Rome IV - Reflux Hypersensitivity (B2)

Why use it

Heartburn is the most common esophageal symptom in clinical practice, affecting 20–40% of adults in Western populations. A large subset of heartburn patients do not have classical GERD: their endoscopy is normal and acid exposure time on pH monitoring is within normal limits. Without a systematic diagnostic framework, these patients are often labelled as "PPI non-responders" and subjected to escalating empirical treatment without a positive diagnosis. The Rome IV B2 framework enables: a precise mechanistic diagnosis (symptom-reflux correlation confirming the esophageal origin of symptoms); differentiation from Functional Heartburn (B1) which requires a different approach; rationale for targeted treatment (pain modulators, CBT, low-dose tricyclic antidepressants); and avoidance of long-term high-dose PPI therapy in patients who are unlikely to benefit.

About

The Rome IV criteria for Reflux Hypersensitivity (category B2) were established by the Rome Foundation Esophageal Disorders Committee and published in Gastroenterology in 2016. Reflux Hypersensitivity is defined as esophageal symptoms (heartburn or chest pain of esophageal origin) occurring in a patient with: (1) normal endoscopy and no evidence that eosinophilic esophagitis (EoE) is the cause; (2) normal esophageal acid exposure time (AET) on ambulatory pH or pH-impedance monitoring (AET <4%); and (3) a positive symptom-reflux correlation on pH-impedance monitoring — symptoms triggered by reflux events (either acid or non-acid), demonstrated by a positive Symptom Index (SI ≥50%) or positive Symptom Association Probability (SAP ≥95%), even though the overall acid burden is within normal limits. Criteria must be fulfilled for the last 3 months, with symptom onset at least 6 months before diagnosis. Reflux Hypersensitivity represents a distinct mechanistic entity from GERD (pathological acid exposure) and from Functional Heartburn (B1 — no symptoms correlated with reflux events on pH-impedance). The pathophysiology involves peripheral and central sensitisation of esophageal afferent neurons: a small number of reflux events, insufficient to constitute pathological GERD, are perceived as intensely painful due to a lowered pain threshold. Reflux Hypersensitivity accounts for approximately 40–60% of patients with persistent heartburn symptoms on PPI therapy in whom endoscopy and pH monitoring are normal.

When to use

• Adults with heartburn or esophageal chest pain that has not responded fully to standard-dose PPI therapy (empirical 8-week trial)
• After upper GI endoscopy has excluded erosive esophagitis, Barrett's esophagus, EoE, and other structural esophageal pathology
• After ambulatory pH or pH-impedance monitoring has demonstrated NORMAL esophageal acid exposure time (AET <4%)
• When ambulatory pH-impedance monitoring shows symptom-reflux correlation (positive SI or SAP) despite normal AET
• Distinguishing Reflux Hypersensitivity (B2) from Functional Heartburn (B1, no symptom-reflux correlation) and from true GERD (abnormal AET)
• Guiding decision to step down or discontinue PPI therapy when B2 is confirmed — pain modulators and psychotherapy are more appropriate first-line treatments
• Patients with persistent heartburn undergoing evaluation for anti-reflux surgery — B2 must be excluded before fundoplication, as surgery is unlikely to benefit B2 patients and may worsen symptoms
• NOT to be applied before endoscopy and pH monitoring have been completed — both are mandatory prerequisites
• NOT applicable when AET is pathological (≥6%) — that represents true GERD regardless of symptom correlation

Formula

Pearls & pitfalls

• The key distinction between Reflux Hypersensitivity (B2) and Functional Heartburn (B1) is the symptom-reflux correlation: B2 has positive SI/SAP on pH-impedance (symptoms triggered by reflux events); B1 has negative SI/SAP (symptoms are not associated with any reflux events). Both have normal AET.
• The key distinction between B2 and true GERD is the AET: GERD has abnormal AET (≥6%); B2 has normal AET (<4% on off-PPI monitoring, <6% threshold used by some centres). The gray zone of AET 4–6% is diagnostically indeterminate.
• pH-impedance monitoring (not pH alone) is essential for B2 diagnosis — combined pH-impedance allows detection of both acid AND non-acid (weakly acidic, weakly alkaline) reflux events and correlates ALL reflux events with symptoms. pH monitoring alone misses non-acid reflux-triggered hypersensitivity.
• The Symptom Index (SI): percentage of symptom episodes preceded by a reflux event within 5 minutes (SI ≥50% = positive). The Symptom Association Probability (SAP): statistical probability that the observed symptom-reflux association is non-random (SAP ≥95% = positive). A positive SI or SAP is sufficient for B2 — the SAP is considered more statistically robust.
• Reflux hypersensitivity is most common in women, patients with anxiety and health anxiety, and patients with prior inadequate PPI responses. A careful psychological history is essential.
• Anti-reflux surgery (fundoplication) is CONTRAINDICATED in patients with B2 without true GERD — multiple case series show high rates of persistent or worsened dysphagia and bloating, and symptom relief is inferior to B2 patients treated medically. Always confirm abnormal AET before referring for surgery.
• Bile reflux (duodenogastroesophageal reflux) may trigger reflux hypersensitivity in post-cholecystectomy or post-gastric surgery patients — pH-impedance with Bilitec probe or bile acid assay in aspirate can be considered in this clinical context.
• Maintenance of a symptom diary concurrent with pH-impedance monitoring is critical — the sensitivity of SI/SAP analysis depends on the patient recording symptoms accurately and contemporaneously during the recording period.
• The temporal relationship between reflux events and symptoms in pH-impedance is defined as a symptom occurring WITHIN 2 minutes (some centres use 5 minutes) of a detected reflux event on the impedance tracing. Ensure the reporting centre uses validated analysis software.
• B2 patients on long-term high-dose PPI therapy should be gradually deprescribed to the minimum effective dose, or considered for cessation with neuromodulator substitution — chronic PPI use carries risks of hypomagnesaemia, C. difficile, fracture, and micronutrient malabsorption.

Next steps

Reflux Hypersensitivity (Rome IV B2) confirmed: Explain the diagnosis — the patient has a real, reproducible symptom triggered by small amounts of reflux that the esophagus has become hypersensitive to, even though the acid burden itself is not abnormal. The goal is to normalise the esophageal pain threshold. Treatment: 1. Reassurance and psychoeducation — explaining the mechanism reduces catastrophising and anxiety-driven symptoms. 2. Neuromodulators (first-line pharmacological therapy): low-dose tricyclic antidepressants (amitriptyline 10–25 mg nocte OR nortriptyline 10–25 mg nocte — preferred as fewer anticholinergic effects) — evidence from multiple RCTs; analgesic benefit at sub-antidepressant doses within 2–4 weeks. SSRIs (citalopram 20 mg/day or sertraline 50 mg/day) as alternatives. Explain that TCAs are used at analgesic not antidepressant doses. 3. Acid suppression: PPI at standard dose may be partially beneficial if any acid reflux events contribute to sensitisation — use once daily, not twice daily (no additional benefit for B2). 4. Cognitive behavioural therapy (CBT): evidence from RCTs for functional esophageal disorders including reflux hypersensitivity. 5. Gut-directed hypnotherapy: emerging evidence. 6. Avoid: anti-reflux surgery (fundoplication) — surgical outcomes in B2 are inferior to true GERD and risk of post-fundoplication symptoms is significant. Criteria NOT met / monitoring not done: complete pH-impedance monitoring before applying B2 diagnosis.

Evidence

Aziz Q, Fass R, Gyawali CP, Miwa H, Pandolfino JE, Zerbib F. Functional Esophageal Disorders. Gastroenterology. 2016;150(6):1368-1379.e2. PMID:27144631. Primary Rome IV reference for B2 Reflux Hypersensitivity. Gyawali CP et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;67(7):1351-1362. PMID:29437910. Establishes pH-impedance thresholds and SAP methodology. Savarino E et al. Functional heartburn has more in common with functional dyspepsia than with non-erosive reflux disease. Gut. 2009;58(9):1185-1191. PMID:19423545. Seminal study separating GERD, RH, and FH using pH-impedance. Patel A et al. Symptom burden and mucosal integrity in refractory heartburn. Clin Gastroenterol Hepatol. 2019;17(2):225-233.

References

1. Aziz Q, Fass R, Gyawali CP, Miwa H, Pandolfino JE, Zerbib F. Functional Esophageal Disorders. Gastroenterology. 2016;150(6):1368-1379.e2. — link
2. Gyawali CP, Kahrilas PJ, Savarino E et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;67(7):1351-1362. — link
3. Savarino E, Zentilin P, Tutuian R et al. The role of nonacid reflux in NERD: lessons learned from impedance-pH monitoring in 150 patients off therapy. Am J Gastroenterol. 2008;103(11):2685-2693. — link
4. Drossman DA (ed). Rome IV: Functional Gastrointestinal Disorders. 4th ed. Raleigh, NC: Rome Foundation; 2016. — link
5. Patel A, Sayuk GS, Kushnir VM, Gyawali CP. Acid-based reflux parameters predict symptom improvement with proton pump inhibitor therapy. Am J Gastroenterol. 2014;109(6):836-844. — link