Thirty Year Perspective on Laryngopharyngeal Reflux (LPR): From Silence to Omnipresence

I have been a laryngologist for 35 years, but 1981 was a watershed year for me. That’s when I stopped doing the oto and rhino parts of otorhinolaryngology. That same year, I first became aware of gastroesophageal reflux disease (GERD) that affected the larynx. I have specialized in laryngology ever since, and laryngopharyngeal reflux (LPR), a term that I coined some time in the 1980s, has been the main focus of my research. (LPR is a condition caused by the backflow of gastric (stomach) contents into the throat and voice box.)

From a personal point of view, the early years of LPR weren’t easy;  people were very skeptical,  even  laughed  when  I  spoke  about  LPR at national meetings. That LPR remains so controversial is surprising to me as there is now credible science, and I believe that clinical observations that I had in the 1980s expressed in my Triological thesis,1 will stand the test of time.

Some people who deserve credit for seminal thinking in LPR and who most influenced me were Nels Olson, Paul Ward, Paul Chodosh, and Bob Toohill. I remember Dr. Olson warning me that LPR was contentious. He told me that some of his academic contemporaries had tried to discredit him because of his beliefs that LPR was ubiquitous and caused a myriad of airway diseases.  Of course, when Dr. Olson talked about reflux, it was GERD. It wasn’t until 1991 that I coined the term laryngopharyngeal reflux, the same year as the publication of my thesis.1 I felt that we needed a new term for the type of “silent” reflux disease that our patients demonstrated. I chose the term laryngopharyngeal reflux to call attention to the fact that the symptoms and manifestations were laryngeal and pharyngeal, that is, not esophageal. I also believed that the diagnosis and treatment of LPR were different than those for GERD.

The idea was to intentionally create a nosological schism between the specialties so that otolaryngologists would consider new ideas that were not yet acknowledged by gastrointestinal (GI) colleagues. Incidentally, the term silent reflux was coined by Dr. Walter Bo, chair of the anatomy department at Wake Forest University, and me. Walter was my patient in 1988, and he had LPR. After I had explained how one could have reflux without heartburn, Dr. Bo rolled his eyes and pronounced, “I see; I have the silent kind of reflux.” “”Yes,” I said, “That’s it … You have SILENT REFLUX.”

Early on I recognized that LPR was controversial, because for almost 5 years I couldn’t get anything published on the subject. Research on the laryngeal findings, the prevalence of LPR, as well as papers about the possible relationship between LPR and laryngeal cancer were rejected outright. Perhaps intended as a warning, the comments of one anonymous reviewer for a prestigious journal were forwarded to me: “Something has to be done about Koufman’s preoccupation with GERD”; and then the reviewer suggested that I might be on the payroll of one of the pharmaceutical companies. This was certainly untrue! I was surprised and disappointed by that communication and its implications; it wasn’t exactly a positive testimonial for peer review.

Even before publication of my thesis,1 it was apparent that resolution of the controversies about the diagnosis and treatment of LPR as well as its causal relationship to airway disease, would require credible bench research, that is, more than pH-monitoring data. Table 1 summarizes some of the types of research that have helped establish LPR as an entity.1–46 Twenty years later, the cell biology of LPR is beginning to yield answers about the epithelial defenses of the larynx, the mechanisms of reflux-related inflammation and tissue injury, and the causal relationship between LPR and many laryngeal diseases.30-37,46

Table 1. Types of LPR Research (and References)

Manifestations and Epidemiology
Symptoms and manifestations of LPR 1–20, 40
Association data (eg, 92% of subglottic stenosis patients have LPR) 1,3–14
Prevalence data (eg, 57% of patients with voice disorders have LPR) 15
Laryngeal findings observational data (eg, the reflux finding score) 1,14–17, 39, 41, 45
Normative control data (eg, normals have LPR between pH 4-5) 25,44
Patterns  and Mechanisms  of LPR (How LPR differs  from GERD)
Pattern of reflux (eg, LPR patients have upright [daytime] reflux) 1,3–5,7,10,19
Lack of esophagitis in LPR (eg, 12% esophagitis, 7% Barrett’s esophagus) 1,22,39
Studies of the refluxate, including stability and activation of pepsins 1,23–25
Studies of vagal reflexes (eg, acid-induced laryngospasm) 8,13,26,27
Diagnosis and diagnostics for LPR 1,3–5,7,10–18,30–36
Treatment 1,5,7,20,29,30,45
Cell Biology  and Beyond
Impact of acid and pepsin on laryngeal epithelium 30,31,33,34,37,46
Comparative studies of laryngeal and esophageal injury thresholds 32
Characterization of the internal environment 21,23,34,30–37,45
Characterization of pepsin binding sites and protein cascade 30,31,33,34
Effects of refluxate on scar formation and carcinogenesis 1–3,6,10,11,31

LPR Is Different Than GERD

In part, I became interested in LPR because I felt there were missing clinical pieces and confounding questions. Even the clinical basics were difficult to understand. For one thing, many LPR patients stated unequivocally that they didn’t have reflux. People generally equate reflux with heartburn; thus, no heartburn, no reflux. It was sometimes difficult trying to explain “silent reflux” to patients with LPR because it is fundamentally counter- intuitive. Then there were also questions like: Why did patients who didn’t use tobacco get laryngeal cancer? Why did vocal process granulomas recur so frequently after surgical removal; or for that matter, why did they arise following endotracheal intubation? What was the cause of sulcus (striking-zone scarring), subglottic stenosis, and arytenoid fixation? Why did patients without apparent lung disease have chronic cough? Many of these questions remain unanswered.

By 1989, we already understood that the mechanisms and patterns of reflux in LPR were different than those of GERD.1,3–5  Most GERD patients had heartburn esophagitis, dysmotility, and a supine (nocturnal) reflux pattern with prolonged periods of esophageal acid/pepsin exposure. Conversely, LPR, patients usually did not have heartburn or esophagitis, and an upright (daytime) reflux pattern predominated.1,3–5,19,20,22  A summary of the typical differences between LPR and GERD is shown in Table 2.

Table 2. Typical Differences Between LPR and GERD

Heartburn and/or regurgitation ++++ +
Hoarseness, cough, dysphagia, globus + ++++
Esophagitis +++ +
Laryngeal inflammation + ++++
Test Results
Erosive esophagitis or Barrett’s +++ +
Abnormal esophageal pH monitoring ++++ ++
Abnormal pharyngeal pH monitoring + ++++
Esophageal dysmotility +++ +
Pattern of Reflux
Supine (nocturnal) reflux ++++ +
Upright (daytime) reflux + ++++
Both abnormal upright and supine reflux + +++
Response  to Treatment
Effectiveness of dietary and lifestyle modification ++ +
Successful treatment with single-dose PPIs* +++ +
Successful treatment with twice-daily PPIs* ++++ +++

One of the key differences between GERD and LPR is that the thresholds for esophageal and laryngeal dam- age are quite different.1,30,31  Based on normative pH monitoring data, one can have up to 50 esophageal reflux (pH<4.0) events, occurring mostly after meals, and that is considered normal; in the larynx, as few as three episodes a week may be too many.1  In addition, pepsin and not acid is the primary injurious component of the refluxate.1,2,23-25,30,31 From animal (mostly esophageal) experiments, we knew that acid and pepsin in combination (i.e., activated pepsin) produced more tissue damage than any other combination of enzymes; adding bile salts to the mix, for example, reduced the potency of the refluxate.1,23,24

Most of the animal experiments used perfusion models with intact epithelium. In designing animal experiments for my thesis, I wanted to mimic the conditions that presumably led to granuloma formation. In a 1985 study, we had reported that subglottic stenosis could be created in a canine model by the combination of epithelial trauma and experimental reflux.2 For my thesis, the idea was to create controlled intracricoid epithelial abrasions in animals followed by the intermit- tent (every other day) application of (a) control substances (saline); (b) HCl acid alone at pH 1.5, 2.0, and 4.0; or (c) acid and pepsin in physiologic proportions also at pH 1.5, 2.0, and 4.0.1  After the initial mucosal injury, painting  of  the  test  substances  was  done  six times over a 2-week period (M, W, F, M, W, F). The next week, the animals were sacrificed, the larynges harvested, and microscopic examinations were performed by a blinded pathologist who scored each for inflammation and tissue damage.

The results showed that control and acid-alone groups were no different, and that most of those larynges showed healing and re-epithelization. On the other hand, the acid and pepsin painted specimens showed tissue damage that was statistically significantly worse than the other groups; and half of the acid/pepsin painted larynges showed mucosal ulceration.1 The data confirmed that it was pepsin and not acid that produced laryngeal tissue damage. The most surprising finding was that there appeared to be comparable damage at pH 1.5, 2.0, and 4.0.1 The previous GI literature that suggested that pepsin was virtually inactive above pH 4.0 was incorrect. On the basis of this laboratory experience, I began further investigations of the biology of human pepsin, its tissue effects, and its possible uses as a diagnostic marker.32,35,36,37

A Diagnostic Dilemma

In 1982, when I first approached my gastroenterology colleagues about the effects of reflux on the larynx and how to make the diagnosis of reflux laryngitis, I was initially rebuffed. Laryngeal symptoms, I was told, occurred as a result of vagally-mediated reflexes, not because of the actual backflow of gastric contents into the throat. However, the GI department was doing ambulatory 24-hour esophageal pH monitoring, and so I sought out a collaborator to test the hypothesis that patients with hoarseness might actually have acid in their throats. I wanted to investigate my patients with two separate pH-monitoring devices, one in the esophagus and another in the pharynx. Thus, ambulatory 24-hour double-probe (simultaneous esophageal and pharyngeal) pH monitoring was born. 3 The first patients studied using ambulatory 24-hour double-probe (simultaneous esophageal and pharyngeal) pH monitoring had unexplained hoarseness and laryngeal inflammation.3,5

About 1990, the reflux symptom index (RSI) and the reflux finding score (RFS) became codified and formalized in my practice, but they were not individually reported as validated outcomes instruments until a decade later.16–18,28,41   These indices are very useful for following the response to treatment over time. For the RSI, there is not an absolute number that is diagnostic of LPR; although from my perspective, it is very uncommon that a patient with a RSI of 20 or more doesn’t actually turn out to have LPR. For the RFS, the comparable “magic number” is 10. It is worth noting that the combination of pseudosulcus and ventricular obliteration are virtually diagnostic of LPR, whereas posterior commissure erythema and pachydermia (posterior commissure hypertrophy) are not as useful diagnostically.

After many years and in spite of considerable experience, I still did not always know the best way to diagnose LPR. pH monitoring sufficed when it was positive, and our normative data suggested that even a single pharyngeal reflux event of pH<4.0  was diagnostic of LPR. But even in those early years, that criterion seemed too narrow. What about a patient who had a lot of reflux at pH 4.1? Was that normal? About two-thirds of the patients whom I believed had LPR on clinical grounds had positive pharyngeal pH studies. Most of the apparent false-negative pH study patients were treated with antireflux medication (as well as dietary and lifestyle modifications) anyway; most got well. Consequently, for the difficult to diagnose patient, a therapeutic trial became an important diagnostic. From my point of view, the laryngeal symptoms and findings both had to improve for antireflux therapy to be considered successful.

In the 1980s, having already rejected radiographic and radionuclide imaging and esophagoscopy because they were insensitive and nonspecific for LPR, I began to look at new pH monitoring criteria as well as for other diagnostics. Since there was evidence that there was at least 70% of peptic activity at pH 4.5 and perhaps as much as 40% activity at pH 5.0,1 in 1991 our pH monitoring laboratory began to report the number of pharyngeal reflux events at pH <5.0 as well as at pH <4.0. We recently reported normative pharyngeal pH monitoring results in 20 carefully selected controls21; 15% (3/20) had some pharyngeal reflux episodes pH <4.0, and 90% (18/20)  had pharyngeal reflux between pH 4.0–5.0, with a mean number of 2.5 such episodes.21

Even though the symptoms and laryngeal findings of LPR have been well-described, and even using expanded pH threshold criteria and therapeutic trials, it is still sometimes difficult to diagnose LPR with certainty. There are so many clinical variables, not the least of which is intermittency. As a gold standard, pH monitoring has had it limits, yet it is still one of the best diagnostics as of this writing as long as there is a pH sensor in the pharynx. pH monitoring without pharyngeal data is virtually meaningless in LPR. In one study, we showed that the positive predictive value of a single esophageal pH probe for the diagnosis of LPR was 49%.  For 25 years I have remained uncomfortable with “threshold pH level” LPR diagnosis.  The idea that reflux events below a certain pH-level are diagnostic of disease didn’t make sense in the light of what we know about peptic injury.31,37  For example, there was no way to compare the potential tissue impact of LPR episodes lasting a few minutes at pH 2 with hours at pH 5.

It is useful to reflect on why Johnson and DeMeester originally selected pH <4.0 as the threshold for determination of an acid-reflux event for esophageal pH monitoring.25  It was relatively arbitrary; however, pH <4.0 was selected for two reasons. First, at the time it was believed that there was little or no peptic activity above pH 4.0; and second, when GI patients with heartburn and GERD were pH-tested, it seemed that the symptom heartburn was associated with pH <4.0 events.25 As it turns out, it has been shown that esophageal damage occurs at pH <4.0 and laryngeal damage at pH <5.0.31,37  However, human pepsin (primarily pepsin 3b) has proteolytic activity across a wide pH-range. Peptic activity is a function of pH, and even at pH 6, there is still 10% peptic activity. In addition, human pepsin is stable at pH 7, and it is likely that it can be reactivated by hydrogen ions from any source, for example, a sip of soda pop.37

Recently, we began to reexamine pH monitoring data by looking at the entire “area under the curve,” that is, the acid exposures at all pH levels (from 1–7), using the pepsin activity curve to modify the relative risk of tissue damage at each pH level. A new system for interpreting pharyngeal pH monitoring data is currently under investigation, as outlined below.

Because of limitations using one pH threshold level, we derived the pepsin injury coefficient (PIC) for each pH level (Table 3) using 1.00 (i.e., 100%) for peak peptic activity at pH 2.0. Then, the number of minutes of pharyngeal exposure in each pH range (intervals were 0.0–1.0, 1.1–2.0, 2.1–3.0, etc) was multiplied by its corresponding PIC, corrected for a complete 24-hour study (1440 minutes). This produced a reflux injury profile (RIP), an injury score for each pH level (Table 3); and the sum of RIP scores was then reported as the reflux injury score (RIS).

Table 5–3. Method of Calculation of the Reflux Injury Profile (RIP), the Reflux Injury Score (RIS), and Case Illustrations

A. Normal
pH >1 >2 >3 >4 >5 >6 >6
PIC* 0.8 1 0.7 0.55 0.4 0.1 0
Min 0 0 0 0 20 400 1020
RIP 0 0 0 0 8 40 0 RIS = 48
B. Abnormal
pH >1 >2 >3 >4 >5 >6 >6
PIC* 0.8 1 0,70 0.55 0.4 0.1 0
Min 0 10 30 100 200 100 100
RIP 0 10 21 55 80 10 0 RIS = 176
C. Abnormal
pH >1 >2 >3 >4 >5 >6 >6
PIC* 0.8 1 0.7 0.55 0.4 0.1 0
Min 10 30 100 200 400 500 200
RIP 8 30 70 110 160 50 0 RIS = 428
D. Abnormal
pH >1 >2 >3 >4 >5 >6 >6
PIC* 0.8 1 0.7 0.55 0.4 0.1 0
Min 0 0 0 0 1000 400 40
RIP 0 0 0 0 400 40 0 RIS = 440

PIC*: Pepsin Energy Score

In Table 3, there are four case illustrations, one normal (A) and three abnormal (B–D). In the normal example, the % time pH <5.0 is only 1% and the RIS is 48. In abnormal case example 3B, the % time pH <4.0 is 10%; the % time pH <5.0 is 17%; and the RIS is 176. It is instructive to compare case examples 3C and 3D. By traditional pH criteria, study C would have been considered to be profoundly abnormal and study D would have been considered normal. For 3C and 3D, the % time pH <4.0 are 27% and 0% respectively, but for % time pH <5.0, they are 51% and 69% respectively. For 3C, the RIS is 428 and it is 440 for 3D.

Figure 5–1. Human pepsin activity curve.

Using the RIP/RIS scoring method, it appears that prolonged pharyngeal exposure at weakly acidic pH may be more damaging than a shorter period of exposure at low pH.  It is important to remember that RIP/RIS scoring is designed for interpretation of pharyngeal reflux testing. The RIP/RIS  are based upon the observation that the esophagus is more robust than the larynx when it comes to mucosal resistance to weakly acidic reflux. 1, 31 The concept of looking at the entire pH test profile is appealing, because it avoids the “which pH threshold?” question. Time will tell whether or not the RIP and RIS prove to be good clinical measures.

Implications of Detection of Pepsin in Airway Secretions

In the early 1990s, we performed an experiment (unreported data) designed to test the hypothesis that pepsin as a relatively large and stable molecule might be a good marker for LPR. Porcine pepsin was sprayed in the throat of rats, which were subsequently sacrificed at intervals from 0 to 5 hours after spraying. At sacrifice, the laryngopharynx of each animal was lavaged with saline and then the samples were assayed for pepsin using a hemolytic (modified Anson) method. As expected, there was a large peak within 15 minutes of spraying of the pepsin. Notably, there was a moderate amount of pepsin detected 5 hours later (and not in the controls).

We subsequently developed a sandwich immunoassay (ELISA) for human pepsin with a sensitivity of 0.1ng/ml and 100% specificity.35,36,43  It did not cross-react with pepsinogen, gastricin, or porcine pepsin. The purpose of the assay was to detect pepsin in saliva and airway secretions. Essentially, we developed a spit-in-a-cup test for gastric reflux, especially LPR. Recently, we tested otolaryngology patients with pH-documented LPR, a group of GI patients with biopsy-proven esophagitis, and normal  controls.36   Fifteen  percent  (3/20) of the control subjects had pepsin detected; although two of those were positive at threshold pepsin levels (~3  ng/ml);  the third had silent GERD and Barrett’s esophagitis, diagnosed by subsequent pH testing and esophagoscopy.36  Pepsin was detected in the expectorated samples of 75% (69/92)  of the LPR patients and 64% (23/36)  of the esophagitis/GERD  group.36  Latter finding was unexpected; but in part, it may help explain why  LPR  remains so  enigmatic:  If  pepsin  is recovered from expectorated samples of GERD patients who do not have LPR symptoms, then possibly local epithelial resistance may play an important role in pre- venting LPR disease.

Cell Biology of LPR and Laryngeal Carcinogenesis

By 1991, I was hungry for basic science research, but it wasn’t until 1995 that I began doing bench research at Wake Forest University in a dedicated laboratory. In 1998, we organized several multidisciplinary LPR meetings in the United Kingdom, including the 1st International Symposium on Human Pepsin (1999), held at the University of York in England. One of my colleagues on the planning committee suggested that we didn’t know enough about pepsin to use such a title. I proposed to get U.K. scientists interested in LPR, especially the cell biology of peptic injury. I may have been the only person who mentioned pepsin that first year. However, out of that meeting and similar ones that followed emerged an international reflux research network. Our first major article on the cell biology of LPR was published in 2001.30 And not long after that, Dr. Nikki Johnston came to work as a molecular biologist in my laboratory at Wake Forest.

We studied pepsin, carbonic anhydrase and E-cadherin, and then the stress proteins in LPR patients and controls as well as in animal and in vitro models. The cell biology of LPR is marvelous, and it has yielded some unexpected findings. For one thing, it revealed that the esophagus was far better defended than the larynx against peptic damage; and even within the larynx, there were differences in the cellular response to acid and pepsin.30–37

Even before our first scientific experiment, we hypothesized that the larynx had at least two biologic compartments in terms of its response to LPR; at least the posterior commissure was different than the rest. Here’s why. Only once in my career had I seen a primary squamous cell carcinoma arise in the posterior commissure and that was in a lifetime nonsmoker. Furthermore, granulomas and other growths did not seem to arise there. The only pathology of the posterior commissure mucosa was posterior commissure hypertrophy (pachydermia) due to LPR. Hence, we reasoned that the posterior commissure  was defended differently than the rest of the larynx; we felt that it was more resistant to reflux and carcinogenesis. Perhaps it had evolved to be more resistant because as a posterior hypopharyngeal structure; it was more directly in the path of LPR than any other part. So from the beginning, we investigated the biology of LPR, we looked at both vocal fold and posterior commissure epithelia as though they might be different. As it turns out, they are, and those differences have clinical and research implications.

The enzyme carbonic anhydrase (CA) is ubiquitous in mammalian cells. It hydrolyzes CO2  to form bicarbonate, and it is believed to be important in maintaining intracellular acid-base balance. Interestingly, with (GERD) esophagitis, the esophageal epithelium actually secretes bicarbonate; not so with the larynx. Not only does the larynx not have a comparable defense, CA in vocal fold epithelium depletes in response to LPR, especially to pepsin.30–33 At the same time, CA increases in the posterior commissure mucosa in response to LPR. So, as CA depletes in the vocal fold, it increases in the posterior commissure. Furthermore, the amount of CA found in posterior commissure epithelium correlates with the reflux symptom index; the higher the RSI, the more CA is found. Does CA have a role in preventing laryngeal carcinoma? Perhaps.

CA is not the only protein in vocal fold epithelium that depletes with LPR.30–34   So too does E-cadherin that makes up the tight junctions (intercellular bridges) between squamous epithelial cells, and most of the stress proteins (previously known as “heat shock” proteins). Using our pepsin peptide antibodies, we performed Western blot analysis of laryngeal tissue from LPR patients and controls. Most all (19/20) LPR patients had tissue-bound  pepsin  and  most  all  controls  (1/20)   did not.36 Furthermore, the finding of pepsin by Western blot was associated with depletion of the protective proteins. The tissue profile of LPR and laryngeal carcinoma is similar (Table 4). The one notable difference is that stress protein HSP70 is depleted in carcinoma, but not in LPR.

Table 4. Human Tissue Protein Profile of Controls, LPR, and Cancer

Controls LPR Cancer
Pepsin None + +

As a clinician, I have observed that LPR findings are virtually always present in patients with vocal fold carcinoma. In the past, clinicians have assumed that those inflammatory findings were due to tobacco use and not reflux. In a paper entitled, Reflux and early laryngeal carcinoma, we presented a prospective series of 50 consecutive patients with T1 laryngeal carcinoma, all of whom had biopsy-proven vocal fold disease and reflux testing.45 Of the study population, 44% (22/50) were smokers, 42% (21/50)  were ex-smokers (with a median duration of smoking cessation of 8 years), and 14% (7/50)  were lifetime nonsmokers. Seventy-six per- cent (38/50) had pH-documented reflux.45

In my thesis,1  I presented some interesting cases; six patients with recurrent leukoplakia that vanished with antireflux treatment, and six nonsmokers who felt to have reflux-related carcinoma. One exemplary case was that of a real estate agent (case example 1 in my thesis). He presented with a 3-mm granuloma-like lesion of the left vocal fold that turned out to be a microinvasive carcinoma. He was a lifetime nonsmoker and non- drinker. I did a local endoscopic laser excision, but it granulated for months without healing. Then I biopsied the granulation and it took another 2 months before it healed. Over the course of 6 years (1980–1986), he developed three small vocal fold carcinomas, each of which was excised. After the third lesion, he had a positive pH study and underwent fundoplication. Two years after that, I excised a benign papilloma from the site of the original carcinoma. At follow-up 10 years later, he had a normal laryngeal examination. This case and the data below suggest that laryngeal papillomas and LPR may be related to laryngeal carcinogenesis.

In an unpublished paper, Papilloma-carcinoma and its possible relationship to gastroesophageal reflux, we reviewed the data of 88 adult-onset papillomas patients followed for 10–12 years, 16% (14/88) of whom had developed squamous cell carcinoma of the lung or laryngopharynx. All 14 had pH-documented LPR; and in addition, 6 were cigarette smokers. Of the remaining 74 patients, there were 14 with LPR, all on antireflux treatment. Thus, treatment of LPR and smoking cessation appear to be important interventions in adult patients with papillomas.

One might hypothesize that the common pathway of LPR and carcinogenesis might be as follows: On the mucosal surface, acid and pepsin break down the mucus barrier; then pepsin binds to epithelial cell membranes. In addition, destruction of E-cadherin (the mortar between squamous epithelial cells) allows the pepsin to get between the surface layers and down to the active basal levels of the epithelium. Tissue-bound pepsin is then   endocytosed.  Once intracellular, it damages protective proteins (e.g., stress proteins) and DNA. A specific effect of carbonic anhydrase depletion may be to further alter acid-base imbalance and lower pH, which could accelerate the cascade of adverse protein consequences. These relationships, including the effects of LPR on immunological status of laryngeal epithelium, remain to be fully elucidated.46

LPR and the Internal Environment

If almost everyone in Chernobyl were to develop cancer, would cancer be normal? LPR remains enigmatic because there still are confounding factors related to its diagnosis and treatment, and because LPR begs the question of what is normal. The finding of pepsin in the secretions of 64% GERD patients36 suggests the possibility that LPR-related diseases may depend more on local epithelial defenses than on the effluence of the refluxate. In other words, people who do not have LPR symptoms/disease (but who have some LPR) may have robustly defended laryngopharyngeal epithelium. And the essential difference between health and LPR disease may depend upon whether or not pepsin is tissue-bound.

The external environment has gotten a lot of attention in the past two decades; however, it is but one component of the internal environment. Table 5 summarizes important elements of the internal environment. These humoral and cellular elements are under the influence of neuromuscular, hormonal, vascular and genetic control, and they are also interdependent. The internal environment is the aerodigestive tract conceptualized as an integrated, multicomponent, multifunction biologic system. That it is in balance in health seems reasonable; however, surprisingly little is known about how all the elements interact, and specifically which factors and sequences cause decompensation and disease. It seems likely, for example, that LPR predisposes to upper respiratory infection (URI) and vice versa. In 2006, I reviewed a series of LPR patients diagnosed by pH-monitoring; 26% (15/57) had the onset of their symptoms with a URI [unreported data]. In addition, seemingly important relationships between LPR and reactive airway diseases remain to be elucidated.

Table 5. Components of the Internal Environment

Acid and Pepsin
Inflammatory mediators (eg, kinins)
Food and drink (that which is ingested)
Mucus and mucus breakdown products
Gastricin, bile, and other digestive enzymes
The external environment (that which is inhaled/breathed)

The concept of LPR as an uncomplicated all-or-nothing disease should be abandoned. Within this context, any single pH threshold diagnostic measure (criterion) seems woefully inadequate. As of this writing, poorly conceived clinical studies (eg, pH monitoring and treatment studies) have only further fueled a confusing and anachronistic model.

The challenge for future clinicians and researchers will be to integrate the whole that has been fragmented, and cell biology holds the key. Multidisciplinary translational research is going to unravel the LPR conundrum. Meanwhile, the internal environment will spawn development of new diagnostics and therapeutics. In the future, examination of the expectorate for mucus breakdown products, kinins, bacteria, and immunoglobulins, in addition to pepsin, may make the diagnosis of LPR noninvasive and definitive. As treatment alternatives to acid-suppression, anti-pepsin therapeutics will be possible by: (1) suppression of production or secretion, (2) prevention of activation of pepsinogen, (3) inactivation of pepsin, and/or (4) prevention of tissue binding.


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13.  Murry T, Tabaee A, Owczarzak V, & Aviv JE. Respiratory retraining therapy and management of laryngopharyngeal reflux in the treatment of patients with cough and paradoxical vocal fold movement disorder. Ann Otol Rhinol Laryngol. 2006:115:754–758.

14.  Payne RJ, Kost KM, Frenkiel S, et al. Laryngeal inflammation assessed using the  reflux finding score in obstructive sleep apnea. Otolaryngol Head Neck Surg. 2006:134:836–842.

15.  Koufman  JA, Amin  M,  &  Panetti  M.  Prevalence of reflux in 113 consecutive patients with laryngeal and voice disorders. Otolaryngol Head Neck Surg. 2000;123:385–388.

16.  Belafsky PC, Postma GN, & Koufman JA. The validity and reliability of the reflux finding score (RFS). Laryngoscope. 2001;111:1313–1317.

17.  Belafsky PC, Postma GN, & Koufman JA. Validity and reliability of the reflux symptom index (RSI). J Voice.2002;16:274–277.

18.  Carrau R, Khidr A, Gold K, et al. Validation of a quality- of-life instrument for laryngopharyngeal reflux. Arch Otol Head Neck Surg. 2005;131:315–320.

19.  Postma GN, Tomek MS, Belafsky PC, & Koufman JA. Esophageal motor function in laryngopharyngeal reflux is superior to that of classic gastroesophageal reflux disease. Ann Otol Rhinol Laryngol. 2001;110:1114–1116.

20.  Koufman JA, Aviv JE, Casiano RR, & Shaw GY. Position statement of the American Academy of Otolaryngology-Head and Neck Surgery on laryngopharyngeal reflux. Otolaryngol Head Neck Surg. 2002;127:32–35.

21.  Koufman JA, Wright SC, Lively MO, Johnston WC, Johnston N, Bishwokarma B, & Postma GN. Normal values for pharyngeal pH monitoring. Presented at the annual meeting  of the American Broncho-Esophagological Association; Orlando Fla; May 1, 2008

22.  Koufman JA, Belafsky PC, Daniel E, et al. Prevalence of esophagitis in patients with pH-documented laryngopharyngeal reflux. Laryngoscope. 2002;112:1606–1609.

23.  Lillemoe KD, Johnson LF, & Harmon JW. Role of the components of the gastroduodenal contents in experimental acid esophagitis. Surgery. 1982,92:276–284.

24.  Johnson LF, & Harmon JW. Experimental esophagitis in a rabbit model: clinical relevance. J Clin Gastroenterol. 1986, 8(Suppl 1):26–44.

25.  Johnson LF. Personal communication. 2000–01.

26.  Loughlin CJ, Koufman JA, Averill DB, et al. Acid-induced laryngospasm in a canine model. Laryngoscope. 1996; 106:1506–1509.

27.  Duke SG, Postma GN, McGuirt Jr. WF, et al. Laryngospasm and diaphragmatic arrest in the immature canine after laryngeal acid exposure: a possible model for sudden infant death syndrome (SIDS). Ann Otol Rhinol Laryngol. 2001;110:729–733.

28.  Belafsky PC, Postma GN, & Koufman KA. Laryngo-pharyngeal reflux symptoms improve before changes in physical findings. Laryngoscope. 2001;111:979–981.

29.  Amin MR, Postma GN, Johnson P, et al. Proton pump inhibitor resistance in the treatment of laryngopharyngeal reflux. Otolaryngol Head Neck Surg. 2001;125:374–378.

30.  Axford SE, Sharp N, Ross PE, Pearson JP, Dettmar PW, Pannetti M, & Koufman JA. Cell biology of laryngeal epithelial defenses in health and disease: preliminary studies. Ann Otol Rhinol Laryngol. 2001;110:1099–1108.

31.  Johnston N, Bulmer D, Gill GA, et al. Cell biology of laryngeal epithelial defenses in health and disease: further studies. Ann Otol Rhinol Laryngol. 2003;112:481–491.

32.  Johnston N, Knight J, Dettmar PW, Lively MO, Koufman J. Pepsin and carbonic anhydrase isoenzyme III as diagnostic markers for laryngopharyngeal reflux disease. Laryngoscope. 2004;114:2129–2134.

33.  Gill GA, Johnston N, Buda A, Pignatelli M, Pearson J, Dettmar PW, & Koufman J. Laryngeal epithelial defense against laryngopharyngeal reflux (LPR): investigations of pepsin, carbonic anhydrase III, pepsin, and the inflammatory  response.  Ann  Otol  Rhinol Laryngol. 2005; 114:913–921.

34.  Johnston N, Dettmar PW, Lively MO, & Koufman J.  Effect  of  pepsin  on  laryngeal  stress  protein  (Sep70, Sep53, and Hsp70) response: Role in laryngopharyngeal reflux disease. Ann Otol Rhinol Laryngol. 2006;115:47–58.

35.  Knight J, Lively MO, Johnston N, Dettmar PW, & Koufman  J.  Sensitive  pepsin  immunoassay  for  detection of  laryngopharyngeal  reflux.  Laryngoscope. 2005;115:1473–1478.

36.  Koufman JA, Lively MO, Rubin M, et al. Use of a sensitive ELISA for the detection of pepsin in the airway secretions  of  patients  with  laryngopharyngeal  reflux  (LPR), gastroesophageal reflux disease (GERD), and healthy controls. Presented at the annual meeting of the American Laryngological Association; Orlando Fla; May 1, 2008.

37.  Johnston N, Dettmar PW, Bishwokarma B, Koufman JA, & Lively MO. Activity/stability  of human pepsin: implications  for  reflux  attributed  laryngeal  disease.  Laryngoscope. 2007;117:1036–1039.

38.  DeMeester TR, Johnson LF, Joseph GJ, Toscano MS, Hall AW, & Skinner DB. Patterns of gastroesophageal reflux in health and disease. Ann Surg. 1976;184:459–470.

39.  Hill RK, Simpson CB, Velazquez R, & Larson N. Pachydermia is not diagnostic of active laryngopharyngeal reflux disease. Laryngoscope. 2004:114:1557–1561.

40.  Koufman JA, & Burke AJ. The etiology and pathogen-esis of laryngeal carcinoma. Otolaryngol Clin North Am. 1997;30:1–19.

41.  Koufman JA. Methods and compositions for the diagnosis of extraesophageal reflux. United States Patent 1996; 5,879,897.

42.  Reulbach TR, Belafsky PC, Blalock PD, Koufman JA, &Postma GN. Occult laryngeal pathology in a community-based  cohort.  Otolaryngol  Head  Neck  Surg. 2001;124: 448- 450.

43.  Westcott CJ, Hopkins MB, Bach KK, et al. Fundoplication for laryngopharyngeal reflux. J Am Coll Surgeons. 2004;199:23–30.

44.  Wetmore RF. Effects of acid on the larynx of the maturing rabbit and their possible significance to the sudden infant death syndrome. Laryngoscope. 1993;103:1242–1254.

45.  Koufman JA, & Cummins MM. Reflux and early laryngeal carcinoma. Presented at the annual meeting of the Southern Section of the Triological Society; Key West, Fla; January 6, 1995.

46.  Rees LEN, Pazmany L, Gutowska-Owsiak D, et al. The mucosal immune response to laryngopharyngeal reflux. Presented at the annual meeting of the American Broncho-Esophagological Association; Orlando, Fla; May 1, 2008).

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