What’s Going On in Patients with Reflux Who Fail Proton Pump Inhibitors

A recent prospective study (J Abdallah et al. Clin Gastroenterol Hepatol 2019; 17: 1073-80) examined adults patients with documented reflux at baseline.  Patients who reported heartburn and/or regurgitation at least twice a week for 3 months (n=16) despite proton pump inhibitor (PPI) therapy were considered PPI failures. Those (n=13) who responded to standard dose PPI for at least 4 weeks were in the “PPI success” group.

Standard PPI dosing in this study:

  • Omeprazole 20 mg per day
  • Esomeprazole 40 mg per day
  • Pantoprazole 40 mg per day

Methods: Both groups (PPI Failure group, PPI Success group) underwent EGD and pH-MII studies. Abnormal acid exposure was considered if pH <4 was present for >4.2%.

Key findings:

  • 12 patients (75%) in the PPI failure group had either functional heartburn or reflux hypersensitivity
  • 4 patients in both groups had abnormal pH test result.
  • There was no statistically significant differences in the number of reflux events, acid exposure or nonacid reflux parameters between patients who failed or those who were successfully treated with PPIs.
  • In the PPI failure group: 25% had persistent GERD, 12.% had overlap with reflux hypersensitivity, and 62.5% had overlap with functional heartburn

My take: The difference between PPI failure and PPI success largely is due to the overlapping presence of functional esophageal disorders.

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#NASPGHAN17 Why Rome IV Criteria are important

More information from this year’s annual NASPGHAN meeting.

This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

The following slides highlight a terrific lecture by Carlo DiLorenzo (Nationwide Children’s Hospital).  Subsequently, I’ve included slides from Miranda van Tilburg (UNC); I was unable to attend her lecture and found some of the slides via twitter.

Key points:

  • Rome IV criteria are helpful, particularly with less common presentations like rumination
  • There has been an increase in nausea.  Morning nausea can be equated as a marker of anxiety until proven otherwise.
  • There is improved wording. “After appropriate medical evaluation, the symptoms cannot be attributed to another condition” may help facilitate the diagnosis of irritable bowel syndrome, for example, in patients with IBD who are in remission.

From Miranda Tilburg:

How Many Kids with Reflux Actually Have Reflux?

A terrific recent retrospective study (LB Mahoney, S Nurko, R Rosen. J Pediatr 2017; 189: 86-91) examined how often children with reflux symptoms actually have reflux.

This study reviewed 45 children ≥5 years (mean age 11.8 years) who had undergone both upper endoscopy and impedance pH study (off PPI therapy). Inclusion criteria: no erosive esophagitis. Common symptoms included heartburn, abdominal pain, chest pain, and regurgitation.

Definitions:

  • Nonerosive reflux disease –had abnormal esophageal acid exposure
  • Reflux hypersensitivity -had normal acid exposure but had a positive symptom association to acid or nonacid reflux
  • Functional heartburn -had normal acid exposure and negative symptom association

Key findings:

  • 44% had functional heartburn, 29% with reflux hypersensitivity (27% acid, 2% nonacid), 27% had nonerosive reflux disease (NERD)
  • Response to a proton pump inhibitor (PPI) was not predictive of reflux phenotype: 58% with NERD, 67% with reflux hypersensitivity, and 55% with functional heartburn. Response to PPI was stated as “at least some symptomatic improvement with PPI use.”  There was not a difference in PPI response among those who received a dose <1 mg/kg and those ≥1 mg/kg.
  • Microscopic esophagitis was present in 17% in NERD, 25% with reflux hypersensitivity, and in 20% of functional heartburn

While this study has limitations, including referral bias, it is likely that these patients are typical for many pediatric gastroenterologists. The authors note that typical patients were “patients who underwent a PPI trial but continued to have persistent symptoms.”

My take: In a pediatric gastroenterology setting, the most common reason for “reflux” is actually functional heartburn.  Thus, in those with persistent symptoms, evaluation with endoscopy and pH probe is worthwhile, especially as there has been more attention to potential risks of PPI therapy.

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pH Probe Testing: Rumors of My Death are Premature

Several years ago, an “obituary” was written for the pH probe (Putnam PE,J Pediatr.  2010; 157(6):878-80) due to the presumed superiority of pH-impedance (pH-MII) studies in detecting gastroesophageal reflux disease (GERD)  As noted in previous blogs (see below), there have remained a number of concerns with the assumption that pH-MII is an improvement over pH studies without impedance.  Several recent studies elaborate on those concerns:

  1. Cheng F-K F, et al. Clin Gastroenterol Hepatol 2015; 13: 867-73
  2. Patel A, et al. Clin Gastroenterol Hepatol 2015; 13: 884-91
  3. Vaezi MF. Clin Gastroenterol Hepatol 2015; 13: 892-94 (editorial)

In the first study, the authors identified 221 patients and retrospectively reviewed GERD testing from 2006-2011.  Prior to testing, 97% had received prescribed PPIs before testing; however, PPIs were discontinued for at least 1 week prior to evaluation which included upper endoscopy, esophageal manometry, and pH-MII.

  • 21 (10%) had erosive esophagitis
  • 61 (27%) had nonerosive reflux disease with increased pH
  • 18 (8%) had nonerosive reflux disease with abnormal impedance
  • 30 (14%) had hypersensitive esophagus
  • 18 (8%) had functional heartburn
  • 30 (14%) had other functional disorders
  • 43 (19%) were undetermined

Thus, this retrospective study showed that the majority (roughly 2/3rds) of patients with GERD symptoms on PPI therapy did not have GERD based on objective testing.  The authors chose to test off PPI therapy “because we postulated that the pretest probability of GERD diagnosis was low, primarily given their lack of response to PPI.”

In the second study, 187 subjects (≥18 years) underwent pH-MII testing in a prospective study from 2005-2010.  49.7% were tested off proton pump inhibitor therapy. Abnormal acid exposure time consistently predicted symptomatic outcome.  The authors note that performing pH-MII off PPI therapy best predicts response to antireflux therapy

In the third reference, the editorial which commented on the second, there are several useful points:

  • “There is little doubt that pH-impedance testing provides a more sensitive means of comprehensively identifying reflux events in a given patient. However, to date, studies have failed to demonstrate that it provides any significant additional clinical benefit.”
  • “Caution must be exercised when incorporating the added objective data from non-acidic or weakly acidic reflux events into treatment decision-making…Studies including Patel et al have not shown that knowledge regarding continued non-acid or weakly acid reflux events alter patient outcomes.”
  • “Wireless pH testing is generally better tolerated and provides longer measurement duration”
  • The use of symptom indices are too subjective.  “Recent data question the use of these indices especially in those with refractory symptoms and minimal reflux by pH or impedance testing.”  SI and SAP could be altered by chance occurrences….”A colleague expert in esophageal diseases …once said: “I know the tests are no good but I don’t know what else to use.'”
  • “Let us simplify our approach on the basis of available data and not use measures that we know are suboptimal at best.”

After looking at these studies and the previous pH probe obituary, I’m reminded of a story.  Several religious leaders were asked what they wanted someone to say at their funeral.  A few stated that they wanted their congregants/flock to comment on their values, like piety and charity.  However, one said, “I hope they say, ‘Look he’s moving!'”

Bottomline: There is no reliable evidence that pH-MII testing improves outcomes over conventional pH probe testing. In fact, the use of pH-MII, by lowering the specificity for GERD, could have a detrimental effect.  With either test, holding acid suppression for 1 week (with PPIs) is likely to be helpful in interpreting the results.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Zoo Atlanta

Zoo Atlanta