Reflux not improving on PPIs despite a normal gastroscopy?

The short answer

A normal gastroscopy and a PPI that hasn't worked are not the end of the road. In my clinic, they are where the real investigation starts.

When someone sees me with reflux symptoms that persist despite a PPI, I don't assume they need a stronger tablet. My first question is what is actually causing the symptoms: ongoing acid reflux, non-acid reflux, abnormal oesophageal function, heightened sensitivity, or another condition that mimics reflux. These feel remarkably similar but need very different treatment.

• Only about 30% of people with typical reflux have visible damage at gastroscopy [1].

• Up to half of people with suspected reflux don't benefit fully from acid suppression [2].

• If acid isn't the main problem, a stronger or different PPI won't fix it. Finding the actual mechanism will [2].

Why a normal gastroscopy misses reflux

• It's a snapshot. It shows the lining on one day, not how often reflux happens or what comes up [3].

• Non-acid reflux leaves no mark. Weakly acidic or bile reflux can cause symptoms with a normal-looking lining.

• Laxity and small hernias are under-called. They need a deliberate look at the junction, with hernia length and valve (Hill) grade recorded [2].

• Eosinophilic oesophagitis can look normal. It is only found if biopsies are taken [4].

Eight explanations for reflux symptoms that won't go away

Not all of these are ongoing reflux; some only mimic it. More than one often applies.

Explanation	Typical clues	Test that confirms it	Targeted treatment
1. Non-acid or bile reflux	Regurgitation, bitter taste, throat clearing, cough	pH-impedance on PPI	Alginate to ease symptoms; reduce reflux volume
2. Reflux the scope underestimates	Normal scope, but frequent or high reflux	Reflux monitoring off PPI	Optimised acid control
3. Oesophageal or gastric dysmotility	Bloating, early fullness, slow clearance	High-resolution manometry; gastric emptying study	Prokinetics if slow emptying is confirmed
4. Constipation and slow transit	Straining, hard stools, reflux worse when bowels are slow	Clinical assessment; transit study	Treat constipation as part of the plan
5. Reflux hypersensitivity or functional heartburn	Burning despite normal acid exposure	pH-impedance with symptom association	Neuromodulator; gut-directed CBT or hypnotherapy
6. Structural failure	Worse lying or bending; hiatus hernia	Expert gastroscopy; manometry	Surgery for selected patients with proven reflux
7. Another oesophagitis	Food sticking, allergies, thrush risk	Oesophageal biopsies	Eosinophilic or antifungal treatment
8. Undertreated acid	Proven reflux, partial PPI benefit; fast PPI metaboliser [6]	Check adherence and dose timing; pH-impedance on PPI	Optimise PPI; potassium-competitive acid blocker

Reflux hypersensitivity means symptoms line up with normal reflux events; functional heartburn means they don't line up with reflux at all [5].

Constipation is a contributor I routinely assess in difficult reflux. The two overlap substantially: people with reflux have 1.6 to 2.7 times the odds of constipation, and worse reflux symptoms when both are present [7]. Overlap doesn't prove cause, but in selected patients, treating constipation and slow gut motility is an important part of getting reflux under control.

What to do next: four steps

1. Review what has already been done. I check the original gastroscopy report and biopsies, how the PPI is being taken, and whether reflux has ever been objectively proven. Often it hasn't [2].

2. Choose the test that answers the right question.

• Reflux not yet proven: reflux monitoring off acid suppression, by wireless capsule (up to 96 hours) or 24-hour pH-impedance [2, 3].

• Reflux proven, symptoms persisting: 24-hour pH-impedance on an optimised PPI, to see whether reflux continues and matches your symptoms [3].

• Suspected motility problem, or surgery being considered: high-resolution manometry [2].

• Repeat gastroscopy: only if the first was incomplete, alarm symptoms appear, eosinophilic oesophagitis is suspected, or a view off PPI is needed [2, 4].

• Reflux scintigraphy: a selective adjunct where reflux reaching the throat or lungs is suspected [8, 9]. It is not a substitute for pH-impedance, which outperformed it in a direct Sydney comparison [10].

Sydney units with deep expertise in these tests include St George Motility Services (Dr Peter Wu) and St Vincent's Centre for Swallowing & Oesophageal Disorders (A/Prof Santosh Sanagapalli). I interpret the results together with your symptoms, because no single test tells the whole story.

3. Treat the mechanism. Alginates to ease non-acid reflux symptoms [11], prokinetics where gastric emptying is confirmed slow, neuromodulation or behavioural therapy for hypersensitivity [2], and stronger acid control when acid is genuinely undertreated.

4. Surgery for selected patients. When testing proves reflux and a hiatus hernia or lax valve is driving it, laparoscopic repair with fundoplication rebuilds the barrier [2, 12]. I refer to A/Prof Garett Smith (North Shore Private) and Dr David Links (Prince of Wales Private).

Vonoprazan: a different way to block acid

Vonoprazan is a potassium-competitive acid blocker. Unlike a PPI, it doesn't need acid to activate, works from the first dose, isn't tied to meal timing, and is less affected by the CYP2C19 variation that makes some people clear PPIs quickly [6].

• In erosive oesophagitis, it healed 92.9% of patients at 8 weeks vs 84.6% on lansoprazole, with the biggest gain in severe disease [13].

• In heartburn with a normal gastroscopy, patients on vonoprazan were heartburn-free on 44.8% of days over the first four weeks, vs 27.7% on placebo, with benefit from day one [14].

Vonoprazan has been approved in Japan since 2014 [15] and in the US since 2023, but it is not registered in Australia. Whether it is appropriate is an individual clinical decision. It is for proven acid reflux; it won't help hypersensitivity or non-acid reflux. I have also studied vonoprazan-based therapy in my published H. pylori research.

When to get checked promptly

Vomiting blood or passing black stools needs emergency care: go to an emergency department or call 000. See your GP promptly for difficulty or pain swallowing, weight loss, anaemia or persistent vomiting. Chest pain always needs a heart cause excluded first.

Getting assessed

I see patients with reflux that hasn't responded to treatment at the Mater Hospital, North Sydney, and Northern Beaches Hospital, Frenchs Forest. A GP referral is required.

General information only, not a substitute for individual medical advice.

Related reading

• Reflux, properly explained: from heartburn to Barrett's

• Functional dyspepsia: when your upper gut hurts and the tests come back normal

• Still constipated after a normal colonoscopy?

• What does a gastroscopy cost in Australia?

References

1. Spechler SJ, et al. Comparison of Los Angeles grades of erosive esophagitis scored by local investigators vs central adjudicators. Clin Gastroenterol Hepatol. 2024;22(12):2526-2528. doi:10.1016/j.cgh.2024.05.007

2. Yadlapati R, Gyawali CP, Pandolfino JE. AGA clinical practice update on the personalized approach to the evaluation and management of GERD. Clin Gastroenterol Hepatol. 2022;20(5):984-994. doi:10.1016/j.cgh.2022.01.025

3. Gyawali CP, et al. Updates to the modern diagnosis of GERD: Lyon consensus 2.0. Gut. 2024;73(2):361-371. doi:10.1136/gutjnl-2023-330616

4. Spergel JM, Dellon ES, et al. Updated international consensus diagnostic criteria for eosinophilic esophagitis: AGREE conference. Ann Allergy Asthma Immunol. 2018;121(3):281-284. doi:10.1016/j.anai.2018.05.035

5. Aziz Q, et al. Functional esophageal disorders. Gastroenterology. 2016;150(6):1368-1379. doi:10.1053/j.gastro.2016.02.012

6. Lima JJ, et al. CPIC guideline for CYP2C19 and proton pump inhibitor dosing. Clin Pharmacol Ther. 2021;109(6):1417-1423. doi:10.1002/cpt.2015

7. Ogasawara N, et al. Overlap between constipation and gastroesophageal reflux disease in Japan. J Neurogastroenterol Motil. 2022;28(2):291-302. doi:10.5056/jnm21065

8. Burton L, Falk GL, Parsons S, et al. Benchmarking of a simple scintigraphic test for gastro-oesophageal reflux disease that assesses oesophageal disease and its pulmonary complications. Mol Imaging Radionucl Ther. 2018;27(3):113-120. doi:10.4274/mirt.10438

9. Khoma O, Burton L, Falk MG, et al. Predictors of reflux aspiration and laryngo-pharyngeal reflux. Esophagus. 2020;17(3):355-362. doi:10.1007/s10388-020-00726-9

10. Shim LSE, Ngu MC, Yau Y, Russo R. Reflux scintigraphy in gastro-esophageal reflux disease: a comparison study with 24 hour pH-impedance monitoring. Scand J Gastroenterol. 2022;57(6):660-664. doi:10.1080/00365521.2022.2029937

11. Leiman DA, et al. Alginate therapy is effective treatment for GERD symptoms: a systematic review and meta-analysis. Dis Esophagus. 2017;30(5):1-9. doi:10.1093/dote/dow020

12. Katz PO, et al. ACG clinical guideline for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2022;117(1):27-56. doi:10.14309/ajg.0000000000001538

13. Laine L, et al. Vonoprazan versus lansoprazole for healing and maintenance of healing of erosive esophagitis. Gastroenterology. 2023;164(1):61-71. doi:10.1053/j.gastro.2022.09.041

14. Laine L, et al. Vonoprazan is efficacious for treatment of heartburn in non-erosive reflux disease. Clin Gastroenterol Hepatol. 2024;22(11):2211-2220. doi:10.1016/j.cgh.2024.05.004

15. Garnock-Jones KP. Vonoprazan: first global approval. Drugs. 2015;75(4):439-443. doi:10.1007/s40265-015-0368-z