THE LONG-TERM RISKS OF PROTON PUMP INHIBITORS

So-called acid reflux is a widespread problem. Check out the space allotted to antacids in the drugstore. Early in December 2009, the Canadian Institute for Health Information released a report indicating that the use of prescription anti-gastroesophageal reflux drugs, i.e. proton pump inhibitors (PPIs) had increased by 60% between 2001-2002 and 2007-2008 based on drug claims by Canadians over 65 in six provinces. In 2007-2008 over 20% of seniors filled prescriptions for PPI drugs. It was also found that PPIs were being used for longer periods of time. The study was based on public insurance data for seniors filling prescriptions for PPI drugs (e.g. Nexium, Prilosec, Prevacid, Protonix). And this does not include over-the-counter PPIs such as Prilosec OTC. This number is not surprising. Gastroesophageal reflux disease (GERD) is one of the most common diseases in the Western world with 44% reported to have symptoms once a month and 20% once a week and 10% daily.1 Mainstream medicine's answer to most problems is a prescription, and GERD is no exception. Some would debate the label "disease."

GERD occurs when stomach fluid is not held back by the sphincter (valve) between the stomach and the esophagus. The acidic liquid serves as a potent irritant to the lower end of the esophagus with associated inflammation, pain, and potential long-term tissue damage and even cancer. The discomfort is commonly described as heartburn. Reflux that reaches the throat can irritate or damage the larynx and vocal cords. The discomfort can be severe enough for sufferers to actively seek help through over-the-counter remedies such as antacids, coating agents or H2-receptor antagonists (e.g. Zantac) and many turn to their physicians who potentially have a number of recommendations, one of which is a prescription PPI drug which changes the stomach pH (the chemist's measure of acidity, 7 being neutral) from 1-2 to 4-6 by inhibiting hydrochloric acid secretion. Non-drug interventions include weight reduction if overweight, avoidance of certain acidic foods, coffee, tea, alcohol and carbonated drinks, eating smaller meals more frequently, not eating at least 3-4 hours before bedtime and elevating the head of the bed by 6 or so inches. Other recommendations include exercise, not smoking, sleeping on the left side and avoiding excessive intake of non-steroidal anti-inflammatory drugs such as ibuprofen.2 The extent to which these non-drug recommendations are evidence-based is beyond the scope of this discussion. One wonders how often patients are told to try these before a prescription for a PPI is written, or if patients even give them a chance. Judging from the amazing number of people worldwide taking PPIs, the answer is probably not very often.

The mechanism involved in GERD is complex but centers on the esophageal sphincter. The sphincter is normally opened by the act of swallowing and otherwise is normally closed. If the sphincter operates only weakly or opens when is should not, acidic fluid can get into the esophagus and cause irritation, inflammation, cellular transformations, etc. A distended stomach full of food can also cause the sphincter to malfunction as can a hiatal hernia, which is a hernia that forms between the sphincter and the stomach. The hernia can trap acidic fluid and inject it when the valve opens. It is thought that most gastric reflux occurs after eating when the stomach is full and is partly due to transient opening of the valve due to a distended stomach.

Untreated GERD can cause formation of scar tissue which if severe can result in swallowing difficulty. Cellular changes caused by the irritation can progress to esophageal cancer, a precursor of which is called Barrett's esophagus. Thus GERD is a potentially serious problem. It is important to recognize that the "disease" ranges from mild to serious, and at the mild end the symptoms may have little clinical relevance. Our human biochemistry is such that stomach acid (hydrochloric acid) is an essential component in a complex digestive process that takes place in the stomach and intestine. It can be argued on general principles that significantly reducing or virtually eliminating stomach acid is such a profound change in the normal stomach milieu and in a major digestive pathway that is not a brilliant idea except over the short term, and that long-term adverse effects should not come as a surprise and need to be balanced against therapeutic benefits which must relate to serious consequences of failure to treat properly.

It appears that prescription PPIs are now being used as first-line treatment for GERD. PPIs are the most potent medications available to reduce gastric acid secretion and are now among the most widely prescribed drugs worldwide. Based on short-term side effects, they appear to be regarded as very safe. However, concerns over long-term safety of PPIs have been continually raised over more than a decade. Also, a number of studies have found that acid-suppressive medications are being inappropriately prescribed in many of the populations studied.

SERIOUS PPI SIDE EFFECTS

There have been several recent reviews of the adverse side effects of long-term use of PPIs.3,4 These include

• Infections. These include Clostridium difficile colitis, bacterial gastroenteritis and colonization of the stomach lining by H. pylori. The risk of C. difficile is particularly acute in the hospital setting but is starting to be seen outside in the communities. Bacteria infecting the intestine normally must pass through the stomach if the inoculation is via ingestion and low pH presents a critical barrier. H. pylori is famous for its connection with stomach and duodenal ulcers. Other infections with elevated risks include salmonella, campylobacter and pneumonia. In all cases there is evidence but of variable strength. A single dose of most PPIs does not maintain the gastric pH > 4 for 24 hours and thus each day there is a period when higher acidity toxic to bacteria can be present. But the elevated risk of H. pylori overgrowth suggests that the acid suppression in this case is sufficient to cause real risk.4-7 The association with respiratory infections in general is suggestive but weak.8 Two doses a day of a PPI, which is not uncommon, can effectively eliminate the protection from infection provided by normal (high) stomach acidity for 24 hours.

• Hip fracture risk. Targownik has recently summarized population-based case-control studies, including a large study reported at the 2009 Digestive Disease Week meeting. The duration of PPI use in these the studies was "within a year" to at least 7 years. Odds ratios were almost all significant and those that were ranged from 30% to 350% increase for the risk of hip fracture associated with the use of PPIs. While this represents significant risk, the mechanism is unknown and may be more complex than simply low calcium absorption in the stomach due to acidity.9 These observational studies do not prove causality but are suggestive and should motivate concern, especially for those taking PPIs without meeting the normal indications, i.e. those subjected to overtreatment.

• Magnesium deficiency, also called hypomagnesemia. This has not been systematically studied. However, recently there have been seven case reports of individuals with very low magnesium levels which resolved after withdrawal of a PPI. The latest was reported in 2009 by Kuipers et al10 who also reviewed earlier reports. The connection with PPI use was reinforced by the recurrence of hypomagnesemia after re-challenge with the PPI. The authors discuss possible mechanisms but are unable to draw significant conclusions. They do point out that PPIs also impact the intestinal acid concentration and that PPI users have more alkaline intestinal milieu. Hypomagnesemia can cause weakness, muscle cramps, cardiac arrhythmia, tremors, confusion, hallucinations, epileptic fits, and hypertension and this is not the complete list.

• Gastric cancer. There have been very few significant studies of the potential connection between PPI use and stomach cancer. In one study which involved 8 years follow-up of over 500,000 patients, non-users of PPIs had a gastric cancer rate of 0.01% whereas for users it was 0.16%.11 The most recent study appears to be Poulsen et al.12 In this paper the authors comment that for patients with H. pylori stomach infection, long-term PPI use has been associated with an increase of atrophic gastritis, a process of chronic inflammation of the stomach leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues. This sequence is regarded as a precursor of stomach cancer. Poulsen et al found that only when the number of prescriptions exceeded 15 (21% of the active users of PPIs in the study) was there a significant increase in gastric cancer with approximately a doubling of the relative risk of incidence. A recent review13 suggest that the evidence is strong enough so that H. pylori eradication is indicated for infected individuals who are candidates for long-term PPI use, but the suggestion is not accompanied by a discussion of preventing recurrence while on a PPI. It is interesting in this context that H. pylori can survive a pH levels between 4 and 8 but only replicate when the pH is between 6 and 8; however, there are regions of the gastric system where this is not relevant.13

While this is a side effect of PPIs it seems to deserve its own section. Many microbes, including those that normally reside in the mouth, can not live at normal stomach pH with pH lower than about 4 being fatal. On the other hand when the pH is above 5 bacterial proliferation is expected. In an interesting study, Vakevainen et al(14,15) examined the gastric pH and bacterial content in the stomachs of eight volunteers, starting with baseline measurements and then inhibiting stomach acid production for seven days with the PPI lansoprazole (Prevacid) twice daily. Thus each subject served as its own control. The researchers were investigating the production of acetaldehyde, a potential carcinogen, from bacterial action on alcohol in the stomach. Subjects drank alcohol diluted with water to correspond to normal drinks. Then their gastric juices were obtained. The first stage was before the PPI treatment and the average stomach pH was 1.3. Very low levels of acetaldehyde were found and attributed to that generated in the saliva during the ingestion of the alcoholic drink. After the PPI treatment, the mean pH of the gastric juices was 6.1 (almost neutral as compared to strongly acid) and there was a huge increase in acetaldehyde and now a large number of different bacteria were found living in the stomach. Most of these bacteria were demonstrated to have the capability to produce acetaldehyde from alcohol. Not only does this illustrate the role of a strongly acidic stomach as a bacterial shield, but once this shield is broken, bacterial colonization which produced acetaldehyde from alcohol was observed. Acetaldehyde is a known local carcinogen and a well-known risk factor for upper digestive tract cancers at the concentrations found in this study. It was already known that strains of Candida albicans from the oral cavity have the capacity to generate acetaldehyde. Furthermore, excessive alcohol consumption is a well-known risk factor for upper digestive tract cancers, although confounding by the use of PPIs was probably not considered. This study provides a possible mechanism since alcohol per se is not carcinogenic. Finally, atrophic gastritis which leads to low stomach acidity and reduced pepsin production is a known risk factor for stomach cancer and can be caused by a persistent bacterial invasion of the stomach. The authors discuss other evidence addressing the biologic plausibility of the acetaldehyde-stomach acid-cancer connection.

ALTERNATIVE INTERVENTIONS

Aside from the non-drug interventions outlined above, a dietary supplementation program for patients with GERD was described recently by Ricardo de Souza Pereira .16 This was a single blind randomized intervention trial where a PPI (omeprazole) was compared with a mixture of supplements (melatonin, 6 mg; tryptophane, 200 mg; vitamin B12, 50 microg; methionine, 100 mg; B6, 25 mg; betaine, 100 mg; and folic acid, 10 mg, all per day). The first phase covered 40 days. Patients randomized to receive the set of supplements (176) all reported complete regression of symptoms after 40 days and the only side effect was sleepiness. Of those randomized to the PPI drug treatment (175), 115 reported regression. During a second phase of the study, those in the drug group who reported residual GERD symptoms were given the supplements for 40 days and reported that all symptoms disappeared. About 30% of patients did not notice the recurrence of GERD but the rest required continued treatment with the supplements and Pereira found that melatonin alone was not effective (personal communication). The author suggests that the action of melatonin may be associated with its ability to inhibit nitric oxide biosynthesis and thus impact the sphincter relaxation associated with GERD symptoms. While there is reason for concern over the high dose of folic acid employed, this amount of folic acid used may not be necessary.

A case history of a GERD patient was presented by Melvyn Werbach the same year and using a similar protocol.1 it was found that treatment with a PPI failed to produce permanent relief after it was discontinued in each of three 20-day trials. When the PPI was used along with a supplement set which included melatonin, vitamins and amino acids, the PPI could be withdrawn after 40 days without a return of symptoms. When the supplements were withdrawn, symptoms returned unless 3 mg of melatonin per day was maintained. This is inconsistent with the experience of Pereira. Werbach also discusses other potential mechanisms whereby melatonin might influence GERD. These include antioxidant effects and stimulation of the immune system.

HIGH STOMACH ACIDITY VS. LOW STOMACH ACIDITY

It is interesting that both supplement programs used in the above studies included betaine hydrochloride, an over-the-counter supplement which is commonly used to raise, not lower stomach acid levels and is employed when a deficiency of acid is interfering with digestion and in fact also causing heartburn. This is sufficiently counterintuitive that one does not often see it recommended though your editor has seen it highly recommended by practicing physicians in some of the newsletters to which he subscribes. But it is worth recalling that in normal healthy individuals, eating stimulates the secretion of hydrochloric acid in amounts required for digestion, and hydrochloric acid is what a chemist calls a strong acid (completely dissociated in water) and these normal healthy individuals do not have GERD! This is the way our digestive biochemistry works when it is in tune with our genetic blueprint, which goes back at least to the Stone Age. A very acid stomach is completely natural and in addition, essential. This is probably even taught in high school!

A frequent suggestion seen on the internet and in the literature is to use betaine hydrochloride as a tool for differential diagnosis. If the symptoms of acid reflux disappear with betaine hydrochloride plus pepsin in a dose-dependent fashion, then the acid reflux problem probably can not be solved by inhibiting acid secretion with a PPI since in fact the problem is not enough acid. Some physicians "titrate" the betaine hydrochloride until it produces acid reflux, and then back off the dose to see if the problem is solved. This approach appears to have some merit since it prevents the recommendation of a therapy that goes in the wrong direction, i.e. decreasing rather than increasing stomach acid. This will probably never be a popular approach since it has two problems: (a) it is counterintuitive and (b) betaine is not a prescription drug and the patient has to be sent to a health food store. Incidentally, Dr. Natasha Campbell-McBride reports in her book Gut and Psychology Syndrome that she has great success with betaine hydrochloride with pepsin in both children and adults with low stomach acid which she finds normally accompanies a dysfunctional gut. Betaine is not without its risks, can be dangerous if one has an ulcer and probably should only be used after consultation with a physician. Knowledge of the actual state of acidity in the stomach would be very helpful. A 24-hour stomach acid measurement technique is available which uses a pill that transmits data to an external radio receiver. Low stomach acid frequently accompanies aging. But stomach acid is not a simple matter like the acid concentration in a laboratory bottle. It varies with the location in the stomach, the proximity to the walls, the stage in the fasting, eating, digesting and emptying cycle, etc. There are remarkable local variations in particular near the exit from the esophagus which are being explored.17

Thus we come to an interesting question. Given that PPI use is widespread and there appears to be a trend toward long-term use, even for reflux problems that are minor, is establishing an abnormal and very much less acidic stomach environment, at least over most of the day, a good idea? In an editorial, McColl and Gillen from the University of Glasgow comment that treating GERD with profound acid inhibition will never be ideal because acid secretion is not the primary underlying defect and patients with reflux disease generally have normal acid secretion.18 They take the position that it is never ideal to treat one abnormality by creating another and that the real target should be the dysfunction of the gastroesophageal barrier. There are other questions such as do PPIs really reduce the risk of esophageal cancer and the incidence and frequency of serious esophageal reflux incidents? Also, what about the fact that low and high stomach acidity can produce some of the same symptoms that lead to a prescription for PPI. Shouldn't this problem in differential diagnosis be addressed first? Let's first examine the problem of the stomach and its normal high level of acidity. If instead the acidity is low, i.e. a higher pH, what are the consequences regarding digestion in the stomach and intestines?

The stomach is normally highly acidic. When a meal is ingested, the pH goes up due to the diluting and buffering and neutralizing action of the food. This triggers hydrochloric acid secretion which rapidly drops the pH back down toward the pre-meal level. The enzyme pepsin is also secreted into the stomach. These two chemicals facilitate the break-up of proteins, which are made up of amino acids, into smaller amino acid chains called peptides, along with some single amino acids. If the stomach lacks acid, this preliminary digestion of protein will be inhibited. When the stomach is functioning properly, these peptides, free amino acids along with the rest of the contents of the meal are passed along to the duodenum and then into the small intestine. During this transit, if the acidity is too low, the mechanism that generates intestinal digestive enzymes and injects bile will fail to trigger or operate properly, setting up the scene for digestive dysfunction in the intestine where fats, carbohydrates, proteins and peptides are broken down and as well, micronutrients such as minerals and vitamins are absorbed and vitamins even synthesized. Partially digested proteins can be passed through the intestinal wall in a dysfunctional intestinal system and trigger allergies and autoimmune reactions. Some are neurologically active molecules which end up in the brain and can act as opiates. Maldigested carbohydrates are consumed by abnormal bacteria in the gut, encouraging their growth and continued colonization. When the intestinal system is dysfunctional, fats are not properly digested if at all and vitamin and mineral metabolism also becomes dysfunctional. Thus stomach acid is a central and critical actor in the whole digestive process.

The high stomach acidity also provides a shield for bacterial invasion, preventing colonization in the stomach and severely limiting bacterial passage into the intestine. Elevated stomach pH removes this barrier and allows bacterial overgrowth in the stomach and the colonization by undesirable bacteria in the intestines. Stomach bacterial overgrowth can disrupt the acid and enzyme biochemistry and lay the groundwork for gastritis and stomach cancer. In the intestine, overgrowth of unfriendly bacteria can cause major dysfunction of the gut which in turn allows undesirable molecules to pass through the walls of the intestine, interferes with digestion, and alters immunity.

We evolved to have a digestive system which accommodates a very low pH in the stomach, uses acidity as part of a complex signalling system, and has a valve at the lower end of the esophagus which prevents this acid stomach fluid from irritating the lining of this tube or getting back to the throat. Acid reflux, irritation of the esophagus, Barrett's esophagus syndrome, and esophageal cancer are abnormal. Given this simplified view, one can ask, does it make sense if the stomach acid is causing pain or irritation in the esophagus, to profoundly change the pH of a complex system which has evolved over eons. Generally when one messes around with complex human biochemical systems to change one critical aspect or treat a symptom, the end result is not good because in fact a cascade of events ensues. The fact that most prescription drugs have lists of side effects that are very long illustrates this. The PPI is no different, as is indicated by the side effects discussed above.

HOW WELL DO PPIs WORK?

PPIs are presumably taken for two reasons. One is to eliminate the pain and discomfort of acid reflux, i.e. heartburn relief, prevent stricture formation in the esophagus, promote healing of an inflamed esophagus and esophageal ulcers and stomach ulcers, and finally, serve a prophylactic in the context of heavy and prolonged use of non-steroidal anti-inflammatory agents. In addition, they are used to prevent the progression of Barrett's esophagus to adenocarcinoma of the esophagus and precursor cellular changes.

Failure of GERD patients to respond to the standard once-a-day PPI dose is common and the typical response is to increase the dose to twice daily. This appears to improve outcome although there do not appear to be relevant data actually proving this.19 Two doses a day extend the acid suppression to practically the entire 24 hour period. For individuals with Barrett's esophagus with so-called macroscopic markers of advanced disease such as strictures, ulcers and nodules, the use of PPIs may reduce the prevalence of these markers. It has been argued that PPI use prior to visual examination (endoscopy) is indicated because the benefit associated with PPI use outweighs the importance of loss of information. Long-term PPI use has been shown to decrease the progression of Barrett's esophagus to dysplasia and cancer.20

But according to critics, PPIs are being prescribed to some individuals who in fact may not have indications justifying this intervention. Also, for this group as well as anyone taking this class of drug, the so-called rebound effect may be significant. In short, when PPI therapy is stopped, there is enhanced acid secretion and this has been observed even in healthy individuals. Thus stopping PPI-use is inducing the symptoms for which it is used therapeutically. Furthermore, this rebound effect makes short-term therapy problematic since patients will want to return to treatment when their symptoms reappear with a vengeance. The stage is set for long-term use.

WHY IS GERD SO COMMON AND INCREASING IN PREVALENCE?

Finally, there is the interesting question as to why GERD is so common. In fact, the sales of PPIs are second only in the US to lipid-lowering drugs. The paradox is that the underlying cause may be related to too little, not too much stomach acid. Dr. Natasha Campbell-McBride in her book Gut and Psychology Syndrome (Ch. 4) points out that in her clinical experience people with abnormal gut flora (bacteria) almost without exception have low stomach acid production. Normal acid secretion is strongly inhibited by toxins produced by Candida, Clostridia and other pathogens. Thus digestive dysfunction in the stomach appears closely related to gut health, and gut health in many individuals is severely compromised by repeated assaults from toxins and antibiotics. Overuse and inappropriate use of antibiotics is widely recognized in a number of contexts as is the end result whereby friendly and essential gut flora are killed off, but this practice appears to continue unabated. Unfriendly bacterial overgrowth is fed in part by high sugar and high carbohydrate diets. It is reasonable to suspect that most individuals do not attempt to rectify the harm done to their gut flora by repeated antibiotic use, or if they do, they use ineffective methods such as yogurt containing insufficient if any bacteria or the wrong strains. A dysfunctional gut impacts the biochemistry involved in signalling and generating stomach acid and stomach digestive enzyme generation, so many individuals with a dysfunctional gut have impaired digestion. This then causes the initial digestive process in the stomach to also be dysfunctional. A stomach that is distended can cause the sphincter to malfunction, and although the acidity of the reflux fluid is lower if low stomach acid is a problem, it is still high enough to be very irritating to the esophageal tissue. Given the predilection to overeat and to eat so rapidly that the brain does not have a chance to tell one that the stomach is full would appear to be a lifestyle component that aggravates GERD.

Thus the counterintuitive treatment of acid reflux with betaine hydrochloride, ideally combined with the stomach digestive enzyme pepsin which is involved in protein digestion, and why betaine was included in the supplemental protocols described above. Incidentally, so-called supplemental digestive enzymes are generally formulated to contain only enzymes that act in on intestinal digestion and thus do not directly improve the digestion process in the stomach.

Furthermore, according to Dr. Campbell-McBride, when stomach acid is low, the acidity of the food and fluid entering the duodenum on its way to the small intestine fails to provide the appropriate pH-dependent signals that regulate the intestinal pH and intestinal digestive enzymes and bile supply, with the result that the dysfunctional digestion that started in the stomach now continues in the intestine. As she points out, this can have severe nutritional and neurological consequences. It is interesting in this connection that three of the major side effects of PPIs are abdominal pain, diarrhea and constipation, all suggestive of gut dysfunction.

The PPI drugs treat the problem of GERD by getting rid of the irritant, namely the stomach acid, but this does not address the real cause of the problem and in the process profoundly alters the entire digestive system in a manner which can only be described as adverse. The popularity of this class of drug is well established, and perhaps even demonizes stomach acid. This would appear to lead in just the opposite direction from a sensible approach, and result in highly abnormal side effects such as bacterial overgrowth in the main part of the stomach as well as other side effects described above.

ACID CONTROL ALTERNATIVES

Over-the-counter antacids such as Tums are the traditional approach to self-treatment of acid reflux and can be effective in treating occasional episodes. Those antacids which simply temporarily neutralize stomach acid are fundamentally distinct from agents which interact with acid secretion. There is also the class of drug called histamine (H2) receptor antagonists (H2RAs) which reduce acid production in the stomach. Readers will recognize such common brands as Pepcid AC, Tagamet and Zantac. These are also used for self-treatment but have largely been replaced, at least in the clinical setting, by the PPIs which are viewed as being more effective. In some jurisdictions, PPIs are also available over the counter which can lead to elective long--term use.

The essential point appears to be the distinction between long-term use and occasional use, and it is the use of H2RAs or PPIs over the long term which represents the most drastic disturbance of the entire digestive system and processes, opens the system to unwanted invasion from unfriendly pathogens and can lead to total system dysfunction.

Finally, diet should be considered when attempting to reduce or eliminate acid reflux. The WebMD website (www.webmed.com/heartburn-gerd) provides a discussion of the common offenders. Included are citrus fruits such as oranges and grapefruit or their juices, tomatoes, garlic, onions, spicy foods and pepper, peppermint, cheese, nuts, avocados, alcohol, caffeine, chocolate and carbonated beverages. A common recommendation is to keep a food log and note the personal culprits and avoid them. However, heartburn induced by a large meal or by reclining after a large meal can be independent of specific food triggers.

CONCLUSIONS