Chronic Proton Pump Inhibitor Use Carries Significant Dangers

Summary

Long Term Use May Cause or Contribute to:

  • Osteoporosis
  • Cardiovascular Disease
  • Barrett’s Esophagitis
  • Esophageal Cancer
  • Hypochlorhydria
    • Poor Digestion
    • Small Intestinal bacterial Overgrowth (SIBO)
    • Multiple GI Symptoms
    • GI Infection
    • Malabsorption
    • Toxicity
  • Reduced gallbladder function
  • Decreased endothelial Nitric Oxide (eNOS)
  • Increased skin aging
  • Elevated Chromogranin A disrupts normal signaling mechanisms

Uses

Proton Pump Inhibitors (PPI) are one of the most commonly prescribed drugs. They are also available over the counter. Doctors prescribe them like candy, apparently under the (incorrect) assumption that they are as safe as candy. Such is not the case. Prilosec (Omeprazole) is the most commonly prescribed PPI with over 50 million prescriptions last year. It and other PPI drugs, acid reducers, and acid blockers (Axid, Nexium, Pepcid, Pepto-Bismol, Prevacid, Protonix, Tagamet, Tums, Zantac) are used to treat frequent heartburn. Other uses include: dyspepsia, stomach and duodenal ulcer, part of a program to eradicate H. pylori, GERD, Barrett’s esophagitis, gastritis and gastrinomas.

Proper Prescription

The Prilosec product insert states that it is to be used daily for only 14 days, and that 14 day courses may be repeated only once every 4 months. The product insert warns “ Stop use and ask a doctor if your heartburn continues or worsens; if you need to take this product for more than 14 days; or if you need to take more than 1 course every 4 months”. The FDA has advised that no more than 3-14 day courses be used per year. Unfortunately, many doctors don’t think there is anything wrong with patients using them for up 20 years! If you have been taking PPI for more than 2 weeks and your doctor has told you that it is perfectly safe, then read on!

Efficacy

How well do PPI work? The Prilosec OTC product insert references two 14-day studies involving 3,120 people. At the end of 14 days, about 70% of the people taking 20mg. of Omeprazole reported complete heartburn relief. When no nighttime heartburn and no more than mild heartburn were added in, the percent reporting relief increased to about 81.4%. What is never stated in television commercials is that about 45% of people taking a placebo for 14 days reported complete relief and 71.2% had only mild heartburn!

It is critical to note that the study referenced in the Prilosec OTC product insert, involving 3,120 people, only discussed symptomatic relief of heartburn. It did not address the root causes of the symptoms, nor did it determine whether any of the patients were actually overproducing stomach acid! Further, it was only a short-term study that failed to follow those people after they stopped taking Omeprazole, so there is no information on whether there was any significant long-term benefit.

The significant question should be how well do PPI work long-term in refractory cases. A 2012 study of 200 people with refractory GERD that occurred at night while in bed was performed. Half the patients took PPI twice daily and the other half took nothing. The study concluded that those on PPI actually had more total episodes of reflux, although fewer were of the acid type.

Method of Action

PPI are a class of drugs that causes prolonged reduction in the production of stomach acid. They work by binding to and blocking the hydrogen/potassium adenosine triphosphate enzyme in the parietal cells of the stomach, preventing the release of acid.

Stated Adverse Effects

Common adverse effects on the product label include: headache, nausea, diarrhea, constipation, stomach pain, fatigue, dizziness, gas, allergic reaction, rash, itch anxiety, depression and myopathies, including rhabdomyolysis (which may be fatal). In addition decreased absorption of Vitamin B12 and other essential minerals are known side effects, of which few prescribing doctors advise their patients. Additional complications can include: increased rate of GI infection with Clostridium difficile, small intestinal bacterial overgrowth (SIBO), spontaneous bacterial peritonitis, fundic gland polyps and microscopic colitis. PPI are contraindicated when used in combination with other drugs, including: warfarin, diazepam (Valium), digoxin, clopidogrel, cilostizol, prescription antifungal or anti-yeast medicines, diazepam, digoxin, tacroimus, mycophenolate mofetil, prescription antoretrovirals and methotrexate. In addition, there are a number of drugs whose absorption is decreased with reduced stomach acid, and therefore may not work as effectively.

The remainder of this article will deal with the potentially serious adverse effects of long-term use of PPI, which are not well known and certainly rarely, if ever discussed by your doctor or pharmaceutical producers of the drugs, nor are they discussed on the product insert. The proper usage of PPI in certain situations that require acute relief of heartburn pain or for ulcer healing is not being questioned. Rather it is the potential grave harm caused by the all-to-common prescription of PPI that may go on for years, that is discussed.

Physiology of Digestion

To understand why in the vast majority of patients, long-term PPI use does not work, and carries substantial health risks, you need to have an understanding of how the digestive system works.

The gastro-intestinal (GI) system extends from the brain to the rectum; it is one that is critical to health, but poorly appreciated. It communicates with the external environment, and actually has its own brain! The surface of the intestines, which is greater than that of a tennis court, is where most of the action occurs. This is where the body decides what to digest and absorb and what to excrete. It is where the outside world meets the inside of the body, so it is an area of battle between our body and other life forms that want to feed on it. The GI system contains the majority of immune cells in the body for good reason. As a result of its interaction with food, living organisms and toxins, the GI system is the major system where things go wrong. The main functions of the GI system are; digestion of fat, carbohydrate and protein; absorption of their constituent parts, excretion of waste and toxins, and to act as a barrier to keep out toxins, poisons, bacteria, viruses and parasites.

Digestion has components that include neurological, chemical, mechanical and hormonal influences. The GI tract may be broken down into distinct areas, which are: mouth (sensing toxins through taste), chewing, salivary digestive enzymes, swallowing; esophagus (transport from mouth to stomach); stomach (production of stomach acid for digestion and pepsin- a digestive enzyme, food storage and mechanical breakdown); small intestine (digestion by mechanical means, pancreatic enzymes and bile); hepato-biliary (bile formation and secretion, neutralization of toxins); and the large intestine which absorbs water and eliminates waste. Let’s talk about the esophagus and stomach in more detail.

The major job of the esophagus is transporting food. It is protected by mucosal secretions. The major problem with the esophagus is erosion from gastro-esophageal reflux (GERD).

The stomach is the main area of protein digestion, which must occur in an acidic environment. One of the truly amazing feats of the body, one that is little appreciated, is that, to go from the average body pH of about 7.2 to the harsh acidic environment of the stomach, pH 1-2.5 requires that the body concentrate hydrogen ions (acid) over 3,000,000 times that of the rest of the body! To create a liter of stomach acid requires 1,500 calories! Food digestion, (especially protein), which begins in the stomach, continues in the small intestine. The food bolus (chyme) passes into the duodenum as a result of smooth muscle contraction (peristaltic movement). This causes a reflex that decreases production of stomach acid (HCL) and also slows further emptying of the stomach. The reflex is triggered by: presence of acid and the mucosal irritation it causes, stretching of the upper duodenum and presence of protein breakdown products (peptides). The presence of HCL, fat and peptides also cause the release of two additional hormones: secretin and cholecystokinin (CCK). One can therefore see how important stomach acid is for the digestive process.

Secretin causes the release of very alkaline sodium and potassium bicarbonate from the pancreas. This neutralizes stomach acid and provides the required alkaline conditions in the small intestine necessary for the continuation of digestion. This also causes a reflex to slow stomach emptying so the proper pH can be maintained.

Fat and protein in the small intestine stimulate the release of CCK, which travels to the pancreas and causes the release of pancreatic enzymes that digest carbohydrate, protein and fat. Similar to the inactive pepsinogen in the stomach, the pancreatic digestive enzymes are also secreted in their inactive form. In the duodenum however, they are activated by an alkaline environment, just the opposite of the stomach, which requires acid to activate pepsinogen.

Fat digestion is a little more complicated. The liver produces 600-1200ml. of bile each day. Bile contains acids that help emulsify fat and turn it into small particles (chylomicrons) that can be further digested by lipase enzymes. Bile acids also aid in transportation of the digested fat through the intestinal mucosal membranes in particles called micelles. Without bile acids, half of the fat is undigested and lost in the stool. Bile also aids in the excretion of excess cholesterol, bilirubin (the end product of red blood cell breakdown) and fat-soluble toxins. CCK stimulates release of bile from the gall bladder.

There are many things that can and do go wrong, and it often starts in the stomach. Low stomach acid (hypochlorhydria) causes issues that continue into the small intestine. Lack of acid leads to poorly digested food to be dumped into the duodenum. Since the conditions are not acid but alkaline, this sets up a situation where secretin and CCK stimulation may be reduced. Any bicarbonate released makes the conditions even more alkaline. Decreased amounts of digestive enzymes are released. Stimulation to the gall bladder is reduced.

Low stomach acid causes failure of sterilization of food, which contains many microorganisms. This, along with too alkaline conditions set the stage for overgrowth of unfriendly bacteria in the small intestine, which is normally host to the friendly, protective lactobacillus bacteria. This also sets the stage for other pathological bacteria, parasites and yeast (Candida) to overproduce. This is called Small Intestinal Bacterial Overgrowth (SIBO), or dysbiosis, and can lead to: inflammation, production of numerous toxins, reduce the production of short chain fatty acids by beneficial bacteria, thereby depriving the intestinal mucosal cells of their primary energy source; reduced production of Vitamin K and some B complex vitamins by friendly bacteria, cause irritable bowel syndrome, hydrogenate essential polyunsaturated fatty acids, block absorption of essential minerals, use essential amino acids leading to deficiencies, turn essential amino acids into toxic products that are absorbed and must be detoxified and excreted, increase the toxic burden of the body causing stress to the liver and kidneys, increase oxidative damage, interfere with the breakdown of bile acids and estrogens increasing the risk for certain cancers, increase the pH of the stool which increases the risk for colon cancer, cause toxic gasses methane and hydrogen sulfate to be produced, over-stresses the normal GI immune system and eventually reduce Secretory IgA, and cause the GI mucosal tight cell junctions to become leaky, leading to “Leaky Gut Syndrome” which increases the risk for food allergies and autoimmune disorders.

Other common causes of dysbiosis include: repeat antibiotic therapy, toxic chemicals and heavy metals, exposure to pathogens and parasites, pancreatic insufficiency, slow bowel transit time (often caused by a low fiber diet), poor immune function, poor diet leading to multiple nutritional deficiencies, excess intake of sugar, refined carbohydrates, junk food, food allergies, (especially gluten and dairy products), sodas and alcohol. Add in hypochlorhydria and you have a recipe for disaster.

Treat the Cause, Not the Effect

It should be apparent that what goes wrong at the top of the system, in the stomach, carries through to the small and large intestine. The logic used by a doctor who prescribes long-term use of PPI would imply that too much stomach acid (hyperchlorhydria) is the cause of your heartburn. On the surface, this makes sense, as acid from the stomach does irritate esophageal tissues. Unfortunately, your doctor makes an assumption that is a leap of faith; that because acid causes esophageal irritation leading to “heartburn”, that the cause of heartburn is too much stomach acid. Your doctor has now assumed that his/her assumption is correct, and prescribes long-term use of PPI with little regard to the consequences. Let’s take a closer look at the faulty logic involved.

First, without performing any testing, your doctor has made the assumption that you are overproducing stomach acid. Of course, since PPI are top sellers, Big Pharma promotes this by inundating you with commercials of happy people who take their product to relieve excess stomach acid. So now, everyone is led to believe that too much acid is the obvious cause of heartburn and that you need to suppress its production. Does this make sense? No- and here is why:

  • Virtually every animal has evolved to produce acid to aid in digestion, as well as to kill microbes that are on food and in water. If production of stomach acid did not confer a significant evolutionary advantage, it would have long ago been selected against. This is obviously not the case, but it is what your doctor is trying to do, when long-term PPI use is prescribed. This is in obvious contradiction to evolutionary facts.
  • By now, you should understand that humans produce stomach acid because it is important in digestion. If this were not the case, then we would have no need for a highly evolved organ, the stomach. This organ is extremely specialized to do one thing; it concentrates acid by up to 3,000,000 (yes that is 3 million) times more than in the blood. It requires a significant amount of energy and biological machinery to do so. Not only does it produce acid, the stomach has to protect itself from acid that can reach a pH of 0.5 (basically pool acid). Try putting pool acid on your skin to see what happens- actually don’t- that was rhetorical. So the stomach has specialized cells that produce mucus that lines the stomach, creating a barrier against acid that would erode the stomach lining. This requires specialized cells and also takes energy. Then the stomach also produces a protein-digesting enzyme, called pepsinogen. This enzyme is also made in specialized stomach cells called chief cells. Of course, it can’t be active in the cells or it would digest them. So the enzyme is secreted in an inactive form that requires stomach acid to activate it to pepsin. The optimal environment for pepsin is pH 2.0. Activity is reduced as the pH increases (acid decreases), so at pH 6.5 it is inactive. Pepsin is one of three protein digesting enzymes in the GI tract and it specializes in breaking apart bonds between specific amino acids, called aromatic amino acids (phenylalanine, tryptophan and tyrosine). No pepsin= decreased protein digestion.
  • If excess stomach acid were the problem, then you would expect to see much more heartburn and GERD in a younger population, who can produce more stomach acid. It is estimated that 50% of people over the age of 60 have hypochlorhydria, yet it is the older population with the most symptoms. Approximately 27% of Medicare patients used GERD medications. 50% of all GERD diagnoses are in the elderly. GERD is most often diagnosed in people over 40, with about 50% of all GERD diagnosis occurring between 45-64 years of age. Add the 27% of Medicare aged patients (over 65) and about 77% of GERD diagnoses occur after age 40.
  • Long-term use of PPI fails the majority of the time. In a 2007 study of 5.672 people who had used PPI for more than 22 days, 1741 had persistent and intense symptoms, 2126 had intermediate symptoms and only 1805 had low symptoms. The researches concluded, “The 2007 NHWS gives support to the hypothesis that persistent and intense GORD (GERD) symptoms despite PPI therapy have a significant and negative impact on both HR-QOL (Health related Quality Of life), and healthcare resource utilization. These findings outline the need for new treatment options for symptomatic GORD patients taking PPI therapy”. This should have been the nail in the coffin for PPI, yet they remain among the most popular drugs.
  • A recent study of 89 patients clearly showed that gastric hypochlorhydria in female patients with dyspepsia was clearly associated with higher pain-related symptom scores.
  • Multiple studies show the association between age and hypochlorhydria:
    1. 80% of the elderly (average age 84) in one study were hypochlorhydric.
    2. Over 30% of people over age 60 suffer from atrophic gastritis, characterized by low stomach acid production, in another study.
    3. Up to 40% of postmenopausal women have low to no basal gastric acid secretion
    4. In a huge study of 3,484 people 27% had no stomach acid (achlorhydria), with a higher incidence in the elderly.
    5. There is a link between atrophic gastritis, stomach infection with the bacteria H.pylori, and low to no stomach acid production. In general, the incidence of H.pylori infections increases with age, so that by age 50, 50% of people are infected. This correlates with the increasing rate of atrophic gastritis and reduced acid output.

It should now be obvious that the correlation between excess stomach acid production and heartburn/GERD is poor. The fact is that low stomach acid has a closer association with the incidence of these symptoms than does high acid. It is not the acidity of the stomach that is the problem; rather it is that the Lower Esophageal Sphincter (LES) does not close properly, allowing for acid to reflux into the esophagus. Let’s explore why this occurs.

Stomach Acid, Gastrin and the Lower Esophageal Sphincter

The LES is the circular muscle between the esophagus and the stomach. It relaxes for entry of food and is normally supposed to close to prevent reflux of food and acid into the esophagus. When you experience symptoms of GERD is when it doesn’t work properly. Thinking about food, smelling it, stretching of the stomach by food, and partially digested proteins stimulate the production of the hormone gastrin. Gastrin causes the release of stomach acid and pepsinogen, which is an inactive protein-digesting enzyme. Stomach acid then activates pepsinogen to create the active enzyme, pepsin, which further assists with the digestion of protein. There is a feedback mechanism that regulates the secretion of gastrin and the subsequent production of stomach acid, when enough has been produced to digest the food.

In addition to stimulating the release of stomach acid, gastrin also stimulates stomach muscles to contract, assisting in the digestion process. Simultaneously it triggers the pyloric sphincter, located between the stomach and first part of the small intestine (duodenum), to contract to reduce the rate of stomach emptying, so food can continue the digestion process properly as it passes through the GI tract. Gastrin, in normal physiological quantities as reached after a normal meal, causes the LES pressure to reduce! This may occur to allow food to more easily pass through the esophagus and into the stomach. This does not mean that the normal reduction of LES pressure causes GERD. It is what is called Transient Lower Esophageal Sphincter Relaxations (TLESR) that are a major cause of GERD. From GERD in the 21st Century, Series #5 “ Transient LES relaxations are a physiologic response to gastric distention that lead to gastric-gas venting and avoidance of gastrointestinal bloating, and may occur with belching, vomiting, or rumination. Not surprisingly, transient LES relaxations are the primary cause of post-prandial reflux”. Gastrin, while lowering LES pressure, did not increase the number of TLESR.

This is where things get spooky! PPI’s actually cause the LES to relax in a dose- dependent manner! In addition, they reduce normal contraction of the LES. The difference is that normal gastrin release at physiological levels occurs during a meal, while the effect of gastrin stimulation by PPI is constant. PPI therapy significantly increases gastrin levels. One study showed that PPI patients had gastrin levels more than 16 times higher than normal patients not on PPI. Gastrin is a hormone. Just like any other hormone, it is important to maintain levels within a narrow range for optimal health. High or low levels of hormones carry consequences. Let’s see what are the penalties for long-term PPI use and elevated gastrin levels.

Deleterious effects of elevated gastrin levels

Do you have Barrett’s esophagitis? Have you been warned that it is a consequence of long-term GERD? Then you will love this! The standard of care for patient’s with Barrett’s is PPI. We know that PPI use elevates gastrin levels. What you didn’t know is that serum gastrin levels are significantly associated with cellular proliferation. Specifically it has been found that gastrin induces a receptor, called the CCK-2 receptor, increasing its levels in patients with Barrett’s by two levels of magnitude (100 times) that of non-Barrett’s controls. This is the cause of overgrowth of abnormal tissue. There is a significant association between Barrett’s and esophageal cancer, hence PPI may increase the risk for developing esophageal cancer.

Increased risk of GI infections

So you have learned that the stomach produces acid, and a protein-digesting enzyme called pepsin. It also stores food while it is being digested and moves it along to the duodenum when it is ready for further digestion. It also does one more critical thing that is related to acid production. Acid kills bugs (bacteria, viruses, mold, fungus, yeast and parasites) that enter the body on food and water. PPI’s stop acid production, which also stops the bug killing. This then significantly affects your microbiome (the bugs that live in you). This can lead to dysbiosis (bad bugs), SIBO and outright infections.

Patients with low stomach acid have excessive growth of bacteria in the digestive tract and a much higher incidence of gastrointestinal infections. Modern treatment of GERD with acid secretion inhibitors creates a similar low acid state. Suppression of gastric acid secretion causes a dose dependent increased risk of a wide variety of intestinal infections especially for people over 65, immune compromised persons, sick patients with a reduced resistance, and travelers to tropical areas. Studies and reviews of multiple studies have shown an increased risk of community acquired pneumonia associated with gastric acid inhibitor treatments. A study of 186 children, 91 of whom were being treated with PPI and H2 blockers, clearly showed a significant increase in both GI infections (gastroenteritis) and pneumonia. The researches stated that the effects of therapy on increased infections remained after treatment was stopped! A recent article in the prestigious journal JAMA about the serious GI bacterial infection with Clostridium difficile concluded “”PPI use is surely associated with the development of C difficile-associated diarrhea, and less PPI use should lead to less disease.”

SIBO

Normally, few bacteria live in the upper part of the small intestine. Their numbers normally increase the further along the intestine you go. Small intestinal bacterial overgrowth is a condition where there are increased numbers of bacteria living in the small intestine. This leads to major GI problems, including gas, bloating, altered motility, pain, poor digestion, etc. The bacteria produce gasses including carbon dioxide, methane and hydrogen. This can be measured with a hydrogen breath test. A positive test is indicative of SIBO. In a study of 450 people, SIBO was found in 50% of patients using PPI. The rate of SIBO increased after 1 year of PPI use. The rate of SIBO in PPI users was over 800% that of a normal population.

Now you gotta love this- SIBO is a potential cause of GERD! Why? The gasses produced increase abdominal pressure, which naturally increases reflux. They also cause the LES to relax, making reflux easier. So Big Pharma sells a product that gives temporary relief of reflux symptoms, while at the same time, increasing the underlying causes of those symptoms, essentially guaranteeing that the patient will use PPI for forever. What a great business!

Leaky Gut Syndrome

A recent study examined whether the PPI, esomeprazole (Nexium), affects the barrier function of the upper GI tract. A compromised GI barrier (Leaky Gut Syndrome), has many adverse consequences, including being a cause of GERD. Perhaps the worst concern is that Leaky Gut is a primary cause of many autoimmune conditions, which are rampant in the USA, having increased dramatically in the past 50 years. (Interestingly along with a huge increase in PPI use). 37 patients with GERD and 25 healthy controls were tested. Nexium caused significant leak across the upper GI tract mucosal barrier of patients taking the drug for the first time. The leak occurred quickly, within days of first taking the drug. The leak was also reversed within days of stopping the medication. They concluded, “This is the first patient-based study showing that a PPI compromises upper GI barrier function. There are potential implications for transmucosal leak of other medications that a patient on a PPI may be taking, as well as possible leak of endogenous peptides/proteins. The clinical consequences of this phenomenon are currently unknown, but are potentially important”. In other words, Nexium caused Leaky Gut Syndrome within days of starting its usage. Imagine what damage long-term usage of PPI may do to the GI barrier system!

Hip Fractures

PPI’s reduce calcium (and other essential nutrient) absorption due to a reduction of HCL. Minerals and vitamins are usually found tightly bound to protein molecules, which must first be digested for the nutrient to be available for absorption. As we know, stomach acid is needed for proper protein digestion. PPI may also act to increase the rate of bone breakdown. A huge study on patients with hip fractures concluded that use of PPI for more than one year significantly increased the risk of hip fracture; that the longer the usage past one year the greater the frequency of fracture; and that the higher the dose of PPI, the higher the risk. What they didn’t say, but which is obvious is that long-term PPI use increases the risk for osteoporosis.

Gallbladder Function

PPI’s reduce the normal motor (muscular contraction) function of the gallbladder. After discontinuation of PPI, normal function returns in the majority of patients studied. In a study performed on normal subjects given PPI for only 30 days, reduced gallbladder function was seen in 15/19 subjects. In addition, 27% of the subjects began having gallbladder-related symptoms. The authors concluded, “Short-term PPI therapy reduces gallbladder motility in healthy volunteers. Chronic PPI therapy may pose a risk for long-term gallbladder dysfunction and biliary complications.”

Malabsorption

It would be a safe bet to say that if you have no stomach acid, if you can’t activate the protein-digesting enzyme pepsin, if your gallbladder isn’t functioning; and you get SIBO because you don’t have any acid to kill the bugs; that you probably aren’t going to be able to obtain essential nutrients from your food. This in turn will cause a whole host of problems, such as osteoporosis. I would be willing to bet that if tested, virtually all of the essential nutrients will be absorbed at lower levels. Research shows that the following are affected:

  1. Vitamin B12- Prolonged PPI use reduces levels. Giving RDA replacement levels do not increase this decline.
  2. PPI use can inhibit magnesium transport in the intestine. Long-term PPI users can totally deplete their magnesium stores, with severe consequences.
  3. Vitamin C
  4. Iron
  5. Calcium

Cardiovascular Disease

Just when you thought it couldn’t get any worse! Long-term use of PPI’s are associated with an increased risk for heart attack and vascular disease. A June 2015 study reviewed over 16 million (that’s a lot!) clinical documents on 2.9 million individuals to see if PPI increased the risk of heart attack (MI) in the general population. Their conclusions were that PPI use led to a 116% increase in MI and a whopping 200% increase in mortality!

There may be multiple mechanisms at work here. PPI’s reduce levels of essential nutrients critical to normal function of the heart and vascular endothelium. Decreased Vitamin B12 levels are associated with increased homocysteine, a known risk marker for cardiovascular disease. In addition PPI increase the levels of another chemical that is highly detrimental to cardiovascular health. Asymmetric dimethyl arginine (ADMA) appreciably increases in PPI treated individuals due to inhibition of the enzyme DDAH. Increased ADMA reduces a critical regulator of normal function of the lining of blood vessels (vascular endothelium) called endothelial nitric oxide (eNOS), which causes dilation of the blood vessels due to relaxation of the smooth muscles lining the vessels. .

But it gets even worse. Not only do PPI increase ADMA, which directly competes with eNOS, but also eNOS is further reduced by a second mechanism.

Nitric oxide (NO2) is a regulator of many cellular functions whose discovery led to it being named the “Molecule of the Year” in 1992 and Nobel prizes for the discoverers in 1998. A family of enzymes catalyzes its production from the amino acid arginine. Recently a second mechanism for the creation of NO2 was discovered that involves stomach acid. The levels of NO2 in air expelled directly from the stomach are 100 times higher than from the lungs. When pre-treated with PPI, the amount of NO2 produced by the stomach was decreased a remarkable 95%! NO2 created by stomach acid may be important for maintaining the integrity of the normal stomach lining, so PPI may impair this function.

Not only is eNOS involved with maintaining normal smooth muscle tone of the vascular endothelium, it is also involved with many other regulatory functions, including: insulin secretion, airway tone, growth of new blood vessels, embryonic heart and coronary artery and valve development, reducing platelet adhesion and aggregation to the lining of blood vessels (reducing plaque formation), increases the antioxidant enzyme Superoxide Dismutase (SOD), regulates DNA methylation and transcription, and a host of other critical functions.

Skin Aging

In a 2010 paper, two researchers suggest that PPI can promote skin aging by two distinct mechanisms. They state that the lowered acidity of the stomach in turn causes an increased alkalinity of lysosomes (intracellular organelles that contain a variety of enzymes that function in an acidic environment). This in turn suppresses transforming growth factor beta (TGF-B), a protein that controls proliferation and differentiation of many cell types. They also state that PPI inhibit an enzyme called lysyl oxidase by reducing copper transport. This enzyme cross-links new collagen to make new skin.

What the heck is Chromogranin A (CgA)?

The adrenal medulla, and heart secrete CgA. It is used as a marker in the diagnosis of neuroendocrine tumors, meaning that in many tumors its level increases significantly above the normal range. Well guess what? PPI also increases CgA levels. A study of GERD patients on PPI showed that only 5 days of PPI therapy was enough to start increasing CgA levels, and that the higher the PPI dose, the greater the increase. After 6 months of PPI therapy both CgA and gastrin levels were markedly elevated. The good news is that levels significantly decreased after 5 days of PPI cessation.

A 10-year study of 470 elderly patients with heart failure concluded that CgA could identify those who were at increased risk for mortality. CgA isn’t just a marker for neuroendocrine tumors and heart failure. It is a protein that is released with catecholamines (epinephrine and nor-epinephrine) in response to appropriate stimuli. It is a pro-hormone that is split into several peptides that have biological activity. A thorough review of relevant literature between 1985 and 2013 showed 209 references. This review article concluded that CgA had broad-spectrum regulatory activity of the endocrine, cardiovascular, immune systems; glucose and calcium homeostasis. Some of the active peptides had opposite effects and unbalanced production of peptides can play a role in several diseases. Chronic PPI use disrupts normal CgA signaling mechanisms through prolonged elevation.

Solutions, Not Assumptions

It doesn’t do much good to tell you the dangers of PPI unless there is a solution to your problem. If you are a long-term user and still have problems, then it should be obvious that the root causes of your condition have not been addressed. Fortunately, finding the root causes of your GERD, can successfully resolve the condition. If you have used PPI for a prolonged period of time, there probably is no single, magic pill to take. By chronically blocking the production of stomach acid, a chain of events has occurred, much like knocking over a line of dominoes. One problem leads to another, so in the end there is a whole host of potential problems created. To successfully treat the underlying reasons why you have GERD, you need to know what those reasons are.

Fortunately there are Functional Diagnostic Medicine lab tests that will help identify the reasons you have GERD. The following tests are recommended:

  • Heidelberg Gastric pH Analysis: This test checks for your ability to produce stomach acid. Since hypochlorhydria is a primary reason for the development of GERD, one must start by correcting problems at the top of the GI tract so that the effects carry all the way through
  • Comprehensive Digestive Stool Analysis (CDSA): this test can help determine the species of bacteria living in you and whether you have bacterial overgrowth or pathogenic bacteria, such as H. pylori or C. difficile. Included in this test are a number of parameters of GI function, such as immune function, inflammation, levels of beneficial short-chain fatty acids, pancreatic digestive enzyme secretion, and more
  • SIBO breath test: This test determines if you have overgrowth of bacteria contributing to your problems by measuring the levels of hydrogen and methane gasses.
  • Food Allergy Testing: Sensitivities to foods contribute to gastritis, intestinal inflammation, a chronic immune response and possibly Leaky Gut Syndrome

Once the underlying causes are identified, specific, natural treatments may be used to address each issue. The basic program is called “The 4 R GI Restoration Protocol”. It consists of the following:

  • Remove: Eliminate all identified food allergens to reduce a major source of inflammation. Even if not identified on your food allergy testing, remove all gluten, dairy and yeast sources. Remove all alcohol and refined sugars and processed foods. The Paleo diet is an excellent choice as it removes the major food allergens and irritants.
  • Replace: If your testing has shown low stomach acid, replace with Betaine HCL and Pepsin. Pancreatic enzymes should be used to supplement digestive function. A hypoallergenic medical meal replacement powder that contains a full array of essential nutrients is needed to replace protein and essential nutrients that have been lost due to malabsorption.
  • Repopulate: Based on the results of your CDSA, the appropriate probiotics can be prescribed. In general, a broad-based, high potency probiotic containing multiple species and strains should be used. If dysbiotic bacteria are present, there are a variety of natural products that will kill or significantly reduce their numbers. Prebiotics may be used to help feed the friendly bacteria you have reintroduced.
  • Repair: The GI tract cells must be repaired and regenerated. In addition to making sure that an optimal supply of essential vitamins and minerals is given, there are a number of Nutriceuticals that can accelerate healing, including: Glutamine, Butyrate, Zinc Carnosine and DGL. Inflammation can be reduced with Curcumin, Resveratrol, Vitamin D and Omega-3 EFA’s. Aloe Vera, Slippery Elm Bark, Marshmallow Root can all sooth the GI tract. Perilla leaf extract can help normalize GI motility and relieve discomfort. Reflux can be treated with Alginic Acid. When mixed with stomach contents, Alginic Acid expands and creates a “raft” that floats on top of the stomach, blocking contents from refluxing into the esophagus. Peppermint oil and Limonene can sooth inflamed GI tissues.

Summary

Short-term use of PPI of 14 days is generally safe, but not terribly effective at curing reflux and GERD. There are multiple root causes, with excess stomach acid being the least likely reason. Low stomach acid, poor diet, bacterial overgrowth and food sensitivities all play a role. Long-term use of PPI carries many risks, including increased risk of osteoporosis; cardiovascular disease; essential nutrient deficiencies; reduced gallbladder function; decreased levels of the critical signaling molecule, endothelial nitric oxide; increased levels of the regulatory molecule Chromogrannin A; decreased stomach acidity, which can lead to poor digestion, SIBO, Malabsorption, GI infection toxicity, and GI symptoms. PPI significantly increases gastrin levels, which causes cellular proliferation, increasing the risk of Barrett’s esophagitis and therefore esophageal cancer.

Proper treatment includes identifying root causes of the condition through appropriate lab testing, and treating those causes with a comprehensive program that removes offending foods, replaces low stomach acid and digestive enzymes, repopulates beneficial intestinal flora and repairs damaged GI tissues.

References

  1. Wikipedia “Proton Pump Inhibitors”
  2. Prilosec OTC Product Monograph for Healthcare Professionals http://www.prilosecotc.com/en-us/hcp/prilosec-otc-dosage
  3. Gastroesophageal Reflux Disease (GERD) Hospitalizations in 1998 and 2005 –  HCUP-US Home Page. Retrieved March 5, 2012, from: http://www.hcup-us.ahrq.gov/reports/statbriefs/sb44.jsp
  4. Gastroesophageal Reflux Disease (GERD). (n.d.). Office  of Medical Informatics –   College of Medicine – University of Florida. Retrieved March 5, 2012, from: http://medinfo.ufl.edu/~gec/coa1/gerdfaq.html
  5. Fasting hypochlorhydria with gram positive gastric flora is highly prevalent in healthy old people. 1992 Oct; 33(10): 1331–1337.
  6. Fasting gastric pH and its relationship to true hypochlorhydria in humans. http://www.ncbi.nlm.nih.gov/pubmed/2070698#
  7. Fundic atrophic gastritis in an elderly population. Effect on hemoglobin and several serum nutritional indicators. J Am Geriatr Soc. 1986 Nov;34(11):800-6.
  8.      Basal and histalog-stimulated gastric secretion in control subjects and in patients with peptic ulcer or gastric cancer. Gastroenterology 1963;45:15-26.
  9. The diagnosis and treatment of achlorhydria: ten-year study. J Amer Ger Soc 1967;15:786-791.
  10. Nutrition Review, Gastric Balance: heartburn Not Always Caused by Excess Acid, Apr. 22,2013
  11. Townsend letter for Doctors and Patients, The Unseen Epidemic: The Linked Syndromes of Achlorhydria and Atrophic Gastritis
  12. Correlation between serum gastrin concentration and rat stomach histidine decarboxylase activity. J Physiol 1974 Dec;243(2):483-98.
  13. Secretory gastric function and the development of reflux esophagitis in peptic ulcer, PMID 3247698
  14. Burden of Gastro-Oesophageal Reflux Disease in Patients with Persistent and Intense Symptoms Despite Proton Pump Inhibitor Therapy: A Post Hoc Analysis of the 2007 National Health and Wellness Survey. Clinical Drug Investigation:1 October 2011 – Volume 31 – Issue 10 – pp 703-715
  15. Effect of gastrin-17 on lower esophageal sphincter characteristics in man. Dig Did Sci. 1997 Dec; 42(12): 2547-51
  16. Pathophysiology of GERD: Lower Esophageal Sphincter Defects. Practical Gastroenterology May 2004
  17. Proton pump inhibitors omeprazole, lansoprazole and pantoprazole induce relaxation in the rat lower oesophageal sphincter. J Pharm Pharmacol. 2011 Oct;63(10):1295-300.
  18. Diagnosis of a gastrinoma in patients on proton pump inhibitor therapy. Endocrine Abstracts 2004 8 P45.
  19. Effect of prolonged treatment with proton pump inhibitors on serum gastrin levels and the fundus mucosa. Preliminary results. Gastroenterol Clin Biol. 1995 Oct;19(10):811-7
  20. Does fasting serum gastrin predict gastric acid suppression in patients on proton-pump inhibitors? Dig Dis Sci 2000 Jan;45(1)34-9
  21. Gastric hypochlorhydria is associated with an exacerbation of dyspeptic symptoms in female patients. J Gastroenterol. 2013 Feb;48(2):214-21.
  22. Gastrin induces proliferation in Barrett’s metaplasia through activation of the CCK2 receptor. Gastroenterology. 2003 Mar;124(3):615-25.
  23. Intestinal infections due to inhibition of gastric acid secretion in reflux disease. Ned Tijschr Geneeskd. 1999 Dec 11;143(50):2511-4.
  24. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics. 2006 May;117(5):e817-20.
  25. C difficile Infection Linked to Proton Pump Inhibitors. JAMA Intern Med. 2013;173:1359-1367, 1367-1368
  26. Increased Incidence of Small Intestinal Bacterial Overgrowth During Proton Pump Inhibitor Therapy. Clin Gastroenterology and Hepatology. 2010; 8:504-508.
  27. Esomeprazole induces upper gastrointestinal tract transmucosal permeability increase. Aliment Pharmacol Ther. 2008 Dec1;28(11-12):1317-25.Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture. 2006;296:2947-2953.
  28. Proton pump inhibitors reduce gallbladder function. Surg Endosc. 2006 Sep;20(9):1364-7
  29. Do Acid-Lowering Agents Affect Vitamin B12 Status in Older Adults. 2008; 9: 162-167.
  30. Severe hypomagnesaemia in long-term users of proton-pump inhibitors. Clinical Endocrinology. 2008; 69: 338-341.
  31. Clinical Endocrinology. 2008; 69: 338-341. Ther Adv Drug Saf. 2013 Jun; 4(3): 125–133.
  32. Effect of Proton Pump Inhibitors on Vitamins and Iron. The American Journal of Gastroenterology 104, S5-S9 (March 2009).
  33. Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population. PLOS ONE, June 10, 2015.
  34. Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation. 2013 Aug 20;128(8):845-53.
  35. Intragastric nitric oxide production in humans: measurement from expelled air. Gut 1994; 34: 1543-1546.
  36. https://en.wikipedia.org/wiki/Endothelial_NOS
  37. Regulation of gastric mucosal integrity by endogenous nitric oxide:interactions with prostanoids and sensory neuropeptides in the rat. Br. J. Pharmocol. 1990, 99, 607-611.
  38. http://www.pubfacts.com/detail/20470945/Can-proton-pump-inhibitors-accentuate-skin-aging
  39. Clinical significance of elevated serum chromogranin A levels. Scand J Gastroenterol. 2004 Oct;39(10):969-73.
  40. Effect of proton-pump inhibitor therapy on serum chromogranin a level. Digestion. 2011;84(1):22-8.
  41. Plasma chromogranin A is a marker of death in elderly patients presenting with symptoms of heart failure. Endocr Connect. 2014 Mar 11;3(1):47-56.
  42. Biological function and clinical relevance of chromogranin A and derived peptides. Endocrinee Connections (2014) 3, R45-R54