This purple monster can be quite the pill

 

“Proton-pump inhibitor therapy is now being prescribed for a wide variety of upper gastrointestinal symptoms on the basis that they might be acid induced and therefore may benefit from such treatment. This increasingly liberal usage of these powerful drugs is due to a number of factors, including reduced concerns about potential side effects, reduced cost, and the lack of alternative therapies for upper gastrointestinal symptoms. This liberal employment of proton-pump inhibitor therapy has been recommended recently by many national and international guidelines based on “number needed to treat” and health economic analyses. As a consequence, a substantial proportion, if not majority, of patients now prescribed proton-pump inhibitor therapy do not have acid-related symptoms and therefore have no true indication for such therapy. The current finding that these drugs induce symptoms means that such liberal prescribing is likely to be creating the disease the drugs are designed to treat and causing patients with no previous need for such therapy to require intermittent or long-term treatment. It is likely also that treatment of mild reflux symptoms with such therapy may aggravate the underlying disease and lead to an increased requirement for long-term therapy.”

Evidence That Proton-Pump Inhibitor Therapy Induces the Symptoms it Is Used to Treat, Division of Cardiovascular & Medical Sciences, University of Glasgow, Gardiner Institute.

 

Abbreviations:

C. difficile: Clostridium difficile
EE: erosive esophagitis
F. nucleatum: Fusobacterium nucleatum
PPIs: proton pump inhibitors
GERD: gastroesophageal reflux disease
GI: gastrointestinal
H2 blockers: histamine 2 blockers, H2-receptor antagonists
NSAIDs: non-steroidal anti-inflammatory drugs
SIBO: small intestinal bacterial overgrowth
SIFO: small intestinal fungal overgrowth
SIFBO: small intestinal fungal and bacterial overgrowth

When most people are confronted with stomach indigestion or acid reflux, the first remedy they seek is some type of drug. And the market has long responded with a host of potions, elixirs and pills to relieve these unpleasant symptoms.

I don’t think there’s a family alive that doesn’t have something or other in their medicine cabinet to combat these unpleasant feelings. Walk into any drug store on the planet and you’ll find shelves brimming with various concoctions to deal with indigestion and acid reflux.

In today’s post, I’ll discuss three classes of drugs that many take to deal with stomach upset. Of the three, I’ll be spending most of my time talking about the most powerful: proton pump inhibitors.

Antacids are the first group of drugs: Alka-Seltzer®, Maalox®, Rolaids® and Tums®. Gaviscon®, which coats the stomach lining with foam, is another well-known brand. Pepto-Bismol® and Kaopectate® contain bismuth subsalicylate that many also use to control indigestion. All of these are readily available over-the-counter in the U.S. and are often a mainstay of home treatment.

This class of drugs have very transitory and mild effects on acid reflux. Because of this, their side effects are also quite tame. That doesn’t mean you can’t cause yourself some gastrointestinal (GI) trouble if you take lots of these drugs. Nevertheless, it will require some effort to cause any lasting damage to GI function.

A second and more powerful class of drugs are the histamine 2 blockers (also known as H2 blockers or H2-receptor antagonists). Remember from the first post in this series that histamine increases stomach acid secretion. These drugs work by blocking the histamine 2 receptors used to produce this effect.

In the United States, some of these drugs are available over-the-counter and in higher doses by prescription only. Popular brands are: famotidine (Pepcid® as a prescription, Pepcid-AC® as an over-the-counter medication, Fluxid®), cimetidine (Tagamet® and Tagamet-HB®), nizatidine (Axid® and Axid AR®) and ranitidine (Deprizine®, Zantac®).

These drugs are quite effective at suppressing stomach acid and therefore carry more chance of side effects than antacids. But when it comes to acid suppression, their abilities pale in comparison to proton pump inhibitors (PPIs).

The first PPI was omeprazole (Prilosec®, Omesec®, Zegerid®). It was first introduced in 1989.

Since then, other PPIs have come to market: lansoprazole (Prevacid®) in 1995, rabeprazole (AcipHex®) in 1999, pantoprazole (Protonix®) in 2000, esomeprazole (Nexium®) in 2001 and dexlansoprazole (Dexilant®, Kapidex®) in 2009. Prilosec is available over-the-counter in the United States, but at a lower dose than its prescription counterpart.

In the United States Nexium® (of purple-pill fame) made by AstraZeneca is the second biggest selling prescription drug on the market. It is outsold only by Abilify®, an antidepressant medication manufactured by Bristol-Myers Squibb.

PPIs are often prescribed for the following conditions:

  • Esophagitis: inflammation of the esophagus lining caused by repeated exposure to stomach acid.
  • Scarring of the esophagus that can make the esophagus narrower.
  • Worsening of asthma, chronic cough, or pulmonary fibrosis brought about by gastroesophageal reflux disease (GERD).
  • Barrett’s esophagus.
  • To heal a stomach ulcer caused by taking daily nonsteroidal anti-inflammatory drugs (NSAIDs) like Advil® or Aleve®.
  • To heal a stomach ulcer as a result of H. pylori infection.

Because PPIs are far more effective at suppressing stomach acid than either antacids or H2 blockers, they have shown high efficacy in treating these conditions.

In those with bleeding peptic ulcers, treatment with PPIs reduces the need for blood transfusions and surgery, and lessens the length of hospital stays. (1) PPIs have also demonstrated effectiveness in treating those who develop ulcers from long-term NSAID use. (2) (3)

PPIs are also successfully used in conjunction with antibiotics for the eradication of ulcers caused by H. pylori. An antibiotic/PPI combination has been shown to increase the rate of ulcer healing and lower recurrence. (4)

PPIs have also proven highly effective in healing erosive esophagitis (EE). EE is inflammation of the esophagus and a common outcome of GERD. Patients with EE can go on to develop other complications like bleeding, narrowing of the esophagus, problems swallowing food and Barrett’s esophagus.

Studies have shown that the use of PPIs heals EE in 84% of patients who take these drugs. (5) PPIs are also very effective in those diagnosed with Barrett’s esophagus in comparison to those on less powerful H2 blockers. (6)

Nevertheless, it has been estimated that between 25% and 70% of those taking these medications long-term have none of these cited conditions. (7) As you may have gleaned from this statistic, no one has any clue how large this group really is. So this means that a sizable segment of the population is taking these drugs for reasons other than those cited above.

Any medication proven more effective than a placebo (whether made by a pharmaceutical company or by a supplement manufacturer) always carries the risk of side effects. Therefore, the benefits derived from taking a drug must be weighed against these negatives to accurately determine if the person is helped more than harmed by its use.

Sadly, when it comes to PPIs too many physicians have only relied on the adverse side effects reported to them by the manufacturers of these medications. AstraZeneca, maker of Nexium®, lists the following adult side effects from taking their PPI:

  • diarrhea
  • headache
  • abdominal pain
  • nausea
  • flatulence
  • constipation
  • dry mouth

On the face of it, these are side effects that many GERD sufferers would happily tolerate to derive relief from their symptoms. And many physicians reading this same list would also consider these adverse effects acceptable given the alternative.

However, as you’ll soon see, this catalog of effects is woefully incomplete. While I have no doubt these adverse effects are accurate for short-term use, they grossly understate what these drugs do over the long-term. And unfortunately, the long-term is not as long as many doctors or patients think.

While the following side effects are mainly applicable to PPIs, everything that follows is also true to some extent for H2 blockers and antacids. That said, being less effective at suppressing stomach acid, their side effects are comparably less intense.

PPIs and Small Intestinal Fungal and Bacterial Overgrowth (SIFBO)

As I explained in part one, stomach acid is not an evolutionary mistake. Among its many essential roles is the destruction of swallowed pathogens before they have a chance of colonizing the intestines.

Consistently lowering stomach acid is equivalent to swinging the front door of your house wide open to allow all manner of thieves, rapists and murderers free rein to your possessions and family. There is no credible authority whom I’m aware of who disputes this protective role of hydrochloric acid.

Nevertheless, three studies from American researchers have concluded that when it comes to PPIs, basic gastric physiology is apparently no guide to assessing risk. These studies make the claim that PPI use is not significantly associated with developing small intestinal bacterial overgrowth (SIBO). (8) (9) (10)

Now, let me state at the outset that I don’t believe you can treat all claims about the consequences of lowering stomach acid equally. Any researcher that claims that consistently lowering stomach acid by using PPIs is not a contributing factor to contracting SIFBO is not starting from the same place as someone who claims otherwise. Why?

Because to make that claim requires medical science to reconsider what has up to now been an accepted fact, namely that the low pH of stomach acid is a very effective bactericidal barrier against swallowed pathogens. So anyone making that claim must meet a higher burden of proof.

Luckily for medical textbook editors and their authors, no revisions are necessary. Other studies, most of them European, have found that taking PPIs daily for eight weeks or longer increases the risk of developing gut dysbiosis.

However, this still raises the question as to how these various studies came to different conclusions.

Well, if you are Dr. Michael D. Crowell, professor of medicine at the Mayo Clinic in Phoenix, and lead author of the latest American study showing no such association, you apparently blame it on the dietary habits of Europeans:

“Over the last decade, nine studies using different tests for detecting SIBO [small intestinal bacterial overgrowth] have addressed the association between SIBO and PPI intake, and have demonstrated conflicting findings. This means that it is quite likely that other factors may also influence GHBT (glucose hydrogen breath testing) positivity. For example, it is easy to speculate that differences in diet might affect the study results. The majority of the studies suggesting a positive association between PPI use and SIBO were conducted in Europe, while the studies suggesting a negative association were from the United States raising the hypothesis that differences in dietary factors in different geographical location might affect the study results.” (10)

You see my foie gras scented European readers, the reason you guys apparently experience higher SIBO risk has nothing to do with the PPIs some of you take, but with all that weird-ass food you apparently eat. And as any clueless American knows, everyone who lives in Europe eats exactly the same type of food from the fjords of Norway to the Cyclades of Greece.

Gee, I wonder if my trip to Europe five years ago caused my SIBO? Damn you Europeans and your bizarre cuisine!

But seriously, I thank Dr. Crowell for including that hypothesis in his paper for it provided me a desperately needed bit of comic relief during a taxing research project. Lucky for me at the time, I was firmly seated and escaped injury from convulsive laughter.

I could spend an entire post explaining how Dr. Crowell’s study could not remotely answer the question it posed. However, I’d rather spend my time on studies from a part of the world (Europe) where the scientific method apparently still counts for something.

A recently published meta-analysis reviewed the eleven studies that had up to that point investigated whether PPI use increased the risk of developing SIFBO, including the aforementioned American studies. (11) This meta-analysis confirmed that in six of the eleven studies, there was a statistically significant risk of developing small bowel dysbiosis while on long-term PPI treatment.

The researchers then subdivided these various studies into how they diagnosed SIBO. In those studies that relied on less sensitive breath tests, no significant association was noted. However, in those studies that relied on a sample taken from the small intestine during endoscopy, the association was found to be significant.

Further analysis showed that those studies that followed the same subjects before and after PPI treatment were more likely to demonstrate a statistically significant association than studies that used a separate group of non-PPI users. And this speaks to a major flaw in those studies that did not find an association.

All the American studies looked at the records of people who had previously tested positive for SIBO and then tried to determine if these patients were more likely to have used PPIs before their diagnoses. But as many of you already know, SIBO is not only caused by impaired gastric-barrier function. It is also, and mainly, caused by slowed intestinal movement or intestinal dysmotility.

To answer this question scientifically, you would have to prospectively follow two groups of people who are confirmed to be free of SIBO. One group would be given a placebo while the other was given a PPI. Only after following both groups over time could you possibly arrive at an answer.

However, even if the study is designed in this manner you still can’t entirely control for confounding caused by decreased intestinal movement between groups. As was made clear in the last post, opioids from drugs and food, as well as binge drinking can cause someone to develop SIBO apart from any disturbances in gastric-barrier function. Nonetheless, in such a study you have a far better chance of controlling for these confounding variables than was the case in any of the American trials that relied on past medical records.

The authors of this meta-analysis go on to state:

“This meta-analysis explored the relationship between PPI use and the risk of SIBO, an area that continues to remain controversial. Given the large patient population analyzed in this study, we believe that it contributes significantly to scientific knowledge and clinical care of patients taking PPIs. When a highly accurate diagnostic test (duodenal/jejunal aspirate culture) was used, PPI use appeared to increase the risk of SIBO. Along with studies linking other adverse events to chronic acid suppression, such as pneumonia, bone loss, and enteric infections, these results highlight the potential toxicity of PPIs, the need for judicious application, and the importance of medication reduction when reaching treatment goals.”

Whew! That’s great news for my European readers. You may now go back to eating all those strange and oh so exotic foods! Just be sure to hold the PPIs.

The results of this meta-analysis were later confirmed by a recent American study (12), one I might add that renewed my faith in the ability of Americans to utilize the scientific method. This study relied on aspirate collected from the small intestine to diagnose not only overgrowth of bacteria in the small intestine, but overgrowth of fungus.

It found that PPI use was an independent risk factor, along with slowed intestinal movement, for developing both overgrowth of bacteria and yeast in the small bowel.

These researchers found that forty-nine of sixty-five patients (75%) who were taking PPIs for prolonged periods of time had small bowel bacterial or fungal overgrowth. This was true regardless of whether the patient reported or exhibited slowed intestinal movement:

“We found a higher prevalence of overgrowth in PPI users than those recently reported [100/200 (50%)] by Lombardo et al. The higher yield in our study is most likely due to the use of small intestinal aspirate and aerobic/anaerobic/fungal culture (generally considered a gold standard, although invasive) for a diagnosis of overgrowth as opposed to the use of a less sensitive glucose hydrogen breath test…in the previous studies. Also glucose breath test cannot diagnose SIFO [small intestinal fungal overgrowth].”

By the way, this is one of the few studies I’ve come across in the peer-reviewed literature that acknowledges fungal overgrowth as a contributing factor in GI disturbances and for that reason deserves its own extended quote:

“One novel finding of our study was the detection of fungal organisms in the 24 patients who only had a positive culture for candida. Unlike SIBO, where there is some recent information, there is virtually no data regarding normal concentrations of fungi in the proximal small bowel. This may in part be due to the slow-growing nature of the fungal organisms and also a lack of knowledge of this possibility. Although the concentration of fungal overgrowth in the proximal bowel is considered to be very low, we identified that 27% of our patients had positive fungal culture. This observation merits further study and confirmation.

Although candida infections are usually seen in the neonatal, elderly or immunocompromised individuals or those on steroids, or repeated antibiotic use, our findings suggest that fungal organisms are not uncommonly present in patients with chronic GI complaints. In one study, candida was the most common organism identified in nasogastric aspirates from the proximal GI tract of preoperative patients with GI disorders (malignancy, inflammatory bowel disease, and benign conditions). Another study identified fungal growth in stool cultures of six patients with diarrhoea and abdominal pain. Apart from these anecdotal case reports, there has been no systematic study of the prevalence and clinical presentation of small intestinal fungal organisms in patients with chronic, unexplained GI symptoms.

The clinical manifestations of SIBO are nonspecific and include symptoms such as gas, bloating, abdominal pain and diarrhoea. More serious manifestations of bacterial overgrowth of the small bowel include malabsorption syndromes, weight loss, malnutrition, vitamin deficiency and anaemia. Symptoms of SIFO are, however, not known but based on our study we believe that SIFO shares the same set of symptoms as SIBO. Our study was unable to identify a single symptom or cluster of symptoms that can clinically recognise patients with either SIBO or SIFO. Thus, symptoms were generally poor predictors of bacterial and/or fungal overgrowth. However, SIBO and/or SIFO were prevalent in over 50% of this patient population with dysmotility and chronic use of PPI and should be considered in the differential diagnosis of patients with nonspecific chronic GI complaints.

We would advocate screening for SIBO in symptomatic patients who have known dysmotility or taking PPIs. The glucose breath test is widely used as a non-invasive method of diagnosing SIBO. Screening for SIBO can start with a non-invasive glucose hydrogen breath test and, if test results are negative and if clinical suspicion remains high, aspiration and culture of small bowel contents may be considered. At present, culture of small bowel aspirate appears to be the only method of identifying fungal organisms in the small bowel.” (12)

None of this surprises me in the least, hence my insistence on terming the condition SIFBO rather than SIBO. Nor should it surprise any of you who’ve been reading this blog for any length of time.

Returning to PPIs, just how long does it take for these medications to increase the risk of developing SIFBO? Well, one study noted that at eight weeks of daily use, a considerable portion of the study participants had developed bowel symptoms like bloating, flatulence, abdominal pain, diarrhea and constipation. (13)

The longer the PPI treatment went on, the worse the symptoms became:

“Our data show that after 8 weeks of PPI treatment a substantial percentage of patients developed bowel symptoms at significant level i.e. bloating, flatulence, abdominal pain and diarrhoea in 43%, 17%, 7% and 2% of the cases, respectively. Interestingly, after 6 months of PPI treatment, the percentage of patients complaining of bowel symptoms further increased and bloating, flatulence, abdominal pain, diarrhoea and constipation were reported in 52%, 33%, 24%, 17% and 2% of cases, respectively. These symptoms are very similar to those referred by patients with IBS [irritable bowel syndrome].”

Again, for anyone who didn’t fall asleep during their physiology class when the instructor covered the protective role of stomach acid, this is to be expected.

Development of SIFBO will, of course, lead to a long string of health consequences starting with increased intestinal permeability, endotoxemia, chronic inflammation and cortisol release. I won’t go into that here as I’ve already covered those health consequences in other posts. Suffice it to say that good health will elude anyone whose intestines are overpopulated with pathogens and depleted of beneficial gut flora.

PPIs and Their Effects on Bone

A number of studies have shown an association with long-term PPI use and fractures of the spine, wrists, hip and forearm. (14) (15) (16) (17) (18) Why?

Well I can think of several reasons right off the bat. First is the role of stomach acid in liberating calcium from the food you eat that I covered in part one. If you can’t properly digest calcium, you’re going to have a pretty tough time keeping those bones healthy.

Another major reason is gut dysbiosis. You have no hope of effectively digesting and absorbing the nutrients contained in the food you eat, including calcium, if your small intestine is depleted of the beneficial lactobacillus species that call that part of the digestive tract home. Yet that is what will happen if the small intestine is colonized by bacterial and fungal pathogens.

The role played by dysbiosis probably explains the consistent finding of hypomagnesemia (low magnesium levels) in those taking PPIs for extended periods of time. (19) Magnesium, along with calcium and phosphorus, is essential for proper bone health. The low levels of magnesium seen in long-term PPI users speaks not only to bone fracture risk, but increased SIFBO prevalence.

Another explanation for increased osteoporosis risk is B12 deficiency. Recall that stomach acid is necessary for the proper assimilation of this nutrient. As B12 is also integral to developing healthy bones, its deficiency would be associated with an increased risk of bone fractures. (20)

As covered below, the use of PPIs consistently leads to elevated levels of the hormone gastrin, a condition known as hypergastrinemia. Hypergastrinemia leads to hyperparathyroidism.

The parathyroid glands (not to be confused with the thyroid) maintain the body’s calcium level within a narrow range. Hyperparathyroidism caused by hypergastrinemia would cause the breakdown of bone to increase blood calcium levels. Finally, elevations in cortisol secretion from an active case of SIFBO will always cause thinning bones as cortisol is a catabolic hormone.

PPIs and Hypergastrinemia

In part one of this series, I mentioned that one of the side effects of attempting to stop PPI use was rebound acid reflux. And the reason this is so is because one of the rarely mentioned side effects of regular PPI use is increased gastrin production.

Recall that gastrin is the hormone produced by the enteroendocrine G-cells in the stomach, pancreas and the duodenum. It acts on stomach parietal cells to stimulate the release of hydrochloric acid.

Gastrin release is typically shut down when stomach acid levels reach proper levels, and is stimulated when stomach acid needs to be produced after eating. Because PPIs are extremely effective at suppressing stomach acid, the gastrin-releasing cells never get the feedback signal to turn off gastrin release, so it keeps pouring out.

Gastrin has a trophic or growth-promoting action on all cells, including the parietal cells of the stomach. So when stomach acid is reduced via the use of acid-suppressing drugs, and in particular PPIs, growth of the cells responsible for hydrochloric acid production increases dramatically.

Increased gastrin release also causes growth in oxyntic glands found in the body of the stomach, and stimulation of enterochromaffin-like (ECL) cells. This in turn increases the release of histamine. Again recall that histamine also acts to increase stomach acid production.

The rapid increase in cell growth can cause stomach polyps to form in about 7 to 10% of people who take PPIs for twelve months or more. These polyps are usually benign and go away once PPI therapy ceases. However, in those with a family history of stomach cancer, there is a risk of these polyps turning malignant.

The increase in number and mass of hydrochloric-acid producing cells remains unnoticed as long as PPI use continues. Nevertheless, once someone decides to stop taking these drugs, stomach acid production rebounds and along with it the acid reflux and heartburn that initiated the therapy. (21)

One study found that fourteen days after discontinuing a three-month course of PPIs, gastric-acid secretions increased by 50% over baseline. (22) Other researchers have noted that this increase in acid release persists for about two to three months after PPI use is discontinued. (23)

In one study, 120 healthy volunteers with no history of acid reflux were randomly assigned to two groups, one taking a PPI and the other a placebo for two months. Researchers were blind as to which group was which. (24)

At the end of the two-month period, all subjects were given the placebo for four weeks. During weeks two, three and four of this four-week, post-PPI treatment period, 44% of those who had taken PPIs began experiencing heartburn, acid reflux and stomach indigestion. This was in contrast to 15% in the placebo group.

Keep in mind that none of these folks had complained of any of these symptoms prior to beginning the trial. I suspect that some of the participants taking the PPI also developed a case of SIFBO that remained undiagnosed.

In my informal conversations with both doctors and patients, this side effect of PPIs is not widely known, which may explain why so many people are hooked on these medications. When they attempt to stop them symptoms come roaring back.

Of course the tapering of the PPI causes the patient to again complain to their physician who will in all likelihood just write another script. Both the patient and doctor remain unaware that the medication is causing the very symptoms it was meant to relieve.

I must say this is a fantastic way to keep people hooked on these medications and immensely profitable for the companies that manufacture them. Damn if I’m not in the wrong business!

PPIs, Clostridium difficile and Other Intestinal Infections

There has been a consistent association seen between extended PPI use and the onset of Clostridium difficile (C. difficile) infections. (25) (26) C. difficile infections cause chronic and foul diarrhea, and afflict many elderly people in both senior care centers and hospitals.

However, C. difficile isn’t the only pathogen shown to take advantage of low stomach acid. Salmonella, Shigella, Escherichia coli and Campylobacter are also more likely to infect folks on acid-suppressing medications. It wouldn’t surprise me in the slightest to learn that the large outbreaks of food poisoning seen in the United States in recent years are due not only to eating improperly handled food, but to decreases in protective stomach acid caused by this class of drugs.

But then again, what would you expect to happen if the very substance nature designed to prevent or severely limit intestinal infections was being obliterated by the daily use of these powerful medications?

PPIs, Iron Malabsorption and Anemia

Hydrochloric acid is necessary for converting ferric iron to more assimilable ferrous iron. Vitamin C is also a necessary adjunct to proper iron metabolism. However, vitamin C is unstable at high stomach pH and less able to aid in proper iron absorption.

It is therefore unsurprising that anemia is consistently associated with chronic PPI use. (27) Furthermore, iron, like all nutrients requires a healthy small intestinal brush border for its assimilation.

A small intestine inflamed by an overgrowth of bacterial and fungal pathogens is not one conducive to absorption, iron or otherwise. And let’s not forget that pathogens must derive their iron from our diet to survive. In the case of active SIFBO, any iron that is not absorbed is more apt to be utilized by pathogens rather than the host.

PPIs and Delayed Stomach Emptying

In part one, I discussed how important stomach acid is for breaking down or denaturing proteins. One of the first symptoms of low stomach acid is an inability to digest a protein-rich meal. I suspect this is one reason many people try vegetarian diets when confronted with stomach issues.

Taking acid-suppressing drugs, especially PPIs, exacerbates the problem. If you’ve wondered why that steak or pork chop you just ate is sitting like a lump in your stomach, well now you know.

Ironically, as I explained in part two, delayed stomach emptying is the number-one cause of acid reflux and heartburn. This probably explains why so many people on these drugs still experience intermittent acid reflux, which no doubt encourages them to take more of the drug.

PPIs and Cancer

I’ve already explained how gastrin has trophic or growth-promoting effects. These effects, however, are not just limited to healthy cells.

Recall that PPIs are used to treat Barrett’s esophagus, a possible outcome of uncontrolled GERD. The reason behind this protocol is to prevent a small yet susceptible segment of this population from developing esophageal cancer.

There is some evidence, however, that the hypergastrinemia caused by using PPIs may actually accelerate the progression of Barrett’s to cancer. (28) Higher gastrin levels are associated with an increased risk of abnormal tissue development in the esophagus and adenocarcinomas.

There was a recently published study out of the UK that reported a 50% increase in esophageal cancer rates over the last forty years. This time period overlaps with the introduction and use of PPIs in the treatment of GERD. Could the very drugs used to treat Barrett’s esophagus be a contributing factor in this cancer upsurge? I don’t know, but I think it’s certainly possible.

Cancers of the stomach and the intestinal tract have also tracked the increasing use of PPIs. (29) (30) And while there is no evidence that PPI use is significantly associated with colon cancer development, I harbor serious concerns.

In my post on Alcohol and the Gastrointestinal Tract, I noted how a recent study identified Fusobacterium nucleatum (F. nucleatum) as being involved in the genesis and progression of colon cancer. (31) These researchers showed how this bacteria is capable of adhering to the wall of the colon and inducing cell mutations and inflammation. Genetic markers for this bacteria in colon cancer patients were found to be 10 to 100 times higher than in healthy controls.

As I wrote in that post, this bacteria is normally present in the oral cavity, which begs the question of why an oral bacteria is thriving in the colon. As I noted, for colonization of this bacteria to occur in the large intestine two things must happen: 1) compromised gastric-barrier function and 2) large bowel dysbiosis. Compromised gastric-barrier function in order for the bacteria to survive transit through the stomach, and colonic dysbiosis to allow it to adhere to the gut wall and begin its cell-mutating mayhem.

Putting aside gastrin’s ability to increase cellular growth of both healthy and cancerous tissue, the ability of PPIs to lower gastric-barrier defenses while increasing the risk of both small and large bowel dysbiosis is troubling to say the least. If F. nucleatum is found to be the cause of colon cancer, or even partly responsible for its development, the long-term use of PPIs has unsettling implications for those on these medications.

PPIs and Zollinger-Ellison Syndrome

In part one, I briefly mentioned Zollinger-Ellison syndrome. This is a syndrome that results in increased production of stomach acid due to hypergastrinemia. The elevated levels of gastrin are caused by neuroendocrine tumors usually in the pancreas, although these tumors can also be found in the small intestine.

About 60% of these tumors are malignant and require surgical removal to prevent their spread. Sadly, an increasing number of people with this disorder are going undiagnosed because they are assumed to just have GERD and placed on PPIs. While these medications do offer symptom relief, they have no effect on the progression of these tumors. Failure to screen for this syndrome can therefore lead to the discovery of the cancer well past the point of curative care.

PPIs and Increased Intestinal Permeability

Low stomach acid always impairs proper protein digestion, and the same is true for low stomach acid caused by acid-suppressing medications. In conditions where stomach pH becomes more alkaline, the possibility rises that large undigested protein fragments or peptides may elicit allergic reactions should they cross the gut wall.

This is of great concern because PPIs have been shown to increase gut permeability in a dose-response manner. (32) In one study, adults treated with PPIs for three months or more showed increases in IgE levels. (33) IgE stands for a class of antibodies known as immnoglobulin E.

IgEs main function is to offer immunity against parasites. However, IgEs are also implicated in allergic diseases like asthma, allergic rhinitis, food allergies and atopic dermatitis.

In this study, researches noted that:

“Adult patients treated with antisecretory medications [PPIs] for 3 months have been found to develop a rise in their IgE antibody levels and new, foodspecific IgE antibodies. These data establish a plausible mechanism whereby acid-suppressive medications, by interfering with the peptic digestion of food allergens and increasing mucosal permeability, might lead to the development of food allergy. The time course of the introduction and subsequent widespread usage of PPIs with the emergence of eosinophilic esophagitis [an allergic inflammatory condition of the esophagus] fits well with the hypothesis that PPIs may play an etiological [causative] role.”

The implications of this are quite huge. For not only are we talking about the possible development of food allergies, but also the initiation of countless autoimmune disorders. Improperly digested food proteins that cross the gut wall will always elicit an antibody immune response. Should the structure of the exogenous protein resemble protein structures within the body, then it becomes probable that these antibodies will also attack similarly constructed host tissue.

Further confirmation for the role of PPIs in allergy development comes from a study out of Britain published this past autumn. (34) It followed women who had been prescribed PPIs during their pregnancy. I’ll let the authors speak for themselves:

“These results suggest that the use of gastric acid-suppressive medications during pregnancy is associated with an increase in the risk for development of asthma in the child. The trend towards increased risk was present in children of women exposed to PPIs and/or H2ra [H2 receptor antagonists] and when the exposure occurred during the third trimester of pregnancy…

…The observed association between prenatal exposure to acid-suppressive drug and asthma in our study is consistent with the findings of Dehlink et al., Andersen et al. and Kallen et al. and also with findings from an unpublished study using a case-crossover design in the University Groningen pregnancy database in which we defined cases as toddlers who were prescribed asthma medications at least two times before the age of 5 years. Since we showed the minimal influence of confounding in the associations, the validity of earlier reports is supported by our findings. The precise mechanisms by which acid-suppressive drugs may cause asthma are hypothetical. It has been proposed that neutralized gastric acid levels prevent adequate digestion of antigens in the adult stomach. While antigens normally degrade into oligopeptides to enter the gastrointestinal tract, these can now induce a T-helper (Th)-2 response and immunoglobin (Ig)-E sensitization of the immune system. If crossing the placenta, these antigens could induce allergic sensitization of the foetus. This hypothesis is supported by a study in pregnant mice showing a Th2-dominant immune response in the offspring caused by gastric acid suppression.”

Another hypothesis that may explain this increase in asthma would be the development of SIFBO in both mothers and infants. If these women were already suffering from SIFBO prior to their pregnancy, the use of PPIs would only make the situation worse. Conversely, if they didn’t have SIFBO, the use of these medications could lead to its development.

A baby’s gut flora is only as healthy as the mother who delivers it. Disturbances here, along with increased exposure to improperly digested proteins, could easily set the child up for gut dysbiosis and allergic misery.

This study looked only at asthma. Would we see an association with other developmental disorders?

If the risk of developing asthma in offspring can be increased by using these agents, it’s well past the time for medical professionals to shed their belief in the inherent harmlessness of these medications especially in regards to pregnant women.

PPIs and Pneumonia

There have been some studies that have claimed that extended PPI use predisposes to developing pneumonia in elderly populations. However, other studies have shown no statistically significant association. A 2010 meta-analysis on this issue concluded that PPI use may increase the risk of developing pneumonia in senior care facilities, but called for further research as the studies it analyzed were too disparate in methodology to reach any scientifically valid conclusions. (35)

The rationale for believing that PPIs may predispose to bacterial pneumonia centers around the possibility of un-killed bacteria in the stomach being aspirated to the lungs. However, I can think of another reason susceptibility to pneumonia, and infections in general, may be more prevalent in those on extended courses of PPIs.

There is little question that long-term use of these drugs increases the risk of developing SIFBO and other intestinal infections. SIFBO always calls forth an immune response due to increased intestinal permeability, translocation of gut bacteria, undigested proteins and other antigens to systemic circulation. That, in turn, causes stimulation of the hypothalamic-pituitary-adrenal axis and increased cortisol secretion as I covered here.

One of the best-known side effects of chronic cortisol release is suppressed immunity against bacterial, viral, fungal and parasitic organisms. The more pervasive gut dysbiosis is, the more immune compromised the individual.

In the elderly, a population already at a disadvantage when it comes to immune function, chronic cortisol secretion would be expected to manifest itself as increased susceptibility to all sorts of infections, including respiratory ones. The situation would be further compounded by disturbances in sleep caused by this same chronic elevation in cortisol.

Conclusion

PPIs and other acid-suppressing drugs have a place in short-term medical care. Certainly, in those being treated for bleeding ulcers, suppressing stomach acid is a medical necessity where the benefit far outweighs the cost. And there is little doubt that in those dealing with erosive esophagitis, short courses of these medications can give the esophagus the time needed to heal from the pervasive onslaught of refluxed stomach acid.

However, long-term use of these drugs (and by long-term I mean eight weeks or longer) begins to present some very serious risks to the patient, risks that the users of these drugs are largely ignorant of because many of their doctors are similarly unaware of them. I suspect a major reason for this is because the makers of these drugs and their sales reps do what they can to keep it that way.

Nevertheless, concern about the side effects of extended PPI use is growing. Click on this link, and you’ll be redirected to the FDA’s website where an expanding list of advisories about these drugs can be found. However, this list is still incomplete. For example, no mention is made of the risk for developing SIFBO, GI cancers, hypergastrinemia or allergies.

To those who are now on these drugs and wish to get off them, I caution against doing so abruptly. Hypergastrinemia is going to increase stomach upset and acid reflux for a minimum of two months after you quit. Tapering their use, or switching to an H2 receptor blocker or antacid, can help mitigate some of these withdrawal symptoms until things return to normal.

Discussing options with your doctor is strongly recommended, however be prepared for many to insist that there is little harm in continuing their use. And merely stopping these drugs will do your GERD little good if you don’t institute the recommendations I outlined in the last post.

If the reason you’ve decided to go off acid-suppressing drugs includes intestinal upset, then I would strongly recommend a visit to a gastroenterologist to be checked for SIBO. If SIBO is detected, assume as a matter of course that you also have a fungal overgrowth. Antibiotics are useless against yeast so you should ask for an anti-fungal to take along with your prescribed antibiotic.

If your physician balks, show him the lengthy quote from the above study that found a high prevalence of fungal overgrowth in those taking PPIs and diagnosed with SIBO. The reality is that many of you will have to educate your doctors on this issue as most physicians do not keep up with the latest scientific findings in this area.

And what of those people who seek their salvation in an acid-suppressing pill, and not through the changes I outlined in part two? Sadly, there is nothing anyone can do to help these folks.

They will go on to develop many of the complications I wrote about. That will lead to further medical treatment to treat the problems caused by their continued PPI use. This medical merry-go-round can easily go on for decades, much to the detriment of the patient.

Stomach acid is not the enemy, but a very necessary part of what keeps us well nourished and free from disease. Treatment centered around the long-term suppression of this vital substance is bound to lead to unintended consequences that are far worse than the diseases it ‘treats’.

Unfortunately, I don’t see the over prescribing of these drugs changing anytime soon. These medications are immensely profitable for the pharmaceutical companies that manufacture them, and their use is enshrined in standard-of-care protocols everywhere.

In the United States, a large and ongoing advertising campaign has indelibly drilled the image and message of the “little purple pill” into the brains of anyone who watches television or reads a magazine. However, what really should be front and center in the minds of those viewing these ads is our purple monster at the top of this post. That’s what really comes out to play after using these medications for any extended period of time.

I have no illusions that my humble blog will have much of an effect in stopping this gastrointestinal carnage. I guess I should count myself lucky that PPI use increases sales of probiotics and prebiotics as people desperately seek solutions to their gut dysbiosis and resulting misery. But in reality, I feel more saddened than grateful to see so many suffer unnecessarily.

Apart from conditions like Zollinger-Ellison syndrome, hiatal hernia, stomach tumors, certain pregnancies and SIFBO, GERD is a condition that is entirely self-caused by the use of the drugs and dietary habits I discussed in the last post. As such, it can be remedied by avoiding these practices without resorting to acid-suppressing medications.

If you are not willing to do this then all I can say is good luck. God knows you’ll need it.

Comments are closed.

Post Navigation