Principles of Dietary & Lifestyle Modification in the Management of Acid Reflux

This is about reflux friendly eating

The world is changing and the most significant trends in the contemporary management of reflux-related disease are: (1) The prevalence of reflux and esophageal cancer is increasing;1-9 (2) The medical treatment failure rate with PPIs (proton pump inhibitors) is increasing;1-3,10 and (3) Effective reflux management depends mainly on dietary and lifestyle variables.1,2,11

Globalization and urbanization have brought about dramatic changes in where, when, and what people eat. Fifty years ago, most people ate at home, and prepackaged foods and beverages were uncommon. Today, most big soft drink and fast-food companies are global brands, and by comparison people everywhere are being exposed to much higher levels of food additives than a generation ago. As the world’s diet has become Americanized, reflux has followed.  See and purchase my best-selling book, Dropping Acid: The Reflux Diet Cookbook & Cure … yes, it’s a cure for many people.

Increasing Prevalence of Reflux Disease and Reflux-Related Esophageal Cancer

The prevalence of acid reflux disease—both esophageal reflux (i.e., GERD, gastroesophageal reflux disease) and airway reflux (i.e. LPR, laryngopharyngeal reflux)—has increased dramatically in our lifetimes.1-5 Using a Poisson model and an analysis of 17 prevalence studies published from 1976-2005, El-Serag4 showed that the average rate of increase of reflux disease since 1976 was 4% per year (P < .0001).

An even more ominous trend is the skyrocketing increase in the prevalence of esophageal cancer in the U.S.6-8 Based upon National Cancer Institute data, esophageal cancer is the fastest growing cancer in the country having increased 850% since 1975.6 During this same period, its mortality has increased seven-fold  despite increased esophageal surveillance.1,6-8 In addition, the prevalence of Barrett’s esophagus, the reflux-related precursor to esophageal cancer, is very high.8,9 Furthermore, Reavis, et al. reported that patients with hoarseness and chronic cough (airway symptoms) had Barrett’s esophagus just as frequently (8%) as reflux patients with heartburn.9 Today, routine esophageal screening is recommended for both symptomatic airway reflux and esophageal reflux patients.1,2,12,13

Reflux Disease Is Now Common in Young People

In the past reflux was primarily a disease of overweight middle-aged people. But now we are finding that many reflux patients are neither obese nor older.1,2,14 This trend toward younger and younger, not-overweight, patients with more and more severe reflux has been observed by other experienced clinicians.15

In 2010, we estimated the prevalence of airway and esophageal reflux (LPR and GERD) in the United States by interviewing a geographically random sample of 656 U.S. citizens.1,2 (The interviews carefully elicited all reflux symptoms and medications.) The data revealed that an astonishing 40% had reflux disease, 22% having classic esophageal reflux (GERD) and another 18% having airway reflux (LPR).1,2 There were no statistical differences seen between age, gender, and regions of the country. The most striking and unanticipated finding was that 37% of the 21-30 year-old age group had reflux.1,2

Cell Biology of Reflux: Clinical Implications

The popular term acid reflux is a misnomer. It is pepsin (not acid) that does most of the airway and esophageal tissue damage from reflux; however, pepsin requires acid for its activation.1,2,11,13,16-21 Therein lies the cause of some of the confusion regarding the pathophysiology of reflux disease. Pepsin causes inflammation and damages airway mucosa, especially the surface epithelium, in a variety of ways.

First, pepsin destroys the protective mucus barrier.16,22 Second, it damages the mortar between squamous epithelial cells (E-cadherin), allowing pepsin to penetrate deeply to the active basal layers of the epithelium.1,20 Third, once pepsin binds to cell membranes, it is endocytosed; and once inside the cell depletes vital protective proteins, including carbonic anhydrase and stress proteins.1,2,19-21,23-27 Interestingly, using laryngeal cell lines, Johnston et al.28 has reported that pepsin upregulated genetic markers for squamous cell carcinoma.

In patients with LPR, post-cricoid biopsies show pepsin in the tissue demonstrated by Western blot analysis and immunohistochemistry (IHC). We have previously reported that 95% of patients with clinical and pH-documented LPR had tissue-bound pepsin (5% of controls).23 In addition, pepsin requires very little acid to become active, i.e., proteolytic (digests protein).13,16,20,21

Figure 1 shows the pepsin IHC of a biopsy from the posterior glottis of a patient with airway reflux. Once pepsin is tissue bound, acid from any source can activate it; that’s why acidic foods and beverages cause inflammation.1,2,11,16

Figure 1: Reflux Laryngitis: IHC for Human Pepsin 3b

Pepsin is the brown material and it is found both intracellular and extracellular. It is important to recognize that human pepsin is remarkably stable, and it retains proteolytic activity up to pH 6.5 depending on the substrate.21 At pH 6.5, for example human pepsin 3b (by far the most abundant type) is able to digest collagen.21 Peak peptic activity (100%) occurs at pH 2, but there is still some (~10%) activity at pH 621; see Figure 2. In other words, clinical reflux disease (LPR) is associated with tissue-bound pepsin,19-21,23-28 and we have previously shown that laryngeal damage occurs at pH 5.0 or less.20

Figure 2: Human Pepsin 3b Activity Curve21

The clinical significance of finding 50-90% of peptic activity in the pH 4.6-2.5 range is that almost all bottled and canned foods and beverages (all soft drinks) today are manufactured in that pH range to kill bacteria and prolong shelf life.1,2

How the World’s Diet Has Changed Since WWII

The dramatic increases in reflux over the past forty years cannot be explained by the obesity epidemic alone. Coincident with the reflux epidemic, the world’s diet has changed.1,2 In our lifetimes, there have been four unhealthy dietary trends2:

(1) Increased saturated fat
(2) Increased high-fructose corn syrup
(3) Increased exposure to organic pollutants (e.g., DDT, PCBs, dioxins)
(4) Increased dietary acidity (and other food additives)

The last of these trends—increased dietary acid—may hold the key to understanding the contemporary reflux epidemic and the dramatic increases in esophageal cancer.1-10

In 1973, following an outbreak of food poisoning, the U.S. Congress mandated that the Food and Drug Administration (FDA) take responsibility for assuring the safety of processed food by establishing “Good Manufacturing Practices.”1,2,29-31 How was this accomplished? Through acidification of bottled and canned foods, which was intended to prevent bacterial growth and prolong shelf life.1,2,29 From the 1979 Title 21 Act:

“Acidified foods should be so manufactured, processed, and packaged that a finished equilibrium pH value of pH <4.6 is achieved. If the finished equilibrium pH is 4.0 or below, then the measurement of acidity of the final product may be made by any suitable method.”1,2,31

Today, two generations later, the FDA has never wavered from this path and has apparently never questioned the possibility that acidification of the food supply might have potential adverse health consequences. In other words, the FDA encourages food manufacturers to reduce the pH of their products to less than 4.0, the same pH level as stomach acid (Figure 3).  In the U.S., the arc of reflux and esophageal cancer epidemics appears to closely follow soft drink consumption.2,32,33

Fig. 3: These Beverages (many deemed "Healthy") Are Very Acidic (pH 2.4-2.9). Click on photo to enlarge???

At the end of World War II, the average American consumed four (4) eight-ounce soft drinks per week. In 2010, the average 12-29-year-old young American drank forty-nine (49) eight-ounce soft drinks per week, an average of seven per day.2,33 The number provided by the America Beverage Association for this group is 606 liters per year, or almost two liters a day.33

In addition to acid as a major food additive, the FDA allows over 300 other chemicals be added to food that are “generally regarded as safe” (GRAS).1,2,30,31 Many of these GRAS food additives were “grandfathered in” in the 1970s without the benefit of contemporary state-of-the-art scientific scrutiny.2,31 Thirteen percent of these additives are acids, and there is no evidence that the FDA (or anyone else) has ever studied the long-term effects of these GRAS.

Excessive Dietary Acid Is the Missing Link

Why are reflux disease and esophageal cancer epidemic? Many years ago, when esophageal cancer was relatively uncommon, reflux patients usually presented in middle age. Today, we are seeing comparable disease in patients in their 20s.1 Over-acidity in the diet is the missing link, which explains the reflux epidemic and the increasing rates of Barrett’s and esophageal cancer.2

Today, even “organic” baby food is acidified. We measured the pH of an “organic” banana baby food and found the pH to be 4.3. Normally, the pH of banana is about 5.7. But this so-called “organic” banana had had acid added. Indeed, most bottled and canned foods and beverages are pH <4,1,2 because phosphoric, acetic, ascorbic, and/or citric acids are added. Sometimes the food label may just read “vitamin C enriched” or “vitamin C enhanced.”

Dietary and Lifestyle Modification

In the twenty years since publication of my Triological thesis,16 the number of Americans with reflux disease has doubled.1,4 In addition, it is clear that when it comes to reflux diseases, particularly airway reflux, the medical establishment has missed the boat by a mile. Furthermore, it is now clear that for airway reflux, the PPI-treatment failure rates (regardless of dose) are very high. Medication does not control reflux for most people, especially those with silent airway reflux. And, if the medication does help, should such patients have to stay on medication for life?

For most patients with reflux, “cleaning up” their diet and their lifestyle is the essential therapeutic action for getting well.1,2 When a patient’s reflux is bad, there is a (downward) vicious cycle going on. The more one refluxes; the more one refluxes. This is because reflux causes inflammation of the esophagus and its valves, and that inflammation further compromises the esophageal and valve function. Thus, more reflux begets worsening esophageal function, which in turn, begets more reflux. This is a downward spiral.

Thankfully, the opposite is true, that is, as inflammation and reflux improves, esophageal and valvular function improves as well so that there is less subsequent reflux. The point is that healthy function can be restored and that diet and lifestyle are far more important than medication; however, for many patients with severe reflux dietary and lifestyle changes are needed as well as medication at the beginning. That is why the Induction (“Detox”) Reflux Diet helps so much: Reduce acid and pepsin coming from below (from the stomach) for two weeks using medication, and at the same time, reduce damaging acid (that activates pepsin) coming from above during that same two week period. (Today, many of our patients are being treated by diet alone, i.e., without medication.)

Evolution of the Induction (“Detox”) Reflux Diet

For more than 25 years, LPR patients in the author’s practice were prescribed PPIs with or without a nighttime H2-antagonist, as well as limited nutritional and lifestyle counseling. The latter consisted of a list of do’s and don’ts (Table 1).

Table 1: Traditional Antireflux Diet and Lifestyle Modification Program
If you use tobacco, you must quit, because smoking causes reflux
Don’t wear clothing that is too tight, especially trousers, corsets, and belts
Avoid exercising, esp. weight-lifting, swimming, jogging, and yoga after eating
Do not lie down just after eating; do not eat within 2-3 hours of bedtime
Elevate the head of your bed if you are a nighttime refluxer (hoarse in the morning)
Limit your intake of red meat, butter, cheese, eggs, and anything with caffeine
Completely avoid fried food, high-fat meats, onions, tomatoes, citrus fruit (and fruit juice),
carbonated beverages (soda), beer, hard liquor, wine, mints, and chocolate

For many years we recognized that carbonated beverages, particularly caffeinated cola drinks, were a major risk factor for the development of airway reflux. Indeed, excessive consumption of carbonated beverages continues to be the single most common identified cause of medical treatment failure among our patients.1,2 Based upon clinical experience, we also began to limit our patients’ intake of citrus and hot (pepper) sauces. Other than those few specifics, the antireflux diet did not change much over the years; that is, until recently.1,2,11

With publication of the 2007 paper, Activity/stability of human pepsin: Implications for reflux attributed laryngeal disease,21 showing peptic activity up to pH 6.5; and having previously reported finding pepsin in the laryngeal biopsies of most patients with LPR20,23; we recognized that tissue-bound pepsin in LPR might be activated by exogenous hydrogen ions from any, including a dietary source.1,2 Consequently, we began measuring the pH of common foods and beverages and restricting airway reflux patients from consuming anything pH <5 for a trial period of two weeks. This appeared to be beneficial for patients.

In 2008, we began to systematically measure the pH of common foods and beverages, and as a consequence of finding acid in almost everything we tested, we began to strictly limit the acid intakes of our LPR patients, with outstanding results. As we measured the pH of more and more foods, the Induction Reflux (“Detox”) Diet evolved. Soon we had lists of good and bad foods and beverages. In the ensuing years, we refined the Induction Reflux Diet to exclude recognized reflux “trigger” foods as well as anything pH <5.1,2 The basic elements of the Induction Reflux Diet in its present form are shown in Table 2, and Table 3 provides the complete list for the Induction Reflux Diet.

Table 2: Basics of the Two-Week Induction Reflux Diet
Grilled/baked/broiled/boiled fish, shellfish, and poultry
All vegetables (except onions, tomatoes, garlic, and peppers)
Breads, rice, grains, low-sugar cereals, oatmeal, and tofu
Melons, bananas, ginger, agave, Manuka honey, chamomile tea
Low-fat soy, almond, coconut or cow milk, alkaline water pH >8
Finally, one cup of coffee or caffeinated tea per day allowed

Table 3: Induction Reflux Diet: What You Can Eat
Agave
Aloe vera (read label: make sure no acid added)
Artificial sweetener (max. 2 teaspoons per day)
Bagels and (non-fruit) low-fat muffins
Banana (great snack food)
Beans (black, red, lima, lentils, etc.)
Bread (especially whole grain and rye)
Caramel (max. 4 tablespoons per week)
Celery (great snack food)
Chamomile tea (most other herbal teas are not acceptable)
Chicken (grilled/broiled/baked/steamed; no skin)
Chicken stock or bouillon
Coffee (max. one cup per day; best with milk)
Egg whites
Fennel
Fish (including shellfish, grilled/broiled/baked/steamed)
Ginger (ginger root, powdered or preserved)
Graham crackers
Herbs (excluding all peppers, citrus, garlic, and mustard)
Honey (Manuka honey is preferred honey)
Melon (honeydew, cantaloupe, watermelon)
Mushrooms (raw or cooked)
Oatmeal (all whole-grain cereals)
Olive oil (max. 2 tablespoons per day)
Parsley
Popcorn (plain or salted, no butter)
Potatoes (all of the root vegetables except onions)
Rice (healthy, especially brown rice, is a staple during induction)
Skim milk (alternatively, soy or Lactaid skim milk)
Soups (homemade with noodles and low acid veggies)
Tofu
Turkey breast (organic, no skin)
Vegetables (raw or cooked, but no onions, tomatoes, garlic, or peppers)
Vinaigrette (max. 1 tablespoon per day; you must toss salads)
Whole-grain breads, crackers, and breakfast cereals

We have previously reported successful results of the Induction Reflux Diet in twenty patients with recalcitrant (PPI-resistant) airway reflux.1 All twenty of the study subjects claimed excellent compliance with the prescribed diet, and 95% improved on the low acid diet. Three subjects became completely asymptomatic, and another went from an initial RSI (reflux symptom index) of 28 to a post-diet RSI of 4. The mean pre-diet RSI34 (an index based on patient reported symptoms taken at each visit) was 14.8 and the mean post-diet RSI was 8.6 (P= 0.023); the mean RSI improvement was Δ-6.3. The mean pre-diet RFS35 (reflux finding score based on laryngoscopy) was 12.0, and the mean post-diet RFS was 8.3 (P< 0.001).1

Four Phases of Dr. Koufman’s the Reflux Diet

There are four phases of my reflux diet: (1) Induction, (2) Transition, (3) Maintenance, and (4) Longevity. To reiterate, the purpose of the two-week Induction Reflux Diet is to wash out pepsin and restore more normal functioning of antireflux defenses.

The Induction Reflux Diet has been the cornerstone of the author’s dietary and lifestyle program for patients with both airway and esophageal reflux. An additional adjunctive therapy that has been added within the last year is alkaline water. We evaluated a natural artesian alkaline (pH 8.8) water (Evamor™) in the laboratory and found that it instantaneously and permanently denatured pepsin; it also had good buffering capacity.11

The Induction Reflux Diet is still recommended for just the first two weeks with a gradual reintroduction of some additional fatty foods and other “historically refluxogenic” foods. Cheese, eggs, meats, sauces, and condiments are allowed in moderation as flavorings, but the key elements of the other phases of the reflux diet are that it remains relatively low-acid (not no-acid) and low-fat (not no-fat).

With fatty foods in particular, we teach patients moderation, using tasty fats as flavorings rather than as main ingredients. We also introduce the concept of pH balancing. The idea is that favored acidic foods may be combined with non-acidic foods. Acidic fruits, for example, that are not allowed to be eaten by themselves may be fine if added to breakfast cereal with milk (preferably low-fat milk) that has a high pH. Many of my patients report that alkaline water is a key variable to their recovery.

Finally, during the reflux diet, particularly during induction, there is no eating allowed within four hours of bed. Even if a person eats healthy food, eating too late can be a problem. It actually takes 4 hours for the stomach to empty completely. After the induction, the time between eating and recumbency can be 2-4 hours.

Here’s an example. I had a patient who was a restaurant manager. He would get off work at 11 p.m., and by midnight, he’d have eaten dinner and already gone to bed. He was frustrated that his reflux medication wasn’t helping as he awoke every morning with terrible heartburn and sometimes in the middle of the night, too. To make matters worse, he also told me that dinner was usually his biggest meal of the day. When he told me his story, I explained that he didn’t have a chance of beating his reflux as long as he was eating dinner before bed, he replied,” I pretty much knew that you were going to say that; I guess that I am going to have to make some big changes, huh?”  “Not really,” I told him, just take a break to eat your dinner before 8 p.m.”

Night eating is a major cause of reflux, obesity, diabetes, hypertension, snoring, and sleep apnea. Reflux patients who go to bed with a full stomach are going to reflux. Just as bad, by the way, is lying on the sofa after dinner. Actually, the best thing a person can do after dinner is take a walk. Even after induction, night eating is one of the biggest risk factors for both airway and esophageal reflux.

Based upon many years of examining pH-monitoring data, we know that most patients with airway reflux (LPR) are upright (daytime) refluxers, often with many (relatively short) periods of laryngopharyngeal acid/pepsin exposure. On the other hand, for airway reflux patients with supine (nocturnal) reflux, acid/pepsin contact times are often hours long. Such prolonged reflux episodes result in far more severe laryngopharyngeal inflammation and damage. Indeed, a single 2-6 hour supine nocturnal reflux event can produce hoarseness, sore throat, and cough symptoms that can last several weeks.

After induction, comes Phase II, Transition. This phase requires trial and error on the part of the patient as foods and beverages are added back. I usually start by adding back egg yolks, condiments, and some additional fruits (those that are relatively low-acid, such as pears and red apples) and some meats (those that are relatively low-fat, such as white pork and lean beef).

Three-egg omelets are made with just one yolk as an example of low-fat (not no-fat) eating, and when it comes to meats, portion control is as important. Patients are instructed to use/order all dressings, condiments, cheeses, and sauces on the side so that they can use relatively small amounts. Wine and cocktails may be added back with the admonition that these must be limited to one per day, and not too late in the evening.

During the Transition Phase, which can last months, there must be a lot of trial and error with foods. The truth is that everyone with reflux is different, and even foods that are forbidden during the induction phase may be well-tolerated, including onions, tomatoes, garlic, and peppers.  These are all idiosyncratic foods, that is some patients can tolerate some but not others, and some are better cooked than raw, e.g., tomatoes and onions. Some people can tolerate garlic flavorings but not garlic itself … and so on.

It is also important to point out that different patients have different trigger foods, which are foods that cause symptoms, sometimes immediate symptoms like throatburn.  Even items on the best-for-reflux food list are trigger foods for some patients.

During the transition phase, the key endpoints are the patient’s symptoms and the laryngeal examination. The author employs the Reflux Finding Score (RFS) for every reflux patient at every visit and the RFS should be lower (more normal) as time passes. In addition, during Transition, I attempt to get patient off antireflux medications, at least off PPIs.  H2-antagonists, such as ranitidine, can be used up to 150 mg q.i.d. without problems, even during pregnancy. Furthermore, H2-antagonists are perfectly acceptable as ad hoc medications, taken as needed.  Ranitidine may be preemptively taken before dinner and before bed by patients if they know they are going to be eating later than usual or eating foods that may be problematic. The same is not true of PPIs that often are associated with hyperacidity “rebound” after they are discontinued.

During the Third Phase, Maintenance, the patient can sustain a “healthy lifestyle” such that her/his reflux is under control for a prolonged period. In addition, during this phase, the patient will easily manage eating in restaurants, and he/she will feel that healthy eating is easy.

We call the final, Fourth Phase, Longevity, the patient has no reflux, is close to her/his ideal body weight, and effortlessly eats at home or dines out without fear of having reflux. In this phase, patients are not on reflux medication. Sound too good to be true? Longevity takes work and persistence, and sometimes the help of a nutritionist. But it is true that normal physiology can be established in many reflux patients with incredibly outstanding long-term outcomes. This is, after all, proof that reflux is primarily a disease of what we eat and when we eat it.

In summary, excessive acid and fat in the diet, as well as late night eating and alcohol in excess, are the most important reversible lifestyle-related factors contributing to the development of chronic airway (and esophageal) reflux. For the reflux sufferer, tobacco and highly-acidic beverages, such as soft drinks, should be totally and permanently avoided.

With customized dietary and lifestyle modifications, about two-thirds of reflux patients can be managed successfully. Without such, all other treatments are usually doomed to failure.  One final note: From a public health point of view, it would probably be very beneficial to have the pH of all bottled and canned foods and beverages printed (by law) on nutritional labels. Please help any way you can with this effort!

References

  1. Koufman JA. Low-Acid Diet for Recalcitrant Laryngopharyngeal Reflux: Therapeutic Benefits and Their Implications. Ann Otol Rhinol Laryngol 120:281-87, 2011.
  2. Koufman JA, Stern JC, Bauer MM. Dropping Acid: The Reflux Diet Cookbook & Cure. Reflux Cookbooks LLC (The Reflux Cookbooks LLC), Midpoint Trade Books (Distributor), New York, 2010.
  3. El-Serag H, Becher A, Jones R. Systematic Review: Persistent Reflux Symptoms on Proton Pump Inhibitor Therapy in Primary Care and Community Studies. Alimentary Pharmacology and  Therapeutics. Blackwell Publishing, Ltd., Pages 1-18, 2010.
  4. El-Serag HB. Time trends of gastroesophageal reflux disease: A systematic review. Clin Gastroenterol Hepatol 2007;5:17-26.
  5. Altman KW, Stephens RM, Lyttle CS, et al. Changing impact of gastroesophageal reflux in medical and otolaryngology practice. Laryngoscope 2005;115:1145-53.
  6. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005;97:142-6.
  7. Lund O, Hasenkam JM, Aagaard MT, Kimose HH. Time-related changes in characteristics of prognostic significance in carcinomas of the oesophagus and cardia. Br J Surg 1989;76:1301.
  8. Conio M, Blanchi S, Lapertosa G, et al. Long-term endoscopic surveillance of patients with Barrett’s esophagus. Incidence of dysplasia and adenocarcinoma: A prospective study. Am J Gastroenterol 2003;98:1931-9.
  9. Reavis KM, Morris CD, Gopal DV, Hunter JG, Jobe BA. Laryngopharyngeal reflux symptoms better predict the presence of esophageal adenocarcinoma than typical gastroesophageal reflux symptoms. Ann Surg 2004;239:849-56.

10.  Amin MR, Postma GN, Johnson P, Digges N, Koufman JA. Proton pump inhibitor resistance in the treatment of laryngopharyngeal reflux. Otolaryngol Head Neck Surg 2001;125:374-8.
11.  Koufman JA, Johnston N. Potential Benefits of pH 8.8 Alkaline Drinking Water as an Adjunct in the Treatment of Reflux Disease. Ann Otol Rhinol Laryngol 121:431-34, 2012.
12.  Amin MR, Postma GN, Setzen M, Koufman JA. Transnasal esophagoscopy: A position statement from the American Broncho-Esophagological Association. Otolaryngol Head Neck Surg 2008;138:411-3.
13.  Koufman JA. Perspective on Laryngopharyngeal Reflux: From Silence to Omnipresence. Classics in Voice and Laryngology. Branski R, Sulica L, Eds. Pages 179-266, Plural Publishing, San Diego, 2009.
14.  Halum SL, Postma GN, Johnston C, Belafsky PC, Koufman JA. Patients with isolated laryngopharyngeal reflux are not obese. Laryngoscope 2005;115:1042-5.
15.  Koufman JA. Personal communications with Dr. Robert Sataloff (Philadelphia, PA) and Dr. John Hunter (Portland, OR)
16.  Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): A clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991;101 (Suppl. 53):1-78.
17.  Lillemoe KD, Johnson LF, Harmon JW. Role of the components of the gastroduodenal contents in experimental acid esophagitis. Surgery 1982;92:276-84.
18.  Johnson LF, Harmon JW. Experimental esophagitis in a rabbit model. Clinical relevance. J Clin Gastroenterol 1986;8 (Suppl 1):26-44.
19.  Axford SE, Sharp S, Ross PE, Pearson JP, Dettmar PW, Panetti M, Koufman JA.  Cell biology of laryngeal epithelial defenses in health and disease: Preliminary studies.  Ann Otol Rhinol Laryngol 2001;110:1099-1108.
20.  Johnston N, Bulmer D, Gill GA, Panetti M, Ross PE, Pearson JP, Pignatelli M, Axford A, Dettmar PW, Koufman JA.  Cell biology of laryngeal epithelial defenses in health and disease: Further studies. Ann Otol Rhinol Laryngol 2003;112:481-91.
21.  Johnston N, Dettmar PW, Bishwokarma B, Lively MO, Koufman JA. Activity/stability of human pepsin: Implications for reflux attributed laryngeal disease. Laryngoscope 2007;117:1036-9.
22.  Orlando RC, Powell DW, Carney CN. Pathophysiology of Acute Injury in Rabbit esophageal Epithelium. J Clin Invest 1981;68:286-93.
23.  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;114:2129-34.
24.  Knight J, Lively MO, Johnston N, Dettmar PW, Koufman JA. Sensitive pepsin immunoassay for detection of laryngopharyngeal reflux. Laryngoscope 2005;115:1473-8.
25.  Gill GA, Johnston N, Buda A, Pignatelli M, Pearson J, Dettmar PW, Koufman J. Laryngeal epithelial defenses against laryngopharyngeal reflux (LPR): Investigations of pepsin, carbonic anhydrase III, pepsin, and the inflammatory response.  Ann Otol Rhinol Laryngol 2005;114:913-21.
26.  Johnston N, Dettmar PW, Lively MO, Koufman JA.  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.
27.  Samuels TL, Johnston N. Pepsin as a marker of extraesophageal reflux. Ann Otol Rhinol Laryngol 2010;119:203-8.
28.  Johnston N, Yan JC, Hoekzema CR, et al. pepsin promotes Proliferation of Laryngeal and Pharyngeal Epithelial Cells. Laryngoscope 2012;122:1317-25.
29.   “Acidified Foods.” Code of Federal Regulations—Title 21—Food and Drugs Chapter I, Department Of Health And Human Services Subchapter B—Food for Human Consumption Part 114. United States Food and Drug Administration. Arlington, VA, Washington Business Information, 2010.
30.  “Generally Recognized as Safe Food Additives: FDA Database of Selected GRAS Substances.”  United States Food and Drug Administration. National Technical Information Service, Springfield, VA, 2009.
31.  “Food Safety: FDA Should Strengthen Its Oversight of Food Ingredients Determined to Be Generally Recognized as Safe (GRAS).”  GAO-10-246: United States Government Accountability Office, February 3, 2010.
32.  Bellis M. Introduction to Pop: The History of Soft Drinks Timeline. About.com (http://inventors.about.com/od/sstartinventions/a/soft_drink.htm)
33.  Lobbying 2009: American Beverage Association. Center for Responsive Politics. (http://www.opensecrets.org/lobby/clientlbs.php?year=2009&lname=American+Beverage+Assn&id) March, 2010.
34.  Belafsky PC, Postma GN, Koufman JA.  Validity and reliability of the reflux symptom index (RSI). J Voice 2002;16:274-7.
35.  Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS).  Laryngoscope 2001;111:1313-17.

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