Gastroesophageal Reflux Phenotypes and “Where Rome, Lyon, and Montreal Meet”

A useful review (DA Katzka et al. Clin Gastroenterol Hepatol 2020; 18: 767-76) discusses the phenotypes of gastroesophageal reflux and related disorders.   The authors note that consensus initiatives (Montreal, Rome, and Lyon) have looked at these disorders from different perspectives and their goal was to merge their perspectives.

Table 1 lists the major phenotypes:

  • Nonerosive reflux disease
  • Reflux hypersensitivity
  • Functional heartburn
  • Erosive esophagitis (low grade and high grade).  LA grade A esophagitis “can be found in approximately 6% of asymptomatic controls”
  • Barrett’s esophagus
  • Reflux chest pain syndrome
  • Regurgitation-dominant reflux disease: “need to differentiate from rumination and achalasia”
  • Laryngopharyngeal reflux
  • Chronic cough  “although reflux may contribute, it is rarely the dominant pathophysiology… more amenable to GERD therapy when accompanied by typical reflux symptoms”

Figure 1 provides a model for the pathogenesis of GERD. Figure 2 describes the relationship between reflux phenotypes and PPI responsiveness:

In those with typical reflux symptoms: 

  • esophagitis healing 84% with PPI Rx compared to 28% with placebo (NNT =1.8)
  • heartburn relief (with and without esophagitis) 56% with PPI Rx compared to 16% with placebo (NNT =4.4)
  • heartburn relief without esophagitis 40% with PPI Rx compared to 13% with placebo (NNT =3.7)
  • regurgitation relief (with and without esophagitis) 47% with PPI Rx compared to 30% with placebo (NNT =5.9)

In those with atypical reflux symptoms:

  • chest pain relief with objective GERD 74% with PPI Rx compared to 20% with placebo (NNT =1.6) (Studies used a 50% reduction in pain as opposed to complete elimination…opens the door for a greater placebo response)
  • chest pain relief without objective GERD 29% with PPI Rx compared to 23% with placebo (NNT =16.7) (Studies used a 50% reduction in pain as opposed to complete elimination…opens the door for a greater placebo response)
  • chronic cough with objective GERD 33% with PPI Rx compared to 9% with placebo (NNT =4.2)
  • chronic cough without objective GERD 31% with PPI Rx compared to 27% with placebo (NNT =25)
  • reflux laryngitis (without heartburn, complete resolution) 15% with PPI Rx compared to 16% with placebo
  • poorly-controlled asthma (without heartburn)-exacerbations per year: 2.5 with PPI Rx compared to 2.3 with placebo 
  • *references for this figure provided

Other useful points:

  • “An exception to the de-emphasizing the relationship of GERD to an extraesophageal syndrome is with lung transplantation, which …has unique considerations…the sequelae of untreated GERD …may lead to accelerated mortality from allograft injury…data have suggested that PPIs may be effective at prolonging allograft survival.”
  • The authors state that escalating PPI/antisecretory treatments for esophagitis is often effective but this approach has limited applicability for other indications and can result in overuse. “Similarly, failing to recognize the modulating effects of anxiety, hypervigilance, and visceral and central hypersensitivity on symptom severity has greatly oversimplified the problem.”

My take (borrowed in part from authors): PPIs work well for esophagitis and documented reflux; “the broad spectrum of syndromes [are] much less amenable to PPI therapy in any dose.”

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Salivary Pepsin Doesn’t Pass Muster for Evaluation of Reflux

For quite a long time, I thought the expression was “Pass Mustard”.

A recent study (F Dy et al. J Pediatr 2016; 177: 53-8) shows that testing salivary pepsin is probably a waste of time in assessing for extraesophageal reflux disease. The authors prospectively recruited 50 children who underwent multiple studies including 24-hour pH-MII testing. The idea of pepsin as a biomarker has some plausibility since it is produced in the stomach and its presence in the oropharynx (or airway) would be unexpected.  Since salivary pepsin does not require invasive diagnostic testing, it would be useful if it had adequate sensitivity and specificity.

Key findings:

  • 21 of 50 (42%) were salivary pepsin-positive with a median concentration of 10 ng/mL.  Pepsin was detected in 6 of 21 with abnormal impedance testing and 8 of 21 with abnormal pH results (per Table 1 –the discussion used a denominator of 11 for each of these results)
  • There was no significant correlation between salivary pepsin-positivity compared with salivary pepsin-negative for reflux episodes, acid reflux, nonacid reflux or any other reflux variable.

  • The authors also reiterate in the discussion that clinical trials, evaluating reflux and chronic cough, “have failed to find a consistent relationship between measure dreflux and clinical response.”
  • The authors note that bronchoscopy pepsin correlation with esophageal reflux monitoring was similarly low in sensitivity
  • The authors note that “one-third of healthy asymptomatic adults have pepsin detected in their saliva.”  In this study, 38% (15 of 39) of children had pepsin detected despite normal impedance results.

My take:  While this study mainly shows that pepsin detected in the saliva has no practical use in correlation with reflux, the bigger picture is the uncertain relationship of reflux as a causal association with chronic cough.

Any of the reflux-esophageal gurus care to comment?

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