also be easily diagnosed with suggests that the etiology of dysphagia in many patients re-
endoscopy and pH/impedance monitoring of the esophagus. mains unknown and is the subject of discussion in this review.
Scleroderma esophagus may lead to recalcitrant reflux dis- The majority of the patients seen in my clinical practice
ease and esophageal stricture. During the last 3 decades, (Mittal) fall into this category. A brief review of physiology of
EOE has attracted significant interest.6 Endoscopy with bi- peristalsis is presented before its discussion in the context of
opsy showing an eosinophil count of
15 HPF allows one to dysphagia and why these patients may have normal esopha-
make a definitive diagnosis of EOE.7 A normal endoscopy geal function testing.
and biopsy in patients with dysphagia should be followed by
high-resolution manometry impedance high resolution
manometry impedance (HRMZ) study to assess the esoph- Physiology of Esophageal Peristalsis
ageal motor and lower esophageal sphincter function.8 The The neuromuscular apparatus of the smooth muscle distal
Chicago Classification of esophageal motility disorders has esophagus is endowed with an integrated system that has the
allowed specific criteria to diagnose esophageal motility capacity to alternate from relaxation that reduces resistance to
disorders into major (achalasia, nutcracker/jackhammer bolus flow (relaxation), to contraction that actively drives the
esophagus, esophagogastric junction outflow obstruction bolus flow. Bayliss and Starling, at the turn of the 19th century
(EGJOO), and absent peristalsis) and minor ones (ineffective studied peristalsis in the small and large intestines of dogs and
peristalsis, fragmented peristalsis).9 These criteria are based observed that peristalsis consists of initial inhibition, followed
on the contraction phase of peristalsis. Except for patients by contraction (“the law of intestine”).18,19 Along those lines,
with achalasia esophagus and EGJOO, the reason for esophageal peristalsis also consists of initial inhibition followed
dysphagia in patients with major and minor motility disor- by excitation. Each swallow initiates an esophageal contraction
ders remains unclear because minor motor disorders are (primary peristalsis) following a latency period in the proximal
seen not infrequently in asymptomatic individuals.10 Also, it skeletal and distal smooth muscle esophagus. The latency in the
is not clear why patients with supernormal contraction skeletal muscle esophagus is due to the sequential activation of
phase of peristalsis, ie, nutcracker esophagus and jack- neurons in the nucleus ambiguous of the vagus nerve nucleus.
hammer esophagus should have dysphagia.11,12 Further- On the other hand, in the case of smooth muscle esophagus, the
more, 30%–50% of patients referred for HRMZ study with latency is related to either a central (sequential activation of
dysphagia turn out to have a normal study and can be neurons in the dorsal motor nucleus of vagus) or a peripheral
classified into functional dysphagia (FD)13,14 (Figure 1). Ac- mechanism.20 The latter can be either neurogenic (myenteric
cording to the ROME criteria, FD is characterized by sensation plexus and inhibitory motor neurons), or myogenic21 (syncy-
of abnormal esophageal bolus transit with no evidence of tium formed by the muscles through which depolarization
structural lesions, i.e., gastroesophageal reflux disease, EOE, spreads sequentially). Nitric oxide containing nerves in the
and histopathology-based esophageal motor disorders.8 FD is myenteric plexus play an important role in the inhibitory phase
a diagnosis of exclusion; and its prevalence in the general of peristalsis and the latency period.22 One can measure the
population is not clear. Seven percent and 8% of the re- latency period in-vivo (distal latency) from the high-resolution
spondents from a house holder survey reported dysphagia manometry (HRM) -recording; it is the time interval from the
that was unexplained by the questionnaire ascertained dis- onset of swallow (onset of upper esophageal sphincter (UES)
orders, with less than 1% reporting frequent dysphagia.15,16 relaxation) to the onset of contraction in the most distal part of
Zero point six percent of patients with functional gastroin- the esophagus.23 A shorter distal latency (<4.5 sec) is a hall-
testinal disease complain of frequent dysphagia.17 Since the mark of diffuse esophageal spasm, and it is due to the impaired
majority of patients referred for HRMZ studies have normal inhibitory, nitric oxide containing nerves of the myenteric
barium swallow, normal endoscopy, and normal esophageal plexus.22,24 Indirect evidence of inhibition during peristalsis can
mucosal biopsy, one can argue that patients with normal also be observed in human recordings with repetitive swal-
HRMZ studies would likely fit into the category of FD. Above lowing (deglutitive inhibition).25 If one swallows twice, less

Figure 1. (A–C) Prevalence of esophageal motor disorders in patients with dysphagia referred for esophageal manometry from
3 tertiary care centers.
2024 Dysphagia in patients with normal esophageal function tests 111

than 2 seconds apart, the 2nd swallow inhibits the contraction travels through the esophagus.32 Above implies that the
from the first swallow. Multiple swallows at short intervals degree of inhibition in the distended segment varies and the
result in only 1 contraction, which follows the last swallow. maximal inhibition during peristalsis in the esophagus is
Electro-physiologic recordings provide direct proof of inhibi- located at the point of peak distension, which moves
tion and contraction during esophageal peristalsis.26 Both, sequentially through the esophagus. In other words, similar
primary peristalsis27 (swallow-induced) and secondary peri- to contraction, the inhibition/distension wave also travels
stalsis28 (esophageal distension-induced) result in hyperpo- sequentially through the esophagus during peristalsis
larization and depolarization of the resting membrane (Figure 2). Thus, as timing and amplitude of the contraction
potential of the smooth muscle, which are equivalent of inhi- are the markers of the excitatory phase, the timing and
bition and excitation, respectively. The inhibition results in amplitude of distension is a marker of the inhibitory phase
receptive relaxation, which allows distension of the esophagus of peristalsis. In healthy subjects, the 2 phases of peristalsis
before contraction so that the latter can propel the bolus with are spatiotemporally linked, and breakage of this linkage
minimal resistance. can be a marker of the peristaltic dysfunction. Measuring
Unlike the lower esophageal sphincter, manometry re- luminal distension during peristalsis is challenging and not
cordings do not reveal a resting tone in the esophagus and done routinely in the current clinical practice.
therefore relaxation of the esophagus can’t be recorded by
manometry.29 To demonstrate relaxation of the esophagus,
Sifrim created artificial high-pressure zones in the esoph- Measuring Luminal Cross-sectional
agus by distending small balloons and observed its relaxa-
Area/esophageal Distension During
tion in normal subjects but not in patients with diffuse
esophageal spasm.30,31 Ultrasound imaging studies reveal Peristalsis
that during swallow-induced peristalsis, the esophagus Barium esophagogram is a simple method to assess the
distends in the shape of an “American Football”, as the bolus esophageal diameter during peristalsis. Schatzki reported

Figure 2. Bolus moves through the esophagus in the shape of an “American Football” during peristaltic transport during
primary and secondary peristalsis, recorded by 3 different methods: 1) ultrasound image derived data, 2) Antegrade
contraction recorded by Endoflip technique, and 3) impedance derived luminal cross-sectional area of the esophagus.
112 Mittal and Zifan Gastro Hep Advances Vol. 3, Iss. 1

maximal esophageal diameter of 40 mm in the context of esophagus is likely related to the location, it might be distal
Schatzki ring.33 Others found maximal diameter of distal esophagus or phrenic ampulla.38
esophagus, ranging from 20 to 33 mm (median 25 The impedance methodology is another possible tech-
mm).34–37 The reason for this large range is likely is related nique to measure the luminal CSA, it has been used in many
to number of factors; 1) barium esophagograms are not organ systems, ie, heart, stomach, and esophagus. One can
done in a standardized manner, and thus are highly oper- record left ventricular volume, cardiac ejection fraction,41
ator dependent, 2) bolus volume, viscosity and subject gastric volume and gastric emptying42,43 using impedance
posture (supine, prone, or upright) are important de- methodology. Since 1980’s, impedance technique has been
terminants of the luminal dimensions during peristalsis, 3) in use to measure the CSA of a distended balloon in the
single vs multiple swallows during bolus passage may make esophagus, in-vivo.44 Functional luminal imaging probe,
a difference in the esophageal distension (luminal di- currently used in clinical practice, is also based on the
mensions) and, 4) definition of distal esophagus may vary Ohm’s law of electricity and impedance principles.45 It
because the phrenic ampulla, widest portion of the esoph- actually measures luminal CSA, which is then converted
agus, is likely a part of the stomach because axial shortening mathematically to diameter, based on the assumption of a
of the esophagus results in a physiological sliding hiatus circular geometry of the esophagus. The HRMZ catheters
hernia with each peristaltic contraction, 5) abdominal currently used for routine clinical manometry studies have
compression during swallow study if done, increases intraluminal impedance electrodes located every 2 cm along
resistance to outflow and may increases the luminal diam- the length of the esophagus. These impedance recordings
eter. A single-plane, 2D X Ray imaging allows one to mea- are currently used to detect whether bolus clearance during
sure the width of the esophagus, which is called its peristalsis is complete or incomplete. Kim found a signifi-
diameter. Bear in mind that the transit of bolus through a cant linear correlation between the luminal CSA measured
tube is dependent on its luminal cross-sectional area (CSA). by intraluminal US imaging and inverse of impedance (also
If the esophagus were to distend in a circular fashion during called admittance).46 The difficulty though is that subjects
peristalsis, the luminal CSA calculation from the esophageal may swallow air residing in the oropharynx, along with the
width seen on barium swallow study would be valid. swallowed saline bolus,38 which confounds the impedance
However, such is not the case, as revealed by intraluminal values recorded in the esophagus and hence confounds the
ultrasound imaging and computerized tomography (CT) accurate measurement of esophageal luminal CSA.47 One
scan imaging. Based on the CT scan imaging, esophagus can mitigate above situation by swallowing in the Trende-
expands 33% more in the lateral than in anterior-posterior lenburg position, air being lighter than liquid gets separated
direction during distension.38 Also bear in mind that small during transit through the esophagus.47 Nguyen48,49 and
changes in the diameter can make large difference in the Omari50,51 found that following swallow of saline bolus, the
luminal CSA, (CSA ¼ pr,2 r being the radius). The CSA for nadir impedance (a marker of maximal luminal CSA/
diameters of 13 mm, 15 mm, 17 mm and 20 mm would be, distension) travels sequentially through the esophagus.
133 mm2, 177 mm2, 227 mm2, and 314 mm2, respectively. Luminal CSA measured by impedance technique recordings
Our laboratory has used high-frequency intraluminal performed with the subject in the Trendelenburg position, is
ultrasound catheters for almost 30 years to study luminal similar to the one measured by intraluminal US images,
distension during reflux events and peristalsis.39,40 Using 2 (median value of 125 mm2, at 7 cm above LES).47 Therefore,
high-frequency intraluminal ultrasound catheters located at it is possible to record luminal CSA/distension during
2 cm and 10 cm above the lower esophageal sphincter peristalsis from the HRMZ recordings, thus opening the door
(LES), it was observed that similar to contraction, the for recording distension-contraction plots of peristalsis
esophagus also distends sequentially along the length of the during routine clinical manometry studies. Omari has
esophagus during peristalsis.32 Furthermore, the esophagus championed the use of automated impedance manometry in
distends in the shape of an “American Football” (not in a patients with oropharyngeal swallowing disorders52 and
cylindrical fashion) at each location in the esophagus during nonobstructive dysphagia,50 which in principle is similar to
peristalsis. The “American Football” shape of the bolus the concept of distension-contraction plots.
during esophageal transit is also observed during barium
swallow if one records transit following a single swallow,
especially in the supine position. Endoflip studies that re- Characteristics of Distension
cord distension-induced esophageal peristalsis also reveal
Contraction Waveforms in Normal
above phenomenon during repetitive antegrade contraction
(Figure 2). Mean CSA at 12 cm and 2 cm above the LES were Subjects
120 mm2 and 275 mm2 as recorded by ultrasound (US) In normal subjects, using concurrent MII, manometry
images in one study (10 ml bolus and subject in supine and X-Ray fluoroscopy, 4 phases of liquid bolus flow tied to
position).32 The CT scan images show CSA values of pressure topography landmarks can be identified.53 The
approximately 160, 180 and 395 mm2 at the level of carina, phase I (accommodation phase) represents the time be-
left atrium, and phrenic ampulla, respectively (10 ml bolus tween the opening and closing of the UES during which
in the supine position). The difference in CSA in the distal bolus is propelled by the pharyngeal pump into the
2024 Dysphagia in patients with normal esophageal function tests 113

esophagus. Phase II (compartmentalization phase) repre- the lower edge of UES to the CDP of peristaltic contraction.
sents the time period between the UES closure, to the arrival The CDP is located above phrenic ampulla, and thus values
of the contraction wave in the transition zone. No bolus reported in our publications do not include the phrenic
leaves the esophagus during phase I and II. Phase III ampullary region. We are not certain whether the imped-
(esophageal emptying phase) is the time during which ance technique can measure phrenic ampullary distension
peristaltic contraction propels bolus to the contraction values accurately; the reason is that the stomach and
deacceleration point (CDP).54 Phase IV (ampulla emptying esophagus are lined by columnar and squamous epitheliums
phase) is the time from the CDP to the completion of bolus that have low and high impedance values, respectively. Axial
transit into the stomach. Distension-contraction plots reveal shortening of the esophagus during peristalsis results in
that esophageal distension during passage of bolus during relative movement between the sensors on the manometry
peristalsis varies along the length of the esophagus. The catheter and esophagus, eg, a sensor locate in the lower
distension values increase from proximal to the distal esophageal sphincter before swallow may moves into the
location in the esophagus.55,56 Based on barium swallow stomach during peristalsis. Before peristalsis, the recording
studies and CT imaging, the phrenic ampulla is the location electrode located in the esophagus may move into the
of maximally luminal distension. The computer software phrenic ampulla with peristalsis and can confound the
program (Distension Plots) allows one to visualize disten- luminal CSA calculation.
sion (measured from the impedance part of HRMZ re- Several studies show the effect of bolus volume and
cordings) and contraction (measured by pressure sensors) viscosity, and posture on the characteristics of esophageal
in several formats, ie, waveforms, color topographical plots contraction waveforms.57–59 Distension-contraction plots
and videos of esophageal distension during peristalsis. shows a similar effect of the above variables on the ampli-
These recordings show the amplitude and location of tude of distension waveforms during primary peri-
distension and temporal correlation between contraction stalsis60,61 (Figure 3). In addition, these studies also show
and distension during bolus transit through the esophagus alterations in the temporal correlation between distension
at close intervals (every 1–2 cm). For the numerical anal- and contraction waveforms during esophageal transit. Ten
ysis, instead of quantifying distension at one specific loca- milliliters of 0.5 N saline, swallowed in the Trendelenburg
tion in the esophagus, DPlot provides the average distension position has been used for our studies because we reasoned
value in 4 equal segments of the esophagus, starting from that a 5 ml bolus used during clinical studies is not enough

Figure 3. Effect of posture and bolus viscosity on the distension-contraction waveforms. Esophageal distension shown as
waveform and contraction as color heat map. Saline bolus in the supine position arrives much faster in the mid and distal
esophagus as compared to the Trendelenburg position (A and C). The latter position slows the speed of bolus and bolus
travels closer to the contraction wave along the length of the esophagus. Viscous bolus moves slowly through the esophagus
in close relationship with the onset of contraction. Supine (B) vs Trendelenburg (D) position with viscous bolus did not influence
the temporal relationship between contraction and dissension waveform. Reproduced with permission from Mittal RK, Muta K,
Ledgerwood-Lee M, et al. Relaionship between distension-contraction waveforms during esophageal peristalsis: effect of
bolus volume, viscocity and posture:In Press. Am J Physiol 2020; 319(4):G454–G467.
114 Mittal and Zifan Gastro Hep Advances Vol. 3, Iss. 1

volume to study esophageal distension and it is less likely to type 3 achalasia (same entity as diffuse esophageal spasm in
distinguish patients from normal. The important charac- prior literature), impedance recordings reveal that distal
teristics of distension waveform during peristalsis are 1) the esophagus empties completely, however, ultrasound imaging
lumen distends in the shape of an “American Football” at reveals that distal to the bolus, there is luminal occlusion and
each location, along the entire length of the esophagus, 2) thinning of the muscle layers 669,70 (Figure 4). As a conse-
the peak of distension moves sequentially along the quence, bolus is compressed between the contraction prox-
esophagus, 3) amplitude of distension increases from the imal to bolus and luminal occlusion distal to bolus. Latter
proximal to distal location along the length of esophagus, results in high bolus pressure and bolus travelling closer to
and 4) peak distension velocity and bolus flow rate decrease the contraction peak. Abnormality in the phrenic ampulla
from proximal to distal location in the esophagus.62 With phase of emptying can been seen in patients with the
regards to the temporal correlation between distension and obstructive crus of the diaphragm (hiatus).71 The esophagus
contraction waveform, the important features are; the empties completely in these patients, but the bolus is trapped
pharyngeal pump propels swallowed bolus into the mid in the phrenic ampulla may reflux back into the esophagus at
esophagus quickly (without any assistance from esophageal the termination of peristaltic contraction, especially if the LES
contraction) resulting in a significant time interval between pressure were to be low.
the distension and contraction waves in the proximal, mid, With the ability to measure luminal CSA, and temporal
and at times in the distal esophagus. On the other hand, correlation between the peak distension and contraction
there is a closer temporal correlation between the from HRMZ recordings, studies show abnormal patterns of
contraction and distension wave in the distal esophagus. luminal distension and temporal correlation between
Trendelenburg position and increase in bolus viscosity in- distension and contraction in patients with nutcracker
creases the amplitude of distension, decreases velocity of esophagus, EGJOO and function dysphagia (Figures 5 and 6).
bolus movement, and distance traveled by bolus due to The 3 parameters that distinguish patients from normal are
pharyngeal pump.62 Distension-contraction waveforms are 1) rapid bolus flow through the proximal and midesophagus
more closely aligned with each other throughout the length resulting in a shorter time interval (T1) between the onset
of esophagus with a viscous bolus. of swallow and peak luminal distension in the distal
The luminal distension may affect contraction and vice esophagus, 2) lower amplitude of luminal distension or CSA,
versa via several mechanisms. Larger distension resulting in and 3) a shorter time interval between the peak luminal
an increase in the muscle fiber length will generate greater distension and peak contraction and a smaller duration of
contraction based on the length-tension principle described distension wave during peristalsis.72 The first 2 parameters
in the context of cardia muscles (Starling principle). Luminal are related, they are the due to a narrow lumen esophagus
distension by a moving bolus can influence contractions and during the distension phase of peristalsis. As expected by
vice versa, also through the activation of peripheral and the Poiseuille law of physics, swallowed bolus propelled by
central neural reflex pathways.63 Greater distension results the pharyngeal pump will travels faster through a narrow as
in greater esophageal wall tension, an important stimulus compared to wide lumen esophagus, and thus arrives in the
for the activation of vagal and spinal sensory pathways distal esophagus faster. An analogy of the above may be
associated with the conscious perception of swallowing and seen in daily life, eg, constricting the opening of a garden
esophageal symptoms.64–66 hose results in an increase in the velocity of ejected water
stream which gets further into the lawn. A shorter time
interval between the distension and contraction wave is due
to dynamic obstruction to flow cause by luminal collapse
Bolus Flow and Distension Contraction
distal the bolus that compresses bolus between the
Patterns in Patients With Dysphagia contraction and luminal closure distal to bolus.48,69,70
Ineffective esophageal contractions (low amplitude, A solid food challenge test during manometry, champ-
fragmented, or failed) following a swallow result in either no ioned by Sweiss, Fox and others over many years show that
clearance or incomplete bolus clearance from the esoph- a greater number of patients with dysphagia have abnormal
agus.67 The latter is also observed in patients with achalasia esophageal motility and reproduction of dysphagia symp-
esophagus. However, the patterns of esophageal emptying are tom during manometry studies with a solid food than with
different in the 3 types of achalasia. In patients with achalasia saline bolus swallows.73–75 In one of their reports, only 35%
type 1, characterized by low amplitude or absent esophageal of patients with dysphagia were found to have major
contraction and impaired LES relaxation, the entire swal- motility disorders with saline swallows as compared to 67%
lowed bolus remains in the esophagus when there is no with solid bolus (cheese and onion pasties or soft-cooked
assistance from gravity (supine position).68 In patients with long grain rice).73 More impressive was the reproduction
type 2 achalasia, a unique pattern of longitudinal muscle of symptoms during manometry study, which is extremely
contraction leads to reduction in the esophageal luminal rare with saline swallows (1%), as compared to 61% with
volume that results in esophageal pan-pressurization, and if the solid food. A likely explanation for the above is that that
and when esophageal pressure exceeds LES pressure there is a solid bolus requires a wider lumen than the liquid bolus to
partial/incomplete esophageal emptying.68 In patients with get through the esophagus. The differences in contractions
2024 Dysphagia in patients with normal esophageal function tests 115

Figure 4. m-Mode US image at 5 cm above the LES along with impedance line tracing to show the relationship between bolus
arrival, bolus clearance, luminal distension, and muscle thickness with swallows in normal subject (A), and 3 patients with
achalasia esophagus type 3 (B–D). X axis is time in these recordings. Yellow arrows show that unlike normal subject, there is
luminal closure before arrival of bolus in achalasia 3 esophagus which results in delayed arrival of bolus in the distal esophagus
and bolus travelling closer to the contraction wave. D shows luminal opening, followed by collapse (green arrow) and then
opening again in this swallow. Time 1 ¼ time between the onset of swallow and bolus arrival, Time 2 ¼ time between bolus
arrival and bolus clearance. Reproduced with permission from Park S, Zifan A, Kumar D, et al. Genesis of esophageal
pressurization and bolus flow patterns in patients with achalasia esophagus. Gastroenterology 2018;155:327–336.

between the liquid and solid bolus swallows is likely due to disorders.78 However, many patients with minor motility
relative obstruction to the passage of solid bolus through disorders may present with significant dysphagia and
the esophagus. There are many challenges, however, with weight loss. A recent study found that the anxiety score is a
using solid food during routine manometry studies: 1) better predictor of symptom severity than the manometric
studies take longer time, 2) standardized meal must vary abnormalities.78 It is difficult to know though whether
according to the ethnicity and liking of the individual, and greater anxiety is because of greater dysphagia severity or
3) one can’t assume that normality of motor patterns is vice versa. Dysphagia is often associated with incomplete
identical with different types of solid foods. We suspect, that emptying of the esophagus during peristalsis, eg in achalasia
the above challenges have prevented wide acceptance of esophagus, the column of liquid barium in the upright po-
solid food challenge during routine clinical HRMZ studies. sition of > 5 cm, at 1 minutes after swallowing of 100–200
ml of barium is a marker of symptom relief.79 During
manometry investigations, however, it is rare for patients to
Genesis of Esophageal Symptoms complain of dysphagia with incomplete bolus clearance.80
Wall tension and strain are important stimuli for the acti-
Based on the Alteration in Bolus Flow
vation of physiological and nociceptive afferents located in
Pattern the spinal and vagus nerves.65,66 Balloon distension in the
Dysphagia is an important symptom of all patients with esophagus generates circumferential passive tension in the
motility disorders. However, in general, there is a poor esophageal wall. Heathy subjects perceive balloon disten-
correlation between the severity of symptoms and severity sion at all levels in the esophagus; however, the proximal
of manometric abnormalities.76,77 Patients with achalasia esophagus appears most sensitive to this stimulus which
esophagus have greater symptom severity (dysphagia most likely relates to regional differences in the wall ten-
associated with weight loss) as compared to other motility sion, sensory afferent innervation and/or mechanoreceptor
116 Mittal and Zifan Gastro Hep Advances Vol. 3, Iss. 1

Figure 5. Distension-contraction plots in

a normal subject (A), a patient with
nutcracker esophagus (C), function
dysphagia (B) and esophagogastric
junction outflow obstruction (D). Disten-
sion is seen as waveform and contrac-
tion as a color topograph. Note that the
bolus arrives in the distal esophagus
much ahead of the contraction. Also
note that the amplitude of distension is
smaller in patients. Finally, note the dif-
ference in the distension waveform be-
tween normal and patients.

density.29,81,82 In healthy subjects who perceive dysphagia found luminal occlusion and thinning of the muscle layers
with solid boluses, dysphagia sensation is associated with distal to the bolus during peristalsis, which results in a
bolus hold-up within the lumen of the proximal esophagus contraction wave pushing bolus against resistance,70
in the transition zone. Hold-up of a noncompressible solid (Figure 4). Similarly, in patients with high-amplitude
bolus causes a sustained luminal distension. Might be that esophageal contractions, EGJOO and FD, contraction wave
the circular muscle contracting and moving over the static propels liquids through a narrow esophagus that results in
bolus produces dysphagia sensation, and conscious aware- larger luminal pressure and greater wall tension during the
ness.83 The mechanisms of symptom generation in the distension wave of peristalsis.84 Patients generally do not
setting of complete bolus clearance is likely different. In report dysphagia during manometry studies, when swal-
patients with type 3 achalasia/diffuse esophageal spasm, we lowing saline bolus. Majority of the patients have symptoms

Figure 6. Distension-contraction plots in a normal subject (A), a patient with nutcracker esophagus (C), function dysphagia (B) and
esophagogastric junction outflow obstruction (D). Serial images during one swallow in each subject. These 4 subjects are same as
in Figure 5. Note the differences in the temporal relationship between distension and contraction in normal subject vs patients.
Also the amplitude of distension is smaller in patients with dysphagia but different diagnosis based on the manometry study.
2024 Dysphagia in patients with normal esophageal function tests 117

Pathogenesis of Low Distensibility of

Esophageal Wall in Patients With
Motility Disorders
A recent study found that patients with FD have stiffer or
less compliant esophageal wall as compared to normal
subjects. Hill (1938)86 proposed that the compliance func-
tion (volume change relative to pressure change) of a
muscular tube is related to 3 factors: 1) viscoelastic ele-
ments or the connective tissue within the muscle, 2)
viscoelastic properties of the muscle itself, and 3) active
muscle contraction. Proximal and distal esophagus are made
of skeletal and smooth muscles, respectively, and these have
different compliances as revealed by supraphysiological
levels of distending pressure.29,81,82 The majority of the
described esophageal motility disorders affect the distal/
smooth muscles esophagus which has tone that reduces its
compliance thus making the lumen less distensible at the
time of initial opening until such time as neural inhibitory
mechanisms are activated to cause muscle relaxation. Lack
of descending inhibition or impaired relaxation of the cir-
cular and longitudinal muscle layers during peristalsis
would be an example of the active element of esophageal
wall reducing luminal distensibility. Studies show that pa-
tients with nutcracker esophagus87 and EOE88 have dis-
coordination between the circular and longitudinal muscle
layers of the esophagus, which can cause low distensi-
bility.89 An increase in muscle thickness (muscle hypertro-
phy in nutcracker esophagus and other motility disorders90)
and mucosal fibrosis in patients with EOE are examples of
passive elements that may reduce esophageal distensibility.
On the other hand, FD patients whilst exhibiting dysregu-
lated bolus flow and distensibility patterns do not generally
have an increase in the muscle layer thickness at baseline or
Figure 7. The schematic show relationship between at peak distension.91 We have observed that unlike normal
contraction and distension in normal subject (top row), subjects, patients with achalasia esophagus show lack of
patient with functional dysphagia (middle row) and patient
sliding between the LES and crural diaphragm,92 which we
with achalasia 3 esophagus (bottom row) Top row: The
believe might be another factor causing low distensibility in
esophagus distends in the shape of an “American Football”
ahead of the contraction. Middle row: Note a narrow lumen the bolus domain segment of the esophagus during peri-
esophagus distal to the contraction wave that results in stalsis. It is likely that more than one factor is responsible
rapid transit of bolus to the distal esophagus. Bottom row: for the low esophageal wall compliance in the motility dis-
Note, luminal occlusion distal the distension that impedes orders of esophagus.
the bolus flow.

when swallowing solid rather than the liquid bolus.85 It is Conclusion

likely that the wall stress and strain values achieved during High-resolution manometry (HRM) and Chicago classi-
liquid bolus transit are not high enough to produce symp- fication9 have been a huge step forward in the diagnosis of
toms, and not representative of what happens during solid esophageal motility disorders. However, majority of patients
bolus swallow. We believe that dysphagia related to the seen in the current clinical practice of the first author of this
bolus flowing through a narrow lumen esophagus is anal- paper fall into the category of FD, which raises the question,
ogous to the dyspnea sensation experienced by patients why so many patients with dysphagia have normal esoph-
with bronchospasm (air flowing through a narrow trachea- ageal function testing? The simple answer may be that the
bronchial tree). It may be that higher than normal tension current techniques used to measure esophageal distension
value observed in patients during manometry studies is a during peristalsis are not adequate. The HRM and current
marker of abnormality, which become clinically significant scheme of classifying esophageal motor disorders in the
with solid bolus swallows result in dysphagia sensation. current format emphasize only half of the story of
118 Mittal and Zifan Gastro Hep Advances Vol. 3, Iss. 1

peristalsis, probably the less important of the 2 halves, ie, Gastrointestinal Study. Clin Gastroenterol Hepatol 2005;
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Received March 17, 2023. Accepted August 30, 2023.
peristalsis by the integrated function of circular and
longitudinal muscle layers in health and disease. Am J Correspondence:
Physiol Gastrointest Liver Physiol 2016;311:G431–G443. Address correspondence to: Ravinder K. Mittal, MD, ACTRI, 9500 Gillman
Drive, MC 0061, La Jolla, California 92093-0990. e-mail: [email protected].
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increased esophageal muscle thickness in patients with Authors’ Contributions:
Ravinder K. Mittal: manuscript writing and figure generation, Ali Zifan: figure
esophageal symptoms. Am J Gastroenterol 2007; generation and manuscript writing.
102:137–145.
91. Kwiatek MA, Hirano I, Kahrilas PJ, et al. Mechanical Conflicts of Interest:
Ravinder K. Mittal and Ali Zifan have copyright/patent protection for the
properties of the esophagus in eosinophilic esophagitis. computer software (Dplots). Ravinder K. Mittal is a member of the Board of
Gastroenterology 2011;140:82–90. Editors. Their paper was handled in accordance with our conflict of interest
92. Mittal RK, Ledgerwood M, Caplin M, et al. Hiatal fibrosis policy. See https://www.ghadvances.org/content/authorinfo#conflict_of_
interest_policy for full details.
in achalasia esophagus. Am J Physiol Gastrointest Liver
Physiol 2023;325:G368–G378. Funding:
This work was supported by NIH Grant R01 DK109376.
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peristaltic dysfunction in peptic esophagitis. Gastroen- Ethical Statement:
terology 1986;91:897–904. The study did not require the approval of an institutional review board.
94. Ahuja NK, Clarke JO. Scleroderma and the esophagus. Reporting Guidelines:
Gastroenterol Clin North Am 2021;50:905–918. Not applicable for this article type.