Diagnostic Challenges in Unusual Causes of Refractory GERD-Like Symptoms

Abstract

Background: Refractory gastroesophageal reflux disease (GERD) describes persistent
reflux‑like symptoms despite optimized proton pump inhibitor therapy and is frequently driven
by alternative or overlapping pathologies rather than uncontrolled acid exposure.

Aim: To review unusual causes of refractory GERD‑like symptoms, with emphasis on
pathophysiology, diagnostic pitfalls, and practical evaluation strategies for achalasia,
eosinophilic esophagitis, belching and rumination disorders, gastroparesis, and Zollinger-Ellison
syndrome (ZES).

Material and methods: A review of selected literature was conducted using the PubMed database.
The search was performed using keywords including “refractory GERD,” “PPI refractory,”
“achalasia,” “gastroparesis,” “esophageal motility disorders,” and “case reports”.

Results: Achalasia, eosinophilic esophagitis, behavioural belching and rumination, gastroparesis,
and gastrinoma‑driven acid hypersecretion all produce GERD‑like complaints yet require
distinct diagnostic tools such as high‑resolution manometry, esophageal biopsies, impedance-
pH monitoring, gastric emptying studies, and fasting gastrin measurement. Failure to recognize
these entities risks inappropriate escalation of antireflux therapy, unnecessary surgery, and
progression to complications.

Conclusions: Systematic physiologic and endoscopic evaluation of PPI‑refractory symptoms is
essential to uncover uncommon causative conditions, align therapy with underlying mechanisms,
and prevent mislabeling patients with simple GERD when they harbour distinct motility,
inflammatory, behavioural, or neuroendocrine disorders.