When Manometry and Functional Lumen Imaging Probe Disagree: The Current Limitations of the Chicago Classification Version 4.0 and Probable Extended Indications of Functional Lumen Imaging Probe

Abstract

High-resolution manometry (HRM) has revolutionized evaluation of esophageal motility disorders, offering detailed pressure topography and refined diagnostic criteria codified through the Chicago classification (CC). However, patients with dysphagia may present with borderline or near-normal HRM findings, exhibiting clinically significant symptoms. CC version 4.0 (v4.0) addresses such scenarios by recommending provocative maneuvers and ancillary tests, notably functional lumen imaging probe (FLIP) and timed barium esophagography. However, growing evidence indicates that FLIP, which measures luminal distensibility under balloon distention, can detect structural or biomechanical abnormalities, such as hypertrophy or fibrosis, that remain inconspicuous on HRM. These discordant findings point to limitations in CC v4.0. FLIP complements HRM by assessing passive tissue properties and capturing balloon-induced contractility, thereby unmasking subtle esophageal wall stiffness not always reflected in integrated relaxation pressure or standard peristaltic metrics. Such discrepancies can arise in early or atypical achalasia, esophagogastric junction outflow obstruction, eosinophilic esophagitis, and even epiphrenic diverticula, where “normal” manometry may belie significant pathology. Present CC v4.0 guidelines do not specify how to incorporate FLIP-derived measures or reconcile disagreements with timed barium esophagography results, leaving certain phenotypes—including repetitive simultaneous contractions—under-recognized. These gaps underscore an overreliance on integrated relaxation pressure alone and insufficient integration of evolving FLIP technology. Thus, standardizing FLIP protocols, establishing normative distensibility data, and clarifying management pathways for manometry-FLIP discordance remain critical. Prospective, multicenter studies are needed to investigate long-term clinical outcomes and to refine how FLIP metrics can be formally integrated into future CC iterations. Ultimately, multimodal, symptom-driven approaches that leverage both HRM and FLIP are essential to fully characterize esophageal dysmotility and optimize therapy.

Introduction

Esophageal dysphagia arises from a diverse array of organic and functional causes.¹ Although high-resolution manometry (HRM) and the Chicago classification (CC) framework have vastly improved the characterization of esophageal motility disorders, certain patients with normal or borderline manometric findings remain clinically symptomatic.^2,3 In these scenarios, the functional lumen imaging probe (FLIP) often detects abnormalities in the luminal distensibility, suggesting that pathologic processes may be underappreciated by HRM alone.^4,5 The latest iteration, CC version 4.0 (v4.0), has integrated the use of ancillary tests such as FLIP and timed barium esophagography (TBE) to address such borderline findings; however, challenges persist.^5-7 This review delves into the clinical ramifications of discordant findings between HRM and FLIP, highlighting the under-recognized limitations of the current classification system and potential avenues for further refinement.

Dysphagia and the Utility of Manometry

Dysphagia, a common symptom with various etiologies, ranges in prevalence from 2% to 10% based on self-reported difficulty in swallowing.^8,9 In one large-scale, cross-sectional study of the United States population, the prevalence of dysphagia was observed to be 16%.¹⁰ While organic causes (eg, strictures and malignancies) are well recognized, identifying dysphagia related to esophageal motility disorders can be challenging.¹ Identifying motility-related dysphagia requires advanced diagnostic tools, as traditional imaging and endoscopy can be inconclusive in several functional cases.¹ Over the past 2 decades, HRM has greatly advanced the investigation of these disorders by providing detailed spatiotemporal pressure plots of the esophagus.¹¹

Emergence of the Chicago Classification and Its Evolution

The development of HRM in the early 2000s led to more precise diagnostic approaches for esophageal motility disorders, including achalasia.^11,12 Novel metrics such as the integrated relaxation pressure (IRP), which is defined as the median of the lowest 4 seconds of esophagogastric junction (EGJ) pressure after swallowing, have enhanced diagnostic accuracy and allowed the classification of achalasia into distinct subtypes (Types I, II, and III).^12-14 Refinements to these parameters were codified in successive versions of the CC, moving from v1.0 and v2.0 (which redefined esophageal motor disorders) to v3.0 (which standardized achalasia subtypes with cutoffs and the reintroduction of ineffective esophageal motility).^15-17 However, sporadic cases of achalasia with a normal IRP prompted further revisions, culminating in CC v4.0.^5,18,19 This latest version emphasizes multiple patient positions (supine and upright) during HRM to account for the postural influences on esophageal pressures.⁵ Provocative testings, including multiple rapid swallows and the rapid drink challenge, may unmask subtle motility abnormalities,^5,20,21 and ancillary diagnostic tools, notably FLIP and/or TBE, to clarify borderline or inconclusive diagnoses.⁵ With these additions, CC v4.0 attempts to reduce indeterminate findings and strengthen the criteria for esophageal motility disorders, such as EGJ outflow obstruction (EGJOO) and ineffective esophageal motility (IEM).^{5, 22, 23} A formal diagnosis of EGJOO in CC v4.0 requires elevated IRP (in both supine and upright positions) plus clinically relevant symptoms (eg, dysphagia and non-cardiac chest pain) and supporting evidence from TBE or FLIP.^5,24

Functional Lumen Imaging Probe as a Complementary Diagnostic Tool

Principles of Impedance Planimetry

FLIP is generally performed during endoscopy with the patient placed under sedation.²⁵ It uses high-resolution impedance planimetry to measure the luminal cross-sectional area, pressure, and distensibility (calculated by dividing cross-sectional area by pressure) in response to controlled volumetric distension.²⁶ Subsequently, FLIP panometry provides a color-coded esophageal diameter topography plotted over a space–time continuum, much like how esophageal pressure topography is presented in high-resolution manometry, but also showing intrabag pressure under a standardized, stepwise volumetric distension protocol.²⁷ This approach enables the derivation of biomechanical esophageal function metrics that help further characterize EGJ opening mechanics, esophageal body distensibility, and the contractile response to distension (ie, secondary peristalsis).^26,27 Unlike HRM, FLIP does not rely on patient-initiated swallowing but rather assesses the response of the esophageal wall to a graded distending force (balloon inflation).^7,28

Assessment of Passive Mechanical Properties

Tissue stiffness and fibrosis

FLIP is well suited for identifying changes in the esophageal wall (eg, hypertrophy and fibrosis) that can reduce compliance without necessarily altering the HRM parameters.^4,7,29

Subtle hypertrophy or inflammation

Conditions such as eosinophilic esophagitis (EoE) often exhibit near-normal or mildly abnormal manometry, demonstrating reduced distensibility due to subepithelial fibrosis or inflammation.^7,30,31 A recent meta-analysis reported that the pooled prevalence of manometry-confirmed motility abnormalities of EoE was 53% (95% confidence interval, 43-63%), including minor disorders such as IEM and fragmented peristalsis.³² This finding implies that although fibrosis or wall stiffening of EoE may reduce the luminal distensibility, which can be readily detected by FLIP, manometric changes can remain subtle or classified only as minor abnormalities.^25,30

A study showed that, in comparison to healthy controls, patients with EoE exhibit reduced esophageal distensibility, defined by a metric called the “distensibility plateau.”³³ The clinical significance of this reduced distensibility in EoE was highlighted by its correlation with greater risk of food impaction and more severe symptoms.³⁴ Patients receiving topical steroids, an elimination diet, and/or proton pump inhibitors showed an improvement in their distensibility plateau on FLIP, and this improvement was a stronger predictor of symptom relief than biopsy eosinophil counts.³⁵ Collectively, these findings suggest that measuring the esophageal distensibility via FLIP may be useful for monitoring their response to therapy.³⁵

Active Contractile Response

Recent iterations of FLIP technology (eg, FLIP panometry) can detect contractile patterns induced by balloon distention, offering insights into secondary or reflexive muscle activity.^25-27,36 This partial view of active muscle mechanics, combined with the measurement of passive tissue properties, complements the purely pressure-based manometric assessment.^26,29

Understanding Discordant Findings: Why High-resolution Manometry and Functional Lumen Imaging Probe May Disagree

The CC v4.0 and American College of Gastroenterology Guidelines for esophageal function testing recommend that patients exhibiting obstructive symptoms but inconclusive or borderline findings on HRM undergo additional diagnostic assessments, which may include FLIP panometry.^5,37 According to CC v4.0, EGJOO cannot be definitively diagnosed based on HRM alone; clinically significant symptoms and evidence of obstruction from a non-manometric test are required to confirm that the HRM pattern is meaningful.⁵ FLIP panometry can validate an EGJOO diagnosis and also help identify which patients could benefit from therapies targeting the lower esophageal sphincter (LES), such as pneumatic dilation, peroral endoscopic myotomy (POEM), or others.³⁸

Moreover, FLIP panometry offers further insight into esophageal dysmotility in cases where CC v4.0 findings are inconclusive for achalasia.⁵ Under CC v4.0, achalasia subtypes require an elevated median IRP alongside absent contractility (types I and II) or a pattern of esophageal spasm without peristalsis (type III) on HRM.^39,40 However, some individuals with strong clinical suspicion for achalasia (based on obstructive symptoms or abnormal TBE) may display a normal IRP or some degree of peristalsis on HRM.³⁹ In these situations, FLIP panometry can identify nonocclusive esophageal contractions that are not detected by HRM, thereby confirming or ruling out achalasia.^36,37,39

Clinical observations increasingly highlight that some patients exhibit normal or near-normal manometry but show significantly reduced EGJ distensibility on FLIP.

Mechanistic Differences

HRM captures the “outside-in” force generated by inward luminal pressure, relying on active contractions and relaxations of the esophageal musculature.⁷ Consequently, without voluntary bolus swallows, HRM does not yield significant data (Fig. 1A).⁷ In contrast, the FLIP evaluates the “inside-out” structural or passive compliance of the esophageal wall, namely, its capacity to expand under an external distending force (Fig. 1B).⁷ Notably, FLIP can measure the EGJ-distensibility index (DI) even under general anesthesia, making patient cooperation unnecessary.⁷ Thus, HRM assesses the active, inward contractility of the esophageal lumen, whereas FLIP characterizes the passive, outward distensibility.⁷ Therefore, these 2 tests are complementary to each other.⁷

Figure 1.

Illustration of manometry and functional lumen imaging probe (FLIP) measurements in the human gastrointestinal (GI) tract. (A) Manometry, which is conventionally used, quantifies the active, inward contractility of the GI tract and thus requires patient-initiated bolus swallows. Without active swallowing, manometry cannot generate meaningful signals. (B) In contrast, FLIP evaluates the passive, outward distensibility of the GI tract by measuring its response to balloon inflation, while also detecting some degree of active muscle contraction and tone as part of the esophageal distension reflex. Moreover, FLIP assesses the distensibility of the esophageal wall—including the mucosa and inner and outer muscle layers—from inside the lumen. Given their differing methods of assessment, these 2 tests complement each other.

Subclinical or Subtle Pathology (Hypertrophy or Fibrosis)

Early or mild muscle hypertrophy, low-grade eosinophilic infiltration, or collagen deposition can stiffen the esophageal wall without dramatically altering the HRM metrics.^4,7,29

Case Examples of Probable Extended Indications of Functional Lumen Imaging Probe

Repetitive simultaneous contractions: a spastic pattern with normal latency

Patients with repetitive simultaneous contractions (RSCs) (“Lubo pattern”) that do not meet the threshold for disordered motility using CC v4.0 may nonetheless demonstrate abnormally low EGJ distensibility indices on FLIP, explaining persistent dysphagia (Fig. 2A).⁴¹ In an analysis of 684 patients classified with having normal motility or IEM by HRM, 8 patients were found to have esophageal wall thickening on endoscopic ultrasonography or computed tomography (Fig. 2B).⁴¹ During standard esophagogastroduodenoscopy with a conventional adult endoscope, no mucosal abnormalities or obstructive lesions were detected, and endoscopists did not note any unusual resistance while advancing the scope through the esophagus, EGJ, stomach, and duodenum.⁴¹ Of these 8 patients, 7 demonstrated RSCs in at least 1 of the 2 measured positions, occurring in 61% (± 29%) of 10 swallows when supine and 51% (± 30%) of 5 swallows when upright. Four patients who underwent FLIP exhibited a markedly reduced EGJ-DI (1.0 ± 0.5 mm²/mmHg at 60 mL) (Fig. 2C).⁴¹ Subsequently, 2 of these individuals underwent POEM after failing medical therapy; histopathologic evaluation revealed hypertrophied muscle with marginal eosinophilic infiltration.⁴¹ HRM does not effectively capture distensibility.⁴¹ Thus, when RSCs are observed, supplemental testing with FLIP should be considered (Fig 2D).⁴¹ Moreover, POEM may be a viable therapeutic option.⁴¹ Notably, older diagnostic frameworks for distal esophageal spasm, derived from conventional manometry, had already outlined complex criteria for multiple simultaneous contractions in the distal esophagus—criteria that closely parallel the RSC patterns observed in patients with esophageal wall thickening.^42,43

Figure 2.

Example of patients with dysphagia associated with esophageal wall thickening with nonspecific high-resolution manometry (HRM) findings. (A) HRM tracings from patients presenting with repetitive simultaneous contraction (RSC) patterns and poor distensibility according to functional lumen imaging probe (FLIP). Unlike the typical pressurization wave that proceeds from the upper esophageal sphincter to the lower esophageal sphincter, these RSCs displayed focal dispersion and vertical contractions within the smooth muscle-predominant distal segment of the esophagus. (B) Computed tomography scans demonstrating esophageal wall thickening (indicated by red arrows) in patients whose HRM results were normal or revealed ineffective esophageal motility. (C) FLIP panometry and distensibility plots from these patients, showing consecutive, sustained repetitive retrograde contractions—consistent with a spastic-reactive contractile response. (D) Patients with esophageal wall thickening experience dysphagia due to impaired outward luminal distensibility of the esophagus, as assessed by FLIP, despite preserved inward contractility demonstrated by HRM.

Epiphrenic diverticulum: an anatomic deformity associated with dysmotility

Individuals with epiphrenic diverticulum can show normal HRM or only minor nonspecific abnormalities; however, FLIP findings often point to reduced EGJ compliance, indicating the need for a concurrent myotomy if a surgical diverticulectomy is performed.^7,44 Surgeons conventionally cut the EGJ muscle during diverticulectomy for epiphrenic diverticulum to prevent recurrence.^7,45 Nine patients presenting with symptomatic epiphrenic diverticulum were enrolled and analyzed.⁴⁵ The median diverticulum size was 50 mm (interquartile range [IQR], 48-80), and the median septum length was 20 mm (IQR, 20-30).⁴⁵ Among these patients, 5 patients (who had HRM results of 3 normal, 1 IEM, and 1 Jackhammer esophagus) showed reduced EGJ-DI on pre-procedure FLIP.⁴⁵ All 5 patients underwent cardiomyotomy with septotomy irrespective of their HRM findings, resulting in normalization of the DI.⁴⁵ The mean dysphagia score prior to the procedure declined from 2.0 ± 1.0 to 0.4 ± 0.7 at a median follow-up of 11 months (IQR, 4-21).⁴⁵ No serious adverse events necessitating surgical intervention or causing delayed discharge were observed.⁴⁵ Measuring the EGJ-DI with FLIP is a critical step before performing diverticulum POEM.⁷ If FLIP demonstrates impaired EGJ relaxation—reflected by a reduced EGJ-DI—both EGJ POEM and diverticulum POEM of the epiphrenic diverticulum should be considered to prevent dysphagia recurrence.⁷

Distension-mediated obstruction: a novel phenotype of esophageal dysmotility

Distension-mediated obstruction (DMO) is an emerging esophageal disorder characterized by impaired EGJ opening in response to volumetric distension, despite normal EGJ relaxation on conventional HRM. This condition provides a new physiological framework for understanding non-obstructive dysphagia in patients previously classified under functional dysphagia based on Rome IV criteria.⁴⁶ By integrating findings from FLIP panometry, DMO has been recognized as a distinct motility disorder with clinically significant implications for diagnosis and management.

Dysphagia affects a substantial proportion of the population, with nearly 40% of individuals diagnosed with functional dysphagia lacking identifiable structural or motility abnormalities on standard diagnostic tests.^10,47 However, recent studies suggest that a subset of these patients exhibit reduced EGJ opening in response to bolus distension, which may serve as a key mechanistic driver of symptoms.⁴⁸ Jain et al,⁴⁸ demonstrated a correlation between dysphagia severity and decreased EGJ distensibility, even in patients with normal LES relaxation, highlighting the limitations of conventional manometric criteria in identifying esophageal dysfunction. Additionally, Carlson et al.³⁸ classified motility patterns using FLIP panometry in a large cohort, illustrating that reduced EGJ compliance and impaired bolus accommodation can exist independently of traditional achalasia or IEM. Clinically, DMO presents with dysphagia and bolus retention in the absence of endoscopic strictures or abnormalities on HRM, often leading to delayed or missed diagnoses.⁴⁹ The defining feature of DMO is a reduced EGJ-DI < 2.0 mm²/mmHg) and a maximum EGJ diameter < 12 mm on FLIP studies, distinguishing it from primary motility disorders and functional dysphagia.⁴⁹ Given that HRM alone fails to detect this form of obstruction, FLIP has become an essential tool in identifying DMO and guiding appropriate treatment strategies.⁴⁹

Management of DMO is evolving and remains heterogeneous across clinical centers. Current approaches focus on improving EGJ compliance and bolus accommodation through targeted interventions, including LES relaxation therapies (eg, Botox injections or smooth muscle relaxants), LES disruption (pneumatic dilation and POEM) and acid suppression therapy. While some patients respond to conservative management, others may require procedural interventions to improve EGJ function. Notably, therapies aimed at LES hypertonicity and acid suppression have shown promising outcomes, whereas strategies targeting visceral hypersensitivity or swallowing behavior alone appear less effective.

The identification of DMO represents a critical advancement in esophageal diagnostics, underscoring the role of FLIP panometry in bridging the gap between symptom presentation and objective motility findings. Moving forward, further research is needed to refine diagnostic criteria, explore the relationship between DMO and gastroesophageal reflux disease, and optimize long-term treatment outcomes. Recognizing DMO as a distinct clinical phenotype allows for more precise, mechanistically driven treatment approaches, ultimately improving care for patients with dysphagia who previously lacked an identifiable cause.

Limitations of Chicago Classification Version 4.0 and Future Directions

Despite its comprehensive approach, several gaps remain.

Over-dependence on Integrated Relaxation Pressure

The IRP cut-off of manometry is key for diagnosing EGJ dysfunction; yet, this single metric cannot fully account for morphological or biomechanical variations.^5,24,50 Small differences in technique (catheter calibration or patient posture) can yield significant IRP variability.²⁴

Insufficient Integration of Functional Lumen Imaging Probe Metrics

While CC v4.0 recommends ancillary testing, it does not explicitly incorporate FLIP-derived parameters (eg, EGJ-DI and contractile responses) into the formal diagnostic criteria.⁵ As the FLIP technology evolves, the lack of a standardized set of normative data and a universally accepted protocol for volume-based distension challenges the utility of FLIP in routine clinical practice. The recently published, Dallas Consensus looked promising.⁴⁹ The standardized protocol for performance and interpretation based on the Dallas Consensus with further understanding of FLIP panometry might be helpful in difficult clinical cases.⁴⁹

Discordance With Timed Barium Esophagography

TBE assesses the bolus clearance over time, whereas FLIP focuses on structural compliance. In some patients, TBE may appear normal despite profoundly reduced distensibility on FLIP and vice versa. CC v4.0 currently does not clarify how to reconcile conflicting TBE vs FLIP findings in patients with borderline manometry.

Inclusion of Novel Parameters Based on High-resolution Impedance Manometry

High-resolution impedance manometry (HRIM) equipped with densely arranged impedance sensors has shown promising results in assessing bolus transit.^51-56 However, the reliability of HRIM-based parameters has varied across studies.^55,57 Recently, the Chicago group demonstrated that the 4-dimensional manometry parameters derived from HRIM correlate well with the EGJ-DI measured by FLIP.^58-61 Such novel impedance metrics could potentially replace or complement TBE, offering a radiation-free alternative.⁶¹ Given that FLIP is not widely accessible worldwide, these newer parameters may also help clarify ambiguous HRM findings.

Under-recognized Phenotypes

Patterns like RSCs (“Lubo pattern”) or subtle pressurization not meeting IRP thresholds are not explicitly classified in CC v4.0.⁴¹ These under-described phenotypes warrant further exploration to refine diagnostic subcategories, especially for suspected EGJOO or atypical achalasia presentations.

Need for Prospective, Multicenter Studies

Large-scale investigations comparing HRM, FLIP, and TBE outcomes in well-defined dysphagia populations are paramount to refine diagnostic algorithms. Ultimately, data on long-term treatment outcomes (eg, pneumatic dilation, POEM, and pharmacological interventions) linked to FLIP findings will clarify whether abnormal distensibility indices predict response to therapy.

Clinical Implications

For the practicing clinician, discordant HRM-FLIP results underscore the importance of a multimodal, symptom-driven approach.

Persistently Symptomatic Patients With Normal High-resolution Manometry

FLIP or TBE can be considered to identify structural issues (eg, muscle hypertrophy, mild fibrotic changes, and incomplete EGJ relaxation) that may not be apparent on manometry. In instances of reduced distensibility, targeted therapies (endoscopic dilation and POEM) can provide symptom relief.

Borderline or Indeterminate Manometry Findings

Re-evaluation using upright HRM, provocative maneuvers, and FLIP can help solidify the diagnosis, particularly to differentiate functional dysphagia from an early EGJ relaxation disorder.

Surgical Implications

For conditions such as epiphrenic diverticulum or paraesophageal hernia with questionable motility status, FLIP findings can guide the need for surgical myotomy or other interventions alongside repair.⁷

Conclusion

HRM has transformed the evaluation of esophageal motility disorders, allowing precise subtyping and targeted management in several cases. Nonetheless, when manometry appears normal or only mildly abnormal, FLIP can reveal significant reductions in esophageal or EGJ distensibility that explain persistent dysphagia. CC v4.0 has taken important steps to incorporate ancillary testing; however, current guidelines fall short of fully integrating FLIP metrics into the diagnostic framework. Future iterations of the CC should address these discrepancies, codify the role of FLIP-derived indices, and clarify the management pathways in cases of manometry-FLIP discordance. Ultimately, a more holistic evaluation that captures both active and passive esophageal mechanics will improve the diagnostic precision and therapeutic outcomes for patients with esophageal motility disorders.