Rethinking Reflux: The Real Culprit Isn’t Acid—It’s Pepsin

Are We Treating Reflux All Wrong?

If you suffer from acid reflux, you’ve likely been told that stomach acid is the problem. But what if the real issue isn’t acid at all? We now know that pepsin a powerful digestive enzyme, is the primary culprit behind much of the damage associated with reflux. Yet, most treatments focus solely on acid suppression, failing to address the real problem. 

What we commonly call “acid reflux” might be more accurately described as “peptic reflux,” as pepsin—the stomach’s main digestive enzyme—is what harms the throat and airways.

Why Pepsin Matters More Than Acid

Traditional gastroesophageal reflux disease (GERD) primarily affects the esophagus and causes symptoms like heartburn and regurgitation. In contrast, respiratory reflux—also known as laryngopharyngeal reflux (LPR)—occurs when pepsin and other stomach contents travel upward into the throat, sinuses, and lungs.

Because respiratory reflux affects the throat, vocal cords, and airways, many people don’t experience heartburn at all. Instead, symptoms can include:

• Chronic cough
• Shortness of breath
• Hoarseness or voice loss
• Postnasal drip
• Difficulty swallowing
• A lump-in-the-throat sensation
• Sinus pressure and pain
• Ear fullness, pain, and tinnitus

Due to the absence of classic heartburn, respiratory reflux is often misdiagnosed or overlooked. Respiratory reflux is, therefore, silent, i.e., “silent reflux.”

How does Pepsin Reach the Respiratory System?

In a healthy digestive system, two key sphincters—the lower esophageal sphincter (LES) and the upper esophageal sphincter (UES)—work together to maintain stomach contents in the stomach, and not the esophagus and respiratory system. 

The LES is the primary barrier, preventing acid and pepsin from flowing back into the esophagus. However, factors like obesity, overeating, and certain foods can weaken this barrier, allowing stomach contents to escape.

Once past the LES, the UES acts as a secondary defense to protect the throat and airways. When the UES is compromised, even partially, it fails to stop reflux from reaching sensitive areas such as the throat, sinuses, and lungs. In these locations, pepsin can adhere to tissues and be reactivated by acidic foods or beverages, leading to inflammation and progressive tissue damage.

This breakdown in dual sphincter protection underscores how pepsin, once confined to the stomach, can contribute significantly to respiratory reflux and its associated symptoms and diseases.

How Pepsin Damages Tissues Outside the Stomach

Pepsin is an incredibly potent enzyme, capable of breaking down proteins into their smallest components. It is even used in research studies to break down complex molecules into their component parts. 

While pepsin plays a critical role in digestion, it is meant to function only in the stomach. When reflux occurs, pepsin adheres to the delicate tissues of the throat, sinuses, and lungs, which are not designed to withstand its activity.

Once outside the stomach, pepsin can cause:

• Vocal cord damage (leading to voice changes, nodules, polyps, and cancer)
• Postnasal drip, sinusitis, chronic bronchitis, and cough 
• Increased susceptibility to viral and bacterial infections
• Long-term complications, including Barrett’s esophagus, lung disease, COPD, and even cancer

The Link Between Pepsin and Cancer

Pepsin outside the stomach is so damaging, that there is a well-documented connection between pepsin and cancers of the aerodigestive tract (throat, esophagus, and lung). 

In one study we detected pepsin in every laryngeal cancer biopsy examined. And after decades of research and clinical work in this field, I have personally come to believe that while smoking increases cancer risk, reflux may be an essential factor in developing all types of cancer of the respiratory system. 

Pepsin Activation and Deactivation

Understanding when pepsin is active is key to managing its harmful effects. Pepsin is activated by acidic environments, which are influenced by the pH of foods, beverages, and refluxed stomach acid. Its activity levels vary with pH:

• pH 1-4: Highly active, breaking down proteins and damaging tissues
• pH 5-6: Partially active, still capable of causing inflammation
• pH 7: Inactive but remains stored in tissues, ready to reactivate
• pH 8+: Completely deactivated, no longer harmful

Pepsin is most active at pH 2-3, the same acidity as some soft drinks like Coca-Cola. Even at pH 4, pepsin is still active, making all soft drinks a major dietary risk factor for reflux.

Because the pharynx typically has a neutral pH (~7), pepsin can remain dormant but reactivate upon contact with acidic foods or beverages. Only a complete cessation of reflux for 2-4 weeks (Reflux Detox) and a high pH level diet can permanently wash it out and deactivate it.

The Limitations of Current Testing Methods

Diagnosing pepsin reflux is challenging. While pepsin detection kits exist to measure pepsin in saliva and tissue samples, they are unreliable diagnostic tools, and I do not recommend them. Additionally, a negative test result does not rule out pepsin-related disease. Pepsin levels fluctuate throughout the day and can be influenced by food intake. 

Endoscopy is also an unreliable diagnostic tool for reflux-related damage, as it often fails to detect pepsin in affected tissues. Diagnosing respiratory reflux remains a challenge, and it is difficult to find a specialist who is well-versed in this subject and can make a proper diagnosis.

How to Treat Pepsin Reflux

Since pepsin, not acid, is the main problem, treatment should focus on preventing pepsin activation rather than just reducing stomach acid. Key strategies include:

• Following a low-acid alkaline diet to prevent pepsin reactivation. Incorporating fresh vegetables, non-citrus fruits, and lean proteins can help maintain a balanced pH in your digestive system and reduce pepsin activation in the respiratory system. 
• Drinking alkaline water (pH 9.5+) to deactivate pepsin. Alkaline water with a high pH can render pepsin inactive in the respiratory tract. Regular consumption may help reduce the enzyme’s damaging effects on the throat and airway tissues.
• Avoiding carbonated beverages, which can increase reflux. Carbonated drinks activate pepsin in or on your tissue. In addition, they introduce gas into the stomach, which increases internal pressure. This pressure can push stomach contents, including pepsin, back into the esophagus and throat. Remember, carbonated drinks are highly acidic. 
• Using pH strips to check food acidity. By regularly checking pH values of your foods and beverages, you can make more informed dietary choices that favor less acidic options. Ideally, at the start of any antireflux treatment program, your food/beverage intake should be pH 5+.  
• Eliminating alcohol and fatty foods. Certain substances, such as alcohol and fatty foods, are known to relax the lower esophageal sphincter (LES), the barrier that normally prevents reflux. Avoiding these foods and beverages can help maintain a tighter barrier, reducing the likelihood that pepsin will escape into the throat and airways. By the way, caffeine and nicotine both relax the LES.
• Maintaining a healthy weight and avoiding late-night eating. Excess weight increases abdominal pressure, which can force stomach contents upward. Eating late at night can also lead to reflux when you lie down, as gravity no longer aids digestion. Finishing your last meal a few hours before bedtime is an important strategy to heal reflux. 
• Using alginate-based medications before bedtime to prevent nighttime reflux. Alginate-based medications create a physical barrier that floats on top of stomach contents. This barrier helps prevent reflux during sleep by reducing the chances of pepsin and other digestive substances flowing back into the esophagus and throat. I recommend Gaviscon Advance and RefluxRaft.
• Sleeping on an incline to reduce nighttime reflux. Elevating the head during sleep takes advantage of gravity to keep stomach acids and pepsin in place. An inclined sleeping position can help minimize the risk of nighttime reflux.
• For those with severe symptoms, a reflux detox diet may be beneficial. A detox diet involves eliminating potential dietary irritants to reduce inflammation and allow the respiratory and digestive systems to heal.

Why PPIs Fail & The Future of Reflux Treatment

While lifestyle and dietary changes are essential for managing and healing pepsin reflux, many patients wonder whether medications can help. Unfortunately, traditional reflux drugs like Proton pump inhibitors (PPIs) do not effectively address respiratory reflux. PPIs reduce acid but do nothing to stop pepsin from causing damage.

However, new treatments are on the horizon. N-Zyme Biomedical is developing a medication that directly targets pepsin. Fosamprenavir, originally FDA-approved for HIV/AIDS, is being repurposed to neutralize pepsin. 

Unlike PPIs, this drug addresses the root cause of reflux damage. While research is still ongoing, this approach may represent a major breakthrough in reflux treatment.

Conclusion

Reflux isn’t just about acid—it’s about pepsin. By shifting our focus from acid suppression to pepsin control, we can revolutionize reflux treatment and provide lasting relief for millions. Adjusting dietary and lifestyle choices is the first step toward healing.

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For more information about diagnosis and treatment of acid reflux, see two companion books on Amazon: Dr. Koufman’s Acid Reflux Diet and Dropping Acid: The Reflux Diet Cookbook & Cure. If you would like to receive personalized guidance and strategies for lasting relief, consider scheduling an online consultation.