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.”

Related blog posts:

• How to Make a Study Look Favorable for Reflux Surgery Compared to Medical Therapy
• What’s Going On in Patients with Reflux Who Fail to Respond to PPIs?
• How Many Kids with Reflux Actually Have Reflux?
• Why didn’t patient with documented reflux get better with PPI …
• Impedance May Help in Borderline Cases
• Failure of PPI test | gutsandgrowth
• Guidelines on Functional Heartburn
• Better to do a coin toss than an ENT exam to determine reflux
• How Likely is Reflux in Infants with “Reflux-like … – gutsandgrowth
• PPI Webinar
• The Connection Between Anxiety and Gastroesophageal Reflux Disease

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